Diagnostic imaging in the management of patients with metabolic syndrome

&NA; Metabolic syndrome (MetS) is the constellation of metabolic risk factors that might foster development of type 2 diabetes and cardiovascular disease. Abdominal obesity and insulin resistance play a prominent role among all metabolic traits of MetS. Because intervention including weight loss can reduce these morbidity and mortality in MetS, early detection of the severity and complications of MetS could be useful. Recent advances in imaging modalities have provided significant insight into the development and progression of abdominal obesity and insulin resistance, as well as target organ injuries. The purpose of this review is to summarize advances in diagnostic imaging modalities in MetS that can be applied for evaluating each components and target organs. This may help in early detection, monitoring target organ injury, and in turn developing novel therapeutic target to alleviate and avert them.

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title: Intra-abdominal fat is a major determinant of the National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome.
abstract: The underlying pathophysiology of the metabolic syndrome is the subject of debate, with both insulin resistance and obesity considered as important factors. We evaluated the differential effects of insulin resistance and central body fat distribution in determining the metabolic syndrome as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III. In addition, we determined which NCEP criteria were associated with insulin resistance and central adiposity. The subjects, 218 healthy men (n = 89) and women (n = 129) with a broad range of age (26-75 years) and BMI (18.4-46.8 kg/m2), underwent quantification of the insulin sensitivity index (Si) and intra-abdominal fat (IAF) and subcutaneous fat (SCF) areas. The metabolic syndrome was present in 34 (15.6%) of subjects who had a lower Si [median: 3.13 vs. 6.09 x 10(-5) min(-1)/(pmol/l)] and higher IAF (166.3 vs. 79.1 cm2) and SCF (285.1 vs. 179.8 cm2) areas compared with subjects without the syndrome (P < 0.001). Multivariate models including Si, IAF, and SCF demonstrated that each parameter was associated with the syndrome. However, IAF was independently associated with all five of the metabolic syndrome criteria. In multivariable models containing the criteria as covariates, waist circumference and triglyceride levels were independently associated with Si and IAF and SCF areas (P < 0.001). Although insulin resistance and central body fat are both associated with the metabolic syndrome, IAF is independently associated with all of the criteria, suggesting that it may have a pathophysiological role. Of the NCEP criteria, waist circumference and triglycerides may best identify insulin resistance and visceral adiposity in individuals with a fasting plasma glucose <6.4 mmol/l.

title: Obesity Severity and Duration Are Associated With Incident Metabolic Syndrome: Evidence Against Metabolically Healthy Obesity From the Multi-Ethnic Study of Atherosclerosis.
abstract: Although the health risks of obesity compared to normal weight have been well studied, the cumulative risk associated with chronic obesity remains unknown. Specifically, debate continues about the importance of recommending weight loss for those with metabolically healthy obesity.



We hypothesized that relatively greater severity and longer duration of obesity are associated with greater incident metabolic syndrome.  Participants, and Measures: Using repeated measures logistic regression with random effects, we investigated the association of time-varying obesity severity and duration with incident metabolic syndrome in 2,748 Multi-Ethnic Study of Atherosclerosis participants with obesity (body mass index ≥30 kg/m2) at any visit. Obesity duration was defined as the cumulative number of visits with measured obesity and obesity severity by the World Health Organization levels I-III based on body mass index. Metabolic syndrome was defined using Adult Treatment Panel III criteria modified to exclude waist circumference.



Higher obesity severity (level II odds ratio [OR], 1.32 [95% confidence interval, 1.09-1.60]; level III OR, 1.63 [1.25-2.14] vs level I) and duration (by number of visits: two visits OR, 4.43 [3.54-5.53]; three visits OR, 5.29 [4.21-6.63]; four visits OR, 5.73 [4.52-7.27]; five visits OR, 6.15 [4.19-9.03] vs one visit duration of obesity) were both associated with a higher odds of incident metabolic syndrome.



Both duration and severity of obesity are positively associated with incident metabolic syndrome, suggesting that metabolically healthy obesity is a transient state in the pathway to cardiometabolic disease. Weight loss should be recommended to all individuals with obesity, including those who are currently defined as metabolically healthy.

title: Association of hypertension, diabetes, dyslipidemia, and metabolic syndrome with obesity: findings from the National Health and Nutrition Examination Survey, 1999 to 2004.
abstract: Hypertension, diabetes, and dyslipidemia are common conditions associated with obesity. This study provides current estimates of the prevalence of hypertension, diabetes, dyslipidemia, and metabolic syndrome according to the severity of obesity in men and women participating in the 1999 to 2004 National Health and Nutrition Examination Survey (NHANES).



Data from a representative sample of 13,745 US men and women who participated in the NHANES between 1999 and 2004 were reviewed. Overweight and obesity classes 1, 2, and 3 were defined as a body mass index of 25.0 to 29.9, 30.0 to 34.9, 35.0 to 39.9, and> or =40.0 kg/m(2), respectively. Metabolic syndrome was defined according to the 2004 National Heart, Lung and Blood Institute/American Heart Association conference proceedings.



With increasing overweight and obesity class, there is an increase in the prevalence of hypertension (18.1% for normal weight to 52.3% for obesity class 3), diabetes (2.4% for normal weight to 14.2% for obesity class 3), dyslipidemia (8.9% for normal weight to 19.0% for obesity class 3), and metabolic syndrome (13.6% for normal weight to 39.2% for obesity class 3). With normal weight individuals as a reference, individuals with obesity class 3 had an adjusted odds ratio of 4.8 (95% CI 3.8 to 5.9) for hypertension, 5.1 (95% CI 3.7 to 7.0) for diabetes, 2.2 (95% CI 1.7 to 2.4) for dyslipidemia, and 2.0 (95% CI 1.4 to 2.8) for metabolic syndrome.



The prevalence of hypertension, diabetes, dyslipidemia, and metabolic syndrome substantially increases with increasing body mass index. These findings have important public health implications for the prevention and treatments (surgical and nonsurgical) of obesity.

title: Tipping the balance: the pathophysiology of obesity and type 2 diabetes mellitus.
abstract: Obesity plays a major role in the development of type 2 diabetes mellitus, and it has long been accepted that weight loss plays a significant role in diabetes therapy. This weight loss has traditionally been accomplished through lifestyle changes including diet and exercise. What has only more recently gained acceptance is that bariatric surgery may have a role to play in diabetes therapy as well. This article discusses the pathophysiology of type 2 diabetes mellitus and obesity and provides a basic understanding of these diseases, which forms the basis for understanding the importance of weight loss in their treatment.

title: Association of BMI with risk of CVD mortality and all-cause mortality
abstract: To determine the relationship between BMI and risk of CVD mortality and all-cause mortality among Malaysian adults.  Population-based, retrospective cohort study. Participants were followed up for 5 years from 2006 to 2010. Mortality data were obtained via record linkages with the Malaysian National Registration Department. Multiple Cox regression was applied to compare risk of CVD and all-cause mortality between BMI categories adjusting for age, gender and ethnicity. Models were generated for all participants, all participants the first 2 years of follow-up, healthy participants, healthy never smokers, never smokers, current smokers and former smokers.  All fourteen states in Malaysia. Subjects Malaysian adults (n 32 839) aged 18 years or above from the third National Health and Morbidity Survey.  Total follow-up time was 153 814 person-years with 1035 deaths from all causes and 225 deaths from CVD. Underweight (BMI<18·5 kg/m2) was associated with a significantly increased risk of all-cause mortality, while obesity (BMI ≥30·0 kg/m2) was associated with a heightened risk of CVD mortality. Overweight (BMI=25·0–29·9 kg/m2) was inversely associated with risk of all-cause mortality. Underweight was significantly associated with all-cause mortality in all models except for current smokers. Overweight was inversely associated with all-cause mortality in all participants. Although a positive trend was observed between BMI and CVD mortality in all participants, a significant association was observed only for severe obesity (BMI≥35·0 kg/m2).  Underweight was associated with increased risk of all-cause mortality and obesity with increased risk of CVD mortality. Therefore, maintaining a normal BMI through leading an active lifestyle and healthy dietary habits should continue to be promoted.

title: Association of all-cause mortality with overweight and obesity using standard body mass index categories. A systematic review and meta-analysis
abstract: '...lower mortality among overweight and moderately obese patients' but higher mortality for those with a BMI >35.

title: Cardiovascular and Renal Effects of Weight Reduction in Obesity and the Metabolic Syndrome
abstract: Obesity is a critical public health issue worldwide. Patients with obesity have markedly increased morbidity and mortality compared to the general population. The increased health risks of obesity in part are due to its close association with each of the other components of the metabolic syndrome, including hypertension, dyslipidemia, and insulin resistance. Accordingly, obese individuals are at particularly increased risk of cardiovascular disease and chronic kidney disease. Modest weight loss results in improvements in serum cholesterol levels, blood pressure, and glycemic profiles. Lifestyle interventions for weight loss have long been the mainstay of treatment in obesity. However, the existing literature demonstrates limited weight loss sustainability and inconsistent cardiovascular and renal benefits using these modalities. In addition to improvements in intermediate risk factors, surgical interventions provide a more lasting impact on long-term cardiovascular and renal outcomes, though carry higher short-term risks due to perioperative complications.

title: Weight reduction and cardiovascular and metabolic disease prevention: clinical trial update.
abstract: In children and adults, weight gain is accompanied by the early and more aggressive manifestations of well-recognized risk factors for atherosclerotic cardiovascular disease (CVD). Because insulin resistance and the later development of type 2 diabetes mellitus also accompany weight gain, the term cardiometabolic risk is now commonly used to describe this emerging global health problem. Weight loss will improve cardiometabolic risk. However, less is known about the effect of weight loss on the development of disease and, most importantly, type 2 diabetes and CVD outcomes in the form of death, myocardial infarction, and stroke. This review describes current clinical research that uses health-promoting lifestyle interventions, new drugs, and even surgery, which are all aimed at weight loss, reduction in disease manifestations, and improved outcomes. These anticipated data are essential for the future development of effective CVD prevention strategies. Results are awaited with great interest.

title: The metabolic syndrome
abstract: The concept of the metabolic syndrome has existed for at least 80 years. This constellation of metabolic disturbances, all risk factors for cardiovascular disease, was first described in the 1920s by Kylin, a Swedish physician, as the clustering of hypertension, hyperglycaemia, and gout. Later, in 1947, Vague drew attention to upper body adiposity (android or male-type obesity) as the obesity phenotype that was commonly associated with metabolic abnormalities associated with type 2 diabetes and cardiovascular disease. Over the past two decades, a striking increase in the number of people with the metabolic syndrome worldwide has taken place. This increase is associated with the global epidemic of obesity and diabetes. With the elevated risk not only of diabetes but also of cardiovascular disease from the metabolic syndrome, there is urgent need for strategies to prevent the emerging global epidemic. The metabolic syndrome is a master of disguise since it can present in various ways according to the different components that constitute the syndrome. The metabolic syndrome is also known as syndrome X, the insulin resistance syndrome, and the deadly quartet. The constellation of metabolic abnormalities includes glucose intolerance (type 2 diabetes, impaired glucose tolerance, or impaired fasting glycaemia), insulin resistance, central obesity, dyslipidaemia, and hypertension, all well documented risk factors for cardiovascular disease. These conditions co-occur in an individual more often than might be expected by chance. When grouped together, they are associated with increased risk of cardiovascular disease. Lemieux and colleagues have suggested the importance of abdominal obesity and the so-called hypertriglyceridaemic waist phenotype as a central component. Although some strong positions have been taken, the cause of the syndrome is still not settled, as discussed in more detail later.

title: The metabolic syndrome
abstract: The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity. The disorder is defined in various ways, but in the near future a new definition(s) will be applicable worldwide. The pathophysiology seems to be largely attributable to insulin resistance with excessive flux of fatty acids implicated. A proinflammatory state probably contributes to the syndrome. The increased risk for type 2 diabetes and cardiovascular disease demands therapeutic attention for those at high risk. The fundamental approach is weight reduction and increased physical activity; however, drug treatment could be appropriate for diabetes and cardiovascular disease risk reduction.

title: Clinical applications of body composition measurements using DXA.
abstract: Dual-energy X-ray absorptiometry (DXA) scanning was primarily developed for the diagnosis of osteoporosis and was initially applied to studies of the clinically important sites of the lumbar spine, femoral neck, and forearm. The rapid adoption of DXA has led to the development of different, competing generations of equipment. Improvements have been achieved through advances in X-ray generation and detection technology, modification of data acquisition protocols, and implementation of more sophisticated image analysis algorithms. As a result, DXA has been extended to allow the study of the total skeleton and its regional parts, as well as soft-tissue composition measurement. The three major components of the body: fat mass, lean mass, and bone mineral mass, can now be easily measured using a single whole body DXA scan with high precision and low scanning time. The comprehensive view of body composition provided by DXA makes it an attractive technique for a variety of clinical applications such as the prevention of cardiovascular and metabolic diseases, clinical management of different chronic diseases, and monitoring of the impact of treatment regimens on body tissues. In this article we review the contribution DXA has made to the understanding of body composition in clinical studies in adults.

title: Visceral Adiposity and the Prevalence of Hypertension in Japanese Americans
abstract: Visceral adiposity is generally considered to play a key role in the metabolic syndrome, including hypertension. The purpose of this study was to evaluate cross-sectionally whether visceral adiposity is associated with prevalence of hypertension independent of other adipose depots and fasting plasma insulin. Study subjects included 563 Japanese Americans with normal or impaired glucose tolerance or diabetes but not taking oral hypoglycemic medication or insulin at entry. Variables included plasma glucose and insulin measured after an overnight fast and during an oral glucose tolerance test, and abdominal, thoracic, and thigh fat areas by CT. Total fat area (TFA) was calculated as the sum of these fat areas. Hypertension was defined as having a systolic blood pressure ≥140 mm Hg, having a diastolic blood pressure ≥90 mm Hg, or taking antihypertensive medications. Intra-abdominal fat area (IAFA) was associated with a higher prevalence of hypertension. Adjusted odds ratio of hypertension by IAFA was 1.68 for a 1-SD increase (95% CI, 1.20 to 2.37) after adjusting for age, sex, fasting plasma insulin, a nonlinear transformation of 2-hour plasma glucose, and TFA. IAFA remained a significant predictor of prevalence of hypertension even after adjustment for total subcutaneous fat area, abdominal subcutaneous fat area, body mass index, or waist circumference, but no measure of regional or total adiposity was associated with the odds of prevalence of hypertension in models that contained IAFA. Greater visceral adiposity increases the odds of hypertension in Japanese Americans independent of other adipose depots and fasting plasma insulin.

title: Imaging methods for analyzing body composition in human obesity and cardiometabolic disease
abstract: Advances in the technological qualities of imaging modalities for assessing human body composition have been stimulated by accumulating evidence that individual components of body composition have significant influences on chronic disease onset, disease progression, treatment response, and health outcomes. Importantly, imaging modalities have provided a systematic method for differentiating phenotypes of body composition that diverge from what is considered normal, that is, having low bone mass (osteopenia/osteoporosis), low muscle mass (sarcopenia), high fat mass (obesity), or high fat with low muscle mass (sarcopenic obesity). Moreover, advances over the past three decades in the sensitivity and quality of imaging not just to discern the amount and distribution of adipose and lean tissue but also to differentiate layers or depots within tissues and cells is enhancing our understanding of distinct mechanistic, metabolic, and functional roles of body composition within human phenotypes. In this review, we focus on advances in imaging technologies that show great promise for future investigation of human body composition and how they are being used to address the pandemic of obesity, metabolic syndrome, and diabetes.

title: Dual-Energy X-Ray Absorptiometry for Quantification of Visceral Fat
abstract: Obesity is the major risk factor for metabolic syndrome and through it diabetes as well as cardiovascular disease. Visceral fat (VF) rather than subcutaneous fat (SF) is the major predictor of adverse events. Currently, the reference standard for measuring VF is abdominal X‐ray computed tomography (CT) or magnetic resonance imaging (MRI), requiring highly used clinical equipment. Dual‐energy X‐ray absorptiometry (DXA) can accurately measure body composition with high‐precision, low X‐ray exposure, and short‐scanning time. The purpose of this study was to validate a new fully automated method whereby abdominal VF can be measured by DXA. Furthermore, we explored the association between DXA‐derived abdominal VF and several other indices for obesity: BMI, waist circumference, waist‐to‐hip ratio, and DXA‐derived total abdominal fat (AF), and SF. We studied 124 adult men and women, aged 18–90 years, representing a wide range of BMI values (18.5–40 kg/m2) measured with both DXA and CT in a fasting state within a one hour interval. The coefficient of determination (r2) for regression of CT on DXA values was 0.959 for females, 0.949 for males, and 0.957 combined. The 95% confidence interval for r was 0.968 to 0.985 for the combined data. The 95% confidence interval for the mean of the differences between CT and DXA VF volume was −96.0 to −16.3 cm3. Bland‐Altman bias was +67 cm3 for females and +43 cm3 for males. The 95% limits of agreement were −339 to +472 cm3 for females and −379 to +465 cm3 for males. Combined, the bias was +56 cm3 with 95% limits of agreement of −355 to +468 cm3. The correlations between DXA‐derived VF and BMI, waist circumference, waist‐to‐hip ratio, and DXA‐derived AF and SF ranged from poor to modest. We conclude that DXA can measure abdominal VF precisely in both men and women. This simple noninvasive method with virtually no radiation can therefore be used to measure VF in individual patients and help define diabetes and cardiovascular risk.

title: Quantification of visceral fat using dual-energy x-ray absorptiometry and its reliability according to the amount of visceral fat in Korean adults.
abstract: Recently, a fully automated method for segmenting abdominal fat into subcutaneous fat and visceral fat (VF) within the android region using dual-energy X-ray absorptiometry (DXA) has been newly developed. The purpose of this study was to validate a new DXA method by comparing it to the gold standard, computed tomography (CT), in the Korean population. Furthermore, we examined its reliability regarding VF and explored whether it is applicable to the Asian population, which has relatively larger amount of VF. We studied 123 adult men and women, aged 22-73 yr, representing a wide range of body mass index values (17.1-36.0 kg/m(2)), who underwent both DXA and CT in a fasting state within 1 h. The coefficient of determination (r(2)) for regression of the CT on DXA values was 0.892 for females, 0.838 for males, and 0.931 combined. Bland-Altman bias was -451.4 cm(3) with 95% limits of agreement of 149.8 to -1052.6 cm(3). The DXA-measured VF showed a better correlation with CT-measured VF volume than common indices for adiposity, including the body mass index and waist circumference. There was a lesser discrepancy ratio between DXA- and CT-measured VF with an increase of VF volume. DXA, a relatively convenient, inexpensive, and safe method with minimum radiation dosage, can be a reliable technique for VF assessment in the Asian population.

title: DXA-measured visceral adipose tissue predicts impaired glucose tolerance and metabolic syndrome in obese Caucasian and African-American women
abstract: New methods to measure visceral adipose tissue (VAT) by dual-energy X-ray absorptiometry (DXA) may help discern sex, race and phenotype differences in the role of VAT in cardiometabolic risk. This study was designed (1) to compare relationships of DXA-VAT, anthropometric and body composition variables with cardiometabolic risk factors in obese women; (2) to determine which variables most robustly predict impaired glucose tolerance (IGT) and metabolic syndrome (MetSx); and (3) to determine thresholds for DXA-VAT by race.VAT mass (g) and volume (cm3) were measured in 229 obese (body mass index (BMI), 30–49.9) women aged 21–69 years of European-American (EA=123) and African-American (AA=106) descent using the CoreScan algorithm on a Lunar iDXA scanner. Linear regression modeling and areas under the curve (AUC of ROC (receiver operating characteristic) curves) compared relationships with cardiometabolic risk. Bootstrapping with LASSO (least absolute shrinkage and selection operator) regression modeling determined thresholds and predictors of IGT and MetSx.DXA-VAT explained more of the variance in triglycerides, blood pressure, glucose and homeostatic model assessment-insulin resistance (HOMA-IR) compared with anthropometric and other body composition variables. DXA-VAT also had the highest AUC for IGT (0.767) and MetSx (0.749). Including race as a variable and the interaction between VAT and race in modeling did not significantly change the results. Thresholds at which the probability of developing IGT or MetSx was⩾50% were determined separately for AA women (IGT: 2120 cm3; MetSx: 1320 cm3) and EA women (IGT: 2550 cm3; MetSx: 1713 cm3). The odds for IGT or MetSx were fourfold greater with each standard deviation increase in DXA-VAT.Conclusions:DXA-VAT provides robust clinical information regarding cardiometabolic risk in AA and EA obese women and offers potential utility in the risk reduction interventions.

title: The intra- and inter-instrument reliability of DXA based on ex vivo soft tissue measurements.
abstract: Comparison of ex-vivo soft tissue measurements using the GE/Lunar pencil (DPX-L; GE/Lunar Co., Madison, WI) and fan beam (Prodigy dual-energy X-ray absorptiometers (DXA) GE/Lunar Co.).



Intra-instrument reliability was assessed by repeatedly scanning soft tissue phantoms for lean tissue (water) and fat tissue (methanol) using one DPX-L and two identical Prodigy DXAs at fast, medium, and slow scan modes. For each machine, 10 scans of each phantom were performed at each scan speed. The number of scans per instrument totaled 60. Data were analyzed using ANOVA to ascertain whether scan speed affected the intra-instrument reliability and to test whether soft tissue measurements differed among instruments. Percentage fat (phantom density) was the outcome variable.



Intra-instrument reliability, expressed as coefficient of variation, ranged between 0.7% and 5.2% for the DPX-L and 0.4% and 4.5% for the Prodigy, with the lowest coefficients of variation observed when scanning the fat tissue phantom. Scan speed also affected the intra-instrument reliability (p < 0.01). Furthermore, differences in the measurement of percentage body fat for both the lean and fat tissue phantoms were observed among all three absorptiometers (all p < 0.01). After adjusting for scan speed, differences persisted for all three instruments.



Intra- and inter-instrument reliability of DXA machines, even those from the same manufacturer, remains unpredictable. Thus, when measuring body composition using DXA, it is important to consider that even in the absence of measurement bias, the use of different DXA machines, particularly when using a variety of speed settings, will increase the residual error around the true value.

title: Ultrasound as a Tool to Assess Body Fat
abstract: Ultrasound has been used effectively to assess body fat for nearly 5 decades, yet this method is not known as well as many other body composition techniques. The purpose of this review is to explain the technical principles of the ultrasound method, explain the procedures for taking a measurement and interpreting the results, evaluate the reliability and validity of this method for measuring subcutaneous and visceral adipose tissue, highlight the advantages and limitations of ultrasound relative to other body composition methods, consider its utility to clinical populations, and introduce new body composition-specific ultrasound technology. The focus of this review is adipose, although various tissue thicknesses (e.g., muscle and bone) can be measured with ultrasound. Being a portable imaging device that is capable of making fast regional estimates of body composition, ultrasound is an attractive assessment tool in instances when other methods are limited. Furthermore, much of the research suggests that it is reliable, reproducible, and accurate. The biggest limitations appear to be a lack of standardization for the measurement technique and results that are highly dependent on operator proficiency. New ultrasound devices and accompanying software designed specifically for the purpose of body composition assessment might help to minimize these limitations.

title: The clinical importance of visceral adiposity: a critical review of methods for visceral adipose tissue analysis.
abstract: As a result of the rising epidemic of obesity, understanding body fat distribution and its clinical implications is critical to timely treatment. Visceral adipose tissue is a hormonally active component of total body fat, which possesses unique biochemical characteristics that influence several normal and pathological processes in the human body. Abnormally high deposition of visceral adipose tissue is known as visceral obesity. This body composition phenotype is associated with medical disorders such as metabolic syndrome, cardiovascular disease and several malignancies including prostate, breast and colorectal cancers. Quantitative assessment of visceral obesity is important for evaluating the potential risk of development of these pathologies, as well as providing an accurate prognosis. This review aims to compare different methods of measuring visceral adiposity with emphasis on their advantages and drawbacks in clinical practice.

title: Ultrasound Measurements of Visceral and Subcutaneous Abdominal Thickness to Predict Abdominal Adiposity Among Older Men and Women
abstract: Accurate measures of visceral and abdominal subcutaneous fat are essential for investigating the pathophysiology of obesity. Classical anthropometric measures such as waist and hip circumference cannot distinguish between these two fat depots. Direct imaging methods such as computed tomography and magnetic resonance imaging (MRI) are restricted in large‐scale studies due to practical and ethical issues. We aimed to establish whether ultrasound is a valid alternative method to MRI for the quantitative assessment of abdominal fat depots in older individuals. The study population comprised 74 white individuals (41 men and 33 women, aged 67–76 years) participating in the Hertfordshire Birth Cohort Physical Activity trial. Anthropometry included height, weight, waist and hip circumferences. Abdominal fat was measured by ultrasound in two compartments: visceral fat defined as the depth from the peritoneum to the lumbar spine; and subcutaneous fat defined as the depth from the skin to the abdominal muscles and compared to reference measures by MRI (10‐mm single‐slice image). Ultrasound measures were positively correlated with MRI measures of visceral and subcutaneous fat (visceral: r = 0.82 and r = 0.80 in men and women, respectively; subcutaneous: r = 0.63 and 0.68 in men and women, respectively). In multiple regression models, the addition of ultrasound measures significantly improved the prediction of visceral fat and subcutaneous fat in both men and women over and above the contribution of standard anthropometric variables. In conclusion, ultrasound is a valid method to estimate visceral fat in epidemiological studies of older men and women when MRI and computed tomography are not feasible.

title: Abdominal wall fat index, estimated by ultrasonography, for assessment of the ratio of visceral fat to subcutaneous fat in the abdomen.
abstract: To establish a new index of regional fat distribution using ultrasonography for assessment of the ratio of the visceral fat area (V) to the subcutaneous fat area (S) (V/S ratio).



The subjects examined were 62 patients (23 males and 39 females); 51 patients had hyperlipidemia and 11 patients had glucose intolerance. The mean body mass indices ranged from 20.3 to 42.9. The mean age of the patients was 44 +/- 13 years. The thicknesses of the preperitoneal fat layer (P) and subcutaneous fat layer (S) in the abdomen were measured by ultrasonography and the P/S ratio was calculated. The V/S ratio was obtained with radiographic computed tomography.



Of the various P/S ratios examined, the ratio of the maximum thickness of preperitoneal fat to the minimum thickness of subcutaneous fat was most closely correlated with the V/S ratio (r = 0.746, p < 0.0001). This ratio was termed the abdominal wall fat index (AFI). AFI was positively correlated with serum triglyceride levels and negatively correlated with high-density lipoprotein cholesterol (r = -0.312, p < 0.05), whereas the V/S ratio was correlated with triglyceride levels. AFI was positively correlated with basal insulin levels in both men and women.



These results suggest that AFI measured by ultrasonography may be a new indicator of visceral fat deposition, and may reflect metabolic disorders such as lipid metabolism and glucose metabolism disorders.

title: Validity and reproducibility of ultrasonography for the measurement of intra-abdominal adipose tissue
abstract: We studied the validity and reproducibility of a new abdominal ultrasound protocol for the assessment of intra-abdominal adipose tissue. Intra-abdominal adipose tissue was assessed by CT, MRI, anthropometry and ultrasonography on a single day. By ultrasonography the distance between peritoneum and lumbar spine was measured using a strict protocol, including the location of the measurements, pressure on the transducer and respiration. All measurements were repeated after 3 months. The study population consisted of 19 overweight patients with a body mass index (BMI) of 32.9 kg/m2 (s.d. 3.7), intra-abdominal adipose tissue on CT 140.1 cm2 (s.d. 55.9), and a mean ultrasound distance of 9.8 cm (s.d. 2.5). There was a strong association between the CT and ultrasonographic measures: Pearson correlation coefficient was 0.81 (P<0.001). The correlation between ultrasound and waist circumference was 0.74 (P<0.001), the correlation between CT and waist circumference was 0.57 (P=0.01). Ultrasound appeared a good method to diagnose intra-abdominal obesity: the area under the ROC curve was 0.98. During the follow-up period of 3 months, the patients lost on average almost 3 kg of body weight. The correlation coefficient between changes in intra-abdominal adipose tissue assessed by CT and ultrasound was 0.74 (P<0.001). The correlation coefficient of the mean ultrasound distance assessed by two different sonographers at baseline was 0.94 (P<0.001), the mean difference 0.4 cm (s.d. 0.9), and the coefficient of variation 5.4%, indicating good reproducibility of the ultrasound measurements. The results of this validation study show that abdominal ultrasound, using a strict protocol, is a reliable and reproducible method to assess the amount of intra-abdominal adipose tissue and to diagnose intra-abdominal obesity.

title: Validation of the measurement of intra‐abdominal fat between ultrasound and CT scan in women with obesity and infertility
abstract: To compare the means and changes over time of intra‐abdominal fat (IAF) and subcutaneous abdominal fat (SAF) measured by abdominal ultrasound (US) and computerized tomography (CT).

title: The usefulness of mesenterium thickness as an index of visceral fat accumulation
abstract: Visceral fat syndrome, which includes visceral fat accumulation, glucose intolerance, hyperlipidemia, and hypertension, refers to a highly atherogenic state with a cluster of risk factors secondary to visceral fat accumulation. Although X-ray computed tomography (CT) is used commonly in diagnosis of visceral fat accumulation, it is expensive and exposes the patient to radiation. Some indices obtained using ultrasonography, which is fast and easy to use, have been reported. The ratio of the maximum thickness of preperitoneal fat (P) to the minimum thickness of subcutaneous fat (S), the abdominal wall fat index (P/S), is widely used in ultrasonographic diagnosis, however, this ratio tends to vary largely according to examiners. To establish a more reliable ultrasonographic index of visceral fat accumulation, we measured the thickness of the mesenterium, and tried to examine the relation between its thickness and maximum thickness of preperitoneal fat, minimum thickness of subcutaneous fat, and abdominal wall fat index, as well as body mass index, systolic and diastolic blood pressure, and levels of serum triglyceride, high-density lipoprotein cholesterol, total cholesterol, and blood sugar. The subjects were 131 individuals, 98 males and 33 females, averaging 47.0±7.9 years, with a mean body mass index of 24.1±2.6. The mesenterium was measured with a 3.5 or 3.75 MHz convex probe by longitudinal scanning on the left side of the umbilicus of the patient in the supine position. The thickness of the mesenterium correlated positively with maximum thickness of the preperitoneal fat, abdominal wall fat index, body mass index, and levels of serum triglyceride, total cholesterol, and blood sugar, and negatively with levels of high-density lipoprotein cholesterol. When the subjects were divided into a high-M group and a normal-M group, body mass index, triglyceride level, and blood sugar levels in the high-M group were significantly higher and level of high-density lipoprotein cholesterol was significantly lower than in the normal-M group. These results suggest that the thickness of mesenteium measured by ultrasonography may be useful in the diagnosis of accumulation of visceral fat.

title: Absolute reliability of adipose tissue volume measurement by computed tomography: application of low-dose scan and minimal detectable change—a phantom study
abstract: Metabolic syndrome increases the risk of developing diabetes and cardiovascular disease, particularly heart failure. Abdominal obesity is commonly assessed by measurement of the waist circumference, which exhibits a positive correlation with the visceral fat area measured on computed tomography (CT). CT is an excellent technique for measurement of cross-sectional areas of adipose tissue, but the exposure to ionizing radiation limits broad and repeated application in healthy subjects. Our purpose in this study was to determine the reliability of low-dose CT for abdominal fat quantification as compared with a standard CT protocol. A phantom was scanned by use of changes in the volume of vegetable oil, simulating visceral and subcutaneous adipose tissue, and by changes in the tube current–time products (25–300 mAs). We measured the volume of vegetable oil for each mAs value, and we calculated the minimal detectable change (MDC) in the volume by making repeated measurements. The measured volume of vegetable oil at 50 mAs and higher was not significantly different (p > 0.05), but that at 25 mAs was significantly different (p < 0.001), from that at 300 mAs. The MDC was less than 0.4 ml regardless of the mAs value at all mAs values assessed. We suggest that the adipose tissue volume is determined accurately by CT at 50 mAs (75 % reduction of radiation exposure compared with the standard dose).

title: Obesity and diabetes: newer concepts in imaging.
abstract: Quantifying body fat is currently an area of active research. Recent studies have shown that the quantity and location of fat in different compartments have varying clinical significance. This information can now be obtained from computed tomography (CT) or magnetic resonance (MR), and it can inform clinical decision making for patient management. Diabetes patients with insulin resistance and hyperinsulinemia have nonalcoholic fatty liver disease (NAFLD) ranging from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis, typically diagnosed by liver biopsy or serum markers. There is now an emerging role of noninvasive imaging tests such as MR imaging or MR spectroscopy or elastography, which can provide quantitative information and have potential to avoid biopsy. Obese patients with diabetes are also at risk for cardiovascular disease and cancer. There is an emerging role for imaging in early detection of not only structural but also functional abnormalities of myocardium at a subclinical stage. Screening for cancer is currently recommended only for breast, colon, prostate, and cervix. Given wider availability and advances in imaging techniques such as positron emission tomography/CT (faster scans with higher resolution and less ionizing radiation) and better understanding of molecular biology and risk-stratification, more and more cancers are being detected in early stages with better clinical outcomes. Concerns related to cost, overdiagnosis, and unnecessary interventions must be addressed before population-based screening for other cancers is recommended. Based on ongoing imaging research, it is expected that it will be possible to provide more precise measurement of body fat and detect cardiovascular disease and cancers earlier in their course.

title: Clinical significance of visceral adiposity assessed by computed tomography: A Japanese perspective.
abstract: Abdominal obesity, rather than total amount of fat, is linked to obesity-related disorders. Visceral adiposity is an important component of obesity-related disorders in Japanese individuals with a mild degree of adiposity compared with Western subjects. In 1983, our group reported techniques for body fat analysis using computed tomography (CT) and established the concept of visceral fat obesity in which intra-abdominal fat accumulation is an important factor in the development of obesity-related complications, such as diabetes, lipid disorders, hypertension and atherosclerosis. Our group also established ideal imaging conditions for determining abdominal fat area at the umbilical level CT scan. Visceral fat area (VFA) measured in a single slice at L4 level correlated significantly with the total abdominal visceral fat volume measured on multislice CT scan. In a large-scale study of a Japanese population, the mean number of obesity-related cardiovascular risk factors (hypertension, low high-density lipoprotein cholesterolemia and/or hypertriglyceridemia, and hyperglycemia) was greater than 1.0 at 100 cm(2) of VFA, irrespective of gender, age and body mass index. Our group also demonstrated that reduction of visceral fat accumulation subsequent to voluntary lifestyle modification, "Hokenshido", correlated with a decrease in the number of obesity-related cardiovascular risk factors. It is important to select the most appropriate subjects from the general population (e.g., non-obese subjects with a cluster of risk factors for the metabolic syndrome) that are most suitable for body weight reduction, with the goal of preventing atherosclerotic cardiovascular diseases.

title: Body fat distribution, incident cardiovascular disease, cancer, and all-cause mortality.
abstract: The aim of this study was to determine whether ectopic fat depots are prospectively associated with cardiovascular disease, cancer, and all-cause mortality.



The morbidity associated with excess body weight varies among individuals of similar body mass index. Ectopic fat depots may underlie this risk differential. However, prospective studies of directly measured fat are limited.



Participants from the Framingham Heart Study (n = 3,086; 49% women; mean age of 50.2 years) underwent assessment of fat depots (visceral adipose tissue, pericardial adipose tissue, and periaortic adipose tissue) using multidetector computed tomography and were followed up longitudinally for a median of 5.0 years. Cox proportional hazards regression models were used to examine the association of each fat depot (per 1 SD increment) with the risk of incident cardiovascular disease, cancer, and all-cause mortality after adjustment for standard risk factors, including body mass index.



Overall, there were 90 cardiovascular events, 141 cancer events, and 71 deaths. After multivariable adjustment, visceral adipose tissue was associated with cardiovascular disease (hazard ratio: 1.44; 95% confidence interval: 1.08 to 1.92; p = 0.01) and cancer (hazard ratio: 1.43; 95% confidence interval: 1.12 to 1.84; p = 0.005). Addition of visceral adipose tissue to a multivariable model that included body mass index modestly improved cardiovascular risk prediction (net reclassification improvement of 16.3%). None of the fat depots were associated with all-cause mortality.



Visceral adiposity is associated with incident cardiovascular disease and cancer after adjustment for clinical risk factors and generalized adiposity. These findings support the growing appreciation of a pathogenic role of ectopic fat.

title: Reproducibility and Repeatability of Computer Tomography-based Measurement of Abdominal Subcutaneous and Visceral Adipose Tissues
abstract: Excessive accumulation of abdominal adipose tissue is a widely recognized as a major feature of obesity, and it can be quantified by dual-energy x-ray absorptiometry (DXA). However, in a phantom study, the inter- and intra-instrument reliability of DXA remains unpredictable. Thus, we attempted to determine the precision of estimates from computer tomography-based measurements and analysis with AZE Virtual Place software. To determine the inter-rater reproducibility and intra-rater repeatability of adipose tissue area estimates, we used the automatic boundary-tracing function of the AZE Virtual Place to generate cross-sectional areas of subcutaneous and visceral adipose tissues from the abdomen of reconstructed CT images. The variability of inter-rater and intra-rater estimates expressed as the coefficient of variation ranged from 0.47% to 1.43% for subcutaneous adipose tissue and 1.08% to 2.20% for visceral adipose tissue; the optimal coefficient of variation of the fat rate calculation ranged from 0.55% to 1.13%, respectively. There was high and significant correlation between adipose tissue areas as estimated in 40 obese subjects by two raters or repeatedly on 20 obese subjects by either rater. This indicates excellent reproducibility and repeatability via a computer tomography-based measurement of abdominal subcutaneous and visceral adipose tissues.

title: Diagnostic imaging in obesity.
abstract: Magnetic resonance of the body offers different techniques for mapping fat deposits (MR Imaging) and analysis of organs with small amounts of lipids (MR Spectroscopy). Possible approaches for whole-body assessment of adipose tissue are presented and discussed and spectroscopic examinations in different organs are depicted. With magnetic resonance imaging (MRI) it has been shown that obesity per se is not a marker for metabolic failure, but depends on regional variations of body composition and ectopic lipid accumulation. In addition MRI of the brain is a powerful research tool to understand the brain's role in the development and maintenance of obesity and the overconsumption of foods in obese individuals. Sonography has a low accuracy in estimating hepatic steatosis until now. New sonographic methods have been evaluated to detect hepatic steatosis by physical properties of fatty tissue as tissue stiffness, sound absorption or sound speed. Nuclear medicine and in particular Positron Emission Tomography (PET) methods are used to explore central pathophysiology, brown adipose tissue activity and alterations in homeostatic feedback and gut-brain communication.

title: MR-based assessment of body fat distribution and characteristics.
abstract: The assessment of body fat distribution and characteristics using magnetic resonance (MR) methods has recently gained significant attention as it further extends our pathophysiological understanding of diseases including obesity, metabolic syndrome, or type 2 diabetes mellitus, and allows more detailed insights into treatment response and effects of lifestyle interventions. Therefore, the purpose of this study was to review the current literature on MR-based assessment of body fat distribution and characteristics. PubMed search was performed to identify relevant studies on the assessment of body fat distribution and characteristics using MR methods. T1-, T2-weighted MR Imaging (MRI), Magnetic Resonance Spectroscopy (MRS), and chemical shift-encoding based water-fat MRI have been successfully used for the assessment of body fat distribution and characteristics. The relationship of insulin resistance and serum lipids with abdominal adipose tissue (i.e. subcutaneous and visceral adipose tissue), liver, muscle, and bone marrow fat content have been extensively investigated and may help to understand the underlying pathophysiological mechanisms and the multifaceted obese phenotype. MR methods have also been used to monitor changes of body fat distribution and characteristics after interventions (e.g. diet or physical activity) and revealed distinct, adipose tissue-specific properties. Lastly, chemical shift-encoding based water-fat MRI can detect brown adipose tissue which is currently the focus of intense research as a potential treatment target for obesity. In conclusion, MR methods reliably allow the assessment of body fat distribution and characteristics. Irrespective of the promising findings based on these MR methods the clinical usefulness remains to be established.

title: Comparison of localized proton NMR signals of skeletal muscle and fat tissue in vivo: Two lipid compartments in muscle tissue
abstract: In vivo 1H NMR spectra of small volumes‐of‐interest (VOI) were localized in human soleus muscle (8 ml) and compared with volume selective spectra of subcutaneous fat tissue and femoral yellow bone marrow (2 ml). All examinations were performed by the double spin echo (PRESS) localization technique. To provide comparability, spectra of different tissues were recorded using identical sequence timing. Clearly improved resolution of the lipid signals of muscle tissue was obtained using long echo times TE > 200 ms. The spectra of muscle tissue exhibit lipid signals that stem from two compartments with a difference of their resonance frequencies of about 0.2 ppm (Larmor frequency difference 12‐13 Hz at 1.5 T). The existence of two fatty acid compartments is supported by measurements of the relaxation times and line shape analysis. Both compartments contain fatty acids or triglycerides with similar composition. Probably one compartment corresponds to fat cells within muscle tissue, the other compartment with lower Larmor frequency is located within muscle cells.

title: Standardized assessment of whole body adipose tissue topography by MRI
abstract: To assess standardized whole body adipose tissue topography in a cohort of subjects at an increased risk for type 2 diabetes and to compare fat distribution in subgroups regarding anthropometric (age, body mass index [BMI]) and metabolic parameters (insulin sensitivity).

title: Comparison of 3 T MRI and CT for the measurement of visceral and subcutaneous adipose tissue in humans.
abstract: CT is considered the gold standard imaging modality for measurement of visceral adipose tissue area. However, as CT imaging exposes subjects to ionising radiation, a comparable imaging technique without this exposure is desirable, such as MRI. Therefore, we compared the agreement of measures of visceral adipose tissue and subcutaneous adipose tissue area from single-slice images obtained at the umbilicus using a 3 T MRI scanner with single-slice images obtained via CT scan.



64 images were obtained from 27 subjects who underwent MRI and CT scanning on the same day, after 10-12 hours of fasting. Visceral and subcutaneous adipose tissue depots were manually separated and quantified using a multimodality image-processing software program.



We found good agreement between CT and MRI for the measurement of both visceral adipose tissue and subcutaneous adipose tissue. Bland-Altman difference analysis demonstrated a mean bias of -2.9% (as a portion of total abdominal area) for visceral adipose tissue and +0.4% for subcutaneous adipose tissue, as measured by MRI compared with CT.



MRI is a safe, accurate and precise imaging modality for measuring both visceral and subcutaneous adipose tissue, making it a favourable alternative to CT for quantification of these adipose depots.

title: Assessment of Abdominal Fat Using High‐field Magnetic Resonance Imaging and Anthropometric and Biochemical Parameters
abstract: To measure the abdominal subcutaneous fat (SF) and visceral fat (VF) volumes using high‐field magnetic resonance imaging (MRI) and to investigate their association with selected anthropometric and biochemical parameters among obese and nonobese apparently healthy participants.  A cross‐sectional study was conducted by recruiting 167 healthy participants. Abdominal scans were acquired at 3T MRI, and the SF and VF were segmented and their volumes were calculated. Selected anthropometric and biochemical measurements were also determined.  A significant difference (P < 0.05) was observed between normal body weight and overweight and obese participants for SF and VF, total abdominal fat volumes, leptin, resistin, adiponectin and waist circumference. Waist circumferences were measured by tape and MRI. Findings revealed that MRI‐measured fat volumes were different between males and females and had a significant (P < 0.01) strong positive correlation with body mass index, leptin, resistin and WC and had a negative correlation with adiponectin level. MRI‐measured fat volumes were found to correlate moderately with interleukin‐6 and weakly with cholesterol, serum triglyceride and low‐density lipoprotein. Except for cholesterol, all measured biochemical variables and abdominal fat volumes in the current study were significantly associated with body mass index.  All anthropometric and biochemical parameters showed weak‐to‐strong associations with the MRI‐measured fat volumes. Abdominal fat distribution was different between males and females and their correlations with some lipid profiles were found to be sex dependent. These findings revealed that MRI can be used as an alternative tool for obesity assessment.

title: Mechanisms linking obesity to insulin resistance and type 2 diabetes
abstract: Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes. In obese individuals, adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors that are involved in the development of insulin resistance. When insulin resistance is accompanied by dysfunction of pancreatic islet β-cells — the cells that release insulin — failure to control blood glucose levels results. Abnormalities in β-cell function are therefore critical in defining the risk and development of type 2 diabetes. This knowledge is fostering exploration of the molecular and genetic basis of the disease and new approaches to its treatment and prevention.

title: Skeletal Muscle Triglyceride Levels Are Inversely Related to Insulin Action
abstract: In animal studies, increased amounts of triglyceride associated with skeletal muscle (mTG) correlate with reduced skeletal muscle and whole body insulin action. The aim of this study was to test this relationship in humans. Subjects were 38 nondiabetic male Pima Indians (mean age 28 ± 1 years). Insulin sensitivity at physiological (M) and supraphysiological (MZ) insulin levels was assessed by the euglycemic clamp. Lipid and carbohydrate oxidation were determined by indirect calorimetry before and during insulin administration. mTG was determined in vastus lateralis muscles obtained by percutaneous biopsy. Percentage of body fat (mean 29 ± 1%, range 14–44%) was measured by underwater weighing. In simple regressions, negative relationships were found between mTG (mean 5.4 ± 0.3 μmol/g, range 1.3–1.9 μmol/g) and log10M (r = −0.53, P ≤ 0.001), MZ (r = −0.44, P = 0.006), and nonoxidative glucose disposal (r = −0.48 and −0.47 at physiological and supraphysiological insulin levels, respectively, both P = 0.005) but not glucose or lipid oxidation. mTG was not related to any measure of adiposity. In multiple regressions, measures of insulin resistance (log10M, MZ, log10[fasting insulin]) were significantly related to mTG independent of all measures of obesity (percentage of body fat, BMI, waist-to-thigh ratio). In turn, all measures of obesity were related to the insulin resistance measures independent of mTG. The obesity measures and mTG accounted for similar proportions of the variance in insulin resistance in these relationships. The results suggest that in this human population, as in animal models, skeletal muscle insulin sensitivity is strongly influenced by local supplies of triglycerides, as well as by remote depots and circulating lipids. The mechanism(s) underlying the relationship between mTG and insulin action on skeletal muscle glycogen synthesis may be central to an understanding of insulin resistance.

title: Assessment of skeletal muscle triglyceride content by (1)H nuclear magnetic resonance spectroscopy in lean and obese adolescents: relationships to insulin sensitivity, total body fat, and central adiposity.
abstract: The metabolism and composition of skeletal muscle tissue is of special interest because it is a primary site of insulin action and plays a key role in the pathogenesis of insulin resistance. Intramyocellular (IMCL) triglyceride stores are an accessible form of energy that may decrease skeletal muscle glucose utilization, thereby contributing to impaired glucose metabolism. Because of the invasive nature of muscle biopsies, there is limited, if any, information about intramuscular lipid stores in children. The development of (1)H nuclear magnetic resonance (NMR) spectroscopy provides a unique noninvasive alternative method that differentiates intracellular fat from intercellular fat in muscle tissue. The present study was performed to determine whether IMCL and extramyocellular (EMCL) lipid contents are increased early in the development of juvenile obesity and to explore the relationships between IMCL and EMCL to in vivo insulin sensitivity, independently of total body fat and central adiposity in obese and nonobese adolescents. Eight nonobese (BMI 21 kg/m(2), age 11-16 years) and 14 obese (BMI 35 +/- 1.5 kg/m(2), age 11-15 years) adolescents underwent 1) (1)H-NMR spectroscopy to noninvasively quantify IMCL and EMCL triglyceride content of the soleus muscle, 2) a 2-h euglycemic-hyperinsulinemic clamp (40 mU.m(-2).min(-1)) to assess insulin sensitivity, 3) a dual-energy X-ray absorptiometry scan to measure total percent body fat, and 4) magnetic resonance imaging to measure abdominal fat distribution. Both the IMCL and EMCL content of the soleus muscle were significantly greater in the obese adolescents than in the lean control subjects. A strong inverse correlation was found between IMCL and insulin sensitivity, which persisted and became even stronger after controlling for percent total body fat and abdominal subcutaneous fat mass (partial correlation r = -0.73, P < 0.01) but not when adjusting for visceral fat (r = - 0.54, P < 0.08). In obese adolescents, increase in total body fat and central adiposity were accompanied by higher IMCL and EMCL lipid stores. The striking relationships between both IMCL and EMCL with insulin sensitivity in childhood suggest that these findings are not a consequence of aging but occur early in the natural course of obesity.

title: Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study
abstract: Recent muscle biopsy studies have shown a relation between intramuscular lipid content and insulin resistance. The aim of this study was to test this relation in humans by using a novel proton nuclear magnetic resonance (1H NMR) spectroscopy technique, which enables non-invasive and rapid ( ∼ 45 min) determination of intramyocellular lipid (IMCL) content. Normal weight non-diabetic adults (n = 23, age 29 ± 2 years, BMI = 24.1 ± 0.5 kg/m2) were studied using cross-sectional analysis. Insulin sensitivity was assessed by a 2-h hyperinsulinaemic ( ∼ 450 pmol/l)-euglycaemic ( ∼ 5 mmol/l) clamp test. Intramyocellular lipid concentrations were determined by using localized 1H NMR spectroscopy of soleus muscle. Simple linear regression analysis showed an inverse correlation (r = –0.692, p = 0.0017) between intramyocellular lipid content and M-value (100–120 min of clamp) as well as between fasting plasma non-esterified fatty acid concentration and M-value (r = –0.54, p= 0.0267). Intramyocellular lipid content was not related to BMI, age and fasting plasma concentrations of triglycerides, non-esterified fatty acids, glucose or insulin. These results show that intramyocellular lipid concentration, as assessed non invasively by localized 1H NMR spectroscopy, is a good indicator of whole body insulin sensitivity in non-diabetic, non-obese humans.

title: Comparison of 3.0 T proton magnetic resonance spectroscopy short and long echo‐time measures of intramyocellular lipids in obese and normal‐weight women
abstract: To compare correlations of intramyocellular lipids (IMCL) measured by short and long echo‐time proton magnetic resonance spectroscopy (1H‐MRS) with indices of body composition and insulin resistance in obese and normal‐weight women.

title: Muscle triglycerides and mitochondrial function: possible mechanisms for the development of type 2 diabetes
abstract: Obese and type 2 diabetic (T2DM) adolescents present with reduced insulin-stimulated glucose disposal and elevated intramyocellular lipids (IMCL) indicating comparable muscular insulin resistance and increased flux of free fatty acids (FFA) as in adult patients. In humans, the causal relationships between obesity and insulin resistance were examined in detail over the last years.The impact of genetic factors was analyzed in young nonobese nondiabetic first-degree relatives of T2DM (REL-DM), whereas environmental factors were tested by challenging humans without genetic T2DM risk with lipid infusions or high-fat diets.REL-DM exhibit defects in mitochondrial oxidation and phosphorylation. Increased FFA availability results in accumulation of intramyocellular fatty acyl-CoA (FA-CoA) inducing a series of alterations: (i) inhibition of insulin signaling, (ii) reduction of insulin-(in)dependent glucose transport/phosphorylation, (iii) decreased insulin-stimulated glycogen synthesis, (iv) impaired insulin-stimulated oxidative phosphorylation (ATP synthesis), (v) accumulation of ectopic triglycerides (IMCL), (vi) reduced expression of peroxisome proliferator activated receptor γ (PPARγ) coactivator-1 (PGC-1) and PGC-1-controlled genes involved in mitochondrial biogenesis and oxidative phosphorylation and possibly also (vii) initiation of inflammatory processes by activation of PKC and nuclear factor-κB and decreased expression of matrix metalloproteinases (MMPs).CONCLUSIONS:The abnormalities could lead to a vicious cycle in which mitochondrial dysfunction, elevation of intramycellular lipids, impaired lipid oxidation and insulin resistance amplify each other. This is similar to the adaptive changes to fasting, which prevent energy loss during excessive FFA availability. The sequence of events may start with mitochondrial dysfunction in genetic insulin resistance and with increased intramyocellular lipids in environmental insulin resistance.

title: The effect of non-insulin-dependent diabetes mellitus and obesity on glucose transport and phosphorylation in skeletal muscle.
abstract: Defects of glucose transport and phosphorylation may underlie insulin resistance in obesity and non-insulin-dependent diabetes mellitus (NIDDM). To test this hypothesis, dynamic imaging of 18F-2-deoxy-glucose uptake into midthigh muscle was performed using positron emission tomography during basal and insulin-stimulated conditions (40 mU/m2 per min), in eight lean nondiabetic, eight obese nondiabetic, and eight obese subjects with NIDDM. In additional studies, vastus lateralis muscle was obtained by percutaneous biopsy during basal and insulin-stimulated conditions for assay of hexokinase and citrate synthase, and for immunohistochemical labeling of Glut 4. Quantitative confocal laser scanning microscopy was used to ascertain Glut 4 at the sarcolemma as an index of insulin-regulated translocation. In lean individuals, insulin stimulated a 10-fold increase of 2-deoxy-2[18F]fluoro-D-glucose (FDG) clearance into muscle and significant increases in the rate constants for inward transport and phosphorylation of FDG. In obese individuals, the rate constant for inward transport of glucose was not increased by insulin infusion and did not differ from values in NIDDM. Insulin stimulation of the rate constant for glucose phosphorylation was similar in obese and lean subjects but reduced in NIDDM. Insulin increased by nearly twofold the number and area of sites labeling for Glut 4 at the sarcolemma in lean volunteers, but in obese and NIDDM subjects translocation of Glut 4 was attenuated. Activities of skeletal muscle HK I and II were similar in lean, obese and NIDDM subjects. These in vivo and ex vivo assessments indicate that impaired glucose transport plays a key role in insulin resistance of NIDDM and obesity and that an additional impairment of glucose phosphorylation is evident in the insulin resistance of NIDDM.

title: THE [14C]DEOXYGLUCOSE METHOD FOR THE MEASUREMENT OF LOCAL CEREBRAL GLUCOSE UTILIZATION: THEORY, PROCEDURE, AND NORMAL VALUES IN THE CONSCIOUS AND ANESTHETIZED ALBINO RAT 1
abstract: A method has been developed for the simultaneous measurement of the rates of glucose consumption in the various structural and functional components of the brain in vivo. The method can be applied to most laboratory animals in the conscious state. It is based on the use of 2‐deoxy‐D‐[14C]glucose ( as a tracer for the exchange of glucose between plasma and brain and its phosphorylation by hexokinase in the tissues. [14C]DG is used because the label in its product, [14C]deoxyglucose‐6‐phosphate, is essentially trapped in the tissue over the time course of the measurement. A model has been designed based on the assumptions of a steady state for glucose consumption, a first order equilibration of the free [14C]DG pool in the tissue with the plasma level, and relative rates of phosphorylation of [14C]DG and glucose determined by their relative concentrations in the precursor pools and their respective kinetic constants for the hexokinase reaction. An operational equation based on this model has been derived in terms of determinable variables. A pulse of [14C]DG is administered intravenously and the arterial plasma [14C]DG and glucose concentrations monitored for a preset time between 30 and 45min. At the prescribed time, the head is removed and frozen in liquid N2‐chilled Freon XII, and the brain sectioned for autoradiography. Local tissue concentrations of [14C]DG are determined by quantitative autoradiography. Local cerebral glucose consumption is calculated by the equation on the basis of these measured values.

title: Interactions of impaired glucose transport and phosphorylation in skeletal muscle insulin resistance: a dose-response assessment using positron emission tomography.
abstract: It has been postulated that glucose transport is the principal site of skeletal muscle insulin resistance in obesity and type 2 diabetes, though a distribution of control between glucose transport and phosphorylation has also been proposed. The current study examined whether the respective contributions of transport and phosphorylation to insulin resistance are modulated across a dose range of insulin stimulation. Rate constants for transport and phosphorylation in skeletal muscle were estimated using dynamic positron emission tomography (PET) imaging of 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) during insulin infusions at three rates (0, 40, and 120 mU/m2 per min) in lean glucose-tolerant, obese glucose-tolerant, and obese type 2 diabetic subjects. Parallel studies of arteriovenous fractional extraction across the leg of [18F]FDG and [2-3H] glucose were performed to measure the "lumped constant" (LC) (i.e., the analog effect) for [18F]FDG to determine whether this value is affected by insulin dose or insulin resistance. The value of the LC was similar across insulin doses and groups. Leg glucose uptake (LGU) also provided a measure of skeletal muscle glucose metabolism independent of PET. [18F]FDG uptake determined by PET imaging strongly correlated with LGU across groups and across insulin doses (r = 0.81, P < 0.001). Likewise, LGU correlated with PET parameters of glucose transport (r = 0.67, P < 0.001) and glucose phosphorylation (r = 0.86, P < 0.001). Glucose transport increased in response to insulin in the lean and obese groups (P < 0.05), but did not increase significantly in the type 2 diabetic group. A dose-responsive pattern of stimulation of glucose phosphorylation was observed in all groups of subjects (P < 0.05); however, glucose phosphorylation was lower in both the obese and type 2 diabetic groups compared with the lean group at the moderate insulin dose (P < 0.05). These findings indicate an important interaction between transport and phosphorylation in the insulin resistance of obesity and type 2 diabetes.

title: Measurement of skeletal muscle glucose utilization by dynamic 18F-FDG PET without arterial blood sampling
abstract: ObjectiveSkeletal muscle glucose utilization (SMGU) can be measured by 18F-FDG PET to characterize insulin resistance. The aim of this study was to determine whether femoral muscle SMGU can be measured without arterial blood sampling by sequential PET imaging of the thoracic and femoral regions. MethodsTen patients with possible insulin resistance underwent dynamic 18F-FDG PET of the femoral region during hyperinsulinaemic euglycaemic clamping (group A), and femoral muscle SMGU was calculated using PET data of various time periods and measured arterial input. SMGU was also calculated using venous plasma activity, instead of arterial activity, as input during the late phase. Another five patients underwent sequential PET of the thoracic and femoral regions after single tracer injection (group B). The input function was estimated from aorta activity on thoracic images during the early phase and from venous activity during the late phase, and SMGU with this estimated input was compared with that with measured arterial input. ResultsIn group A, exclusion of early dynamic PET data from analysis had essentially no effect on the calculated SMGU, and partial substitution of venous activity for arterial activity only marginally changed the estimates. The difference between SMGUs with measured and estimated inputs was minimal in group B. ConclusionFemoral muscle SMGU can be calculated without femoral imaging early after tracer injection, and the input function can be assessed using data of thoracic imaging and venous blood samples. These results support the validity of measuring femoral muscle SMGU without arterial sampling, simultaneously with measurement of myocardial glucose utilization.

title: Visceral adiposity and hepatic steatosis at abdominal CT: association with the metabolic syndrome.
abstract: Visceral adiposity and hepatic steatosis may correlate with the metabolic syndrome but are not currently among the diagnostic criteria. We evaluated these features at unenhanced MDCT.



Semiautomated measurements of subcutaneous fat area, visceral fat area, and visceral fat percentage were obtained at the umbilical level at unenhanced MDCT of 474 adults (217 men, 257 women; mean age, 58.3 years) using a dedicated application (Fat Assessment Tool, EBW version 4.5). Unenhanced liver attenuation was also recorded. Metabolic syndrome was defined using the criteria proposed by the International Diabetes Federation in 2005.



The prevalence of metabolic syndrome was 35.0% (76/217) among men and 35.8% (92/257) among women. The area under the receiver operating characteristic curve (AUC) for visceral fat area was 0.830 (95% CI, 0.784-0.867) in men and 0.887 (0.848-0.918) in women (p = 0.162). The AUC for subcutaneous fat area was 0.865 (0.823-0.899) in men and 0.762 (0.711-0.806) in women (p = 0.024). The AUC for visceral fat percentage was 0.527 (0.472-0.581) in men and 0.820 (0.774-0.859) in women (p < 0.001). The AUC for liver attenuation was 0.706 (0.653-0.754). Thresholds of subcutaneous fat area greater than 204 cm(2) in men, visceral fat area greater than 70 cm(2) in women, and liver attenuation less than 50 HU yielded a sensitivity and specificity of 80.3% and 83.7%; 83.7% and 80.0%; and 22.0% and 96.7%, respectively. Visceral fat area was elevated in 55% of patients without metabolic syndrome (11/20) but with a documented cardiovascular event or complication and in 32.1% of patients with a body mass index of 30 kg/m(2) or less.



Accumulation of visceral fat was the best predictor for metabolic syndrome in women. Unexpectedly, the percentage of visceral fat was a poor predictor for metabolic syndrome in men and subcutaneous fat area was best. Decreased liver attenuation was insensitive but was highly specific for metabolic syndrome. The implications of these sex-specific differences and the relationship of fat-based CT measures to cardiovascular risk warrant further investigation.

title: Interactions Between Delivery, Transport, and Phosphorylation of Glucose in Governing Uptake Into Human Skeletal Muscle
abstract: Skeletal muscle accounts for a large proportion of insulin-stimulated glucose utilization. It is generally regarded that much of the control over rates of uptake is posited within the proximal steps of delivery, transport, and phosphorylation of glucose, with glucose transport as the main locus of control. Whether insulin modulates the distribution of control across these steps and in what manner remains uncertain. The current study addressed this in vivo using dynamic positron emission tomography (PET) imaging of human muscle with sequential injections of three tracers ([15O]H2O, [11C]3-O-methyl glucose [3-OMG], and [18F]fluoro-deoxy glucose [FDG]) that enabled quantitative determinations of glucose delivery, transport, and its phosphorylation, respectively. Lean, healthy, research volunteers were studied during fasting conditions (n = 8) or during a euglycemic insulin infusion at 30 mU/min per m2 (n = 8). PET images were coregistered with magnetic resonance imaging to contrast glucose kinetics in soleus, a highly oxidative muscle, with tibialis anterior, a less oxidative muscle. During fasting conditions, uptake of [11C]3-OMG was similar in soleus and tibialis anterior muscles, despite higher delivery to soleus (by 35%; P < 0.01). Uptake of [18F]FDG was also similar between muscle during fasting, and glucose transport was found to be the dominant locus of control (90%) for glucose uptake under this condition. Insulin increased uptake of [11C]3-OMG substantially and strongly stimulated the kinetics of bidirectional glucose transport. Uptake of [11C]3-OMG was higher in soleus than tibialis anterior muscle (by 22%; P < 0.01), a difference partially due to higher delivery, which was again found to be 35% higher to soleus (P < 0.01). The uptake of [18F]FDG was 65% greater in soleus compared with tibialis anterior muscle, a larger difference than for [11C]3-OMG (P < 0.01), indicating an added importance of glucose phosphorylation in defining insulin sensitivity. Analysis of the distribution of control during insulin-stimulated conditions revealed that most of the control was posited at delivery and transport and was equally divided between these steps. Thus, insulin evokes a broader distribution of control than during fasting conditions in governing glucose uptake into skeletal muscle. This redistribution of control is triggered by the robust stimulation of glucose transport, which in turn unmasks a greater dependence upon delivery and glucose phosphorylation.

title: Dynamic PET imaging reveals heterogeneity of skeletal muscle insulin resistance.
abstract: Skeletal muscle insulin resistance (IR) often precedes hyperglycemia and type 2 diabetes. However, variability exists within different skeletal muscle types and can be influenced by 3 primary steps of control: glucose delivery, transport, and phosphorylation. We performed dynamic positron emission tomography imaging studies to determine the extent to which heterogeneity in muscle type and control of insulin action contribute to IR.



Thirteen volunteers from normal weight to obese underwent dynamic positron emission tomography imaging of [15O]H2O, [11C]3-O-methylglucose, and [18F]fluorodeoxyglucose, measuring delivery, transport, and phosphorylation rates, respectively, in soleus and tibialis anterior muscle during a hyperinsulinemic-euglycemic clamp. Subjects were classified as insulin-sensitive (IS) or insulin-resistant (IR) based on the median systemic glucose infusion rate needed to maintain euglycemia.



In soleus, transport kinetic rates were significantly higher (P<.05) in IS (0.126±0.028 min(-1)) vs IR (0.051±0.008 min(-1)) subjects. These differences were not as evident in tibialis anterior. These differences were paralleled in overall insulin-stimulated tissue activity, higher in IS (0.017±0.001 mL·cm3·min(-1)) vs IR (0.011±0.002 mL·cm3·min(-1)) in soleus (P<.05), without significant differences in tibialis anterior. No significant differences were observed for either muscle in delivery or phosphorylation. Both muscle types displayed a control shift from an even distribution among the steps in IS to transport exerting greater control of systemic insulin sensitivity in IR.



Lower glucose transport rates are the major feature underlying IR preceding type 2 diabetes, although substantial heterogeneity in insulin action across muscle types highlight the complexity of skeletal muscle IR.

title: Whole-Body Imaging of Tissue-specific Insulin Sensitivity and Body Composition by Using an Integrated PET/MR System: A Feasibility Study.
abstract: To develop, evaluate, and demonstrate the feasibility of a whole-body protocol for simultaneous assessment of tissue-specific insulin-mediated fluorine 18 (18F) fluorodeoxyglucose (FDG) influx rates, tissue depots, and whole-body insulin sensitivity (referred to as the M value).  An integrated positron emission tomography (PET)/magnetic resonance (MR) imaging system combined with hyperinsulinemic euglycemic clamp (HEC) was used. Dynamic whole-body PET imaging was used to determine the insulin-mediated 18F-FDG tissue influx rate (Ki) in the whole-body region by using the Patlak method. M value was determined with the HEC method at PET imaging. Tissue depots were quantified by using water-fat separated MR imaging and manual segmentations. Feasibility of the imaging protocol was demonstrated by using five healthy control participants and five patients with type 2 diabetes. Associations between M value and Ki were studied in multiple tissues by using the Pearson correlation.  Positive correlations were found between M value and Ki in multiple tissues: the gluteus muscle (r = 0.875; P = .001), thigh muscle (r = 0.903; P , .001), calf muscle (r = 0.825; P = .003), and abdominal visceral adipose tissue (r = 0.820; P = .004). A negative correlation was found in the brain (r = 20.798; P = .006). The MR imaging-based method for quantification of tissue depots was feasible for determining adipose tissue volumes and fat fractions.  This PET/MR imaging protocol may be feasible for simultaneous assessment of tissue-specific insulin-mediated 18F-FDG influx rates, tissue depots, and M value.

title: Cardiovascular consequences of metabolic syndrome.
abstract: The metabolic syndrome (MetS) is defined as the concurrence of obesity-associated cardiovascular risk factors including abdominal obesity, impaired glucose tolerance, hypertriglyceridemia, decreased HDL cholesterol, and/or hypertension. Earlier conceptualizations of the MetS focused on insulin resistance as a core feature, and it is clearly coincident with the above list of features. Each component of the MetS is an independent risk factor for cardiovascular disease and the combination of these risk factors elevates rates and severity of cardiovascular disease, related to a spectrum of cardiovascular conditions including microvascular dysfunction, coronary atherosclerosis and calcification, cardiac dysfunction, myocardial infarction, and heart failure. While advances in understanding the etiology and consequences of this complex disorder have been made, the underlying pathophysiological mechanisms remain incompletely understood, and it is unclear how these concurrent risk factors conspire to produce the variety of obesity-associated adverse cardiovascular diseases. In this review, we highlight current knowledge regarding the pathophysiological consequences of obesity and the MetS on cardiovascular function and disease, including considerations of potential physiological and molecular mechanisms that may contribute to these adverse outcomes.

title: Excessive Sympathetic Activation in Heart Failure With Obesity and Metabolic Syndrome: Characteristics and Mechanisms
abstract: Congestive heart failure is characterized by sympathetic activation, which has also been described in the metabolic syndrome. No information exists, however, as to whether the sympathostimulating effects of these 2 conditions summate when heart failure is complicated by the metabolic syndrome, leading to an exceedingly high adrenergic drive. This is clinically relevant, because in heart failure sympathetic activation is closely related to mortality. We studied 48 control subjects (age: 58.4±1.6 years, mean±SEM) and 89 age-matched heart failure patients (New York Heart Association class II), of whom 47 were without and 42 were with metabolic syndrome. Measurements included blood pressure (Finapres), heart rate (ECG), and sympathetic nerve traffic (microneurography) at rest and during baroreceptor manipulation. Waist circumference, blood pressure, and metabolic variables were greater in heart failure with metabolic syndrome than in heart failure without metabolic syndrome and in control subjects. Left ventricular ejection fraction and end-diastolic diameter were similarly altered in the 2 heart failure groups. Compared with control subjects, sympathetic nerve activity was greater in heart failure patients without metabolic syndrome (64.7±3.2 versus 45.8±2.9 bursts/100 heartbeats; P<0.01), a further pronounced increase being detected in those with metabolic syndrome (80.9±3.2 bursts/100 heartbeats; P<0.01). In the multivariate analysis, waist circumference and body mass index were the variables most closely related to sympathetic activation. Compared with control subjects, baroreflex responses were significantly attenuated in the 2 heart failure groups, the impairment being more marked in the group with than without metabolic syndrome. Thus, obesity and metabolic syndrome potentiate the sympathetic activation characterizing heart failure. This potentiation is likely to mainly depend on metabolic and baroreflex mechanisms.

title: Obesity cardiomyopathy: pathophysiology and evolution of the clinical syndrome.
abstract: Obesity produces an increase in total blood volume and cardiac output because of the high metabolic activity of excessive fat. In moderate to severe cases of obesity, this may lead to left ventricular dilation, increased left ventricular wall stress, compensatory (eccentric) left ventricular hypertrophy, and left ventricular diastolic dysfunction. Left ventricular systolic dysfunction may occur if wall stress remains high because of inadequate hypertrophy. Right ventricular structure and function may be similarly affected by the aforementioned morphologic and hemodynamic alterations and by pulmonary hypertension related to the sleep apnea/ obesity hypoventilation syndrome. The term obesity cardiomyopathy is applied when these cardiac structural and hemodynamic changes result in congestive heart failure. Obesity cardiomyopathy typically occurs in persons with severe and long-standing obesity. The predominant causes of death in those with obesity cardiomyopathy are progressive congestive heart failure and sudden cardiac death.

title: Diastolic dysfunction in diabetes and the metabolic syndrome: promising potential for diagnosis and prognosis
abstract: Cardiac disease in diabetes mellitus and in the metabolic syndrome consists of both vascular and myocardial abnormalities. The latter are characterised predominantly by diastolic dysfunction, which has been difficult to evaluate in spite of its prevalence. While traditional Doppler echocardiographic parameters enable only semiquantitative assessment of diastolic function and cannot reliably distinguish perturbations in loading conditions from altered diastolic functions, new technologies enable detailed quantification of global and regional diastolic function. The most readily available technique for the quantification of subclinical diastolic dysfunction is tissue Doppler imaging, which has been integrated into routine contemporary clinical practice, whereas cine magnetic resonance imaging (CMR) remains a promising complementary research tool for investigating the molecular mechanisms of the disease. Diastolic function is reported to vary linearly with age in normal persons, decreasing by 0.16 cm/s each year. Diastolic function in diabetes and the metabolic syndrome is determined by cardiovascular risk factors that alter myocardial stiffness and myocardial energy availability/bioenergetics. The latter is corroborated by the improvement in diastolic function with improvement in metabolic control of diabetes by specific medical therapy or lifestyle modification. Accordingly, diastolic dysfunction reflects the structural and metabolic milieu in the myocardium, and may allow targeted therapeutic interventions to modulate cardiac metabolism to prevent heart failure in insulin resistance and diabetes.

title: Selective Heart Rate Reduction Improves Metabolic Syndrome–related Left Ventricular Diastolic Dysfunction
abstract: Enhanced heart rate observed in metabolic syndrome (MS) contributes to the deterioration of left ventricular (LV) function via impaired LV filling and relaxation, increased myocardial O2 consumption, and reduced coronary perfusion. However, whether heart rate reduction (HRR) opposes LV dysfunction observed in MS is unknown.  We assessed in Zucker fa/fa rats, a rat model of MS, the cardiovascular effects of HRR induced by the If current inhibitor S38844 (3 mg·kg−1·d−1).  Delayed short-term (4 days) and long-term (90 days) HRR induced by S38844 reduced LV end-diastolic pressure and LV end-diastolic pressure–volume relation, increased myocardial tissue perfusion, decreased myocardial oxidized glutathione levels, and preserved cardiac output, without modifying LV end-systolic pressure and LV end-systolic pressure–volume relation, although only long-term S38844 opposed LV collagen accumulation. Long-term S38844 improved flow-induced endothelium-dependent dilatation of mesenteric arteries, while metabolic parameters, such as plasma glucose levels, and Hb1c, were never modified.  In rats with MS, HRR induced by the If inhibitor S38844 improved LV diastolic function and endothelium-dependent vascular dilatation, independent from modifications in metabolic status. Moreover, this improvement in cardiac function involves not only immediate effects such as improved myocardial perfusion and reduced oxidative stress but also long-term effects such as modifications in the myocardial structure.

title: Mineralocorticoid Receptor Antagonism Treats Obesity-Associated Cardiac Diastolic Dysfunction
abstract: Patients with obesity and diabetes mellitus exhibit a high prevalence of cardiac diastolic dysfunction (DD), an independent predictor of cardiovascular events for which no evidence-based treatment exists. In light of renin-angiotensin-aldosterone system activation in obesity and the cardioprotective action of mineralocorticoid receptor (MR) antagonists in systolic heart failure, we examined the hypothesis that MR blockade with a blood pressure–independent low-dose spironolactone (LSp) would treat obesity-associated DD in the Zucker obese (ZO) rat. Treatment of ZO rats exhibiting established DD with LSp normalized cardiac diastolic function, assessed by echocardiography. This was associated with reduced cardiac fibrosis, but not reduced hypertrophy, and restoration of endothelium-dependent vasodilation of isolated coronary arterioles via a nitric oxide–independent mechanism. Further mechanistic studies revealed that LSp reduced cardiac oxidative stress and improved endothelial insulin signaling, with no change in arteriolar stiffness. Infusion of Sprague-Dawley rats with the MR agonist aldosterone reproduced the DD noted in ZO rats. In addition, improved cardiac function in ZO-LSp rats was associated with attenuated systemic and adipose inflammation and an anti-inflammatory shift in cardiac immune cell mRNAs. Specifically, LSp increased cardiac markers of alternatively activated macrophages and regulatory T cells. ZO-LSp rats had unchanged blood pressure, serum potassium, systemic insulin sensitivity, or obesity-associated kidney injury, assessed by proteinuria. Taken together, these data demonstrate that MR antagonism effectively treats established obesity-related DD via blood pressure–independent mechanisms. These findings help identify a particular population with DD that might benefit from MR antagonist therapy, specifically patients with obesity and insulin resistance.

title: Metabolic syndrome, left ventricular hypertrophy and carotid atherosclerosis in hypertension: A gender-based study
abstract: The influence of gender on the association between metabolic syndrome (MS) and subclinical organ damage (OD) has been poorly investigated. The aim of this study was to investigate whether the risk of developing left ventricular hypertrophy (LVH) and carotid atherosclerosis is different in men and women with MS.  A total of 3752 untreated and treated hypertensive patients (mean age 53.3 ± 12.6, 52.7% men) were considered for this analysis. All patients underwent standard ultrasonographic investigations searching for LVH and carotid atherosclerosis. The MS was defined according to ATP III criteria.  LVH was more prevalent in women and men with the MS compared with their counterparts (58% vs 34% and 48% vs 33%, respectively, p < 0.001). This was also the case for carotid plaque prevalence (61% vs 42% and 57% vs 44%, p < 0.001). The prevalence of OD was not different between men and women with MS, after adjusting for confounders. In multivariate analysis, abdominal obesity was the most important MS component independently related to LVH in both genders, followed by blood pressure. As for carotid plaques, blood pressure, hyperglycemia and hypertriglyceridemia turned out to be independent correlates regardless of gender.  Our data indicate that MS is associated with a higher risk of LVH and carotid atherosclerosis irrespective of gender; these findings do not support a gender influence in the association between MS and subclinical OD.

title: The impact of obesity on the left ventricle: the Multi-Ethnic Study of Atherosclerosis (MESA).
abstract: The purpose of this study was to evaluate the relationship of left ventricular (LV) remodeling assessed by cardiac magnetic resonance to various measures of obesity in a large population-based study.



Obesity is a well-known risk factor for cardiovascular disease, yet its relationship with LV size and function is poorly understood.



A total of 5,098 participants (age 45 to 84 years; 48% men) in the Multi-Ethnic Study of Atherosclerosis who were free of clinically apparent cardiovascular disease underwent cardiac magnetic resonance to assess LV size and function as well as measures of obesity, including body mass index, waist-to-hip ratio and waist circumference, and cardiovascular risk factors. Fat mass (FM) was estimated based on height-weight models derived from bioelectrical impedance studies. The associations of obesity measures with LV size and function were evaluated using linear spline regression models for body mass index and multivariable regression models for other measures of obesity; they were displayed graphically using generalized additive models.



LV mass and end-diastolic volume were positively associated with measures of obesity in both sexes after adjustment for risk factors (e.g., 5.7-g and 6.9-g increase in LV mass per 10-kg increase in FM in women and men, respectively [p < 0.001]). LV mass-to-volume ratio was positively associated with increased body mass index, waist-to-hip ratio, waist circumference, and estimated FM (e.g., 0.02-g/ml and 0.06-g/ml increase in mass-to-volume ratio per 10-kg increase in FM in women and men, respectively [p < 0.001]). The increased mass-to-volume ratio was due to a greater increase in LV mass relative to LV end-diastolic volume. All associations were stronger for men than for women. Ejection fraction showed no significant association with measures of obesity.



Obesity was associated with concentric LV remodeling without change in ejection fraction in a large, multiethnic cohort study.

title: Assessment of Left Ventricular Mass by Cardiovascular Magnetic Resonance
abstract: Left ventricular hypertrophy is associated with significant excess mortality and morbidity. The study and treatment of this condition, in particular the prognostic implications of changes in left ventricular mass, require an accurate, safe, and reproducible method of measurement. Cardiovascular magnetic resonance is a suitable tool for this purpose, and this review assesses the technique in comparison with others and examines the clinical and research implications of the improved reproducibility.

title: Is left ventricular diastolic dysfunction independent from presence of hypertension in metabolic syndrome? An echocardiographic study.
abstract: It has been shown that left ventricular diastolic dysfunction (LVDD) develops in patients with metabolic syndrome (MetS). However, there is not sufficient evidence in the literature to determine whether this condition is due to increase in blood pressure, which is frequently encountered in MetS. The purpose of this study was to test the hypothesis whether LVDD in MetS is independent from the presence of hypertension.



A total of 60 patients diagnosed with MetS and 30 healthy people, who were age- and gender-matched with the patient group, were included in the study as the control group. In the study group, 30 of the patients were normotensive whereas the other 30 had hypertension. Conventional echocardiographic examinations and tissue Doppler imaging were performed besides measurements of demographic and biochemical parameters.



In the hypertensive MetS group, early diastolic filling flow (E), early diastolic mitral annular velocity (E'), and E/A ratio were significantly lower compared to the control group. Late diastolic filling flow (A), deceleration time (DT), late diastolic mitral annular velocity (A'), and E/E' ratio were higher in the hypertensive MetS group than the control group. In the normotensive MetS group, E, E', and E/A ratio were also lower compared to the control group whereas DT, A', and E/E' ratio were higher.



These findings support the idea that LVDD may develop in patients with MetS even in the absence of hypertension. In addition, co-existence of hypertension with MetS contributes to further worsening of diastolic functions.

title: Early Detection of Regional and Global Left Ventricular Myocardial Function Using Strain and Strain-rate Imaging in Patients with Metabolic Syndrome
abstract: Strain and strain-rate imaging (SRI) have been found clinically useful in the assessment of cardiac systolic and diastolic function as well as providing new insights in deciphering cardiac physiology and mechanics in cardiomyopathies, and identifying early subclinical changes in various pathologies. The aim of this study was to evaluate the regional and global left ventricular (LV) myocardial function in metabolic syndrome (MS) with SRI so that we can provide more myocardial small lesions in patients with MS, which is robust and reliable basis for early detection of LV function.  Thirty-nine adults with MS were enrolled in the study. There was a control group of 39 healthy adults. In addition to classic echocardiographic assessment of LV global functional changes, SRI was used to evaluate regional and global LV function.  Peak systolic strain (S), peak systolic strain-rate (SR-s), peak diastolic strain-rate (SR-e).  There were no statistically significant differences between MS and controls in all traditional parameters of LV systolic function. On the other hand, significant differences were observed between MS and the control group in most of the parameters of S, SR-s, SR-e in regional LV function. Multiple stepwise regression analyses revealed that S and SR significantly were negatively correlated with blood pressure, waist circumference, fasting plasma glucose, uric acid, suggesting that risk factories were relevant to regional systolic dysfunction.  In MS with normal LV ejection fraction, there was regional myocardial dysfunction, risk factors contributed to the impairment of systolic and diastolic function of the regional myocardium. Assessment of myocardial function using SRI could be more accurate in MS patient evaluation than conventional echocardiography alone.

title: Metabolic Syndrome, Strain, and Reduced Myocardial Function: Multi-Ethnic Study of Atherosclerosis
abstract: Subclinical cardiovascular disease is prevalent in patients with Metabolic Syndrome (MetSyn). Left ventricular (LV) circumferential strain (εCC) and longitudinal strain (εLL), assessed by Speckle Tracking Echocardiography (STE), are indices of systolic function: shortening is indicated by negative strain, and thus, the more negative the strain, the better the LV systolic function. They have been used to demonstrate subclinical ventricular dysfunction in several clinical disorders.  We hypothesized that MetSyn is associated with impaired myocardial function, as assessed by STE.  We analyzed Multi-Ethnic Study of Atherosclerosis (MESA) participants who underwent STE and were evaluated for all MetSyn components.  Among the 133 participants included [women: 63%; age: 65 ± 9 years (mean ± SD)], the prevalence of MetSyn was 31% (41/133). Individuals with MetSyn had lower εCC and lower εLL than those without MetSyn (-16.3% ± 3.5% vs. -18.4% ± 3.7%, p < 0.01; and -12.1% ± 2.5% vs. -13.9% ± 2.3%, p < 0.01, respectively). The LV ejection fraction (LVEF) was similar in both groups (p = 0.09). In multivariate analysis, MetSyn was associated with less circumferential myocardial shortening as indicated by less negative εCC (B = 2.1%, 95%CI:0.6 3.5, p < 0.01) even after adjusting for age, ethnicity, LV mass, and LVEF). Likewise, presence of MetSyn (B = 1.3%, 95%CI:0.3 2.2, p < 0.01) and LV mass (B = 0.02%, 95% CI: 0.01-0.03, p = 0.02) were significantly associated with less longitudinal myocardial shortening as indicated by less negative εLL after adjustment for ethnicity, LVEF, and creatinine.  Left ventricular εCC and εLL, markers of subclinical cardiovascular disease, are impaired in asymptomatic individuals with MetSyn and no history of myocardial infarction, heart failure, and/or LVEF < 50%.

title: Does the metabolic syndrome impact left-ventricular mechanics? A two-dimensional speckle tracking study
abstract: To evaluate left-ventricular mechanics estimated by two-dimensional echocardiography (2DE) speckle tracking analyses in patients with the metabolic syndrome.  This cross-sectional study included 95 untreated patients with metabolic syndrome and 65 controls similar by sex and age. Metabolic syndrome was defined by the presence of at least three ATP-AHA-NHLB criteria. All the patients underwent adequate laboratory analyses and complete 2DE examination.  2DE global longitudinal and circumferential strain was significantly decreased in the metabolic syndrome group, whereas 2DE global radial strain was similar between the observed groups. The left-ventricular torsion was similar between the metabolic syndrome participants and the controls; whereas the left-ventricular untwisting rate was significantly increased in the metabolic syndrome group. The increasing number of the metabolic syndrome criteria induces progressive reduction of the left-ventricular longitudinal strain from the individuals with no metabolic syndrome risk factors to the individuals with five metabolic syndrome criteria. The same pattern was not noticed for left-ventricular circumferential and radial strain. The combination of increased blood pressure, abdominal obesity and increased fasting glucose level was associated with the higher level of left-ventricular mechanical impairment comparing with other clusters of the metabolic syndrome components. The multivariate analysis of the metabolic syndrome criteria showed that 24-h mean blood pressure, waist circumference and fasting glucose level were independently associated with 2DE global longitudinal and circumferential myocardial strain, and left-ventricular untwisting rate. The interaction between sex and metabolic syndrome significantly impacts the left-ventricular longitudinal strain and untwisting rate.  Left-ventricular mechanics assessed by 2DE strain is significantly impaired in the metabolic syndrome patients. Among all metabolic syndrome components, blood pressure, waist circumference and fasting glucose level are the most responsible for damage of left-ventricular deformation.

title: Myocardial deformation and twist mechanics in adults with metabolic syndrome: Impact of cumulative metabolic burden
abstract: The aim of the study is to characterize left ventricular (LV) myocardial mechanics in adults with metabolic syndrome (MetS), and elucidate the effects of multiple risk‐factors on myocardial function using speckle tracking echocardiography (STE); a more sensitive method than conventional echocardiography for detecting subclinical myocardial dysfunction.

title: Subclinical left ventricular systolic dysfunction in patients with metabolic syndrome: A case-control study using two-dimensional speckle tracking echocardiography
abstract: The dramatic increase in the prevalence of metabolic syndrome is associated with more increased cardiovascular morbidity and mortality in this group. Some recent studies suggested that metabolic syndrome is associated with increased risk of subclinical left ventricular (LV) systolic dysfunction. In the present cross-sectional case-control study, the utility of two-dimensional speckle tracking echocardiography (STE) was examined to detect early LV systolic dysfunction in this population.  A total of 75 clinically asymptomatic subjects with left ventricular ejection fraction (LVEF) ≥ 55%, 39 without metabolic syndrome and 36 with metabolic syndrome, matched for gender and age, were enrolled in this case-control study. Metabolic syndrome was diagnosed using the National Cholesterol Education Program/Adult Treatment Panel III criteria. LV systolic function was assessed by STE-derived global and segmental longitudinal strain (εLL).  Global εLL was significantly lower in patients with metabolic syndrome compared with normal population (−18.41 ± 2.20% vs. −21.2 ± 2.1%, P < 0.001). Segmental εLL was significantly lower in patients with metabolic syndrome in comparison to control group except for basal anteroseptal (−19.95 ± 2.90% vs. −21.15 ± 3.30%, P = 0.106), basal anterolateral (−17.5 ± 5.0% vs. −18.3 ± 4.1%, P = 0.437), and basal inferolateral segments (−18.1 ± 6.3% vs. −18.9 ± 4.1%, P = 0.526).  STE-derived longitudinal LV strain (εLL), a marker of subclinical cardiovascular disease, is impaired in asymptomatic individuals with metabolic syndrome and normal LVEF.

title: Strain/Strain Rate Imaging of Impaired Left Atrial Function in Patients with Metabolic Syndrome
abstract: Metabolic syndrome (MS) predisposes to left ventricular dysfunction and heart failure, however, alterations in left atrial (LA) function in MS are unknown.  We aimed to use strain/strain rate (SR) imaging to investigate the effect of MS on LA function.  This prospective case control study included a total of 100 subjects divided in to 75 metabolic syndrome (MS) patients referred to Al-Azhar university hospital outpatient clinic for evaluation and treatment of hypertension and/or diabetes mellitus and 25 age and sex matched apparently healthy volunteers as a control group. All subjects underwent conventional echocardiographic examination and assessment of LA function by speckle tracking. Partial correlation and multiple stepwise regression analyses were used to determine the risk factors for impaired LA function.  Compared with the controls, the MS patients showed significantly lower levels of mean strain, mean peak systolic SR and mean peak early diastolic SR (P<0.05 for all), with no difference in the mean peak late diastolic SR. Central obesity, hypertension, dyslipidemia and uncontrolled diabetes were independent risk factors for impaired LA function.  SR imaging is reliable in assessing LA function in MS patients.

title: Impaired left ventricular systolic and diastolic function in patients with metabolic syndrome as assessed by strain and strain rate imaging.
abstract: The present study aimed to investigate cardiac structural and functional alterations in patients with metabolic syndrome (MS) and to compare those with control subjects. Strain and strain rate (SR) imaging were preformed in 200 patients with MS and 197 normal subjects. The patients were further divided into Group 1 (with three metabolic disorders) and Group 2 (with four metabolic disorders) to elucidate the influence of different metabolic components on left ventricular (LV) functions. LV diastolic and systolic functions were determined by the mean systolic strain, SR-LVs and SR-LVe. There were no differences in LVEF among the three groups. However, the mean systolic strain, SR-LVs and SR-LVe, were significantly decreased in Group 1 and Group2 when compared with control subjects (all P<0.001). The mean systolic strain and SR-LVe were lower in Group 2 than Group 1 (all P<0.05). Stepwise multiple regression analyses revealed that the W-H ratio was an independent predictor of the LV systolic function, whereas W-H ratio, HDL cholesterol and SBP were independent predictors of LV diastolic function. In summary, our results demonstrated that LV systolic and diastolic functions were impaired in patients with metabolic syndrome even if they have normal LVEF. Strain and SR imaging would be a sensitive and feasible method to detect subclinical abnormalities in those populations.

title: Review of journal of cardiovascular magnetic resonance 2010
abstract: There were 75 articles published in the Journal of Cardiovascular Magnetic Resonance (JCMR) in 2010, which is a 34% increase in the number of articles since 2009. The quality of the submissions continues to increase, and the editors were delighted with the recent announcement of the JCMR Impact Factor of 4.33 which showed a 90% increase since last year. Our acceptance rate is approximately 30%, but has been falling as the number of articles being submitted has been increasing. In accordance with Open-Access publishing, the JCMR articles go on-line as they are accepted with no collating of the articles into sections or special thematic issues. Last year for the first time, the Editors summarized the papers for the readership into broad areas of interest or theme, which we felt would be useful to practitioners of cardiovascular magnetic resonance (CMR) so that you could review areas of interest from the previous year in a single article in relation to each other and other recent JCMR articles . This experiment proved very popular with a very high rate of downloading, and therefore we intend to continue this review annually. The papers are presented in themes and comparison is drawn with previously published JCMR papers to identify the continuity of thought and publication in the journal. We hope that you find the open-access system increases wider reading and citation of your papers, and that you will continue to send your quality manuscripts to JCMR for publication.

title: Effect of lifestyle intervention plus rosiglitazone or placebo therapy on left ventricular mass assessed with cardiovascular magnetic resonance in the metabolic syndrome
abstract: BackgroundTo evaluate the effect of lifestyle intervention in conjunction with rosiglitazone or placebo therapy on left ventricular (LV) mass, using cardiovascular magnetic resonance (CMR) in the metabolic syndrome.MethodsThe present study was a pre-specified substudy of a double-blind randomized controlled trial evaluating the effect of lifestyle intervention in conjunction with rosiglitazone or placebo therapy on carotid artery atherosclerosis in the metabolic syndrome. From this original study population, 10 subjects from the placebo group and 10 from the rosiglitazone group were randomly selected. At baseline and follow-up (52 weeks), clinical and laboratory measurements were assessed and a CMR-examination was performed to evaluate LV mass indexed for body surface area (LV mass-I). Subsequently, the effect of therapy (rosiglitazone vs. placebo) and clinical and laboratory variables on LV mass-I was evaluated.ResultsIn both groups, body mass index, waist circumference, systolic and diastolic blood pressure significantly decreased during follow-up. Interestingly, LV mass-I significantly decreased in the placebo group (48.9 ± 5.3 g/m2 vs. 44.3 ± 5.6 g/m2, p < 0.001) indicating reverse remodeling, whereas LV mass-I remained unchanged in the rosiglitazone group (54.7 ± 9.9 g/m2 vs. 53.7 ± 9.2 g/m2, p = 0.3). After correction for systolic and diastolic blood pressure and triglyceride, the kind of therapy (rosiglitazone vs. placebo) remained the only significant predictor of LV mass-I reduction.ConclusionsLifestyle intervention resulted in a reduction of LV mass-I in the metabolic syndrome, indicating reverse remodeling. However, rosiglitazone therapy may have inhibited this positive reverse remodeling.

title: Evaluation of diastolic function by three-dimensional volume tracking of the mitral annulus with cardiovascular magnetic resonance: comparison with tissue Doppler imaging
abstract: BackgroundMeasurement of mitral annulus (MA) dynamics is an important component of the evaluation of left ventricular (LV) diastolic function; MA velocities are commonly measured using tissue Doppler imaging (TDI). This study aimed to examine the clinical potential of a semi-automated cardiovascular magnetic resonance (CMR) technique for quantifying global LV diastolic function, using 3D volume tracking of the MA with conventional cine-CMR images.Methods124 consecutive patients with normal ejection fraction underwent both clinically indicated transthoracic echocardiography (TTE) and CMR within 2 months. Interpolated 3D reconstruction of the MA over time was performed with semi-automated atrioventricular junction (AVJ) tracking in long-axis cine-CMR images, producing an MA sweep volume over the cardiac cycle. CMR-based diastolic function was evaluated, using the following parameters: peak volume sweep rates in early diastole (PSRE) and atrial systole (PSRA), PSRE/PSRA ratio, deceleration time of sweep volume (DTSV), and 50% diastolic sweep volume recovery time (DSVRT50); these were compared with TTE diastolic measurements.ResultsPatients with TTE-based diastolic dysfunction (n = 62) showed significantly different normalized MA sweep volume profiles compared to those with TTE-based normal diastolic function (n = 62), including a lower PSRE (5.25 ± 1.38 s−1 vs. 7.72 ± 1.7 s−1), a higher PSRA (6.56 ± 1.99 s−1 vs. 4.67 ± 1.38 s−1), a lower PSRE/PSRA ratio (0.9 ± 0.44 vs. 1.82 ± 0.69), a longer DTSV (144 ± 55 ms vs. 96 ± 37 ms), and a longer DSVRT50 (25.0 ± 11.0% vs. 15.6 ± 4.0%) (all p < 0.05). CMR diastolic parameters were independent predictors of TTE-based diastolic dysfunction after adjusting for left ventricular hypertrophy, hypertension, and coronary artery disease. Good correlations were observed between CMR PSRE/PSRA and early-to-late diastolic annular velocity ratios (e′/a′) measured by TDI (r = 0.756 to 0.828, p < 0.001).Conclusions3D MA sweep volumes generated by semi-automated AVJ tracking in routinely acquired CMR images yielded diastolic parameters that were effective in identifying patients with diastolic dysfunction when correlated with TTE-based variables.

title: MR imaging evaluation of cardiovascular risk in metabolic syndrome.
abstract: Metabolic syndrome has become an important public health problem and has reached epidemic proportions globally. Metabolic syndrome is characterized by a cluster of metabolic abnormalities in an individual, with insulin resistance as the main characteristic. The major adverse consequence of metabolic syndrome is cardiovascular disease, which is often already present without clinical signs or symptoms. In this early stage of disease, interventions (eg, lifestyle intervention, medication) can be used to prevent further cardiovascular deterioration or even to reverse cardiovascular disease. Therefore, risk stratification on an individual basis and early detection of cardiovascular disease are essential. Magnetic resonance (MR) imaging is a powerful tool for demonstrating cardiovascular risk factors in metabolic syndrome, such as increased fat depots and arterial stiffening. Furthermore, MR imaging is an established modality for the assessment of myocardial function. This review provides a summary of the current MR applications in metabolic syndrome and discusses how these MR techniques can be used to identify subclinical cardiovascular damage.

title: Measurement of left ventricular velocities: phase contrast MRI velocity mapping versus tissue-doppler-ultrasound in healthy volunteers.
abstract: The aim of this study was the comparison of phase contrast magnetic resonance imaging (PCMRI) measurements of left ventricular velocities in a physiological in vivo setting with tissue-Doppler-ultrasound (tissue Doppler imaging: TDI) data in healthy volunteers. Images were acquired in short axis view using a flow compensated black blood k-space segmented gradient echo sequence. Velocity encoding was performed by adding a bipolar gradient after each rf-pulse to the otherwise identical pulse sequences. Full in-plane velocity information of the moving heart was obtained in 16 heartbeats within one breath-hold measurement. Twenty-nine healthy volunteers (mean age=25 years) were examined with both imaging modalities. Both PCMRI and TDI demonstrate a biphasic profile of radial velocities over the cardiac cycle. Intraindividual comparison of left ventricular velocity data acquired using PCMRI and TDI show a very good correspondence with r-values of 0.97. The in vivo study in 29 healthy volunteers demonstrates a high validity of time-resolved phase contrast measurements for the analysis of left ventricular myocardial velocities.

title: Cardiac MR imaging: state of the technology.
abstract: Recent developments in magnetic resonance (MR) imaging of the heart have refocused attention on the potential of MR and continue to attract intense interest within the radiology and cardiology communities. Improvements in speed, image quality, reliability, and range of applications have evolved to the point where cardiac MR imaging is increasingly seen as a practical clinical tool. As is often the case with MR imaging, not all of the most powerful techniques are necessarily easy to master or understand, and many-nonspecialists and specialists alike-are challenged to stay abreast. This review covers some of the major milestones that have led to the current state of cardiac MR and attempts to put into context some concepts that, although technical, have a real impact on the diagnostic power of cardiac MR imaging. Topics discussed include functional imaging, myocardial viability and perfusion imaging, flow quantification, and coronary artery imaging. A review such as this can only scratch the surface of what is a dynamic interdisciplinary field, but the hope is that sufficient information and insight are provided to stimulate the motivated reader to take his or her interest to the next level.

title: Gender and Hypertension-Related Remodeling Influences Left Ventricular Torsion Assessed by Tagged Cardiac Magnetic Resonance in Asymptomatic Individuals : The Multi-Ethnic Study of Atherosclerosis
abstract: Dept of Cardiology, Johns Hopkins University, Baltimore, MD; Offices of Biostatistics Research, National Heart, Lung and Blood Institute, Bethesda, MD; Dept of Internal Medicine/Cardiology, Wake Forest University Health Sciences, Winston-Salem, NC; Dept of Radiology, UCLA School of Medicine, Los Angeles, CA; Dept of Biostatistics, University of Washington, Seattle, WA; National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health Clinical Center, Bethesda, MD

title: Two‐Dimensional Strain and Twist by Vector Velocity Imaging in Adolescents With Severe Obesity
abstract: The prevalence of severe obesity is increasing worldwide in adolescents. Whether it is associated with functional myocardial abnormalities remains largely unknown, potentially because of its frequent association with other cardiovascular risk factors and also use of insensitive techniques to detect subclinical changes in myocardial function. We used 2D vector velocity imaging (VVI) to investigate early changes in left ventricular (LV) myocardial function in youths with isolated severe obesity. Thirty‐seven asymptomatic severely obese adolescents free of diabetes and hypertension, and 24 lean controls were enrolled. LV longitudinal, basal, and apical circumferential strain, strain rate (SR), rotations, and LV twist were measured. Obese adolescents had greater LV mass and reduced systolic and early diastolic tissue Doppler imaging (TDI) velocities than lean counterparts. L strain (−24%) and systolic and early diastolic SR were also diminished in the obese, whereas no intergroup differences existed for the circumferential deformation indexes. LV twist was more pronounced in the obese (+1.7°, P < 0.01) on account of greater apical rotation only (4.1 ± 0.9 vs. 5.2 ± 1.2°, P < 0.01), potentially compensating for the loss in longitudinal function. Systolic—diastolic coupling, an important component of early filling and diastolic function, was maintained with severe obesity. No intergroup differences were reported regarding time to peak values for all VVI indexes highlighting that dynamics of strain and twist/untwist along the cardiac cycle was preserved with severe obesity. Isolated severe obesity in adolescents, at a preclinical stage, is associated with changes in myocardial deformation and torsional mechanics that could be in part related to alterations in relaxation and contractility properties of subendocardial fibers.

title: Left ventricular mechanical dysfunction in diet-induced obese mice is exacerbated during inotropic stress: a cine DENSE cardiovascular magnetic resonance study
abstract: BackgroundObesity is a risk factor for cardiovascular disease. There is evidence of impaired left ventricular (LV) function associated with obesity, which may relate to cardiovascular mortality, but some studies have reported no dysfunction. Ventricular function data are generally acquired under resting conditions, which could mask subtle differences and potentially contribute to these contradictory findings. Furthermore, abnormal ventricular mechanics (strains, strain rates, and torsion) may manifest prior to global changes in cardiac function (i.e., ejection fraction) and may therefore represent more sensitive markers of cardiovascular disease. This study evaluated LV mechanics under both resting and stress conditions with the hypothesis that the LV mechanical dysfunction associated with obesity is exacerbated with stress and manifested at earlier stages of disease compared to baseline.MethodsC57BL/6J mice were randomized to a high-fat or control diet (60 %, 10 % kcal from fat, respectively) for varying time intervals (n = 7 – 10 subjects per group per time point, 100 total; 4 – 55 weeks on diet). LV mechanics were quantified under baseline (resting) and/or stress conditions (40 μg/kg/min continuous infusion of dobutamine) using cine displacement encoding with stimulated echoes (DENSE) with 7.4 ms temporal resolution on a 7 T Bruker ClinScan. Peak strain, systolic strain rates, and torsion were quantified. A linear mixed model was used with Benjamini-Hochberg adjustments for multiple comparisons.ResultsReductions in LV peak longitudinal strain at baseline were first observed in the obese group after 42 weeks, with no differences in systolic strain rates or torsion. Conversely, reductions in longitudinal strain and circumferential and radial strain rates were seen under inotropic stress conditions after only 22 weeks on diet. Furthermore, stress cardiovascular magnetic resonance (CMR) evaluation revealed supranormal values of LV radial strain and torsion in the obese group early on diet, followed by later deficits.ConclusionsDifferences in left ventricular mechanics in obese mice are exacerbated under stress conditions. Stress CMR demonstrated a broader array of mechanical dysfunction and revealed these differences at earlier time points. Thus, it may be important to evaluate cardiac function in the setting of obesity under stress conditions to fully elucidate the presence of ventricular dysfunction.

title: Evaluation of left ventricular rotation in obese subjects by velocity vector imaging.
abstract: Obesity is a well-known risk factor in the development of cardiovascular disease. We hypothesize that early left ventricular (LV) dysfunction secondary to obesity could be signalled by abnormal LV rotation.



This prospective study examined 60 subjects divided into two groups: obese group with body mass index (BMI) >or=30 and control group with BMI <25. The peak rotation, twist, and torsion of the left ventricle were studied in obese and control subjects, using velocity vector imaging. Age and gender were comparable between the two groups. Obese subjects had higher BMI, waist circumference, fasting glucose, triglycerides, systolic and diastolic blood pressure, low-density lipoprotein cholesterol, and lower high-density lipoprotein cholesterol (P < 0.05). In obese subjects, LV mass and LV mass index were increased, and the ratio of mitral early and late diastolic filling velocity was decreased (P < 0.05). In obese subjects, the peak twist and torsion of the left ventricle displayed a lower trend, and the peak rotation of the left ventricle apex decreased significantly (3.81 +/- 2.09 degrees vs. 5.77 +/- 3.27 degrees , P < 0.001).



Obesity was associated with changes in LV rotation. Velocity vector imaging is a feasible and reproducible echocardiographic technique for the detection of early subclinical LV dysfunction.

title: Blood oxygenation level-dependent MRI for assessment of renal oxygenation
abstract: Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) has recently emerged as an important noninvasive technique to assess intrarenal oxygenation under physiologic and pathophysiologic conditions. Although this tool represents a major addition to our armamentarium of methodologies to investigate the role of hypoxia in the pathogenesis of acute kidney injury and progressive chronic kidney disease, numerous technical limitations confound interpretation of data derived from this approach. BOLD MRI has been utilized to assess intrarenal oxygenation in numerous experimental models of kidney disease and in human subjects with diabetic and nondiabetic chronic kidney disease, acute kidney injury, renal allograft rejection, contrast-associated nephropathy, and obstructive uropathy. However, confidence in conclusions based on data derived from BOLD MRI measurements will require continuing advances and technical refinements in the use of this technique.

title: Obesity-metabolic derangement exacerbates cardiomyocyte loss distal to moderate coronary artery stenosis in pigs without affecting global cardiac function.
abstract: Obesity associated with metabolic derangements (ObM) worsens the prognosis of patients with coronary artery stenosis (CAS), but the underlying cardiac pathophysiologic mechanisms remain elusive. We tested the hypothesis that ObM exacerbates cardiomyocyte loss distal to moderate CAS. Obesity-prone pigs were randomized to four groups (n = 6 each): lean-sham, ObM-sham, lean-CAS, and ObM-CAS. Lean and ObM pigs were maintained on a 12-wk standard or atherogenic diet, respectively, and left circumflex CAS was then induced by placing local-irritant coils. Cardiac structure, function, and myocardial oxygenation were assessed 4 wk later by computed-tomography and blood oxygenation level dependent (BOLD) MRI, the microcirculation with micro-computed-tomography, and injury mechanisms by immunoblotting and histology. ObM pigs showed obesity, dyslipidemia, and insulin resistance. The degree of CAS (range, 50-70%) was similar in lean and ObM pigs, and resting myocardial perfusion and global cardiac function remained unchanged. Increased angiogenesis distal to the moderate CAS observed in lean was attenuated in ObM pigs, which also showed microvascular dysfunction and increased inflammation (M1-macrophages, TNF-α expression), oxidative stress (gp91), hypoxia (BOLD-MRI), and fibrosis (Sirius-red and trichrome). Furthermore, lean-CAS showed increased myocardial autophagy, which was blunted in ObM pigs (downregulated expression of unc-51-like kinase-1 and autophagy-related gene-12; P < 0.05 vs. lean CAS) and associated with marked apoptosis. The interaction diet xstenosis synergistically inhibited angiogenic, autophagic, and fibrogenic activities. ObM exacerbates structural and functional myocardial injury distal to moderate CAS with preserved myocardial perfusion, possibly due to impaired cardiomyocyte turnover.

title: Relationships between components of metabolic syndrome and coronary intravascular ultrasound atherosclerosis measures in women without obstructive coronary artery disease: the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation Study.
abstract: In women, metabolic syndrome (MetS) is associated with higher risk of ischemic heart disease-related adverse outcomes versus individual components. We examined the relationship of MetS to subclinical coronary atherosclerosis.



Women (n = 100) undergoing coronary angiography for suspected ischemia but without obstructive coronary artery disease (CAD) underwent intravascular ultrasound (IVUS) of a segment of the left coronary artery. A core lab, masked to other findings, assessed IVUS measures and normalized volume measures to pull-back length. MetS [defined using ATPIII criteria (fasting glucose ≥ 100 mg/dl per revised NCEP guideline)] and its components were entered into multiple regression models to assess associations with IVUS measures.



Detailed IVUS measurements were available in 87 women. Mean age was 54 ± 10 years, 36% had MetS, and 78% had atheroma. Comparing women with MetS versus without MetS, significant differences were observed for seven IVUS atherosclerosis measures, but were not significant after adjusting for the MetS components. Systolic blood pressure and waist circumference components remained independently positively associated with the IVUS measures after adjusting for age, diabetes, CAD family history, dyslipidemia, smoking, and hormone replacement.



In women with signs and symptoms of ischemia and no obstructive CAD, MetS is associated with coronary atherosclerosis presence and severity. However, these associations appear largely driven by components of waist circumference and systolic blood pressure versus MetS cluster. This supports the concept that MetS is a convenient clustering of risk factors rather than an independent risk predictor, and emphasizes that the critical factors for coronary atherosclerosis are potentially modifiable.

title: Impact of metabolic syndrome on tissue characteristics of angiographically mild to moderate coronary lesions integrated backscatter intravascular ultrasound study.
abstract: We assessed the impact of metabolic syndrome (MetS) on the tissue characteristics of coronary plaques using integrated backscatter intravascular ultrasound (IB-IVUS).



Metabolic syndrome is associated with the increasing risk of cardiovascular disease.



We identified MetS by the definition of the National Cholesterol Education Program in Adult Treatment Panel III criterion. Non-target coronary lesions with mild to moderate stenosis were measured by conventional and IB-IVUS parameters using 40-MHz (motorized pullback 0.5 mm/s) intravascular catheter. A total of 20 IB-IVUS images were recorded at an interval of 0.5 mm for 10 mm length in each plaque. The 3-dimensional analyses were performed using commercially available software.



The prevalence of MetS was 61 patients (50%) with 73 lesions (49%) among 122 patients with 148 lesions. Patients with MetS showed a significant increase in percentage lipid area (38 +/- 19% vs. 30 +/- 19%, p = 0.02) and percentage lipid volume (39 +/- 17% vs. 33 +/- 17%, p = 0.03), and they also showed a significant decrease in percentage of fibrous volume (57 +/- 14% vs. 61 +/- 13%, p = 0.03). Multivariate regression analysis after adjustment for potentially confounding risk factors showed that MetS remains correlated independently with the percentage of lipid volume (r = 0.223, p = 0.01). Logistic regression analysis after adjusting for confounding and non-MetS coronary risk factors showed that MetS (odds ratio 4.00, 95% confidence interval 1.33 to 12.0, p = 0.01) is proved to be an independent predictor of the lipid-rich plaque.



Metabolic syndrome is associated with lipid-rich plaques, contributing to the increasing risk of plaque vulnerability.

title: Hyperglycemia effect on coronary disease in patients with metabolic syndrome evaluated by intracoronary ultrasonography
abstract: Metabolic syndrome (MS) is characterized by dyslipidemia, central obesity, hypertension and hyperglycemia. However, type 2 diabetes mellitus (T2DM) may or may not be present in metabolic syndrome. MS and T2DM are considered important cardiovascular risk factors, but the role of hyperglycemia in coronary disease is still contested in the literature. Therefore, we decided to evaluate the effect of hyperglycemia on the severity of coronary disease in MS patients, with or without T2DM, submitted to coronary angiography (CA) and intravascular ultrasonography (IVUS).  This is a cross sectional, observational study with 100 MS patients (50% with T2DM), 60% male. All of the patients had been referred for CA procedures. The obstruction was considered severe when stenosis was greater than 70% and moderate if it was between 50–69%. Patients detected with a moderate obstruction by CA were indicated to IVUS. A minimal luminal area of less than 4mm2 detected by IVUS was also considered severe. IDF criteria were used to define Metabolic Syndrome and T2DM diagnosis was defined according to the American Diabetes Association criteria. Student’s t-test and Pearson Chi-square were used for statistical analysis, considering p < 0.05 statistically significant.  The majority of T2DM patients presented severe arterial lesions (74% vs 22%, p<0.001). Using CA procedure, 12% of T2DM had moderate obstructions, compared to 38% of the non-diabetic group (p< 0.05). 8% of patients with moderate lesions by CA were diagnosed with a luminal area less than 4mm2 using IVUS. This luminal area was significantly smaller in the T2DM group than in the control group (3.8mm2 ± 2.42. vs 4.6mm2 ± 2.58, p = 0.03).  Patients with MS and T2DM submitted to angiography and IVUS, had more severe coronary lesions compared to MS patients without diabetes. This finding suggests that beyond insulin resistance that is present in MS, hyperglycemia may also play a role in the development of atherosclerotic disease. IVUS was useful for diagnosing 8% of severe cases initially considered to be moderate obstructions when using just CA in this scenario.

title: Features of Coronary Plaque in Patients With Metabolic Syndrome and Diabetes Mellitus Assessed by 3-Vessel Optical Coherence Tomography
abstract: The pathophysiological basis for the association between metabolic syndrome (MetS) and coronary artery disease is not well understood. We sought to characterize coronary plaques in patients with MetS by using optical coherence tomography.  We identified 451 coronary plaques from 171 subjects who underwent optical coherence tomographic imaging in 3 coronary arteries. Subjects were divided into 3 groups: diabetes mellitus (DM, n=77), MetS (n=35), and a control group (C group, n=59) without DM or MetS. Optical coherence tomographic analysis included the presence of lipid-rich plaque, maximum lipid arc, lipid-core length, lipid index (LI), fibrous cap thickness, and thin-cap fibroatheroma. We defined LI as mean lipid arc multiplied by lipid-core length. Lipid-core length and LI were significantly greater in DM and MetS than in C group (lipid-core length: 7.7±4.0 and 7.0±3.8 versus 5.5±2.4 mm; P<0.001 and P=0.012, and LI: 1164±716 and 1086±693 versus 796±417 mm; P<0.001 and P=0.008). Maximum lipid arc was significantly greater in DM than in C group, whereas no significant difference was observed between MetS and C group (196±45°, 187±42° versus 176±52°; P=0.002 and P=0.182). Fibrous cap thickness and thin-cap fibroatheroma showed no significant difference among the 3 groups. In multivariate analysis, DM and MetS were independently associated with LI, whereas only acute coronary syndrome was the independent predictor for thin-cap fibroatheroma.  Compared with control subjects, coronary plaques in MetS contain larger lipid. However, the MetS criteria used in this study could not distinguish the vulnerable features such as thin-cap fibroatheroma, suggesting the necessity of complementary information to identify patients at high risk for cardiovascular events.

title: Can cardiac computed tomography predict cardiovascular events in asymptomatic type-2 diabetics?: results of a long term follow-up
abstract: BackgroundDoubts remain about atherosclerotic disease and risk stratification of asymptomatic type-2 diabetic patients (T2DP). This study aims to evaluate the usefulness of calcium score (CS) and coronary computed tomography (CT) angiography (CTA) to predict fatal and non fatal cardiovascular events (CVEV) in T2DP.MethodsEighty-five consecutive T2DP undergoing CT (Phillips Brilliance, 16-slice) with CS and CTA were prospectively enrolled in a transversal case-control study. Patients were followed for 48 months (range 18 - 68) to assess CVEV: cardiovascular death, acute coronary syndrome, revascularisation and stroke. Potential predictors of CVEV were identified. Predictive models based on clinical features, CTA and CS were created and compared.ResultsPerforming CT impacted T2DP treatment. Cardiovascular risk was lowered during follow-up but metabolic control remained suboptimal. CVEV occurred in 11.8% T2DP (3.1%/year). CS ≥86.6 was predictor of CVEV over time, with a high negative predictive value, an 80% sensitivity and 74.7% specificity. Although its prognostic value was not independent of the presence/absence of obstructive CAD, adding CS and CTA data to clinical parameters improved the prediction of CVEV: the combined model had the highest AUC (0.888, 95%CI 0.789-0.987, p < 0.001) for the prediction of the study endpoints.ConclusionsCS showed great value in T2DP risk stratification and its prognostic value was further enhanced by CTA data. Information provided by CT may help predict CVEV in T2DP and potentially improve their outcome.

title: Is Metabolic Syndrome Predictive of Prevalence, Extent, and Risk of Coronary Artery Disease beyond Its Components? Results from the Multinational Coronary CT Angiography Evaluation for Clinical Outcome: An International Multicenter Registry (CONFIRM)
abstract: Although metabolic syndrome is associated with increased risk of cardiovascular disease and events, its added prognostic value beyond its components remains unknown. This study compared the prevalence, severity of coronary artery disease (CAD), and prognosis of patients with metabolic syndrome to those with individual metabolic syndrome components. The study cohort consisted of 27125 consecutive individuals who underwent ≥64-detector row coronary CT angiography (CCTA) at 12 centers from 2003 to 2009. Metabolic syndrome was defined as per NCEP/ATP III criteria. Metabolic syndrome patients (n=690) were matched 1:1:1 to those with 1 component (n=690) and 2 components (n=690) of metabolic syndrome for age, sex, smoking status, and family history of premature CAD using propensity scoring. Major adverse cardiac events (MACE) were defined by a composite of myocardial infarction (MI), acute coronary syndrome, mortality and late target vessel revascularization. Patients with 1 component of metabolic syndrome manifested lower rates of obstructive 1-, 2-, and 3-vessel/left main disease compared to metabolic syndrome patients (9.4% vs 13.8%, 2.6% vs 4.5%, and 1.0% vs 2.3%, respectively; p<0.05), while those with 2 components did not (10.5% vs 13.8%, 2.8% vs 4.5% and 1.3% vs 2.3%, respectively; p>0.05). At 2.5 years, metabolic syndrome patients experienced a higher rate of MACE compared to patients with 1 component (4.4% vs 1.6%; p=0.002), while no difference observed compared to individuals with 2 components (4.4% vs 3.2% p=0.25) of metabolic syndrome. In conclusion, Metabolic syndrome patients have significantly greater prevalence, severity, and prognosis of CAD compared to patients with 1 but not 2 components of metabolic syndrome.

title: Myocardial blood flow quantification for evaluation of coronary artery disease by computed tomography.
abstract: During the last decade coronary computed tomography angiography (CTA) has become the preeminent non-invasive imaging modality to detect coronary artery disease (CAD) with high accuracy. However, CTA has a limited value in assessing the hemodynamic significance of a given stenosis due to a modest specificity and positive predictive value. In recent years, different CT techniques for detecting myocardial ischemia have emerged, such as CT-derived fractional flow reserve (FFR-CT), transluminal attenuation gradient (TAG), and myocardial CT perfusion (CTP) imaging. Myocardial CTP imaging can be performed with a single static scan during first pass of the contrast agent, with monoenergetic or dual-energy acquisition, or as a dynamic, time-resolved scan during stress by using coronary vasodilator agents (adenosine, dipyridamole, or regadenoson). A number of CTP techniques are available, which can assess myocardial perfusion in both a qualitative, semi-quantitative or quantitative manner. Once used primarily as research tools, these modalities are increasingly being used in routine clinical practice. All these techniques offer the substantial advantage of combining anatomical and functional evaluation of flow-limiting coronary stenosis in the same examination that would be beneficial for clinical decision-making. This review focuses on the state-of the-art and future trends of these evolving imaging modalities in the field of cardiology for the physiologic assessments of CAD.

title: Cardiac MR imaging: current status and future direction.
abstract: Coronary artery disease is currently a worldwide epidemic with increasing impact on healthcare systems. Magnetic resonance imaging (MRI) sequences give complementary information on LV function, regional perfusion, angiogenesis, myocardial viability and orientations of myocytes. T2-weighted short-tau inversion recovery (T2-STIR), fat suppression and black blood sequences have been frequently used for detecting edematous area at risk (AAR) of infarction. T2 mapping, however, indicated that the edematous reaction in acute myocardial infarct (AMI) is not stable and warranted the use of edematous area in evaluating therapies. On the other hand, cine MRI demonstrated reproducible data on LV function in healthy volunteers and LV remodeling in patients. Noninvasive first pass perfusion, using exogenous tracer (gadolinium-based contrast media) and arterial spin labeling MRI, using endogenous tracer (water), are sensitive and useful techniques for evaluating myocardial perfusion and angiogenesis. Recently, new strategies have been developed to quantify myocardial viability using T1-mapping and equilibrium contrast enhanced MR techniques because existing delayed contrast enhancement MRI (DE-MRI) sequences are limited in detecting patchy microinfarct and diffuse fibrosis. These new techniques were successfully used for characterizing diffuse myocardial fibrosis associated with myocarditis, amyloidosis, sarcoidosis heart failure, aortic hypertrophic cardiomyopathy, congenital heart disease, restrictive cardiomyopathy, arrhythmogenic right ventricular dysplasia and hypertension). Diffusion MRI provides information regarding microscopic tissue structure, while diffusion tensor imaging (DTI) helps to characterize the myocardium and monitor the process of LV remodeling after AMI. Novel trends in hybrid imaging, such as cardiac positron emission tomography (PET)/MRI and optical imaging/MRI, are recently under intensive investigation. With the promise of higher spatial-temporal resolution and 3D coverage in the near future, cardiac MRI will be an indispensible tool in the diagnosis of cardiac diseases, coronary intervention and myocardial therapeutic delivery.

title: Renal relevant radiology: renal functional magnetic resonance imaging.
abstract: Because of its noninvasive nature and provision of quantitative measures of a wide variety of physiologic parameters, functional magnetic resonance imaging (MRI) shows great potential for research and clinical applications. Over the past decade, application of functional MRI extended beyond detection of cerebral activity, and techniques for abdominal functional MRI evolved. Assessment of renal perfusion, glomerular filtration, interstitial diffusion, and parenchymal oxygenation turned this modality into an essential research and potentially diagnostic tool. Variations in many renal physiologic markers can be detected using functional MRI before morphologic changes become evident in anatomic magnetic resonance images. Moreover, the framework of functional MRI opened a window of opportunity to develop novel pathophysiologic markers. This article reviews applications of some well validated functional MRI techniques, including perfusion, diffusion-weighted imaging, and blood oxygen level-dependent MRI, as well as some emerging new techniques such as magnetic resonance elastography, which might evolve into clinically useful tools.

title: The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction.
abstract: Recent studies indicate that magnetic resonance imaging (MRI) after the administration of contrast material can be used to distinguish between reversible and irreversible myocardial ischemic injury regardless of the extent of wall motion or the age of the infarct. We hypothesized that the results of contrast-enhanced MRI can be used to predict whether regions of abnormal ventricular contraction will improve after revascularization in patients with coronary artery disease.



Gadolinium-enhanced MRI was performed in 50 patients with ventricular dysfunction before they underwent surgical or percutaneous revascularization. The transmural extent of hyperenhanced regions was postulated to represent the transmural extent of nonviable myocardium. The extent of regional contractility at the same locations was determined by cine MRI before and after revascularization in 41 patients.



Contrast-enhanced MRI showed hyperenhancement of myocardial tissue in 40 of 50 patients before revascularization. In all patients with hyperenhancement the difference in image intensity between hyperenhanced regions and regions without hyperenhancement was more than 6 SD. Before revascularization, 804 of the 2093 myocardial segments analyzed (38 percent) had abnormal contractility, and 694 segments (33 percent) had some areas of hyperenhancement. In an analysis of all 804 dysfunctional segments, the likelihood of improvement in regional contractility after revascularization decreased progressively as the transmural extent of hyperenhancement before revascularization increased (P<0.001). For instance, contractility increased in 256 of 329 segments (78 percent) with no hyperenhancement before revascularization, but in only 1 of 58 segments with hyperenhancement of more than 75 percent of tissue. The percentage of the left ventricle that was both dysfunctional and not hyperenhanced before revascularization was strongly related to the degree of improvement in the global mean wall-motion score (P<0.001) and the ejection fraction (P<0.001) after revascularization.



Reversible myocardial dysfunction can be identified by contrast-enhanced MRI before coronary revascularization.

title: Application of technetium-99m sestamibi single photon emission computed tomography in acute myocardial infarction: measuring the efficacy of therapy.
abstract: Infarct size and myocardial salvage measured by technetium (Tc)-99m sestamibi single photon emission computed tomography (SPECT) imaging have been applied as surrogate endpoints in clinical trials of acute myocardial infarction (MI). The major advantage of these endpoints over mortality is the ability to use much smaller sample sizes to compare different treatment strategies in acute MI. Multiple categories of evidence validate SPECT infarct size and myocardial salvage as surrogate endpoints, including: association with other variables used to measure infarct size; association with markers of myocardial perfusion; identification of myocardial fibrosis in pathology specimens; prediction of improvement in dysfunctional myocardial segments following revascularization; correlation between infarct size and mortality; and, demonstration that therapies which result in smaller infarct size also result in better clinical outcome in the same patients. These SPECT endpoints have been applied in over 30 clinical acute MI trials. Approximately one-third of these trials reported positive results in the intervention group or a subset of the intervention group. SPECT infarct size and myocardial salvage are the most extensively validated and widely applied surrogate endpoints in the setting of acute MI.

title: SPECT and PET in ischemic heart failure
abstract: Heart failure is a common clinical syndrome associated with significant morbidity and mortality worldwide. Ischemic heart disease is the leading cause of heart failure, at least in the industrialized countries. Proper diagnosis of the syndrome and management of patients with heart failure require anatomical and functional information obtained through various imaging modalities. Nuclear cardiology techniques play a main role in the evaluation of heart failure. Myocardial single photon emission computed tomography (SPECT) with thallium-201 or technetium-99 m labelled tracers offer valuable data regarding ventricular function, myocardial perfusion, viability, and intraventricular synchronism. Moreover, positron emission tomography (PET) permits accurate evaluation of myocardial perfusion, metabolism, and viability, providing high-quality images and the ability of quantitative analysis. As these imaging techniques assess different parameters of cardiac structure and function, variations of sensitivity and specificity have been reported among them. In addition, the role of SPECT and PET guided therapy remains controversial. In this comprehensive review, we address these controversies and report the advances in patient’s investigation with SPECT and PET in ischemic heart failure. Furthermore, we present the innovations in technology that are expected to strengthen the role of nuclear cardiology modalities in the investigation of heart failure.

title: Cardiovascular disease risk stratification with stress single-photon emission computed tomography technetium-99m tetrofosmin imaging in patients with the metabolic syndrome and diabetes mellitus.
abstract: The metabolic syndrome represents a constellation of risk factors caused by insulin resistance, dyslipidemia, hypertension, and obesity, resulting in elevated coronary disease risk. From a multicenter prospective registry of 7,849 patients, the relation among the metabolic syndrome, diabetes, and risk stratification with stress technetium-99m tetrofosmin single photon-emission computed tomography (SPECT) was evaluated. The percentage of stress myocardial defects was calculated as < or = 5%, 5.1% to 10%, 10.1% to 15%, and > 15%. A Cox proportional-hazards model was used to estimate cardiovascular death or myocardial infarction (n = 752). Of 7,849 patients, 42% had the metabolic syndrome. Patients with the metabolic syndrome had an 84% 2-year event-free survival rate, lower than patients with normal metabolic status (p <0.0001). In patients with the metabolic syndrome, the percentage of moderate to severely abnormal SPECT findings ranged from 11% to 44% for those with 3 to 5 risk factors for the metabolic syndrome. There was an additive relation between the number of risk factors for the metabolic syndrome and the extent and severity of abnormalities in SPECT findings (p <0.0001). Patients with 5 risk factors for the metabolic syndrome were at the greatest risk, with hazard ratios from 7.8- to 14.1-fold for mild to severely abnormal SPECT findings. For diabetic patients requiring combined oral and insulin therapy, relative risk ratios increased from 15 to 21.4 for patients with > 5% to > 15% stress myocardial perfusion defects. In conclusion, cardiovascular prognosis is affected by the degree of metabolic dysfunction, and stress-induced reductions in myocardial perfusion provide an accurate means for near-term risk stratification.

title: Obesity and the challenges of noninvasive imaging for the detection of coronary artery disease.
abstract: Obesity is a significant health problem that could potentially lead to increased cardiovascular risk. Noninvasive imaging plays an important role in the evaluation of cardiovascular symptoms and risk of these patients. Selection of the appropriate test in the diagnosis of obstructive coronary artery disease in this unique population is important. In this article, we focus on the strengths, limitations, and recommendations of the various noninvasive cardiac imaging modalities available in the detection of obstructive coronary artery disease. We have suggested an algorithm to help direct investigation. Ultimately, patient management should be individualized based on clinical judgement, test availability, and local expertise.

title: Hybrid PET/CT and PET/MRI imaging of vulnerable coronary plaque and myocardial scar tissue in acute myocardial infarction
abstract: AbstractBackgroundFollowing an acute coronary syndrome, combined CT and PET with 18F-NaF can identify coronary atherosclerotic plaques that have ruptured or eroded. However, the processes behind 18F-NaF uptake in vulnerable plaques remain unclear.
Methods and ResultsTen patients with STEMI were scanned after 18F-NaF injection, for 75 minutes in a Siemens PET/MR scanner using delayed enhancement (LGE). They were then scanned in a Siemens PET/CT scanner for 10 minutes. Tissue-to-background ratio (TBR) was compared between the culprit lesion in the IRA and remote non-culprit lesions in an effort to independently validate prior studies. Additionally, we performed a proof-of-principle study comparing TBR in scar tissue and remote myocardium using LGE images and PET/MR or PET/CT data. From the 33 coronary lesions detected on PET/CT, TBRs for culprit lesions were higher than for non-culprit lesions (TBR = 2.11 ± 0.45 vs 1.46 ± 0.48; P < 0.001). Interestingly, the TBR measured on the PET/CT was higher for infarcted myocardium than for remote myocardium (TBR = 0.81 ± 0.10 vs 0.71 ± 0.05; P = 0.003). These results were confirmed using the PET/MR data (TBR = 0.81 ± 0.10 for scar, TBR = 0.71 ± 0.06 for healthy myocardium, P = 0.03).
ConclusionsWe confirmed the potential of 18F-NaF PET/CT imaging to detect vulnerable coronary lesions. Moreover, we demonstrated proof-of-principle that 18F-NaF concurrently detects myocardial scar tissue.

title: Towards coronary plaque imaging using simultaneous PET-MR: a simulation study.
abstract: Coronary atherosclerotic plaque rupture is the main cause of myocardial infarction and the leading killer in the US. Inflammation is a known bio-marker of plaque vulnerability and can be assessed non-invasively using fluorodeoxyglucose-positron emission tomography imaging (FDG-PET). However, cardiac and respiratory motion of the heart makes PET detection of coronary plaque very challenging. Fat surrounding coronary arteries allows the use of MRI to track plaque motion during simultaneous PET-MR examination. In this study, we proposed and assessed the performance of a fat-MR based coronary motion correction technique for improved FDG-PET coronary plaque imaging in simultaneous PET-MR. The proposed methods were evaluated in a realistic four-dimensional PET-MR simulation study obtained by combining patient water-fat separated MRI and XCAT anthropomorphic phantom. Five small lesions were digitally inserted inside the patients coronary vessels to mimic coronary atherosclerotic plaques. The heart of the XCAT phantom was digitally replaced with the patient's heart. Motion-dependent activity distributions, attenuation maps, and fat-MR volumes of the heart, were generated using the XCAT cardiac and respiratory motion fields. A full Monte Carlo simulation using Siemens mMR's geometry was performed for each motion phase. Cardiac/respiratory motion fields were estimated using non-rigid registration of the transformed fat-MR volumes and incorporated directly into the system matrix of PET reconstruction along with motion-dependent attenuation maps. The proposed motion correction method was compared to conventional PET reconstruction techniques such as no motion correction, cardiac gating, and dual cardiac-respiratory gating. Compared to uncorrected reconstructions, fat-MR based motion compensation yielded an average improvement of plaque-to-background contrast of 29.6%, 43.7%, 57.2%, and 70.6% for true plaque-to-blood ratios of 10, 15, 20 and 25:1, respectively. Channelized Hotelling observer (CHO) signal-to-noise ratio (SNR) was used to quantify plaque detectability. CHO-SNR improvement ranged from 105% to 128% for fat-MR-based motion correction as compared to no motion correction. Likewise, CHO-SNR improvement ranged from 348% to 396% as compared to both cardiac and dual cardiac-respiratory gating approaches. Based on this study, our approach, a fat-MR based motion correction for coronary plaque PET imaging using simultaneous PET-MR, offers great potential for clinical practice. The ultimate performance and limitation of our approach, however, must be fully evaluated in patient studies.

title: Cardiac steatosis and left ventricular function in men with metabolic syndrome
abstract: BackgroundEctopic accumulation of fat accompanies visceral obesity with detrimental effects. Lipid oversupply to cardiomyocytes leads to cardiac steatosis, and in animal studies lipotoxicity has been associated with impaired left ventricular (LV) function. In humans, studies have yielded inconclusive results. The aim of the study was to evaluate the role of epicardial, pericardial and myocardial fat depots on LV structure and function in male subjects with metabolic syndrome (MetS).MethodsA study population of 37 men with MetS and 38 men without MetS underwent cardiovascular magnetic resonance and proton magnetic spectroscopy at 1.5 T to assess LV function, epicardial and pericardial fat area and myocardial triglyceride (TG) content.ResultsAll three fat deposits were greater in the MetS than in the control group (p <0.001). LV diastolic dysfunction was associated with MetS as measured by absolute (471 mL/s vs. 667 mL/s, p = 0.002) and normalized (3.37 s-1 vs. 3.75 s-1, p = 0.02) LV early diastolic peak filling rate and the ratio of early diastole (68% vs. 78%, p = 0.001). The amount of epicardial and pericardial fat correlated inversely with LV diastolic function. However, myocardial TG content was not independently associated with LV diastolic dysfunction.ConclusionsIn MetS, accumulation of epicardial and pericardial fat is linked to the severity of structural and functional alterations of the heart. The role of increased intramyocardial TG in MetS is more complex and merits further study.

title: Myocardial, Perivascular, and Epicardial Fat
abstract: Myocardial fat content refers to the storage of triglyceride droplets within cardiomyocytes. In addition, the heart and arteries are surrounded by layers of adipose tissue, exerting vasocrine and paracrine control of the subtending tissues. The rapid development of the field of noninvasive imaging has made it possible to quantify ectopic fat masses and contents with an increasing degree of accuracy. Myocardial triglyceride stores are increased in obesity, impaired glucose tolerance, and type 2 diabetes. The role of intramyocardial triglyceride accumulation in the pathogenesis of left ventricular (LV) dysfunction remains unclear. Increased triglyceride content is associated with states of fatty acid overload to the heart, saturating the oxidative capacity. It may initially serve as a fatty acid sink to circumscribe the formation of toxic lipid species and subsequently foster cardiac damage. Epicardial and perivascular fat depots may exert a protective modulation of vascular function and energy partition in a healthy situation, but their expansion turns them into an adverse lipotoxic, prothrombotic, and proinflammatory organ. They are augmented in patients with metabolic disorders and coronary artery disease (CAD). However, the progressive association between the quantity of fat and disease severity in terms of extent of plaque calcification or noncalcified areas, markers of plaque vulnerability, and number of vessels involved is less confirmed. Functional or hybrid imaging may contribute to a better definition of disease severity and unveil the direct myocardial and vascular targets of adipose tissue action.

title: Human epicardial adipose tissue: a review.
abstract: We discuss the anatomy, physiology, and pathophysiology of epicardial adipose tissue and its relationship to coronary atherosclerosis. Epicardial fat stores triglyceride to supply free fatty acids for myocardial energy production and produces adipokines. It shares a common embryological origin with mesenteric and omental fat. Like visceral abdominal fat, epicardial fat thickness, measured by echocardiography, is increased in obesity. Epicardial fat could influence coronary atherogenesis and myocardial function because there is no fibrous fascial layer to impede diffusion of free fatty acids and adipokines between it and the underlying vessel wall as well as the myocardium. Segments of coronary arteries lacking epicardial fat or separated from it by a bridge of myocardial tissue are protected against the development of atherosclerosis in those segments. However, when epicardial fat is totally absent in congenital generalized lipodystrophy, coronary atherosclerosis can still occur. Macrophages are more numerous and densely packed in the periadventitial fat of human atherosclerotic coronary arteries with lipid cores than in that of fibrocalcific or nonatherosclerotic coronary arteries. In obese patients with multiple cardiovascular risk factors, epicardial fat around atheromatous coronaries secretes several proinflammatory cytokines and is infiltrated by macrophages, lymphocytes, and basophils. Epicardial adipokine expression in obesity without coronary atherosclerosis has not been determined. In nonobese patients, epicardial fat around atheromatous coronary arteries expresses proinflammatory cytokines but produces either less adiponectin, a vasoprotective adipokine, than fat around nonatheromatous coronaries or a similar amount compared with thoracic subcutaneous fat. Further studies should be done to test the hypothesis that adipokines produced by and released from human epicardial adipose tissue might contribute locally to the pathogenesis of coronary atherosclerosis.

title: Left ventricular diastolic function in type 2 diabetes mellitus is associated with myocardial triglyceride content but not with impaired myocardial perfusion reserve
abstract: To study myocardial perfusion reserve and myocellular metabolic alterations indicated by triglyceride content as possible causes of diastolic dysfunction in patients with type 2 diabetes mellitus, preserved systolic function, and without clinically evident coronary artery disease.

title: Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus.
abstract: The purpose of this study was to compare myocardial triglyceride content and function between patients with uncomplicated type 2 diabetes mellitus (T2DM) and healthy subjects within the same range of age and body mass index (BMI), and to study the associations between myocardial triglyceride content and function.



T2DM is a major risk factor for cardiovascular disease. Increasing evidence is emerging that lipid oversupply to cardiomyocytes plays a role in the development of diabetic cardiomyopathy, by causing lipotoxic injury and myocardial steatosis.



Myocardial triglyceride content and myocardial function were measured in 38 T2DM patients and 28 healthy volunteers in the same range of age and BMI by proton magnetic resonance (MR) spectroscopy and MR imaging, respectively. Myocardial triglyceride content was calculated as a percentage relative to the signal of myocardial water.



Myocardial triglyceride content was significantly higher in T2DM patients compared with healthy volunteers (0.96 +/- 0.07% vs. 0.65 +/- 0.05%, p < 0.05). Systolic function did not significantly differ between both groups. Indexes of diastolic function, including the ratio of maximal left ventricular early peak filling rate and the maximal left ventricular atrial peak filling rate (E/A) and E peak deceleration, were significantly impaired in T2DM compared with those in healthy subjects (1.08 +/- 0.04 ml/s(2) x 10(-3) vs. 1.24 +/- 0.06 ml/s(2) x 10(-3) and 3.6 +/- 0.2 ml/s(2) x 10(-3) vs. 4.4 +/- 0.3 ml/s(2) x 10(-3), respectively, p < 0.05). Multivariable analysis indicated that myocardial triglyceride content was associated with E/A and E peak deceleration, independently of diabetic state, age, BMI, heart rate, visceral fat, and diastolic blood pressure.



Myocardial triglyceride content is increased in uncomplicated T2DM and is associated with impaired left ventricular diastolic function, independently of age, BMI, heart rate, visceral fat, and diastolic blood pressure.

title: Pericardial Fat, Visceral Abdominal Fat, Cardiovascular Disease Risk Factors, and Vascular Calcification in a Community-Based Sample: The Framingham Heart Study
abstract: Pericardial fat may be an important mediator of metabolic risk. Correlations with cardiovascular disease risk factors and vascular calcification in a community-based sample are lacking. We sought to examine associations between pericardial fat, metabolic risk factors, and vascular calcification.  Participants free of cardiovascular disease from the Framingham Heart Study (n=1155, mean age 63 years, 54.8% women) who were part of a multidetector computed tomography study underwent quantification of intrathoracic fat, pericardial fat, visceral abdominal fat (VAT), coronary artery calcification, and aortic artery calcification. Intrathoracic and pericardial fat volumes were examined in relation to body mass index, waist circumference, VAT, metabolic risk factors, coronary artery calcification, and abdominal aortic calcification. Intrathoracic and pericardial fat were directly correlated with body mass index (r=0.41 to 0.51, P<0.001), waist circumference (r=0.43 to 0.53, P<0.001), and VAT (r=0.62 to 0.76, P<0.001). Both intrathoracic and pericardial fat were associated with higher triglycerides (P<0.0001), lower high-density lipoprotein (P<0.0001), hypertension (P<0.0001 to 0.01), impaired fasting glucose (P<0.0001 to 0.001), diabetes mellitus (P=0.0005 to 0.009), and metabolic syndrome (P<0.0001) after multivariable adjustment. Associations generally persisted after additional adjustment for body mass index and waist circumference but not after adjustment for VAT (all P>0.05). Pericardial fat, but not intrathoracic fat, was associated with coronary artery calcification after multivariable and VAT adjustment (odds ratio 1.21, 95% confidence interval 1.005 to 1.46, P=0.04), whereas intrathoracic fat, but not pericardial fat, was associated with abdominal aortic calcification (odds ratio 1.32, 95% confidence interval 1.03 to 1.67, P=0.03).  Pericardial fat is correlated with multiple measures of adiposity and cardiovascular disease risk factors, but VAT is a stronger correlate of most metabolic risk factors. However, intrathoracic and pericardial fat are associated with vascular calcification, which suggests that these fat depots may exert local toxic effects on the vasculature.

title: The Relationship of Ectopic Lipid Accumulation to Cardiac and Vascular Function in Obesity and Metabolic Syndrome
abstract: Storage of lipid in ectopic depots outside of abdominal visceral and subcutaneous stores, including within the pericardium and liver, has been associated with obesity, insulin resistance, and cardiovascular risk. We sought to determine whether anatomically distinct ectopic depots were physiologically correlated and site‐specific effects upon cardiovascular function could be identified. Obese subjects (n = 28) with metabolic syndrome but without known atherosclerotic disease and healthy controls (n = 18) underwent magnetic resonance imaging (MRI) and proton MR spectroscopy (MRS) to quantify pericardial and periaortic lipid volumes, cardiac function, aortic compliance, and intrahepatic lipid content. Fasting plasma lipoproteins, glucose, insulin, and free‐fatty acids were measured. Pericardial and intrahepatic (P < 0.01) and periaortic (P < 0.05) lipid volumes were increased in obese subjects vs. controls and were strongly and positively correlated (P ≤ 0.01) but independent of BMI (P = NS) among obese subjects. Intrahepatic lipid was associated with insulin resistance (P < 0.01) and triglycerides (P < 0.05), whereas pericardial and periaortic lipid were not (P = NS). Periaortic and pericardial lipid positively correlated to free‐fatty acids (P ≤ 0.01) and negatively correlated to high‐density lipoprotein (HDL) cholesterol (P < 0.05). Pericardial lipid negatively correlated to cardiac output (P = 0.03) and stroke volume (P = 0.01) but not to left ventricular ejection fraction (P = 0.46). None of the ectopic depots correlated to aortic compliance. In conclusion, ectopic storage of lipid in anatomically distinct depots appeared tightly correlated but independent of body size. Site‐specific functional abnormalities were observed for pericardial but not periaortic lipid. These findings underscore the utility of MRI to assess individual differences in ectopic lipid that are not predictable from BMI.

title: Epicardial fat from echocardiography: a new method for visceral adipose tissue prediction.
abstract: To validate transthoracic echocardiography as an easy and reliable imaging method for visceral adipose tissue (VAT) prediction. VAT is recognized as an important indicator of high cardiovascular and metabolic risk. Several methods are applied to estimate VAT, with different results.



We selected 60 healthy subjects (29 women, 31 men, 49.5 +/- 16.2 years) with a wide range of body mass indexes. Each subject underwent transthoracic echocardiogram and magnetic resonance imaging (MRI) to measure epicardial fat thickness on the right ventricle. Measurements of epicardial adipose tissue thickness were obtained from the same echocardiographic and MRI views and points. MRI was also used to measure VAT cross-sectional areas at the level of L4 to L5. Anthropometric indexes were also measured.



Subjects with predominant visceral fat accumulation showed higher epicardial adipose tissue thickness than subjects with predominant peripheral fat distribution: 9.97 +/- 2.88 vs. 4.34 +/- 1.98 (p = 0.005) and 7.19 +/- 2.74 vs. 3.43 +/- 1.64 (p = 0.004) in men and women, respectively. Simple linear regression analysis showed an excellent correlation between epicardial adipose tissue and waist circumference (r = 0.895, p = 0.01) and MRI abdominal VAT (r = 0.864, p = 0.01). Multiple regression analysis showed that epicardial adipose tissue thickness (r(2) = 0.442, p = 0.02) was the strongest independent variable correlated to MRI VAT. Bland test confirmed the good agreement between the two methods.



Epicardial adipose tissue showed a strong correlation with anthropometric and imaging measurements of VAT. Hence, transthoracic echocardiography could be an easy and reliable imaging method for VAT prediction.

title: Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: a new indicator of cardiovascular risk.
abstract: Metabolic syndrome is related to multiple cardiovascular risk factors. Visceral adipose tissue (VAT) plays a key role in metabolic syndrome. Easy detection of VAT could be an important tool to increase knowledge of metabolic syndrome. The objective of this study was to study the relationship of echocardiographic epicardial adipose tissue to anthropometric and clinical parameters of metabolic syndrome. We selected 72 consecutive subjects, 46.5 +/- 17.4 yr of age, with a body mass index between 22 and 47 kg/m(2). Each subject underwent transthoracic echocardiogram to measure epicardial fat thickness on right ventricle and magnetic resonance imaging to calculate visceral adipose tissue. Anthropometric, metabolic, and cardiac parameters were also evaluated. Echocardiographic epicardial adipose tissue showed a very good correlation with magnetic resonance imaging abdominal VAT and epicardial fat measurement (Bland-Altman plot and linear regression). Multiple regression analysis showed that waist circumference (r(2) = 0.428; P = 0.01), diastolic blood pressure (r(2) = 0. 387; P = 0.02), and fasting insulin (r(2) = 0.387; P = 0.03) were the strongest independent variables correlated with epicardial adipose tissue. Echocardiographic epicardial adipose tissue could be applied as an easy and reliable imaging indicator of VAT and cardiovascular risk.

title: Metabolic syndrome and ectopic fat deposition: what can CT and MR provide?
abstract: Metabolic syndrome affects 20-30% of adults and is increasing in prevalence, making it a leading public health issue. Radiologists often encounter images of obese patients during routine studies and are in a unique position to address the importance of excess fat and need to be aware of the spectrum of pathologic consequences in different organ systems. In this review, the role of CT and MR imaging in assessment of patients with metabolic syndrome will be reviewed and the constellation of structural and functional changes in the major affected organ systems due to ectopic fatty deposition will be discussed.



We specifically discuss the pathophysiology of metabolic syndrome, visceral versus subcutaneous obesity, cardiac lipomatosis, nonalcoholic fatty liver disease, nonalcoholic fatty pancreas disease, and fat deposition in other organs.



Many of the multisystem manifestations of metabolic syndrome can be visualized on routine CT and MR images and radiologists can provide clinicians with important data regarding anatomic and pathologic distribution of fat in different organs. Perhaps the visualization of the fatty changes will provide tangible evidence to motivate patients to begin lifestyle modification.

title: Volumetric Assessment of Epicardial Adipose Tissue With Cardiovascular Magnetic Resonance Imaging
abstract: Previous studies determined the amount of epicardial fat by measuring the right ventricular epicardial fat thickness. However, it is not proven whether this one‐dimensional method correlates well with the absolute amount of epicardial fat. In this prospective study, a new cardiovascular magnetic resonance imaging (CMR) method using the three‐dimensional summation of slices method was introduced to assess the total amount of epicardial fat.

title: Obesity, blood vessels and metabolic syndrome
abstract: Obesity is rising worldwide at an alarming rate and so is the incidence of obesity‐related disorders, such as the metabolic syndrome, type 2 diabetes and cardiovascular diseases. The obesity‐dependent vascular damage appears to be derived from a variety of changes in the adipose tissue, leading to a chronic inflammatory state and dysregulation of adipocyte‐derived factors. This, in turn, impairs vascular homeostasis by determining an unbalance between the protective effect of the nitric oxide pathway and the unfavourable action of the endothelin‐1 system. In addition, hyperinsulinemia and insulin resistance contribute to vascular dysfunction because the opposing endothelium‐dependent vasodilating and vasoconstrictor effects of insulin are shifted towards a predominant vasoconstriction in patients with obesity. Importantly, emerging evidence suggests that the vascular dysfunction of obesity is not only limited to the endothelium but also involves the other layers of the vessel wall. In particular, obesity‐related changes in vascular smooth muscle seem to disrupt the physiological facilitatory action of insulin on the responsiveness to vasodilator stimuli, whereas the adventitia and the perivascular fat appear to be a source of proinflammatory and vasoactive factors that may contribute to endothelial and smooth muscle cell dysfunction and to the pathogenesis of vascular disease.

title: Hypertension in Metabolic Syndrome: Vascular Pathophysiology
abstract: Metabolic syndrome is a cluster of metabolic and cardiovascular symptoms: insulin resistance (IR), obesity, dyslipemia. Hypertension and vascular disorders are central to this syndrome. After a brief historical review, we discuss the role of sympathetic tone. Subsequently, we examine the link between endothelial dysfunction and IR. NO is involved in the insulin-elicited capillary vasodilatation. The insulin-signaling pathways causing NO release are different to the classical. There is a vasodilatory pathway with activation of NO synthase through Akt, and a vasoconstrictor pathway that involves the release of endothelin-1 via MAPK. IR is associated with an imbalance between both pathways in favour of the vasoconstrictor one. We also consider the link between hypertension and IR: the insulin hypothesis of hypertension. Next we discuss the importance of perivascular adipose tissue and the role of adipokines that possess vasoactive properties. Finally, animal models used in the study of vascular function of metabolic syndrome are reviewed. In particular, the Zucker fatty rat and the spontaneously hypertensive obese rat (SHROB). This one suffers macro- and microvascular malfunction due to a failure in the NO system and an abnormally high release of vasoconstrictor prostaglandins, all this alleviated with glitazones used for metabolic syndrome therapy.

title: Metabolic syndrome and age-related progression of aortic stiffness.
abstract: Aortic stiffness measured from pulse wave velocity (PWV) was studied during a six-year period in a population of subjects with zero to three and more cardiovascular (CV) factors involving hypertension, body mass index, dyslipidemia, hypertriglyceridemia, and hyperglycemia. During the follow-up, the increase in PWV was significantly higher in subjects with three and more CV risk factors (i.e., in subjects with metabolic syndrome) than in subjects with zero, one, or two factors, even after adjustments for confounding factors. Metabolic syndrome involves an increased progression of arterial stiffness with age and, thus, favors premature senescence.



The purpose of the study was to evaluate whether a clustering of metabolic risk factors might accelerate the progression of arterial stiffness with age in subjects with metabolic syndrome (MS).



Arterial stiffness is increased in MS, but the genetic and environmental factors that might influence its progression are unknown.



Four hundred seventy-six subjects were classified at baseline according to their number of cardiovascular (CV) risk factors (from zero to three and more), after adjustment for smoking habits. The CV risk factors were: hypertension, body mass index, dyslipidemia, hypertriglyceridemia, and hyperglycemia, classified according to traditional criterions. Subjects were followed for six years and had, at the beginning and end of the survey, determinations of blood pressure (BP), heart rate (HR), and aortic pulse wave velocity (PWV).



At baseline, BP, HR, plasma creatinine, and PWV were significantly higher (p < 0.001) in the group with three and more CV risk factors than in groups with zero to two risk factors. During the follow-up, the increase in PWV, but not in pulse pressure, was significantly higher (p < 0.01) in the group with three and more risk factors (i.e., metabolic syndrome) than in other groups. Results were unmodified after adjustments for age, gender, baseline values, drug treatment, smoking habits, and mean arterial pressure.



Metabolic syndrome is associated with an increased progression of aortic stiffness with age, supporting premature senescence in these patients.

title: Arterial stiffness and influences of the metabolic syndrome: a cross-countries study.
abstract: Specific clusters of metabolic syndrome (MetS) components impact differentially on arterial stiffness, indexed as pulse wave velocity (PWV). Of note, in several population-based studies participating in the MARE (Metabolic syndrome and Arteries REsearch) Consortium the occurrence of specific clusters of MetS differed markedly across Europe and the US. The aim of the present study was to investigate whether specific clusters of MetS are consistently associated with stiffer arteries in different populations. We studied 20,570 subjects from 9 cohorts representing 8 different European countries and the US participating in the MARE Consortium. MetS was defined in accordance with NCEP ATPIII criteria as the simultaneous alteration in ≥3 of the 5 components: abdominal obesity (W), high triglycerides (T), low HDL cholesterol (H), elevated blood pressure (B), and elevated fasting glucose (G). PWV measured in each cohort was "normalized" to account for different acquisition methods. MetS had an overall prevalence of 24.2% (4985 subjects). MetS accelerated the age-associated increase in PWV levels at any age, and similarly in men and women. MetS clusters TBW, GBW, and GTBW are consistently associated with significantly stiffer arteries to an extent similar or greater than observed in subjects with alteration in all the five MetS components--even after controlling for age, sex, smoking, cholesterol levels, and diabetes mellitus--in all the MARE cohorts. In conclusion, different component clusters of MetS showed varying associations with arterial stiffness (PWV).

title: Review of MRI-based measurements of pulse wave velocity: a biomarker of arterial stiffness.
abstract: Atherosclerosis is the leading cause of cardiovascular disease (CVD) in the Western world. In the early development of atherosclerosis, vessel walls remodel outwardly such that the vessel luminal diameter is minimally affected by early plaque development. Only in the late stages of the disease does the vessel lumen begin to narrow-leading to stenoses. As a result, angiographic techniques are not useful for diagnosing early atherosclerosis. Given the absence of stenoses in the early stages of atherosclerosis, CVD remains subclinical for decades. Thus, methods of diagnosing atherosclerosis early in the disease process are needed so that affected patients can receive the necessary interventions to prevent further disease progression. Pulse wave velocity (PWV) is a biomarker directly related to vessel stiffness that has the potential to provide information on early atherosclerotic disease burden. A number of clinical methods are available for evaluating global PWV, including applanation tonometry and ultrasound. However, these methods only provide a gross global measurement of PWV-from the carotid to femoral arteries-and may mitigate regional stiffness within the vasculature. Additionally, the distance measurements used in the PWV calculation with these methods can be highly inaccurate. Faster and more robust magnetic resonance imaging (MRI) sequences have facilitated increased interest in MRI-based PWV measurements. This review provides an overview of the state-of-the-art in MRI-based PWV measurements. In addition, both gold standard and clinical standard methods of computing PWV are discussed.

title: Carotid pulse wave velocity by magnetic resonance imaging is increased in middle-aged subjects with the metabolic syndrome
abstract: Arterial pulse wave velocity (PWV), an independent predictor of cardiovascular disease, physiologically increases with age; however, growing evidence suggests metabolic syndrome (MetS) accelerates this increase. Magnetic resonance imaging (MRI) enables reliable noninvasive assessment of arterial stiffness by measuring arterial PWV in specific vascular segments. We investigated the association between the presence of MetS and its components with carotid PWV (cPWV) in asymptomatic subjects without diabetes. We assessed cPWV by MRI in 61 individuals (mean age, 55.3 ± 14.1 years; median age, 55 years): 30 with MetS and 31 controls with similar age, sex, body mass index, and LDL-cholesterol levels. The study population was dichotomized by the median age. To remove the physiological association between PWV and age, unpaired t tests and multiple regression analyses were performed using the residuals of the regression between PWV and age. cPWV was higher in middle-aged subjects with MetS than in those without (p = 0.001), but no differences were found in elder subjects (p = 0.313). cPWV was associated with diastolic blood pressure (r = 0.276, p = 0.033) and waist circumference (r = 0.268, p = 0.038). The presence of MetS was associated with increased cPWV regardless of age, sex, blood pressure, and waist (p = 0.007). The MetS components contributing independently to an increased cPWV were hypertension (p = 0.018) and hypertriglyceridemia (p = 0.002). The presence of MetS is associated with an increased cPWV in middle-aged subjects. In particular, hypertension and hypertriglyceridemia may contribute to early progression of carotid stiffness.

title: Obesity, metabolic syndrome, adipocytes and vascular function: A holistic viewpoint
abstract: 1. Obesity is a metabolic disease of pandemic proportions largely arising from positive energy balance, a consequence of sedentary lifestyle, conditioned by environmental and genetic factors. Several central and peripheral neurohumoral factors (the major ones being the anorectic adipokines leptin and adiponecin and the orexigenic gut hormone ghrelin) acting on the anorectic (pro‐opiomelanocortin and cocaine‐ and amphetamine‐regulated transcript) and orexigenic (neuropeptide Y and agouti gene‐related protein) neurons regulate energy balance. These neurons, mainly in the arcuate nucleus of the hypothalamus, project to parts of the brain modulating functions such as wakefulness, autonomic function and learning. A tilt in the anorectic–orexigenic balance, perhaps determined genetically, leads to obesity.

title: Novel measurements of periaortic adipose tissue in comparison to anthropometric measures of obesity, and abdominal adipose tissue
abstract: Perivascular adipose tissue may be associated with the amount of local atherosclerosis. We developed a novel and reproducible method to standardize volumetric quantification of periaortic adipose tissue by computed tomography (CT) and determined the association with anthropometric measures of obesity, and abdominal adipose tissue.Measurements of adipose tissue were performed in a random subset of participants from the Framingham Heart Study (n=100) who underwent multidetector CT of the thorax (ECG triggering, 2.5 mm slice thickness) and the abdomen (helical CT acquisition, 2.5 mm slice thickness). Abdominal periaortic adipose tissue (AAT) was defined by a 5 mm cylindrical region of interest around the aortic wall; thoracic periaortic adipose tissue (TAT) was defined by anatomic landmarks. TAT and AAT were defined as any voxel between −195 and −45 HU and volumes were measured using dedicated semiautomatic software. Measurement reproducibility and association with anthropometric measures of obesity, and abdominal adipose tissue were determined.The intra- and inter-observer reproducibility for both AAT and TAT was excellent (ICC: 0.97 and 0.97; 0.99 and 0.98, respectively). Similarly, the relative intra- and inter-observer difference was small for both AAT (−1.85±1.28% and 7.85±6.08%; respectively) and TAT (3.56±0.83% and −4.56±0.85%, respectively). Both AAT and TAT were highly correlated with visceral abdominal fat (r=0.65 and 0.77, P<0.0001 for both) and moderately correlated with subcutaneous abdominal fat (r=0.39 and 0.42, P<0.0001 and P=0.009), waist circumference (r=0.49 and 0.57, P<0.0001 for both) and body mass index (r=0.47 and 0.58, P<0.0001 for both).Conclusion:Standardized semiautomatic CT-based volumetric quantification of periaortic adipose tissue is feasible and highly reproducible. Further investigation is warranted regarding associations of periaortic adipose tissue with other body fat deposits, cardiovascular risk factors and clinical outcomes.

title: Carotid Intima-Media Thickness and Metabolic Syndrome Components in Obese Children and Adolescents.
abstract: Obesity in children and adolescents contributes to increased prevalence of metabolic and hemodynamic complications, which may impair endothelial function and structure. A high resolution B-mode ultrasound measurement of intima-media thickness (IMT) is a useful tool to assess early, preclinical stage of atherosclerosis. The objective of this study was to evaluate the carotid artery IMT in obese children and its association with insulin resistance and other traditional metabolic syndrome components. The study entailed 80 obese children, aged 5.3-17.9 year and a control group of 31 children. Obesity was defined using the International Obesity Task Force (IOTF) criteria. Metabolic syndrome was defined using the International Diabetes Federation (IDF) criteria of 2007. Each patient's anthropometric measurements, blood parameters, and the carotid IMT were evaluated. Insulin resistance indices were calculated. We found that children with metabolic syndrome had a significantly increased IMT compared to children who did not meet the syndrome criteria (0.62 ± 0.09 mm vs. 0.55 ± 0.18 mm, p = 0.03) and compared to control group (0.62 ± 0.09 vs. 0.52 ± 0.14, p = 0.02). In a multivariable linear regression analysis, IMT correlated with systolic blood pressure (p = 0.005). The results did not show an association between IMT and insulin resistance. We conclude that abdominal obesity and the accompanying components of metabolic syndrome lead to increased carotid IMT. The enhanced systolic blood pressure plays a major role in changing the carotid IMT.

title: Metabolic Syndrome, Inflammation and Atherosclerosis
abstract: The inflammatory component of atherogenesis has been increasingly recognized over the last decade. Inflammation participates in all stages of atherosclerosis, not only during initiation and during evolution of lesions, but also with precipitation of acute thrombotic complications. The metabolic syndrome is associated with increased risk for development of both cardiovascular disease and type-2 diabetes in humans. Central obesity and insulin resistance are thought to represent common underlying factors of the syndrome, which features a chronic low-grade inflammatory state. Diagnosis of the metabolic syndrome occurs using defined threshold values for waist circumference, blood pressure, fasting glucose and dyslipidemia. The metabolic syndrome appears to affect a significant proportion of the population. Therapeutic approaches that reduce the levels of proinflammatory biomarkers and address traditional risk factors are particularly important in preventing cardiovascular disease and, potentially, diabetes. The primary management of metabolic syndrome involves healthy lifestyle promotion through moderate calorie restriction, moderate increase in physical activity and change in dietary composition. Treatment of individual components aims to control atherogenic dyslipidemia using fibrates and statins, elevated blood pressure, and hyperglycemia. While no single treatment for the metabolic syndrome as a whole yet exists, emerging therapies offer potential as future therapeutic approaches.

title: Carotid intima-media thickness and plaque in cardiovascular risk assessment.
abstract: Carotid intima-media thickness (CIMT) has been shown to predict cardiovascular (CV) risk in multiple large studies. Careful evaluation of CIMT studies reveals discrepancies in the comprehensiveness with which CIMT is assessed-the number of carotid segments evaluated (common carotid artery [CCA], internal carotid artery [ICA], or the carotid bulb), the type of measurements made (mean or maximum of single measurements, mean of the mean, or mean of the maximum for multiple measurements), the number of imaging angles used, whether plaques were included in the intima-media thickness (IMT) measurement, the report of adjusted or unadjusted models, risk association versus risk prediction, and the arbitrary cutoff points for CIMT and for plaque to predict risk. Measuring the far wall of the CCA was shown to be the least variable method for assessing IMT. However, meta-analyses suggest that CCA-IMT alone only minimally improves predictive power beyond traditional risk factors, whereas inclusion of the carotid bulb and ICA-IMT improves prediction of both cardiac risk and stroke risk. Carotid plaque appears to be a more powerful predictor of CV risk compared with CIMT alone. Quantitative measures of plaques such as plaque number, plaque thickness, plaque area, and 3-dimensional assessment of plaque volume appear to be progressively more sensitive in predicting CV risk than mere assessment of plaque presence. Limited data show that plaque characteristics including plaque vascularity may improve CV disease risk stratification further. IMT measurement at the CCA, carotid bulb, and ICA that allows inclusion of plaque in the IMT measurement or CCA-IMT measurement along with plaque assessment in all carotid segments is emerging as the focus of carotid artery ultrasound imaging for CV risk prediction.

title: Intravascular ultrasound as a clinical adjunct for carotid plaque characterization.
abstract: Virtual histology intravascular ultrasound (VH IVUS) is valuable for estimating minimal lumen diameter and plaque characterization. The clinical use of IVUS in carotid intervention is not well characterized. We aim to evaluate the role of IVUS in carotid plaque characterization and determine whether it could be predictive of procedure-related microemboli.



From July 2010, patients with severe carotid stenosis who underwent elective carotid stenting procedures were prospectively enrolled. IVUS evaluation was performed before stent placement. Patient demographics, comorbidities, and preoperative images were recorded. Comparison of pre- and postoperative diffusion-weighted magnetic resonance images was used to identify the number of procedure-related microemboli. IVUS-derived minimal lumen diameter and vessel wall plaque characteristics were collected. Univariate and multivariate logistic regressions were used to search for associations between IVUS-derived VH data and incidence of microemboli.



A total of 38 high-risk patients receiving carotid stenting were enrolled. Among them, 25 patients had type I aortic arches and 17 of the patients were symptomatic (preoperative stroke or transient ischemic attack). VH IVUS data did not show strong associations with microemboli, however, a trend was found between the area of fibrous tissue and median or more incidence of microemboli (P = .099). IVUS-defined vessel diameter maximum was associated with median or more incidence of microemboli (P = .042). In addition, median or more incidence of microemboli showed trends with proximal common carotid artery calcification (P = .056) and with being over the age of 80 (P = .06). Contralateral carotid occlusion or high-grade stenosis was associated with postoperative contralateral microemboli (P = .036).



We demonstrate that periprocedural carotid IVUS is clinically feasible. VH IVUS may be helpful in better understanding plaque morphology and determining optimal stent placement. However, its use in predicting microembolization remains limited.

title: Imaging of atherosclerosis: magnetic resonance imaging.
abstract: Atherosclerosis and its thrombotic complications are the major cause of morbidity and mortality in the industrialized countries. Despite advances in our understanding of the pathophysiology, pathogenesis, and new treatment modalities, the absence of an adequate non-invasive imaging tool for early detection limits both the prevention and treatment of patients with various degrees and anatomical localizations of atherothrombotic disease. An ideal clinical imaging modality for atherosclerotic vascular disease should be safe, inexpensive, non-invasive or minimally invasive, accurate, and reproducible, and the results should correlate with the extent of atherosclerotic disease and have high predictive values for future clinical events. High-resolution magnetic resonance imaging (MRI) has emerged as the most promising technique for studying atherothrombotic disease in humans in vivo. Most importantly, MRI allows for the characterization of plaque composition, i.e. the discrimination of lipid core, fibrosis, calcification, and intraplaque haemorrhage deposits. Magnetic resonance imaging also allows for the detection of arterial thrombi and in defining thrombus age. Magnetic resonance imaging has been used to monitor plaque progression and regression in several animal models of atherosclerosis and in humans. Emerging MRI techniques capable of imaging biological processes, including inflammation, neovascularization, and mechanical forces, may aid in advancing our understanding of the atherothrombotic disease. Advances in diagnosis do prosper provided they march hand-in-hand with advances in treatment. We stand at the threshold of accurate non-invasive assessment of atherosclerosis. Thus, MRI opens new strategies ranging from screening of high-risk patients for early detection and treatment as well as monitoring of the target lesions for pharmacological intervention. Identification of subclinical atherosclerosis and early treatment initiation has the potential to surpass conventional risk factor assessment and management in terms of overall impact on cardiovascular morbidity and mortality. Such strategy is currently under clinical investigation.

title: Positron Emission Tomography Imaging of Atherosclerosis
abstract: Atherosclerosis-related cardiovascular events are the leading causes of death in the industrialized world. Atherosclerosis develops insidiously and the initial manifestation is usually sudden cardiac death, stroke, or myocardial infarction. Molecular imaging is a valuable tool to identify the disease at an early stage before fatal manifestations occur. Among the various molecular imaging techniques, this review mainly focuses on positron emission tomography (PET) imaging of atherosclerosis. The targets and pathways that have been investigated to date for PET imaging of atherosclerosis include: glycolysis, cell membrane metabolism (phosphatidylcholine synthesis), integrin αvβ3, low density lipoprotein (LDL) receptors (LDLr), natriuretic peptide clearance receptors (NPCRs), fatty acid synthesis, vascular cell adhesion molecule-1 (VCAM-1), macrophages, platelets, etc. Many PET tracers have been investigated clinically for imaging of atherosclerosis. Early diagnosis of atherosclerotic lesions by PET imaging can help to prevent the premature death caused by atherosclerosis, and smooth translation of promising PET tracers into the clinic is critical to the benefit of patients.

title: The Metabolic Syndrome and Chronic Kidney Disease in U.S. Adults
abstract: People with the metabolic syndrome (hypertension, low high-density lipoprotein cholesterol level, high triglyceride level, high glucose level, and obesity) are at high risk for cardiovascular disease, and cardiovascular disease is associated with chronic kidney disease. However, it is unknown whether the metabolic syndrome is independently associated with chronic kidney disease.  In this population-based study of more than 6000 adults, the risks for chronic kidney disease and microalbuminuria both increased progressively as the number of components of the metabolic syndrome increased from 0 or 1 to 5.  It is difficult to disentangle the effects of the metabolic syndrome from those of hypertension and abnormal glucose metabolism. It is unclear whether treating the metabolic syndrome will prevent chronic kidney disease. The Editors Chronic kidney disease has become an important public health challenge in the United States. According to data from the third National Health and Nutrition Examination Survey (NHANES III), 8.3 million (4.6%) U.S. adults 20 years of age or older have chronic kidney disease (1). Chronic kidney disease is a major risk factor for end-stage renal disease, cardiovascular disease, and premature death (1-7). Identifying and treating risk factors for early chronic kidney disease may be the best approach to prevent and delay adverse outcomes (1). The metabolic syndrome, characterized by abdominal obesity, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol level, high blood pressure, and high fasting glucose level, is a common disorder in the United States (8). For example, 47 million (23.7%) U.S. residents 20 years of age or older have the metabolic syndrome, according to data from NHANES III (9). With the continuous increase in the prevalence of obesity in the United States, the metabolic syndrome is expected to be even more common in the future (10). The metabolic syndrome has been associated with an increased risk for diabetes mellitus and cardiovascular disease, as well as increased mortality from cardiovascular disease and all causes (11-13). However, there are sparse data on the relationship between the metabolic syndrome and risk for chronic kidney disease (14). We examined the association between the metabolic syndrome and risk for chronic kidney disease and microalbuminuria in a large representative sample of U.S. adults who participated in the NHANES III.  The NHANES III was conducted by the National Center for Health Statistics between 1988 and 1994. A detailed description of the study participants and methods has been published elsewhere (15, 16). In brief, a stratified, multistage probability design was used to obtain a representative sample of the civilian noninstitutionalized U.S. general population (15, 16). A subsample of 7832 NHANES III participants who were 20 years of age and older was randomly selected to participate in morning visits at which fasting blood specimens were obtained. Persons without a fasting blood sample (n = 503), women who were pregnant (n = 120) or menstruating (n = 275), and 1 person with kidney failure (estimated glomerular filtration rate <15 mL/min per 1.73 m2) were excluded from the current analysis. Furthermore, persons who were missing measurements for any component of the metabolic syndrome (plasma glucose level, HDL cholesterol level, serum triglyceride level, waist circumference, or blood pressure measurements) were excluded (n = 621). In addition, 95 persons with missing creatinine measurements were excluded from the chronic kidney disease analyses and 94 persons with missing data on urinary albumin and 93 persons with clinical proteinuria (urinary albumincreatinine ratio >300 mg/g) were excluded from the microalbuminuria analyses. After these exclusions, 6217 persons were included in the chronic kidney disease analyses and 6125 persons were included in the microalbuminuria analyses. Exposure Measurements Data from NHANES III were collected during a home interview followed by a detailed physical examination at a mobile examination center or at the participant's home. Information on age; race or ethnicity; sex; years of education completed; history of smoking and hypertension; use of antihypertensive medication, diabetes medication, insulin, and nonsteroidal anti-inflammatory drugs (NSAIDs); alcohol consumption; and physical activity were obtained during the home interview (15, 16). Blood pressure was measured 3 times during the home interview and 3 times during the subsequent evaluation at the mobile examination center by trained observers using a standard protocol (15, 16). Blood pressure for an individual participant was calculated as the average of all available systolic and diastolic readings. Waist circumference was measured according to a standard protocol by a trained NHANES III staff member. For NHANES III participants who were assigned to a physical examination during a morning session, a blood sample was collected after an overnight fast of 8 hours or more. Plasma glucose level was measured with a hexokinase enzymatic reference method (COBAS MIRA, Roche Diagnostics Corp., Indianapolis, Indiana) (15, 16). Serum HDL cholesterol and triglyceride levels were measured enzymatically by using a commercially available reagent mixture (Cholesterol/HP, Boehringer Mannheim, Indianapolis, Indiana), and creatinine was analyzed by the modified kinetic Jaffe reaction method using a Hitachi 737 analyzer (Boehringer Mannheim) (15, 16). The metabolic syndrome was defined by using criteria recommended in the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines (8). Specifically, elevated blood pressure was defined as an average systolic or diastolic blood pressure of 130/85 mm Hg or higher. Low HDL cholesterol level was defined as less than 1.036 mmol/L (40 mg/dL) in men or less than 1.295 mmol/L (50 mg/dL) in women. High serum triglyceride level was defined as 1.695 mmol/L (150 mg/dL) or more. Elevated fasting plasma glucose level was defined as 6.10 mmol/L (110 mg/dL) or more. Finally, abdominal obesity was defined as a waist circumference of 102 cm or more in men or 88 cm or more in women. Participants who reported current use of antihypertensive or antidiabetic medication (insulin or oral agents) were classified as having elevated blood pressure or elevated fasting plasma glucose level, respectively. The metabolic syndrome was defined as the presence of 3 or more of these components (8). Diabetes was defined as a self-reported history of a previous diagnosis of diabetes or a fasting plasma glucose level of 7.0 mmol/L (126 mg/dL) or more. Outcome Measures Two outcomes, chronic kidney disease and microalbuminuria, were used in this analysis. Glomerular filtration rate was calculated by using the abbreviated equation developed by the Modification of Diet in Renal Disease (MDRD) study (17): Estimated glomular filtration rate = 186.3 (serum creatinine level) 1.154 age 0.203 (0.742 if female) (1.21 if black). Serum creatinine level was calibrated for measurement variance between NHANES III and MDRD clinical laboratories (18). Chronic kidney disease was defined as a glomerular filtration rate less than 60 mL/min per 1.73 m2. In addition, we conducted a sensitivity analysis by using serum creatinine level to define chronic kidney disease ( 132.6 mol/L [ 1.5 mg/dL] for men and 114.9 mol/L [ 1.3 mg/dL] for women). During the physical examination, a random untimed urine sample was obtained from all adults. Urinary albumin concentration was measured by solid-phase fluorescent immunoassay on thawed urine specimens (15, 16). Urinary albumin level was not measured on visibly hematuric specimens or those testing positive for hemoglobin by using qualitative test strips. Urinary creatinine level was analyzed by the modified kinetic Jaffe reaction method by using SYNCHRON AS/ASTRA analyzer (Beckman Instruments, Inc., Brea, California). Microalbuminuria was defined as a urinary albumincreatinine ratio of 30 to 300 mg/g, and clinical proteinuria was defined as a urinary albumincreatinine ratio greater than 300 mg/g. Statistical Analyses The prevalence of the metabolic syndrome and its individual components (elevated blood pressure level, high plasma glucose level, high triglyceride level, low HDL cholesterol level, and abdominal obesity) as well as the number of the metabolic syndrome components present (0, 1, 2, 3, 4, or 5) was determined for the overall study sample. Mean values of continuous variables and percentages of categorical variables for exposures, covariates, and outcomes were calculated by metabolic syndrome status. The statistical significance of differences in these characteristics across those with and without the metabolic syndrome was examined by using the Z test (continuous variables) and the Wald chi-square test (categorical variables) in multivariate regression models after adjustment for age, sex, and race or ethnicity. The prevalence of chronic kidney disease and microalbuminuria was determined for participants with and without each of the 5 components of the metabolic syndrome. The prevalence of chronic kidney disease and microalbuminuria was also calculated by the number of metabolic syndrome components present. Logistic regression analysis, adjusted for age, sex, and race or ethnicity, was used to determine the statistical significance of the differences in prevalence. The crude; age-, sex-, and race- or ethnicity-adjusted; and multivariate-adjusted odds ratios of chronic kidney disease and microalbuminuria, separately, were calculated by using logistic regression models with each component of the metabolic syndrome as an exposure of interest. The crude and adjusted odds ratios of chronic kidney disease and microalbuminuria were also determined by clustering the components of the metabolic syndrome. In these analyses, the odds ratios of chr

title: The metabolic syndrome and chronic kidney disease
abstract: &NA; The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including insulin resistance (IR), dyslipidemia, and hypertension, which may also foster development of chronic kidney disease. The mechanisms of MetS‐induced kidney disease are not fully understood. The purpose of this review is to summarize recent discoveries regarding the impact of MetS on the kidney, particularly on the renal microvasculature and cellular mitochondria. Fundamental manifestations of MetS include IR and adipose tissue expansion, the latter promoting chronic inflammation and oxidative stress that exacerbate IR. Those in turn can elicit various kidney injurious events through endothelial dysfunction, activation of the renin‐angiotensin‐aldosterone system, and adipokine imbalance. Inflammation and IR are also major contributors to microvascular remodeling and podocyte injury. Hence, these events may result in hypertension, albuminuria, and parenchymal damage. In addition, dyslipidemia and excessive nutrient availability may impair mitochondrial function and thereby promote progression of kidney cell damage. Elucidation of the link between MetS and kidney injury may help develop preventative measures and possibly novel therapeutic targets to alleviate and avert development of renal manifestations.

title: Metabolic Syndrome and Kidney Stone Disease: A Systematic Review of Literature.
abstract: Worldwide obesity has more than doubled since 1980 with more than 600 million obese patients in 2014. Metabolic syndrome (MetS) is the co-occurrence of metabolic abnormalities, including centrally distributed obesity, hypertension, dyslipidemia, and hyperglycemia. With a concurrent rise in the incidence of kidney stone disease, we wanted to conduct a systematic review focused on the association of MetS to nephrolithiasis.



A systematic review was performed according to the Cochrane and preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines on all English language articles for the following relevant keywords: association, metabolic syndrome, metabolic syndrome traits, syndrome X, nephrolithiasis, kidney stones, and renal calculi. Our inclusion criteria were studies comparing the prevalence of kidney stone disease in patients with and without MetS.



The initial literature search identified 355 potentially relevant studies. After screening, 22 full text articles were reviewed and 6 (219,255 patients) were included in the final review. All studies displayed increasing odds of nephrolithiasis with increasing number of MetS traits, where patients with three or more MetS traits tended to have a higher prevalence of nephrolithiasis. Studies also showed different significant components of MetS contributing to nephrolithiasis.



Our review shows a definite association of MetS with kidney stone disease. Although multifactorial in etiology, lifestyle and dietary factors seem to be increasingly important in prevention of stone disease.

title: Metabolic Syndrome Is a Strong Risk Factor for Minor Ischemic Stroke and Subsequent Vascular Events
abstract: Minor ischemic stroke (MIS) represents a major global public health problem worldwide due to high incidence. The aim of this study was to investigate whether metabolic syndrome (MetS) is a strong risk for MIS and subsequent vascular events (SVE).  A retrospective cohort study was performed examining symptomatic MIS in a Chinese neurologic outpatient population aged over 25 years without history of stroke. MetS was defined using the International Diabetes Federation criteria. MIS was diagnosed by magnetic resonance imaging-diffusion weighted images or fluid-attenuated inversion recovery.  Of 1361 outpatients, a total of 753 (55.3%) patients were diagnosed with MIS; of them, 80% had a score of 0 using the MIS had a 0 score on the National Institutes of Health Stroke Scale. Among these, 303 (40.2%) individuals with MIS were diagnosed with MetS. Diagnosed of MIS with MetS significantly correlated with abdominal obesity (30.7% v.s 18.0%), hypertension (91.1% v.s 81.6%), increased blood glucose (6.9±2.4 v.s 5.0±0.4), dyslipidemia (78.2% v.s 48.2%), and SVE (50.5% v.s 11.3%) when compared with the controls group. On adjusted analysis, the risk of SVE was also significantly associated with three additional MetS criterion (RR,9.0; 95% CI, 5.677–14.46). Using Cox proportional analysis, risk of SVE in patient with MIS was significantly associated with MetS (RR, 3.3; 95% CI, 1.799–6.210), older age (RR, 1.0; 95% CI, 1.001–1.048), and high blood glucose (RR,1.1; 95%CI, 1.007–1.187).  The MetS is a strong risk factor for MIS, and patients presenting with MIS and MetS are at a high risk of SVE. Further studies are required to determine the improvement of Mets prevention in the reduction of MIS and SVE.

title: Obesity and metabolic stone disease
abstract: In this article, we aim to review the data regarding associations between obesity and nephrolithiasis to assist with workup and treatment of these intersecting disorders. As obesity has a multifactorial influence on the risk for urinary stone disease, the complicated mechanisms will be discussed to improve diagnosis and management. Recent findings Obesity and metabolic syndrome interact with nephrolithiasis risk factors to produce a myriad of bodily responses that induce stone formation. For this reason, many societies recommend prompt metabolic workup to evaluate the precise causes of stone formation. Data have shown that dietary and directed medical therapies can produce an excellent therapeutic response in this patient population, although the response may be blunted compared with nonobese patients.  Given the increasing number of obese and overweight patients, the urologist should be familiar with the pathophysiology, workup, and treatment of metabolic stone disease in this population, which are outlined here.

title: Duplex Doppler sonography in renal parenchymal disease. Histopathologic correlation.
abstract: To evaluate the histopathologic changes influencing Doppler measurements of the resistive index (RI) in renal arteries in renal parenchymal diseases, 68 kidneys in 34 consecutive patients with various forms of renal parenchymal diseases were studied by duplex Doppler ultrasound (duplex US) immediately before percutaneous renal biopsy. The RI, renal length, and renal cortical echogenicity were correlated with the amount of glomerular, interstitial, and vascular changes graded on a scale from 0 to 100. The renal vascular resistance and therefore the RI are significantly correlated with the prevalence of arteriolosclerosis, glomerular sclerosis, arteriosclerosis, edema, and focal interstitial fibrosis. There was no significant difference of the RI in five groups of different renal parenchymal diseases. Of 34 patients, 24 presented with an RI less than 0.7, which was thought to be within the normal range so far. Additionally, the RI increases as the patient's age increases, due to higher incidence of arteriosclerosis. Of our patients, 44% presented with normal cortical echogenicity. Quantitative duplex US using the RI does not reliably distinguish different types of renal medical disorders.

title: Intra-renal hemodynamics and carotid intima-media thickness in the metabolic syndrome.
abstract: Metabolic syndrome (MetS) is associated with increased cardiovascular risk. We hypothesize that early vascular changes are already present at the time of diagnosis of MetS. The relationship of different measures of early vascular impairment with body fat distribution and the natural progression of MetS was examined in newly diagnosed subjects non-pharmacologically treated.



246 consecutively enrolled subjects were categorized according to the presence of MetS and type 2 diabetes (T2D). Intra-renal Doppler flow was used to ascertain resistive (RI) and pulsatility (PI) indices as markers of vascular resistance. Carotid intima-media thickness (IMT), cutis-rectis (CR) and rectis-aorta (RA) thicknesses were measured by ultrasonography; RA/CR ratio was used as measure of body fat distribution. Pro-inflammatory cytokines, C-reactive protein, oxidative markers insulin and adiponectin blood concentrations were also measured.



Baseline characteristics demonstrated increasing trends in biochemical, inflammatory, and oxidative parameters from MetS-, MetS+, to MetS+/T2D (p<0.001). After adjusting for age, the same increasing trends across the groups were observed in both sexes in IMT (p<0.001), RI (p<0.001) and PI (p<0.001). IMT correlated with RI (r=0.25; p<0.001), PI (r=0.26; p<0.001), and RA/CR ratio (r=0.43; p<0.001).



Carotid IMT and intra-renal resistances are elevated at an early stage in MetS and are associated with a dysregulated production of fat-derived hormones and cytokines.

title: Radionuclides in Nephrourology, Part 2: Pitfalls and Diagnostic Applications
abstract: Radionuclide renal scintigraphy provides important functional data to assist in the diagnosis and management of patients with a variety of suspected genitourinary tract problems, but the procedures are underutilized. Maximizing the utility of the available studies (as well as the perception of utility by referring physicians) requires a clear understanding of the clinical question, attention to quality control, acquisition of the essential elements necessary to produce an informed interpretation, and production of a report that presents a coherent impression based on data contained in the report and that specifically addresses the clinical question. To help achieve these goals, part 1 of this review addressed the available radiopharmaceuticals, quality control, and quantitative indices, including the measurement of absolute and relative renal function. Part 2 assumes familiarity with part 1 and focuses on the common clinical indications of suspected obstruction and renovascular hypertension; part 2 also summarizes the status of radionuclide renal imaging in the evaluation of the transplanted kidney and the detection of infection, discusses potential pitfalls, and concludes with suggestions for future research. The series of SAM questions accompanying parts 1 and 2 has been designed to reinforce and extend points made in the review. Although the primary focus is the adult patient, aspects of the review also apply to the pediatric population.

title: Metabolic syndrome performs better than the individual factors in predicting renal graft outcome.
abstract: Individual components of the metabolic syndrome (MS), especially obesity and hypertension, have a deleterious effect on renal graft outcome. Whether MS is better than its individual components in predicting the decline of renal function is unknown. We studied the presence of MS and its individual components at 12 months post-transplantation according to the Adult Treatment Panel III classification and their influence on measured graft function.



A cohort of 322 patients who underwent transplantation between 1996 and 2003 and who agreed to have their glomerular filtration rate (GFR) measured by urinary clearance of technetium 99m (Tc*-DTPA) (measured GFR [mGFR]) at 3, 12, 48, 60, and 96 months after transplantation were included. The patients were followed up until patient death, graft loss, or December 2009 (mean follow-up: 3 ± 2.8 years). The linear mixed effect model for longitudinal repeated measures was applied. To compare MS versus its components we used the Akaike information Criterion (AIC) to determine the best model according to the Anderson and Burnham method.



Univariate and multivariate analyses models using MS were more efficient than those using the individual components, which consisted of waist circumference, low high-density lipoprotein-cholesterol, hypertriglyceridemia, hyperglycemia, and systolic and diastolic blood pressure. The AIC was the lowest with MS models indicating better prediction on graft function than the individual components.



MS is a better predictor of mGFR decline than its individual components. It is a valid and precious tool to assess outcomes.

title: Obesity-metabolic derangement preserves hemodynamics but promotes intrarenal adiposity and macrophage infiltration in swine renovascular disease.
abstract: Obesity-metabolic disorders (ObM) often accompany renal artery stenosis (RAS). We hypothesized that the coexistence of ObM and RAS magnifies inflammation and microvascular remodeling in the stenotic kidney (STK) and aggravates renal scarring. Twenty-eight obesity-prone Ossabaw pigs were studied after 16 wk of a high-fat/high-fructose diet or standard chow including ObM-sham, ObM-RAS, Lean-RAS, or Lean-sham (normal control) groups. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed by multidetector computed tomography (CT), renal oxygenation and tubular transport capability by blood-oxygen-level-dependent MRI, and microcirculation by micro-CT for vessel density, and Western blotting for protein expressions of angiogenic factors (VEGF/FLK-1). Renal vein and inferior vena cava levels of inflammatory cytokines were measured to evaluate systemic and kidney inflammation. Macrophage (MØ) infiltration and subpopulations, fat deposition in the kidney, and inflammation in perirenal and abdominal fat were also examined. GFR and RBF were decreased in Lean-STK but relatively preserved in ObM-STK. However, ObM-STK showed impaired tubular transport function, suppressed microcirculation, and stimulated glomerulosclerosis. ObM diet interacted with RAS to blunt angiogenesis in the STK, facilitated the release of inflammatory cytokines, and led to greater oxidative stress than Lean-STK. The ObM diet also induced fat deposition in the kidney and infiltration of proinflammatory M1-MØ, as also in perirenal and abdominal fat. Coexistence of ObM and RAS amplifies renal inflammation, aggravates microvascular remodeling, and accelerates glomerulosclerosis. Increased adiposity and MØ-accentuated inflammation induced by an ObM diet may contribute to structural injury in the post-STK kidney.

title: Increased glomerular filtration rate in early metabolic syndrome is associated with renal adiposity and microvascular proliferation.
abstract: Metabolic syndrome (MetS) is associated with glomerular hyperfiltration and is a risk factor for chronic kidney disease, but the underlying mechanisms are poorly defined. This study tested the hypothesis that increased glomerular filtration rate (GFR) in early MetS is associated with renal adiposity and microvascular proliferation. Twelve MetS-prone Ossabaw pigs were randomized to 10 wk of a standard (lean, n = 6) or atherogenic (MetS, n = 6) diet. Kidney hemodynamics and function, perirenal fat volume, and tubular dynamics were assessed in vivo by multidetector computed tomography (CT) and blood oxygen level-dependent (BOLD)-MRI. Microvascular architecture was assessed ex vivo with micro-CT. Candidate injury mechanisms were evaluated in kidney tissue by Western blotting and histology. Basal GFR, renal blood flow, and renal cortical perfusion and volume were elevated in the MetS group. Perirenal and kidney tissue fat, proximal-nephron intratubular fluid concentration, and endothelial nitric oxide synthase expression were increased in MetS. GFR levels correlated with tissue triglyceride levels. Elevated spatial density of 20- to 40-μm cortical microvessels was accompanied by mild oxidative stress, inflammation, and with proximal tubular vacuolization. Medullary size and perfusion were relatively preserved, and BOLD-MRI showed intact medullary tubular response to furosemide. Increased GFR in early MetS is associated with renal adiposity and microvascular proliferation, which involve mainly the renal cortex and precede significant activation of oxidative stress and inflammation. Renal adiposity and proliferative microvessels may represent novel therapeutic targets for preserving renal function in early MetS.

title: Nephrogenic systemic fibrosis and gadolinium-based contrast agents.
abstract: The strong association between nephrogenic systemic fibrosis (NSF) and exposure to gadolinium-based contrast agents (GBCAs) has greatly affected the care of patients with kidney disease. NSF has been reported in patients with ESRD, CKD, and acute kidney injury (AKI). The majority of cases have occurred in patients with ESRD, but about 20% have been reported in patients with AKI or CKD stages 4 and 5. There is also a risk difference among GBCAs, with the Food and Drug Administration contraindicating 3 linear agents in patients at risk. Given the significant morbidity and mortality of NSF, it is imperative to identify individuals at risk. Although there are no data to support a role for hemodialysis (HD) in reducing the risk for NSF after administration of GBCAs, immediate HD is still recommended within 2 hours. Patients maintained on peritoneal dialysis seem to be at high risk and immediate HD is also recommended. However, this is not the current recommendation for CKD stages 4 and 5, especially with suspected lower risk of noncontraindicated agents. Individualized assessment is important and especially in those patients close to dialysis initiation. Instituting policies is important to address the imaging needs of patients with CKD and AKI while ensuring a balance between benefits and risks.

title: Measurement of kidney perfusion by magnetic resonance imaging: comparison of MRI with arterial spin labeling to para-aminohippuric acid plasma clearance in male subjects with metabolic syndrome.
abstract: Magnetic resonance imaging with arterial spin labeling (MRI-ASL) is a non-invasive approach to measure organ perfusion. We aimed to examine whether MRI-ASL kidney perfusion measurements are related to measurements of renal plasma flow (RPF) by para-aminohippuric acid (PAH) plasma clearance and whether changes of kidney perfusion in response to treatment with telmisartan can be detected by MRI-ASL.



Twenty-four patients with metabolic syndrome and an estimated creatinine clearance according to Cockroft and Gault of > or =60 ml/min were included in the study. Kidney perfusion was assessed by MRI-ASL measurements of a single coronal kidney slice (with flow-sensitive alternating inversion recovery and true fast imaging with steady-state processing sequence) and by measurements of RPF using PAH plasma clearance before and after 2 weeks of treatment with the angiotensin receptor blocker telmisartan. All MRI-ASL examinations were performed on a 1.5 T scanner.



Two weeks of therapy with telmisartan led to a significant increase of RPF (from 313 +/- 47 to 348 +/- 69 ml/min/m, P = 0.007) and MRI-ASL kidney perfusion measurements (from 253 +/- 20 to 268 +/- 25 ml/min/100 g, P = 0.020). RPF measurements were related with MRI-ASL kidney perfusion measurements (r = 0.575, P < 0.001). Changes of RPF measurements and changes of MRI-ASL kidney perfusion measurements in response to treatment with telmisartan revealed a close relationship when expressed in absolute terms (r = 0.548, P = 0.015) and in percentage changes (r = 0.514, P = 0.025).



Perfusion measurement of a single coronal kidney slice by MRI-ASL is able to approximate kidney perfusion and to approximate changes in kidney perfusion due to pharmacological intervention.

title: Magnetic Resonance Imaging: Principles and Techniques: Lessons for Clinicians.
abstract: The development of magnetic resonance imaging (MRI) for use in medical investigation has provided a huge forward leap in the field of diagnosis, particularly with avoidance of exposure to potentially dangerous ionizing radiation. With decreasing costs and better availability, the use of MRI is becoming ever more pervasive throughout clinical practice. Understanding the principles underlying this imaging modality and its multiple applications can be used to appreciate the benefits and limitations of its use, further informing clinical decision-making. In this article, the principles of MRI are reviewed, with further discussion of specific clinical applications such as parallel, diffusion-weighted, and magnetization transfer imaging. MR spectroscopy is also considered, with an overview of key metabolites and how they may be interpreted. Finally, a brief view on how the use of MRI will change over the coming years is presented.

title: Renal Adiposity Confounds Quantitative Assessment of Markers of Renal Diffusion With MRI: A Proposed Correction Method
abstract: Recent studies have indicated that excessive fat may confound assessment of diffusion in organs with high fat content, such as the liver and breast. However, the extent of this effect in the kidney, which is not considered a major fat deposition site, remains unclear. This study tested the hypothesis that renal fat may impact diffusion-weighted imaging (DWI) parameters, and proposes a 3-compartment model (TCM) to circumvent this effect.  Using computer simulations, we investigated the effect of fat on assessment of apparent diffusion coefficient (ADC), intravoxel incoherent motion (IVIM), and TCM-derived pure-diffusivity. We also investigated the influence of magnetic resonance repetition (TR) and echo time (TE) on DWI parameters as a result of variation in the relative contribution of the fat signal. Apparent diffusion coefficient, IVIM and TCM DWI parameters were calculated in domestic pigs fed a high-cholesterol (obese group) or normal diet (lean group), and correlated to renal histology. Intravoxel incoherent motion–derived pure-diffusivity was also compared among 15 essential hypertension patients classified by body mass index (BMI) (high vs normal). Finally, pure-diffusivity was calculated and compared in 8 patients with atherosclerotic renal artery stenosis (ARAS) and 5 healthy subjects using IVIM and TCM.  Simulations showed that unaccounted fat results in the underestimation of IVIM-derived pure diffusivity. The underestimation increases as the fat fraction increases, with higher pace at lower fat contents. The underestimation was larger for shorter TR and longer TE values due to the enhancement of the relative contribution of the fat signal. Moreover, TCM, which incorporates highly diffusion-weighted images (b > 2500 s/mm2), could correct for fat-dependent underestimation. Animal studies in the lean and obese groups confirmed lower ADC and IVIM pure-diffusivity in obese versus lean pigs with otherwise healthy kidneys, whereas pure-diffusivity calculated using TCM were not different between the 2 groups. Similarly, essential hypertension patients with high BMI had lower ADC (1.9 vs 2.1 × 10−3 mm2/s) and pure-diffusivity (1.7 vs 1.9 × 10−3 mm2/s) than those with normal BMI. Pure-diffusivity calculated using IVIM was not different between the ARAS and healthy subjects, but TCM revealed significantly lower diffusivity in ARAS.  Excessive renal fat may cause underestimation of renal ADC and IVIM-derived pure-diffusivity, which may hinder detection of renal pathology. Models accounting for fat contribution may help reduce the variability of diffusivity calculated using DWI.

title: Noninvasive evaluation of renal oxygenation in diabetic nephropathy by BOLD-MRI.
abstract: To evaluate the renal oxygenation in type 2 diabetes by blood oxygenation level dependent magnetic resonance imaging (BOLD-MRI).



Forty-eight patients with type 2 diabetes and 67 healthy controls were recruited. All patients were further divided into four subgroups based on renal functional level. Bilateral renal cortical R2* (CR2*) and medullary R2* (MR2*) values were extracted and quantified on BOLD-MRI, then R2* ratio between medulla and cortex (MCR) was calculated. CR2*, MR2* and MCR were compared among the groups separately. The relationships were analyzed between R2* values and clinical index of renal function.



Compared with controls, MR2* and CR2* in diabetes were significantly increased. The positive relationship was found between MR2* and estimated glomerular filtration rate (eGFR), and CR2* was negatively correlated with eGFR. Interestingly, the MCR increased in early stage of diabetes and decreased along with the aggravation of diabetic nephropathy (DN).



BOLD-MRI can non-invasively detect and assess the renal hypoxia in diabetes. Our findings suggest that hypoxia in medulla is more apparent and earlier than in cortex. During the progression of DN, a reversion of corticomedullary oxygenation gradient can be detected, thus, MCR would be adopted to suppose the progression and prognosis of DN.

title: Renal sinus lipomatosis and body composition in hypertensive, obese rabbits.
abstract: To test whether renal lipomatosis, an accretion of fat in the renal sinus associated with chronic renal infections, abscesses and calculi, can also be caused by rapid weight gain.



New Zealand white rabbits were fed either standard rabbit chow (n = 24) or chow fortified with 10% corn oil plus 5% lard (n = 25) for 8-12 weeks.



The rabbits and constituent tissues were weighed initially, after drying and after organic extractions. Renal tissue cholesterol and triglycerides were measured chemically.



Rabbits made obese by increased fat intake were 1.8 kg heavier than controls (5.5 +/- 0.3 kg vs 3.7 +/- 0.2; n = 24,25), had 1.54 kg more body fat (1.90 +/- 0.25 vs 0.36 +/- 0.11 kg/rabbit; n = 10,9), and had a mean arterial blood pressure that was 9.2 mm Hg greater than controls (95.1 +/- 8.5 vs 85.9 +/- 5.6 mm Hg; n = 23,24). Individual organs grew in mass (lung, 15%; gastrocnemius, 17%; liver, 27%; kidney, 30%) and their parenchyma gained extractable lipids (lung, 5.5 mg/g tissue; gastrocnemius, 9.6 mg/g tissue; liver, 17.9 mg/g tissue). Total renal triglycerides were increased 2.1 fold, from 103 +/- 36 to 219 +/- 59 mg/kidney (n = 8,8), compared to the 5.3 fold increase in whole body fat. Renal cholesterol was increased 1.7 fold, from 7.5 +/- 1.1 to 12.7 +/- 2.9 mg/kidney, (n = 8,8). Within experimental error, the sum of the total renal triglycerides plus the total renal cholesterol equaled the net fat extracted from the renal sinus alone: 95 +/- 29 mg/kidney in lean rabbits and 253 +/- 71 mg/kidney in obese (n = 17,17).



Obesity alone can cause renal lipomatosis. This increased volume of anatomically localized fat may be sufficient to externally compress renal veins and lymphatics, thus altering renal hemodynamic behavior.

title: Para- and perirenal fat thickness is an independent predictor of chronic kidney disease, increased renal resistance index and hyperuricaemia in type-2 diabetic patients.
abstract: Many interfering factors may reduce the reliability of waist circumference (WC) measurement in estimating the risk for chronic kidney disease (CKD) associated with obesity. Therefore, we determined the independent associations of para- and perirenal ultrasonographic fat thickness with the main markers of kidney function.



A cross-sectional study was performed in 151 type-2 diabetic subjects. Para- and perirenal fat thickness was measured from the inner side of the abdominal musculature to the surface of the kidneys. CKD was defined as eGFR < 60 mL min(-1)1.73 m(-2).



Using both univariate and multivariate regression analyses, eGFR, renal resistance index and uricaemia were best predicted by para- and perirenal fat thickness even when BMI and waist circumference were further added in the statistical model (r(2): 0.366, P = 0.001; r(2): 0.529, P = 0.005; r(2): 0.310, P = 0.026, respectively), whereas waist circumference and BMI did not contribute independently of para- and perirenal fat thickness. Albuminuria was predicted by waist circumference but not by para- and perirenal fat thickness. In subjects with waist circumference above the diagnostic values of metabolic syndrome (48M/59F), eGFR significantly and progressively declined across tertiles of para- and perirenal fat thickness (87.0 ± 27.9 vs 83.5 ± 26.0 vs 62.3 ± 30.6 mL min(-1) 1.73 m(-2), adjusted P < 0.0001) despite comparable waist circumference, and an increasing frequency of CKD was observed across tertiles of subjects with waist circumference both below and above the metabolic syndrome diagnostic values (P < 0.05).



Para- and perirenal fat thickness is an independent predictor of kidney dysfunction in type-2 diabetes explaining an important proportion of the variance of eGFR, renal resistance index and uricaemia.

title: Perirenal Fat Promotes Renal Arterial Endothelial Dysfunction in Obese Swine through Tumor Necrosis Factor-α.
abstract: Perirenal fat is associated with poor blood pressure control and chronic kidney disease but the underlying mechanisms remain elusive. We tested the hypothesis that perirenal fat impairs renal arterial endothelial function in pigs with obesity-metabolic derangements.



We studied 14 domestic pigs after 16 weeks of a high fat/high fructose diet (obesity-metabolic derangement group) or standard chow (lean group). Renal blood flow, glomerular ﬁltration rate and visceral fat volumes were studied in vivo by computerized tomography. Renal arterial endothelial function was also studied ex vivo in organ baths.



Pigs with obesity-metabolic derangements demonstrated increased body weight, blood pressure, cholesterol and intra-abdominal fat compared to lean pigs and perirenal fat volume was significantly larger. Renal blood flow and glomerular ﬁltration rate were markedly elevated while urinary protein level was preserved. Ex vivo acetylcholine induced, endothelium dependent vasodilation of renal artery rings was substantially impaired in pigs with obesity-metabolic derangements compared to lean pigs. Endothelial function was further blunted in obesity-metabolic derangement and lean arterial rings by incubation with perirenal fat harvested from pigs with obesity-metabolic derangements but not from lean pigs. It was restored by inhibiting tumor necrosis factor-α. Perirenal fat from pigs with obesity-metabolic derangements also showed increased pro-inflammatory macrophage infiltration and tumor necrosis factor-α expression.



In pigs with obesity-metabolic derangements perirenal fat directly causes renal artery endothelial dysfunction, which is partly mediated by tumor necrosis factor-α.

title: Perirenal fat thickness measured with computed tomography is a reliable estimate of perirenal fat mass
abstract: Deposition of perirenal adipose tissue has been associated with adverse renal and cardiovascular events. We compared various methods to measure perirenal adipose tissue using computerized tomography (CT)-scan and performed correlations with anthropometric measures associated with renal and cardiovascular events. Voluntary overweight and obese subjects undergoing a CT-scan for diagnostic purposes were included in the study. Perirenal adipose tissue volume, adipose tissue area of the renal sinus and perirenal fat thickness were manually measured bilaterally. The intra- and inter-observer coefficient correlations and the correlation between the diverse measures of renal adipose tissue, subcutaneous (SC-)fat and anthropometrics measures were analyzed using Pearson's correlation tests. The forty included patients (24 men, 16 women) had a mean age of 57.6 ± 18.1 years and a mean body mass index of 28.9 ± 2.9 kg/m2. Despite comparable waist circumference, women had a greater SC-fat thickness compared to men, and therefore a smaller amount of visceral fat, as well as smaller perirenal fat volumes. Perirenal fat thickness was better correlated with perirenal fat volume than adipose area of the renal sinus (p <0.02). The adipose area of the renal sinus did not correlate with any anthropometric measures. In women, perirenal fat volume and thickness showed a negative correlation with SC-fat thickness and no correlation with waist circumference. In men, perirenal fat volume and thickness showed a positive correlation with waist circumference and no correlation with subcutaneous fat thickness. In conclusion, perirenal fat thickness measured with CT-scan at the level of the renal veins is a simple and reliable estimate of perirenal fat volume, that correlated negatively with SC-fat in women and positively with waist circumference in men. The adipose area of the renal sinus did not correlate with any anthropometric measure.

title: Quantification of renal steatosis in type II diabetes mellitus using dixon‐based MRI
abstract: To evaluate renal lipid content in subjects with and without type II diabetes mellitus (DM2) using Dixon‐based magnetic resonance imaging (MRI).

title: Changes of renal sinus fat and renal parenchymal fat during an 18-month randomized weight loss trial.
abstract: Data regarding the role of kidney adiposity, its clinical implications, and its dynamics during weight-loss are sparse. We investigated the effect of long-term weight-loss induced intervention diets on dynamics of renal-sinus-fat, an ectopic fat depot, and %renal-parenchymal-fat, lipid accumulation within the renal parenchyma.



We randomized 278 participants with abdominal obesity/dyslipidemia to low-fat or Mediterranean/low-carbohydrate diets, with or without exercise. We quantified renal-sinus-fat and %renal-parenchymal-fat by whole body magnetic-resonance-imaging.



Participants (age = 48 years; 89% men; body-mass-index = 31 kg/m2) had 86% retention to the trial after 18 months. Both increased renal-sinus-fat and %renal-parenchymal-fat were directly associated with hypertension, and with higher abdominal deep-subcutaneous-adipose-tissue and visceral-adipose-tissue (p of trend < 0.05 for all) after adjustment for body weight. Higher renal-sinus-fat was associated with lower estimated-glomerular-filtration-rate and with higher microalbuminuria and %HbA1C beyond body weight. After 18 months of intervention, overall renal-sinus-fat (-9%; p < 0.05 vs. baseline) but not %renal-parenchymal-fat (-1.7%; p = 0.13 vs. baseline) significantly decreased, and similarly across the intervention groups. Renal-sinus-fat and %renal-parenchymal-fat changes were correlated with weight-loss per-se (p < 0.05). In a model adjusted for age, sex, and visceral-adipose-tissue changes, 18 months reduction in renal-sinus-fat associated with decreased pancreatic, hepatic and cardiac fats (p < 0.05 for all) and with decreased cholesterol/high-density lipoprotein-cholesterol (HDL-c) (β = 0.13; p = 0.05), triglycerides/HDL-c (β = 0.13; p = 0.05), insulin (β = 0.12; p = 0.05) and gamma glutamyl transpeptidase (β = 0.24; p = 0.001), but not with improved renal function parameters or blood pressure. Decreased intake of sodium was associated with a reduction in %renal-parenchymal-fat, after adjustment for 18 months weight-loss (β = 0.15; p = 0.026) and hypertension (β = 0.14; p = 0.04).



Renal-sinus-fat and renal-parenchymal-fat are fairly related to weight-loss. Decreased renal-sinus-fat is associated with improved hepatic parameters, independent of changes in weight or hepatic fat, rather than with improved renal function or blood pressure parameters.

title: Liver fat in the metabolic syndrome.
abstract: The liver, once fatty, overproduces components of the metabolic syndrome, such as glucose and lipids. The amount of liver fat in subjects with and without the metabolic syndrome has not been determined. It is unknown which clinically available markers best reflect liver fat content.



Components of the metabolic syndrome as defined by the International Diabetes Federation and liver fat content by proton magnetic resonance spectroscopy were measured in 271 nondiabetic subjects (162 women, 109 men). In addition, other features of insulin resistance (serum insulin, C-peptide), intraabdominal and sc fat by magnetic resonance imaging, and liver enzymes (serum alanine aminotransferase and serum aspartate aminotransferase) were measured.



Liver fat was 4-fold higher in subjects with [n = 116; median 8.2% (interquartile range 3.2-18.7%)] than without [n = 155; 2.0% (1.0-5.0%); P < 0.0001] the metabolic syndrome. This increase in liver fat remained significant after adjusting for age, gender, and body mass index. All components of the metabolic syndrome correlated with liver fat content. The best correlate was waist in both women (r = 0.59, P < 0.0001) and men (r = 0.56, P < 0.0001). Liver fat correlated significantly with serum alanine aminotransferase (r = 0.39, P < 0.0001 for women; r = 0.44, P < 0.0001 for men) and aspartate aminotransferase (r = 0.27, P = 0.0005 for women; r = 0.31, P = 0.0012 for men) concentrations. The best correlates of liver fat were fasting serum insulin (r = 0.61; P < 0.0001 for both women and men) and C-peptide (r = 0.62; P < 0.0001 for both women and men).



Liver fat content is significantly increased in subjects with the metabolic syndrome as compared with those without the syndrome, independently of age, gender, and body mass index. Of other markers, serum C-peptide is the strongest correlate of liver fat.

title: Association Between Quantity of Liver Fat and Cardiovascular Risk in Patients With Nonalcoholic Fatty Liver Disease Independent of Nonalcoholic Steatohepatitis.
abstract: The association between quantity of liver fat and the presence of metabolic syndrome needs to be assessed systematically. We aimed to determine the association between the quantity of liver fat and the presence of the metabolic syndrome in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD), independent of nonalcoholic steatohepatitis (NASH).



We recruited 146 patients with well-characterized biopsy-proven NAFLD and 50 individuals without NAFLD (controls) to participate in a case-control study at the NAFLD Translational Research Unit at the University of California San Diego. Liver fat was quantified in patients with NAFLD and controls using an advanced magnetic resonance imaging-based biomarker, the proton-density-fat-fraction (MRI-PDFF). Patients with NAFLD were divided into groups based on whether they were above or below the median MRI-PDFF value (15.4% in patients with NAFLD); the MRI-PDFF value for controls was less than 5%. The primary outcome was the presence of the metabolic syndrome using Adult Treatment Panel III criteria without and with adjustment for the presence of NASH.



Compared with NAFLD patients with MRI-PDFF values below the median, and compared with controls, NAFLD patients with MRI-PDFF values above the median were more likely to have abdominal obesity (P < .0001), lower levels of high-density cholesterol (P < .0001), higher levels of triglycerides (P < .0001), and higher fasting glucose levels (P < .001). Compared with NAFLD patients with MRI-PDFF values below the median, NAFLD patients with MRI-PDFF above the median were more likely to have the metabolic syndrome (60.3% vs. 44.4%; P < .04), independent of biopsy-detected NASH.



Increased liver fat content in patients with NAFLD is associated with increased rates of the metabolic syndrome, independent of NASH. There appears to be an association between the quantity of liver fat and the risk for cardiovascular disease in patients with NAFLD.

title: Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome.
abstract: Metabolic syndrome is a cluster of metabolic abnormalities that identifies people at risk of diabetes and cardiovascular disease, whereas non-alcoholic fatty liver disease (NAFLD) is defined as a disorder with excess fat in the liver due to non-alcoholic causes. Two key components of metabolic syndrome, glucose and triglycerides, are overproduced by the fatty liver. The liver is therefore a key determinant of metabolic abnormalities. The prevalence of both metabolic syndrome and NAFLD increases with obesity. Other acquired causes for both disorders include excessive intake of simple sugars and physical inactivity. Both disorders predict type 2 diabetes, cardiovascular disease, non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma. Because metabolic syndrome can be defined in many different ways, NAFLD might be a more direct predictor of these diseases. Half of people with NAFLD carry at least one variant (G) allele at rs738409 in the PNPLA3 gene, which is associated with high liver fat content. Steatosis in PNPLA3-associated NAFLD is not accompanied by features of metabolic syndrome. All forms of NAFLD increase the risk of NASH, cirrhosis, and hepatocellular carcinoma.

title: Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings
abstract: The diagnosis of nonalcoholic steatohepatitis (NASH) is defined by the presence and pattern of specific histological abnormalities on liver biopsy. A separate system of scoring the features of nonalcoholic fatty liver disease (NAFLD) called the NAFLD Activity Score (NAS) was developed as a tool to measure changes in NAFLD during therapeutic trials. However, some studies have used threshold values of the NAS, specifically NAS ≥5, as a surrogate for the histologic diagnosis of NASH. To evaluate whether this unintended use of the NAS is valid, biopsy and clinical data from the 976 adults in NASH Clinical Research Network (CRN) studies were reviewed. Biopsies were evaluated centrally by the NASH CRN Pathology Committee. Definite steatohepatitis (SH) was diagnosed in 58.1%, borderline SH in 19.5% and “not SH” in 22%. The NAS was ≥5 in 50% and ≤4 in 49%; in this cohort only 75% of biopsies with definite SH had an NAS ≥5, whereas 28% of borderline SH and 7% of “not SH” biopsies had NAS ≥5. Of biopsies with an NAS ≥5, 86% had SH and 3% “not SH”. NAS ≤4 did not indicate benign histology; 29% had SH and only 42% had “not SH.” Higher values of the NAS were associated with higher levels of alanine aminotransferase and aspartate aminotransferase, whereas the diagnosis of SH was associated with features of the metabolic syndrome.  The diagnosis of definite SH or the absence of SH based on evaluation of patterns as well as individual lesions on liver biopsies does not always correlate with threshold values of the semiquantitative NAS. Clinical trials and observational studies should take these different performance characteristics into account. (HEPATOLOGY 2011)

title: Assessment of inflammation and fibrosis in non‐alcoholic fatty liver disease by imaging‐based techniques
abstract: Non‐alcoholic fatty liver disease (NALFD) is a burgeoning global health problem, and the assessment of disease severity remains a clinical challenge. Conventional imaging and clinical blood tests are frequently unable to determine disease activity (the degree of inflammatory change) and fibrotic severity, while the applicability of histological examination of liver biopsy is limited. Imaging platforms provide liver‐specific structural information, while newer applications of these technologies non‐invasively exploit the physical and chemical characteristics of liver tissue in health and disease. In this review, conventional and newer imaging‐based techniques for the assessment of inflammation and fibrosis in NAFLD are discussed in terms of diagnostic accuracy, radio‐pathological correlations, and practical considerations. In particular, recent clinical studies of ultrasound (US)‐based and magnetic resonance elastography techniques are evaluated, while the potential of contrast‐enhanced US and magnetic resonance spectroscopy techniques is discussed.

title: The diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis compared with liver biopsy: a meta-analysis
abstract: ObjectiveTo meta-analyse the diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis.MethodsFrom a comprehensive literature search in MEDLINE, EMBASE, CINAHL and Cochrane (up to November 2009), articles were selected that investigated the diagnostic performance imaging techniques for evaluating hepatic steatosis with histopathology as the reference standard. Cut-off values for the presence of steatosis on liver biopsy were subdivided into four groups: (1) >0, >2 and >5% steatosis; (2) >10, >15 and >20%; (3) >25, >30 and >33%; (4) >50, >60 and >66%. Per group, summary estimates for sensitivity and specificity were calculated. The natural-logarithm of the diagnostic odds ratio (lnDOR) was used as a single indicator of test performance.Results46 articles were included. Mean sensitivity estimates for subgroups were 73.3–90.5% (US), 46.1–72.0% (CT), 82.0–97.4% (MRI) and 72.7–88.5% (1H-MRS). Mean specificity ranges were 69.6–85.2% (US), 88.1–94.6% (CT), 76.1–95.3% (MRI) and 92.0–95.7% (1H-MRS). Overall performance (lnDOR) of MRI and 1H-MRS was better than that for US and CT for all subgroups, with significant differences in groups 1 and 2.ConclusionMRI and 1H-MRS can be considered techniques of choice for accurate evaluation of hepatic steatosis.

title: A comparison of liver fat content as determined by magnetic resonance imaging-proton density fat fraction and MRS versus liver histology in non-alcoholic fatty liver disease
abstract: Many imaging methods have been defined for quantification of hepatic steatosis in non-alcoholic fatty liver disease (NAFLD). However, studies comparing the efficiency of magnetic resonance imaging-proton density fat fraction (MRI-PDFF), magnetic resonance spectroscopy (MRS), and liver histology for quantification of liver fat content are limited.  To compare the efficiency of MRI-PDFF and MRS in the quantification of liver fat content in individuals with NAFLD.  A total of 19 NAFLD patients underwent MRI-PDFF, MRS, and liver biopsy for quantification of liver fat content. The MR examinations were performed on a 1.5 HDx MRI system. The MRI protocol included T1-independent volumetric multi-echo gradient-echo imaging with T2* correction and spectral fat modeling and MRS with STEAM technique.  A close correlation was observed between liver MRI-PDFF- and histology- determined steatosis (r = 0.743, P < 0.001) and between liver MRS- and histology-determined steatosis (r = 0.712, P < 0.001), with no superiority between them (ƶ = 0.19, P = 0.849). For quantification of hepatic steatosis, a high correlation was observed between the two MRI methods (r = 0.986, P < 0.001). MRI-PDFF and MRS accurately differentiated moderate/severe steatosis from mild/no hepatic steatosis (P = 0.007 and 0.013, respectively), with no superiority between them (AUCMRI-PDFF = 0.881 ± 0.0856 versus AUCMRS = 0.857 ± 0.0924, P = 0.461).  Both MRI-PDFF and MRS can be used for accurate quantification of hepatic steatosis.

title: Initial clinical application of modified Dixon with flexible echo times: hepatic and pancreatic fat assessments in comparison with 1H MRS
abstract: ObjectsHepatic and pancreatic fat content become increasingly important for phenotyping of individuals with metabolic diseases. This study aimed to (1) evaluate hepatic fat fractions (HFF) and pancreatic fat fractions (PFF) using 1H magnetic resonance spectroscopy (MRS) and the recently introduced fast mDixon method, and to examine body fat effects on HFF and PFF, (2) investigate regional differences in HFF and PFF by mDixon.Materials and methodsHFF and PFF were quantified by mDixon with two flexible echo times and by single voxel 1H MRS in 24 healthy subjects. The regional differences of PFF within the pancreas were assessed with mDixon. Abdominal visceral and subcutaneous fat was assessed by T1-weighted MRI at 3T.ResultsBoth methods correlated well for quantification of HFF (r = 0.98, p < 0.0001) and PFF (r = 0.80, p < 0.0001). However, mDixon showed a higher low limit in HFF and PFF. PFF showed no regional differences using mDixon. In addition, both visceral and subcutaneous fat correlated with pancreatic fat, while only visceral fat correlated with liver fat, employing both 1H MRS and mDixon.ConclusionThe novel and fast two-point mDixon exhibits a good correlation with the gold-standard 1H MRS for assessment of HFF and PFF, with limited sensitivity for assessing lower fat content.

title: Quantification of Pancreatic Lipomatosis and Liver Steatosis by MRI: Comparison of In/Opposed-Phase and Spectral-Spatial Excitation Techniques
abstract: The goal of the present study was the assessment of pancreatic and hepatic fat content applying 2 established magnetic resonance (MR) imaging techniques: in-phase/opposed-phase gradient-echo MR imaging and fat-selective spectral-spatial gradient-echo imaging. Results of both approaches were compared, and influences of T1- and T2*-related corrections were assessed. The possibility of a correlation between pancreatic lipomatosis and liver steatosis was investigated. Seventeen volunteers at risk for type 2 diabetes (6 male, 11 female; age, 26–70 years; body mass index, 19.4–41.3 kg/m2; mean, 31.7 kg/m2) were examined. Liver and pancreas fat content were quantified with 2 different gradient-echo techniques: one uses a spectral-spatial excitation technique with 6 binomial radio frequency pulses, which combines chemical shift selectivity with simultaneous slice-selective excitation. The other technique based on double-echo chemical shift gradient-echo MR provides in- and opposed-phase images simultaneously. Influences of T1 and individual T2* effects on results using in-phase/opposed-phase imaging were estimated and corrected for, based on additional T2* measurements. The fat content calculated from images recorded with the fat-selective spectral-spatial gradient-echo sequence correlated well with the fat fraction determined with in-phase/opposed-phase imaging and following correction for T1/T2* effects: pancreas r = 0.93 (P < 0.0001) and liver r = 0.96 (P < 0.0001). In-phase/opposed-phase imaging revealed a pancreatic fat content between 1.6% and 22.2% (mean, 8.8% ± 5.7%) and a hepatic fat fraction between 0.6% and 33.3% (mean, 7.9% ± 9.1%). The fat-selective spectral-spatial gradient-echo sequence revealed a pancreatic lipid content between 3.4% and 16.1% (mean, 9.8% ± 4.0%) and a hepatic fat content between 0% and 28.5% (mean, 8.8% ± 8.3%). With neither technique was a substantial correlation between pancreatic and hepatic fat content found. The presented results suggest that both methods are reliable tools for pancreatic and hepatic fat quantification. However, for reliable assessment of quantitative fat by the in-phase/opposed-phase technique, an additional measurement of T2* seems crucial.

title: Accuracy of MR imaging-estimated proton density fat fraction for classification of dichotomized histologic steatosis grades in nonalcoholic fatty liver disease.
abstract: To evaluate the diagnostic performance of previously proposed high-specificity magnetic resonance (MR) imaging-estimated proton density fat fraction (PDFF) thresholds for diagnosis of steatosis grade 1 or higher (PDFF threshold of 6.4%), grade 2 or higher (PDFF threshold of 17.4%), and grade 3 (PDFF threshold of 22.1%) by using histologic findings as a reference in an independent cohort of adults known to have or suspected of having nonalcoholic fatty liver disease (NAFLD).



This prospective, cross-sectional, institutional review board-approved, HIPAA-compliant single-center study was conducted in an independent cohort of 89 adults known to have or suspected of having NAFLD who underwent contemporaneous liver biopsy. MR imaging PDFF was estimated at 3 T by using magnitude-based low-flip-angle multiecho gradient-recalled-echo imaging with T2* correction and multipeak modeling. Steatosis was graded histologically (grades 0, 1, 2, and 3, according to the Nonalcoholic Steatohepatitis Clinical Research Network scoring system). Sensitivity, specificity, and binomial confidence intervals were calculated for the proposed MR imaging PDFF thresholds.



The proposed MR imaging PDFF threshold of 6.4% to diagnose grade 1 or higher steatosis had 86% sensitivity (71 of 83 patients; 95% confidence interval [CI]: 76, 92) and 83% specificity (five of six patients; 95% CI: 36, 100). The threshold of 17.4% to diagnose grade 2 or higher steatosis had 64% sensitivity (28 of 44 patients; 95% CI: 48, 78) and 96% specificity (43 of 45 patients; 95% CI: 85, 100). The threshold of 22.1% to diagnose grade 3 steatosis had 71% sensitivity (10 of 14 patients; 95% CI: 42, 92) and 92% specificity (69 of 75 patients; 95% CI: 83, 97).



In an independent cohort of adults known to have or suspected of having NAFLD, the previously proposed MR imaging PDFF thresholds provided moderate to high sensitivity and high specificity for diagnosis of grade 1 or higher, grade 2 or higher, and grade 3 steatosis. Prospective multicenter studies are now needed to further validate these high-specificity thresholds.

title: Correlation between liver histology and novel magnetic resonance imaging in adult patients with non‐alcoholic fatty liver disease – MRI accurately quantifies hepatic steatosis in NAFLD
abstract: Conventional magnetic resonance imaging (MRI) techniques that measure hepatic steatosis are limited by T1 bias, T2* decay and multi‐frequency signal‐interference effects of protons in fat. Newer MR techniques such as the proton density‐fat fraction (PDFF) that correct for these factors have not been specifically compared to liver biopsy in adult patients with non‐alcoholic fatty liver disease (NAFLD).

title: Agreement Between Magnetic Resonance Imaging Proton Density Fat Fraction Measurements and Pathologist-Assigned Steatosis Grades of Liver Biopsies From Adults With Nonalcoholic Steatohepatitis.
abstract: We assessed the diagnostic performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in grading hepatic steatosis and change in hepatic steatosis in adults with nonalcoholic steatohepatitis (NASH) in a multi-center study, using central histology as reference.



We collected data from 113 adults with NASH participating in a multi-center, randomized, double-masked, placebo-controlled, phase 2b trial to compare the efficacy cross-sectionally and longitudinally of obeticholic acid vs placebo. Hepatic steatosis was assessed at baseline and after 72 weeks of obeticholic acid or placebo by liver biopsy and MRI (scanners from different manufacturers, at 1.5T or 3T). We compared steatosis estimates by PDFF vs histology. Histologic steatosis grade was scored in consensus by a pathology committee. Cross-validated receiver operating characteristic (ROC) analyses were performed.



At baseline, 34% of subjects had steatosis grade 0 or 1, 39% had steatosis grade 2, and 27% had steatosis grade 3; corresponding mean PDFF values were 9.8%±3.7%, 18.1%±4.3%, and 30.1%±8.1%. PDFF classified steatosis grade 0-1 vs 2-3 with an area under the ROC curve (AUROC) of 0.95 (95% CI, 0.91-0.98), and grade 0-2 vs grade 3 steatosis with an AUROC of 0.96 (95% CI, 0.93-0.99). PDFF cut-off values at 90% specificity were 16.3% for grades 2-3 and 21.7% for grade 3, with corresponding sensitivities of 83% and 84%. After 72 weeks' of obeticholic vs placebo, 42% of subjects had a reduced steatosis grade (mean reduction in PDFF from baseline of 7.4%±8.7%), 49% had no change in steatosis grade (mean increase in PDFF from baseline of 0.3%±6.3%), and 9% had an increased steatosis grade (mean increase in PDFF from baseline of 7.7%±6.0%). PDFF change identified subjects with reduced steatosis grade with an AUROC of 0.81 (95% CI, 0.71-0.91) and increased steatosis grade with an AUROC of 0.81 (95% CI, 0.63-0.99). A PDFF reduction of 5.15% identified subjects with reduced steatosis grade with 90% specificity and 58% sensitivity, whereas a PDFF increase of 5.6% identified those with increased steatosis grade with 90% specificity and 57% sensitivity.



Based on data from a phase 2 randomized controlled trial of adults with NASH, PDFF estimated by MRI scanners of different field strength and at different sites, accurately classifies grades and changes in hepatic steatosis when histologic analysis of biopsies is used as a reference.

title: Hepatic 31P magnetic resonance spectroscopy: a hepatologist's user guide
abstract: Hepatic phosphorus magnetic resonance spectroscopy (31P MRS) offers the exciting potential of studying metabolic processes in the human liver in vivo. Many investigators have utilized 31P MRS to research a broad range of metabolic questions, and there is outstanding potential for this imaging modality in the future. However, at times it is difficult to appreciate this potential because most published series have been small, and comparisons between studies are difficult. Indeed, the published literature contains significant variation in data acquisition and data analysis techniques and, perhaps most importantly, the interpretation of the data itself. As MR technology continues to evolve and more studies are being performed, perhaps a greater consensus of study techniques and endpoints will emerge. This review summarizes the present literature on human hepatic 31P MRS.

title: Nonalcoholic fatty liver disease: detection of elevated nicotinamide adenine dinucleotide phosphate with in vivo 3.0-T 31P MR spectroscopy with proton decoupling.
abstract: To determine if 3.0-T proton-decoupled phosphorus 31 ((31)P) magnetic resonance (MR) spectroscopy can be used to differentiate between stages of nonalcoholic fatty liver disease (NAFLD) by resolving the components of phosphomonoester (PME) and phosphodiester (PDE) and enabling detection of a greater number of other phosphorus-containing compounds.



This study was approved by the ethics committee of Helsinki University Central Hospital, and written informed consent was obtained from all study subjects. A 3.0-T clinical imager was used to obtain proton-decoupled (31)P MR spectra in the liver of control subjects (n = 12), patients with biopsy-proved simple steatosis due to nonalcoholic causes (nonalcoholic fatty liver, n = 13; nonalcoholic steatohepatitis [NASH], n = 9), and patients with cirrhosis (n = 9) to determine PME, phosphoethanolamine (PE), phosphocholine, PDE, glycerophosphocholine (GPC), glycerophosphoryl ethanolamine, uridine diphosphoglucose, nicotinamide adenine dinucleotide phosphate (NADPH), inorganic phosphate, phosphoenolpyruvate, and alpha-, beta- and gamma-nucleotide triphosphate levels. Liver fat was determined with hydrogen 1 MR spectroscopy. Differences between the disease groups were analyzed with one-way analysis of variance.



The PME/(PME + PDE), PME/PDE, and PE/(PME + PDE) ratios were higher and the GPC/(PME + PDE) ratio was lower in patients with cirrhosis than in the other study groups (P < or = .001, one-way analysis of variance). The NADPH/(PME + PDE) ratio was higher in patients with NASH and those with cirrhosis than in control subjects (P < .05, post hoc analyses) and correlated with disease severity (P = .007).



NADPH, a marker of inflammation and fibrinogenic activity in the liver, is increased in patients with NASH and those with cirrhosis. Proton-decoupled (31)P 3.0-T MR spectroscopy shows promise in the differentiation of NAFLD stages.

title: The metabolic syndrome and chronic liver disease.
abstract: The prevalence of the metabolic syndrome (MetS), a cluster of cardiovascular risk factors associated with obesity and insulin resistance, is dramatically increasing in Western and developing countries. This disorder is not only associated with a higher risk of appearance of type 2 diabetes and cardiovascular events, but impacts on the liver in different ways. Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of MetS, and is characterized by triglyceride accumulation and a variable degree of hepatic injury, inflammation, and repair. In the presence of significant hepatocellular injury and inflammation, the picture is defined 'nonalcoholic steatohepatitis' (NASH), that has the potential to progress to advanced fibrosis and cirrhosis. Diagnosis of NASH is based on a liver biopsy, and active search for noninvasive tests is ongoing. Progression of steatohepatitis to advanced fibrosis or cirrhosis has been shown in at least one third of patients followed with paired biopsies. Presence of NASH is associated with lower life expectancy, both due to liver-related death and to an increase in cardiovascular events. The appearance of NAFLD is mainly dependent on increased flow of fatty acids derived from an excess of lipolysis from insulin-resistant adipose tissue. Development of NASH is based on lipotoxicity and is influenced by signals derived from outside the liver and from intrahepatic activation of inflammatory and fibrogenic pathways. The presence of the MetS is also associated with worse outcomes in patients with cirrhosis due to any causes, and has complex interactions with hepatitis C virus infection. Moreover, MetS poses a higher risk of development of hepatocellular carcinoma, not necessarily through the development of NASH-related cirrhosis. In conclusion, the presence of metabolic alterations has a severe and multifaceted impact on the liver, and is responsible for a higher risk of liver-dependent and -independent mortality.

title: Evaluation of hepatic fibrosis: a review from the society of abdominal radiology disease focus panel
abstract: Hepatic fibrosis is potentially reversible; however early diagnosis is necessary for treatment in order to halt progression to cirrhosis and development of complications including portal hypertension and hepatocellular carcinoma. Morphologic signs of cirrhosis on ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) alone are unreliable and are seen with more advanced disease. Newer imaging techniques to diagnose liver fibrosis are reliable and accurate, and include magnetic resonance elastography and US elastography (one-dimensional transient elastography and point shear wave elastography or acoustic radiation force impulse imaging). Research is ongoing with multiple other techniques for the noninvasive diagnosis of hepatic fibrosis, including MRI with diffusion-weighted imaging, hepatobiliary contrast enhancement, and perfusion; CT using perfusion, fractional extracellular space techniques, and dual-energy, contrast-enhanced US, texture analysis in multiple modalities, quantitative mapping, and direct molecular imaging probes. Efforts to advance the noninvasive imaging assessment of hepatic fibrosis will facilitate earlier diagnosis and improve patient monitoring with the goal of preventing the progression to cirrhosis and its complications.

title: Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C
abstract: Transient elastography (TE) has received increasing attention as a means to evaluate disease progression in patients with chronic liver disease.  To assess the value of TE for predicting the stage of fibrosis.  Liver biopsy and TE were performed in 150 consecutive patients with chronic hepatitis C-related hepatitis (92 men and 58 women, age 50.6 (SD 12.5) years on the same day. Necro-inflammatory activity and the degree of steatosis at biopsy were also evaluated.  The areas under the curve for the prediction of significant fibrosis (⩾F2), advanced fibrosis (⩾F3) or cirrhosis were 0.91, 0.99 and 0.98, respectively. Calculation of multilevel likelihood ratios showed that values of TE <6 or ⩾12, <9 or ⩾12, and <12 or ⩾18, clearly indicated the absence or presence of significant fibrosis, advanced fibrosis, and cirrhosis, respectively. Intermediate values could not be reliably associated with the absence or presence of the target condition. The presence of inflammation significantly affected TE measurements in patients who did not have cirrhosis (p<0.0001), even after adjusting for the stage of fibrosis. Importantly, TE measurements were not influenced by the degree of steatosis.  TE is more suitable for the identification of patients with advanced fibrosis than of those with cirrhosis or significant fibrosis. In patients in whom likelihood ratios are not optimal and do not provide a reliable indication of the disease stage, liver biopsy should be considered when clinically indicated. Necro-inflammatory activity, but not steatosis, strongly and independently influences TE measurement in patients who do not have cirrhosis.

title: Extrahepatic Cholestasis Increases Liver Stiffness (Fibroscan®) Irrespective of Fibrosis
abstract: Transient elastography [Fibroscan (FS)] is a novel non-invasive tool to assess liver fibrosis/cirrhosis. However, it remains to be determined if other liver diseases such as extrahepatic cholestasis interfere with fibrosis assessment since liver stiffness is indirectly measured by the propagation velocity of an ultrasound wave within the liver.  In this study we measured liver stiffness immediately before ERCP and 3 to 12 days after successful biliary drainage in patients with extrahepatic cholestasis due to benign or malignant bile duct obstruction. Initially elevated liver stiffness decreased in 13 of 15 patients after intervention, in 10 of them markedly. In 3 patients, liver stiffness was elevated to a degree that suggested advanced liver cirrhosis (mean 15.2 kPa). Successful drainage led to a drop of bilirubin by 2.8 to 9.8mg/dL while liver stiffness almost normalized (mean 7.1 kPa). In all patients with successful biliary drainage, the decrease of liver stiffness highly correlated with decreasing bilirubin (Spearman’ rho=0.67, P<0.05) with a mean decrease of liver stiffness of 1.2±0.56 kPa per 1g/dl bilirubin. Two patients, in whom liver stiffness did not decrease despite successful biliary drainage, had advanced liver cirrhosis and multiple liver metastases, respectively. The relationship between bile duct obstruction and liver stiffness was reproduced in an animal model of bile duct ligation in landrace pigs where liver stiffness increased from 4.6 kPa to 8.8 kPa during 120 min of bile duct ligation and decreased to 6.1 kPa within 30 min after decompression.  Extrahepatic cholestasis increases liver stiffness irrespective of fibrosis. Once extrahepatic cholestasis is excluded e.g. by liver imaging and laboratory parameters, transient elastography is a valuable tool to assess liver fibrosis in chronic liver diseases.

title: Liver stiffness is directly influenced by central venous pressure.
abstract: Liver stiffness (LS) as measured by transient elastography [Fibroscan] offers a novel non-invasive approach to assess liver cirrhosis. Since Fibroscan seems to be unreliable in patients with congestive heart failure, it remains to be determined whether hemodynamic changes affect LS irrespective of fibrosis.



Using landrace pigs, we studied the direct relationship between the central venous pressure and LS measured by Fibroscan. Clamping of the inferior caval vein increased LS from 3.1 to 27.8kPa while reopening reversed LS within 5min to almost normal values of 5.1kPa. We then studied LS as a function of venous pressure in the isolated pig liver by clamping the upper and lower caval, portal vein and hepatic artery. The stepwise increase of intravenous pressure to 36cm of water column (3.5kPa) linearly and reversibly increased LS to the upper detection limit of 75kPa. We finally measured LS in 10 patients with decompensated congestive heart failure before and after recompensation. Initial LS was elevated in all patients, in 8 of them to a degree that suggested liver cirrhosis (median 40.7kPa). Upon recompensation with a median weight loss of 3.0kg, LS decreased in all 10 patients down to a median LS of 17.8kPa. Inflammation could not account for increased LS since initial liver enzyme counts were only slightly elevated and did not change significantly.



LS is a direct function of central venous pressure which should be considered when assessing the degree of fibrosis.

title: Magnetic resonance elastography of liver: Technique, analysis, and clinical applications
abstract: Many pathological processes cause marked changes in the mechanical properties of tissue. MR elastography (MRE) is a noninvasive MRI based technique for quantitatively assessing the mechanical properties of tissues in vivo. MRE is performed by using a vibration source to generate low frequency mechanical waves in tissue, imaging the propagating waves using a phase contrast MRI technique, and then processing the wave information to generate quantitative images showing mechanical properties such as tissue stiffness. Since its first description in 1995, published studies have explored many potential clinical applications including brain, thyroid, lung, heart, breast, and skeletal muscle imaging. However, the best‐documented application to emerge has been the use of MRE to assess liver disease. Multiple studies have demonstrated that there is a strong correlation between MRE‐measured hepatic stiffness and the stage of fibrosis at histology. The emerging literature indicates that MRE can serve as a safer, less expensive, and potentially more accurate alternative to invasive liver biopsy which is currently the gold standard for diagnosis and staging of liver fibrosis. This review describes the basic principles, technique of performing a liver MRE, analysis and calculation of stiffness, clinical applications, limitations, and potential future applications.  Imaging 2013;37:544–555.

title: Magnetic resonance elastography of the liver: preliminary results and estimation of inter-rater reliability
abstract: PurposeThe aim of this study was to estimate inter-rater reliability and validate magnetic resonance elastography (MRE) as a tool to measure liver elasticity.Materials and methodsThe study protocol was approved by the institutional review board at our institution. In all, 10 normal volunteers and 110 patients, who provided written informed consent, were enrolled. The pathological fibrosis score was applied as a standard reference of liver fibrosis in 21 patients. MRE was performed with a 1.5-T magnetic resonance imaging scanner with a cylindrical passive longitudinal shear wave driver placed over the right chest wall to deliver vibrations. A gradient-echo MRE sequence was used to acquire axial wave images, which were automatically converted to elastograms representing elasticity (in kilopascals, or kPa). The region of interest was placed in the right lobe of the liver on elastograms by two raters independently. To evaluate interrater reliability, the intraclass correlation coefficient was calculated. The elasticity measurements correlated with the pathological fibrosis score (F1–F4) in 21 patients.ResultsThe intraclass correlation coefficient was almost perfect (0.993) between the elasticities measured by the two raters. The mean elasticity value for patients with F4 was 5.7 kPa; F3, 4.4 kPa; F2, 3.1 kPa; F1, 2.2 kPa; and F0, 2.1 kPa.ConclusionMRE is a reliable tool to measure liver elasticity.

title: Magnetic resonance elastography (MRE) in assessing hepatic fibrosis: performance in a cohort of patients with histological data
abstract: PurposeThe purpose of this study was to compare fibrosis seen on liver biopsy to MR elastography (MRE) stiffness measurements in normal controls and patients with abnormal transaminases and chronic liver disease.MethodsThe control group consisted of 22 healthy liver transplant donors who by definition had normal transaminases. The patient group (32 patients) was recruited from the Mayo Clinic Arizona hepatobiliary clinic over a 3-year span. All subjects underwent a liver biopsy as part of their evaluation and agreed to MRE within 35 days of biopsy. Non-parametric tests were used to compare the MRE-predicted liver fibrosis to the fibrosis noted on liver biopsy.ResultsAnalysis included 54 subjects (32 patients with chronic liver disease and 22 healthy liver donor candidates). MRE median liver stiffness measurements increased per histologic liver fibrosis stage (one-way ANOVA p = 0.001), with significant correlation between increasing fibrosis stage and stiffness values. Median MRE for control group (2.13 kPa; mean = 2.3 ± 0.6 kPa) was significantly lower than for patient group (3.7 kPa; mean = 4.1 ± 2.1 kPa) (p = 0.003). Significantly, lower median stiffness was seen in zero-to-moderate (F0–2, n = 22) vs. severe fibrosis stages (F3–4, n = 10) 2.80 vs. 5.9 kPa, respectively (p < 0.05). Using a 3.7-kPa cut-off value, the predicted sensitivity and specificity for detecting F0–2 from F3–4 were 91% and 80%, respectively.ConclusionsOur analysis supports previous findings that MRE is a non-invasive and effective method for detection and assessment of liver fibrosis, particularly for discrimination between F0–2 stages and F3–4 stages. MRE may represent a valuable tool to finely discern hepatic fibrosis non-invasively.

title: Ultrasound Elastography and MR Elastography for Assessing Liver Fibrosis: Part 1, Principles and Techniques.
abstract: The purpose of this article is to provide an overview of ultrasound and MR elastography, including a glossary of relevant terminology, a classification of elastography techniques, and a discussion of their respective strengths and limitations.



Elastography is an emerging technique for the noninvasive assessment of mechanical tissue properties. These techniques report metrics related to tissue stiffness, such as shear-wave speed, magnitude of the complex shear modulus, and the Young modulus.

title: Association between non-alcoholic fatty pancreatic disease (nafpd) and the metabolic syndrome: case–control retrospective study
abstract: BackgroundFatty liver is associated with insulin resistance, dyslipidemia, and obesity and is therefore considered a phenotype of metabolic syndrome. However, less is known regarding the metabolic abnormalities associated with non-alcoholic fatty pancreatic disease (NAFPD; fatty pancreas). The present study was performed to ascertain whether fatty pancreas is associated with specific metabolic risk factors and with metabolic syndrome as defined by the Adult Treatment Panel III.MethodsFive-hundred-fifty-seven healthy and consecutive subjects without known hypertension or diabetes and who received a health investigation at the National Taiwan University Hospital Health Management Center were enrolled in this retrospective study. Fatty pancreas was diagnosed via trans-abdominal ultrasonographic findings.ResultsSeventy-two (12.9%) subjects diagnosed with fatty pancreas comprised the fatty pancreas group, and remaining subjects comprised the normal pancreas group. The presence of various demographic and metabolic risk factors was recorded for all subjects, and the two groups were examined for statistically significant differences in these factors. As compared to the absence of fatty pancreas, the presence of the disease was associated with older age and with higher values for each of the following: BMI, abdominal girth/height, abdominal girth (both genders), fasting and postprandial blood glucose, HbA1c, total cholesterol, triglycerides, LDL-cholesterol, systolic blood pressure, and platelet count. In contrast to previously reported findings, serum amylase values were lower in the fatty pancreas as compared to the control group. presence of fatty pancreas represents a meaningful manifestation of metabolic syndrome together with obesity.

title: Pancreatic Ectopic Fat Is Characterized by Adipocyte Infiltration and Altered Lipid Composition
abstract: Sustained exposure to lipids is deleterious for pancreatic islet function. This could be mediated through increased pancreatic fat following increased dietary fat and in obesity, which has implications for the onset of type 2 diabetes. The aims of this study were to determine changes in extent and composition of pancreatic, hepatic, and visceral fat in mice fed a high‐fat diet (HFD, 40% by weight) compared with a control diet (5% fat) of similar fatty acid composition, and to compare composition and extent of pancreatic fat in human type 2 diabetes.

title: Nonalcoholic fatty pancreas disease.
abstract: Obesity leads to fat infiltration of multiple organs including the heart, kidneys, and liver. Under conditions of oxidative stress, fat-derived cytokines are released locally and result in an inflammatory process and organ dysfunction. In the liver, fat infiltration has been termed nonalcoholic fatty liver disease, which may lead to nonalcoholic steatohepatitis. No data are available, however, on the influence of obesity on pancreatic fat and cytokines, and nonalcoholic fatty pancreas disease (NAFPD) has not been described. Therefore, we designed a study to determine whether obesity is associated with increased pancreatic fat and cytokines.



Thirty C57BL/6J lean control and 30 leptin-deficient obese female mice were fed a 15% fat diet for 4 weeks. At 12 weeks of age all animals underwent total pancreatectomy. Pancreata from each strain were pooled for measurement of a) wet and dry weight, b) histologic presence of fat, c) triglycerides, free fatty acids (FFAs), cholesterol, phospholipids, and total fat, and d) interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha). Data were analyzed by Student's t test and Fisher's exact test.



Pancreata from obese mice were heavier (p<0.05) and had more fat histologically (p<0.05). Pancreata from obese mice had more triglycerides, FFAs, cholesterol, and total fat (p<0.05). Triglycerides represented 11% of pancreatic fat in lean mice compared with 67% of pancreatic fat in obese mice (p<0.01). Cytokines IL-1beta and TNF-alpha also were elevated in the pancreata of obese mice (p<0.05).



These data suggest that obese mice have 1) heavier pancreata, 2) more pancreatic fat, especially triglycerides and FFAs, and 3) increased cytokines. We conclude that obesity leads to nonalcoholic fatty pancreatic disease.

title: Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation.
abstract: Studies in Zucker diabetic fatty rats have led to the concept that chronically elevated free fatty acid (FFA) levels can cause apoptosis of triglyceride-laden pancreatic beta-cells as a result of the formation of ceramides, which induce nitric oxide (NO)-dependent cell death. This "lipotoxicity" hypothesis could explain development of type 2 diabetes in obesity. The present study examines whether prolonged exposure to FFA affects survival of isolated normal rat beta-cells and whether the outcome is related to the occurrence of triglyceride accumulation. A dose-dependent cytotoxicity was detected at 5-100 nmol/l of unbound oleate and palmitate, with necrosis occurring within 48 h and an additional apoptosis during the subsequent 6 days of culture. At equimolar concentrations, the cytotoxicity of palmitate was higher than that of oleate but lower than that of its nonmetabolized analog bromopalmitate. FFA cytotoxicity was not suppressed by etomoxir (an inhibitor of mitochondrial carnitine palmitoyltransferase I) or by antioxidants; it was not associated with inducible NO synthase expression or NO formation. An inverse correlation was observed between the percentage of dead beta-cells on day 8 and their cellular triglyceride content on day 2. For equimolar concentrations of the tested FFA, oleate caused the lowest beta-cell toxicity and the highest cytoplasmic triglyceride accumulation. On the other hand, oleate exerted the highest toxicity in islet non-beta-cells, where no FFA-induced triglyceride accumulation was detected. In conditions without triglyceride accumulation, the lower FFA concentrations caused primarily apoptosis, both in islet beta-cells and non-beta-cells. It is concluded that FFAs can cause death of normal rat islet cells through an NO-independent mechanism. The ability of normal beta-cells to form and accumulate cytoplasmic triglycerides might serve as a cytoprotective mechanism against FFA-induced apoptosis by preventing a cellular rise in toxic free fatty acyl moieties. It is conceivable that this potential is lost or insufficient in cells with a prolonged triglyceride accumulation as may occur in vivo.

title: The effect of fatty pancreas on serum glucose parameters in patients with nonalcoholic steatohepatitis.
abstract: Fatty pancreas (FP) is related to obesity, and may have some clinical implications on glucose metabolism. The frequency and importance of FP in patients with nonalcoholic steatohepatitis (NASH) are not clear. This study aimed to investigate: the frequency of FP in patients with NASH, and its effects on serum glucose parameters.



FP was detected and graded by transabdominal ultrasonography (USG) in patients with biopsy-proven NASH and healthy controls. Body Mass Index and waist circumference were recorded, and serum lipids, fasting serum glucose, HbA1c, OGTT 2-h, insulin level, insulin resistance, type 2 diabetes mellitus (DM) and prediabetes rates were detected.



Eighty-four subjects with NASH and 35 healthy controls were enrolled in the study. There was no FP in 41 (48.8%) of the NASH patients according to the study criteria. Forty-three of the NASH patients and 5 of the controls had different grades of fat in their pancreas (51.2% vs. 14%, p=0.001). The HbA1c and OGTT 2-h results were significantly higher in NASH patients with FP compared to those without FP (p=0.003 and p=0.018). The rates of both prediabetes and DM were also found to be significantly increased in NASH patients with FP (p=0.004). The mean waist circumference was higher in patients with FP (p=0.027). Grade of FP by USG showed no effect on study parameters in subgroup analysis.



FP is common in patients with NASH and increases the rate of prediabetes and DM. The coexistence of both NASH and FP has a further impact on glucose metabolism and DM frequency.

title: Exploring the metabolic syndrome: Nonalcoholic fatty pancreas disease
abstract: After the first description of fatty pancreas in 1933, the effects of pancreatic steatosis have been poorly investigated, compared with that of the liver. However, the interest of research is increasing. Fat accumulation, associated with obesity and the metabolic syndrome (MetS), has been defined as “fatty infiltration” or “nonalcoholic fatty pancreas disease” (NAFPD). The term “fatty replacement” describes a distinct phenomenon characterized by death of acinar cells and replacement by adipose tissue. Risk factors for developing NAFPD include obesity, increasing age, male sex, hypertension, dyslipidemia, alcohol and hyperferritinemia. Increasing evidence support the role of pancreatic fat in the development of type 2 diabetes mellitus, MetS, atherosclerosis, severe acute pancreatitis and even pancreatic cancer. Evidence exists that fatty pancreas could be used as the initial indicator of “ectopic fat deposition”, which is a key element of nonalcoholic fatty liver disease and/or MetS. Moreover, in patients with fatty pancreas, pancreaticoduodenectomy is associated with an increased risk of intraoperative blood loss and post-operative pancreatic fistula.

title: Differences in pancreatic volume, fat content, and fat density measured by multidetector-row computed tomography according to the duration of diabetes
abstract: Pancreatic volume and fat content might be associated with β-cell function or insulin resistance (IR). We investigated the difference in pancreatic volume and fat content between age- and body mass index (BMI)-matched normal subjects and patients with having different durations of type 2 diabetes (T2D). We compared pancreatic volume and fat parameters between 50 age- and BMI-matched normal subjects, 51 subjects with newly diagnosed type 2 diabetes (T2D-new), 53 subjects with T2D <5 years (T2D<5Y), and 52 subjects with T2D ≥5 years (T2D≥5Y). Age and BMI were matched to range of ±2 years and ±0.5 kg/m2, respectively. Pancreatic volume and fat were measured by multidetector-row computed tomography with 64 detector-row scanner. The difference in Hounsfield units between pancreas and spleen (HUp–s) was investigated for fat density. Anthropometric and biochemical parameters including the homeostasis model assessment of IR (HOMA-IR) and the insulinogenic index (IGI) were measured. Compared with normal subjects, patients with T2D had significantly smaller pancreatic volume, greater pancreatic fat, and lower HUp–s. Among the groups with T2D, pancreatic volume decreased and pancreatic fat percentage and HUp–s increased from the T2D-new to the T2D<5Y and T2D>5Y groups. Pancreatic volume and fat and HUp–s values were associated with HbA1c and triglyceride levels. Pancreatic volume was correlated with IGI while pancreatic fat and HUp–s values were correlated with HOMA-IR. The current study suggests that pancreatic volume and fat deposition might be associated with the development and progression of T2D in Korean subjects.

title: Quantitative assessment of pancreatic fat by using unenhanced CT: pathologic correlation and clinical implications.
abstract: To assess the relationship between computed tomographic (CT) indexes and histologically measured pancreatic fat in surgical specimens and to evaluate patients with impaired glucose metabolism in a clinical setting.



This retrospective study was institutional review board approved and informed consent was waived. The hospital database was searched for records from November 2008 to April 2009, and 62 patients (42 men and 20 women; mean age, 61.4 years; age range, 21-81 years) who underwent CT within 1 month before pancreatectomy were identified. The histologic pancreatic fat fraction (area ratio of fat to total tissue times 100%) was measured in nontumorous pancreatic tissue. Attenuation was measured in three regions of interest in the pancreas and the spleen on nonenhanced CT images. The difference between pancreatic and splenic attenuation and the pancreas-to-spleen attenuation ratio were calculated. Visceral fat area at the level of the umbilicus was measured on the CT images. Spearman correlation coefficients (ρ) were calculated to examine the correlation between the CT indexes or visceral fat area and the histologic pancreatic fat fraction. A multivariate logistic regression model was used to determine whether CT attenuation indexes and patient age, sex, and visceral fat correlated with impaired glucose metabolism (ie, impaired glucose tolerance, impaired fasting glucose, or presence of diabetes).



The histologic pancreatic fat fraction ranged from 0% to 65.3% and was significantly correlated with the difference between pancreatic and splenic attenuation (ρ = -0.622, P < .01) and the pancreas-to-spleen attenuation ratio (ρ = -0.616, P < .01). The visceral fat area was not correlated with the histologic pancreatic fat fraction (ρ = 0.09, P = .50). The CT attenuation indexes were significant and independent variables predictive of impaired glucose metabolism after adjusting for age, sex, and visceral fat.



Pancreatic fat can be quantified by using CT, and CT attenuation indexes that are applied to the quantification of pancreatic fat are significantly associated with clinical assessment of impaired glucose metabolism.

title: Comparison of Fat–Water MRI and Single‐voxel MRS in the Assessment of Hepatic and Pancreatic Fat Fractions in Humans
abstract: The ability to accurately and noninvasively quantify fatty infiltration in organs such as the liver and the pancreas remains a critical component in understanding the link between obesity and its comorbidities such as type 2 diabetes and fatty liver disease. Single‐voxel (1H) proton magnetic resonance spectroscopy (MRS) has long been regarded as the gold‐standard noninvasive technique for such measurements. Recent advances in three‐dimensional fat–water magnetic resonance imaging (MRI) methods have led to the development of rapid, robust, and quantitative approaches that can accurately characterize the proportion of fat and water content in underlying tissues across the full imaging volume, and hence entire organs of interest. One such technique is called IDEAL (Iterative Decomposition with Echo Asymmetry and Least squares estimation). This article prospectively compares three‐dimensional (3D) IDEAL‐MRI and single‐voxel MRS in the assessment of hepatic (HFF) and pancreatic fat fraction (PFF) in 16 healthy subjects. MRS acquisitions took 3–4 min to complete whereas IDEAL acquisitions were completed in 20‐s breath‐holds. In the liver, there was a strong correlation (slope = 0.90, r2 = 0.95, P < 0.001) between IDEAL and MRS‐based fat fractions. In the pancreas, a poorer agreement between IDEAL and MRS was observed (slope = 0.32, r2 = 0.51, P < 0.02). The discrepancy of PFF is likely explained by MRS signal contamination from surrounding visceral fat, presumably during respiratory motion. We conclude that IDEAL is equally accurate in characterizing hepatic fat content as MRS, and is potentially better suited for fat quantification in smaller organs such as the pancreas.

title: Ectopic fat storage in the pancreas using 1H-MRS: importance of diabetic status and modulation with bariatric surgery-induced weight loss
abstract: Recent literature suggests that ectopic fat deposition in the pancreas may contribute to endocrine and exocrine organ dysfunction, such as type 2 diabetes (T2D), pancreatitis or pancreatic cancer. The aim of this study was to determine factors associated with pancreatic triglyceride content (PTGC), and to investigate the impact of bariatric surgery on ectopic fat pads, pancreatic fat (PTGC) and hepatic fat (In all, 45 subjects (13 lean, 13 obese nondiabetics and 19 T2D, matched for age and gender) underwent 1H-magnetic resonance spectroscopy, computed tomography of the visceral abdominal fat, metabolic and lipidomic analysis, including insulin-resistance homeostasis model assessment (HOMA-IR), insulin-secretion homeostasis model assessment (HOMA-B) and plasma fatty-acid composition. Twenty obese subjects were reassessed 6 months after the bariatric surgery.PTGC was significantly higher in type 2 diabetic subjects (23.8±3.2%) compared with obese (14.0±3.3; P=0.03) and lean subjects (7.5±0.9%; P=0.0002). PTGC remained significantly associated with T2D after adjusting for age and sex (β=0.47; P=0.004) or even after adjusting for waist circumference, triglycerides and HOMA-IR (β=0.32; P=0.04). T2D, C18:1n-9 (oleic acid), uric acid, triglycerides and plasminogen activator inhibitor-1 were the five more important parameters involved in PTGC prediction (explained 80% of PTGC variance). Bariatric surgery induced a huge reduction of both HTGC (−51.2±7.9%) and PTGC (−43.8±7.0%) reaching lean levels, whereas body mass index remained greatly elevated. An improvement of insulin resistance HOMA-IR and no change in HOMA-B were observed after bariatric surgery. The PTGC or HTGC losses were not correlated, suggesting tissue-specific mobilization of these ectopic fat stores.Pancreatic fat increased with T2D and drastically decreased after the bariatric surgery. This suggests that decreased PTGC may contribute to improved beta cell function seen after the bariatric surgery. Further, long-term interventional studies are warranted to examine this hypothesis and to determine the degree to which ectopic fat mobilization may mediate the improvement in endocrine and exocrine pancreatic functions.

title: Quantitative analysis of pancreatic echogenicity on transabdominal sonography: Correlations with metabolic syndrome
abstract: To attempt a quantitative analysis of pancreatic echogenicity on transabdominal ultrasonography (US) and evaluate the correlation between pancreatic echogenicity and metabolic syndrome (MetS).

title: Metabolic Syndrome and the Risk of Mild Cognitive Impairment and Progression to Dementia: Follow-up of the Singapore Longitudinal Ageing Study Cohort.
abstract: The association of the metabolic syndrome (MetS) and component cardiovascular risk factors with the risk of developing mild cognitive impairment (MCI) and MCI progression to dementia is not well established.



To investigate the association of the MetS and its component cardiovascular risk factors with the incidence of MCI and its progression to dementia.



Prospective longitudinal study from September 1, 2003, through December 31, 2009, in communities in 5 districts in the South East region of Singapore. Study participants were a population-based sample of 1519 cognitively normal adults 55 years and older.



Prespecified outcomes were incident MCI and MCI progression to dementia.



The study cohort comprised 1519 participants. Their mean (SD) age was 64.9 (6.8) years, and 64.8% (n = 984) were female. Baseline characteristics associated with an increased risk of incident MCI were MetS (hazard ratio [HR], 1.46; 95% CI, 1.02-2.09), central obesity (HR, 1.41; 95% CI, 1.01-1.98), diabetes mellitus (HR, 2.84; 95% CI, 1.92-4.19), dyslipidemia (HR, 1.48; 95% CI, 1.01-2.15), and 3 or more component cardiovascular risk factors (HR, 1.58; 95% CI, 1.13-2.33). Baseline characteristics associated with an increased risk of MCI progression to dementia were MetS (HR, 4.25; 95% CI, 1.29-14.00), diabetes mellitus (HR, 2.47; 95% CI, 1.92-4.19), and 3 or more component cardiovascular risk factors (HR, 4.92; 95% CI, 1.39-17.4).



The MetS was associated with an increased incidence of MCI and progression to dementia. Identifying individuals with diabetes mellitus or the MetS with or without MCI is a promising approach in early interventions to prevent or slow progression to dementia.

title: Metabolic Syndrome and the Risk of Ischemic Stroke.
abstract: Metabolic syndrome (MetS) is recently proposed as a predictor for the occurrence of vascular defects causing ischemic stroke. However, details on the association of MetS with stroke are scare in our region. The present study aimed to assess the predictive value of MetS and its components for stoke among the Iranian population.



A longitudinal population-based study was conducted on adults aged 35 years or older who were living in 3 districts in central part of Iran and followed for 10 years. Stroke was diagnosed using World Health Organization guidelines, and MetS was defined according to the Adult Treatment Panel-III definition.



Among the 5398 subjects, 2021 suffered from MetS with an incidence of 37.4%. The incidence rates of stroke in those with and without MetS were 2.6% and 1.1%, respectively, with a higher significance in the former group (P = .026). Compared to the controls, participants with stroke exhibited a higher prevalence of some components of MetS including hyperglycemia and hypertension. On Cox proportional hazard analysis, the hazard ratio for a long-term risk of ischemic stroke was 1.37 overall (95% confidence interval: 1.15-1.63, P < .001) in subjects with MetS. Considering different components of MetS, hyperglycemia (hazard ratio = 1.83, P = .011) and hypertension (1.74, P = .019) could effectively predict occurrence of long-term ischemic stroke.



MetS and its main components can be potent predictors for long-term ischemic stroke. Thus, the focus should be on identification and appropriate control of MetS components to prevent stroke occurrence.

title: Metabolic Syndrome, Brain Magnetic Resonance Imaging, and Cognition
abstract: We explored cognitive impairment in metabolic syndrome in relation to brain magnetic resonance imaging (MRI) findings.  We studied 819 participants free of clinical stroke and dementia of the population-based Austrian Stroke Prevention Study who had undergone brain MRI, neuropsychological testing, and a risk factor assessment relevant to National Cholesterol Education Program Adult Treatment Panel III criteria–defined metabolic syndrome. High-sensitivity C-reactive protein (hs-CRP) was also determined.  Of 819 subjects, 232 (28.3%) had metabolic syndrome. They performed worse than those without metabolic syndrome on cognitive tests assessing memory and executive functioning after adjustment for possible confounders. Stratification by sex demonstrated that metabolic syndrome was related to cognitive dysfunction in men but not in women. Only in men was an increasing number of metabolic syndrome components associated with worse cognitive performance. MRI showed no significant differences in focal ischemic lesions and brain volume between subjects with and without metabolic syndrome, and MRI abnormalities failed to explain impaired cognition. Cognitive performance was most affected in male subjects with metabolic syndrome who also had high hs-CRP levels.  Metabolic syndrome exerts detrimental effects on memory and executive functioning in community-dwelling subjects who have not had a clinical stroke or do not have dementia. Men are more affected than women, particularly if they have high inflammatory markers. MRI-detected brain abnormalities do not play a crucial role in these relationships.

title: Microstructural Brain Tissue Damage in Metabolic Syndrome
abstract: We investigated the association between metabolic syndrome risk factors and brain tissue integrity, as assessed by magnetic resonance imaging.  From the Leiden Longevity Study, which is a community-based study of long-lived subjects, their offspring, and partners thereof, 130 subjects (61 men; mean age 66 years) were included. A metabolic syndrome score was computed by summing the individual number of components according to the Adult Treatment Panel III criteria. We performed linear and logistic regression analysis and used standardized β-values to assess the association between metabolic syndrome and brain macrostructure (brain volume and white matter lesion load, lacunar infarcts, and cerebral microbleeds) and microstructure (mean magnetization transfer ratio [MTR], MTR histogram peak height, fractional anisotropy, and mean diffusivity [MD]). Linear and stepwise regression analysis was performed to identify the individual contribution of one metabolic syndrome parameter adjusting for the four other parameters. Models were adjusted for age, sex, and relation to long-lived family.  Brain macrostructure was not associated with metabolic syndrome. In contrast, metabolic syndrome was associated with decreased gray (β = −0.3 P = 0.001) and white matter peak height (β = −0.3, P = 0.002) and increased gray matter MD (β = 0.2, P = 0.01, P = 0.01). Serum HDL cholesterol (β = 0.22, P = 0.012), triglycerides (β =−0.25, P = 0.002), BMI (β =−0.2, P = 0.014), and diastolic blood pressure (β = −0.17, P = 0.047, and β = −0.23, P = 0.009, for gray and white matter, respectively) were independent factors in these changes in brain microstructure.  In early manifest metabolic syndrome, brain tissue decline can be detected. Serum HDL cholesterol, triglycerides, BMI, and diastolic blood pressure were independent factors in brain tissue integrity.

title: Cognitive decline in metabolic syndrome is linked to microstructural white matter abnormalities
abstract: Subjects with metabolic syndrome (MetS) often show worse cognitive performance compared with the healthy population. We investigated whether microstructural white matter abnormalities are associated with cognitive performance in adults with MetS using diffusion tensor MR imaging. A total of 32 subjects with MetS (age 64.8 ± 7.8, 56.25 % female) and 23 age-, gender-, and education-matched healthy controls completed a battery of neuropsychological tests and diffusion tensor imaging (DTI) at 3-T MRI. Brain global and regional volumes, white matter fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (LD) were calculated. The least-square models adjusted for age, sex, HbA1c, hypertension, body mass index, hyperlipidemia, and white matter hyperintensities were used to evaluate the relationship between cognitive function and DTI. The MetS group had worse performance in verbal fluency (VF) and learning and memory function (total VF: T score (p = 0.01), VF: animals T score (p = 0.0001), Hopkins Verbal Learning Test (HVLT): Total recall T score (p = 0.0001), and HVLT: delayed recall T score (p = 0.002), as compared with controls. In the MetS group, abnormalities in diffusivity measures were associated with worse cognitive performance [VF: animals T score and left post-central gyrus-LD (p = 0.0007, radj 0.4), R angular gyrus-RD (p = 0.0008, radj 0.3), L supra-marginal gyrus-RD (p = 0.009, radj 0.2) after adjusting for age, sex, HbA1c, 24 h mean BP, presence of hyperlipidemia, and global white matter hyperintensities]. Microstructural white matter abnormalities in the MetS group might be the underlying mechanisms of worse verbal learning and memory performance.

title: Magnetization transfer MRI in dementia disorders, Huntington's disease and parkinsonism
abstract: Magnetic resonance imaging is the most used technique of neuroimaging. Using recent advances in magnetic resonance application it is possible to investigate several changes in neurodegenerative disease. Among different techniques, magnetization-transfer imaging (MTI), a magnetic resonance acquisition protocol assessing the magnetization exchange between protons bound to water and those bound to macromolecules, is able to identify microstructural brain tissue changes peculiar of neurodegenerative diseases. This review provides a report on the MTI technique and its use in the dementia disorders, Huntington's disease and parkinsonisms, comprehensive of the predictive values of MTI in the identification of early-phase disease.

title: Microstructural white matter changes in metabolic syndrome
abstract: Although metabolic syndrome is associated with cardiovascular disease and stroke, limited information is available on specific brain damage in patients with this syndrome. We investigated the relationship of the syndrome with white matter (WM) alteration using a voxel-based approach with diffusion tensor imaging (DTI).  We compared fractional anisotropy (FA) and apparent diffusion coefficient (ADC) measurements of DTI in 19 patients with metabolic syndrome aged between 50 and 80 years and 19 age-matched controls without any vascular risk factors for the syndrome.  Patients with metabolic syndrome showed an anterior–posterior pattern of deterioration in WM with reduced FA and increased ADC values compared with controls. WM changes were not related to any isolated vascular risk factor.  Although the mechanism of this damage is not clear, the results indicate microstructural white matter alterations in patients with metabolic syndrome, mainly involving the frontal lobe.

title: Effects of Insulin on Brain Glucose Metabolism in Impaired Glucose Tolerance
abstract: Insulin stimulates brain glucose metabolism, but this effect of insulin is already maximal at fasting concentrations in healthy subjects. It is not known whether insulin is able to stimulate glucose metabolism above fasting concentrations in patients with impaired glucose tolerance.  We studied the effects of insulin on brain glucose metabolism and cerebral blood flow in 13 patients with impaired glucose tolerance and nine healthy subjects using positron emission tomography (PET). All subjects underwent PET with both [18F]fluorodeoxyglucose (for brain glucose metabolism) and [15O]H2O (for cerebral blood flow) in two separate conditions (in the fasting state and during a euglycemic-hyperinsulinemic clamp). Arterial blood samples were acquired during the PET scans to allow fully quantitative modeling.  The hyperinsulinemic clamp increased brain glucose metabolism only in patients with impaired glucose tolerance (whole brain: +18%, P = 0.001) but not in healthy subjects (whole brain: +3.9%, P = 0.373). The hyperinsulinemic clamp did not alter cerebral blood flow in either group.  We found that insulin stimulates brain glucose metabolism at physiological postprandial levels in patients with impaired glucose tolerance but not in healthy subjects. These results suggest that insulin stimulation of brain glucose metabolism is maximal at fasting concentrations in healthy subjects but not in patients with impaired glucose tolerance.

title: Neuroimaging in vascular cognitive impairment: a state-of-the-art review
abstract: Imaging is critical in the diagnosis and treatment of dementia, particularly in vascular cognitive impairment, due to the visualization of ischemic and hemorrhagic injury of gray and white matter. Magnetic resonance imaging (MRI) and positron emission tomography (PET) provide structural and functional information. Clinical MRI is both generally available and versatile – T2-weighted images show infarcts, FLAIR shows white matter changes and lacunar infarcts, and susceptibility-weighted images reveal microbleeds. Diffusion MRI adds another dimension by showing graded damage to white matter, making it more sensitive to white matter injury than FLAIR. Regions of neuroinflammatory disruption of the blood–brain barrier with increased permeability can be quantified and visualized with dynamic contrast-enhanced MRI. PET shows metabolism of glucose and accumulation of amyloid and tau, which is useful in showing abnormal metabolism in Alzheimer’s disease. Combining MRI and PET allows identification of patients with mixed dementia, with MRI showing white matter injury and PET demonstrating regional impairment of glucose metabolism and deposition of amyloid. Excellent anatomical detail can be observed with 7.0-Tesla MRI. Imaging is the optimal method to follow the effect of treatments since changes in MRI scans are seen prior to those in cognition. This review describes the role of various imaging modalities in the diagnosis and treatment of vascular cognitive impairment.

title: Longitudinal Effects of Metabolic Syndrome on Alzheimer and Vascular Related Brain Pathology
abstract: This study examines the longitudinal effect of metabolic syndrome (MetS) on brain-aging indices among cognitively normal (CN) and amnestic mild cognitive impairment (aMCI) groups [single-domain aMCI (saMCI) and multiple-domain aMCI (maMCI)].  The study population included 739 participants (CN = 226, saMCI = 275, and maMCI = 238) from the Alzheimer's Disease Neuroimaging Initiative, a clinic-based, multi-center prospective cohort. Confirmatory factor analysis was employed to determine a MetS latent composite score using baseline data of vascular risk factors. We examined the changes of two Alzheimer's disease (AD) biomarkers, namely [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) regions of interest and medial temporal lobe volume over 5 years. A cerebrovascular aging index, cerebral white matter (cWM) volume, was examined as a comparison.  The vascular risk was similar in all groups. Applying generalized estimating equation modeling, all brain-aging indices declined significantly over time. Higher MetS scores were associated with a faster decline of cWM in the CN and maMCI groups but with a slower decrement of regional glucose metabolism in FDG-PET in the saMCI and maMCI groups.  At the very early stage of cognitive decline, the vascular burden such as MetS may be in parallel with or independent of AD pathology in contributing to cognitive impairment in terms of accelerating the disclosure of AD pathology.

title: Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement.
abstract: The metabolic syndrome has received increased attention in the past few years. This statement from the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) is intended to provide up-to-date guidance for professionals on the diagnosis and management of the metabolic syndrome in adults. The metabolic syndrome is a constellation of interrelated risk factors of metabolic origin—metabolic risk factors—that appear to directly promote the development of atherosclerotic cardiovascular disease (ASCVD).1 Patients with the metabolic syndrome also are at increased risk for developing type 2 diabetes mellitus. Another set of conditions, the underlying risk factors, give rise to the metabolic risk factors. In the past few years, several expert groups have attempted to set forth simple diagnostic criteria to be used in clinical practice to identify patients who manifest the multiple components of the metabolic syndrome. These criteria have varied somewhat in specific elements, but in general they include a combination of both underlying and metabolic risk factors. The most widely recognized of the metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose. Individuals with these characteristics commonly manifest a prothrombotic state and a proinflammatory state as well. Atherogenic dyslipidemia consists of an aggregation of lipoprotein abnormalities including elevated serum triglyceride and apolipoprotein B (apoB), increased small LDL particles, and a reduced level of HDL cholesterol (HDL-C). The metabolic syndrome is often referred to as if it were a discrete entity with a single cause. Available data suggest that it truly is a syndrome, ie, a grouping of ASCVD risk factors, but one that probably has more than one cause. Regardless of cause, the syndrome identifies individuals at an elevated risk for ASCVD. The magnitude of the increased risk can vary according to which components of the syndrome are present plus the other, non–metabolic syndrome risk factors in a particular person.

title: Advanced imaging in acute ischemic stroke.
abstract: The evaluation and management of acute ischemic stroke has primarily relied on the use of conventional CT and MRI techniques as well as lumen imaging sequences such as CT angiography (CTA) and MR angiography (MRA). Several newer or less-established imaging modalities, including vessel wall MRI, transcranial Doppler ultrasonography, and 4D CTA and MRA, are being developed to complement conventional CT and MRI techniques. Vessel wall MRI provides high-resolution analysis of both extracranial and intracranial vasculature to help identify previously occult lesions or characteristics of lesions that may portend a worse natural history. Transcranial Doppler ultrasonography can be used in the acute setting as a minimally invasive way of identifying large vessel occlusions or monitoring the response to stroke treatment. It can also be used to assist in the workup for cryptogenic stroke or to diagnose a patent foramen ovale. Four-dimensional CTA and MRA provide a less invasive alternative to digital subtraction angiography to determine the extent of the clot burden and the degree of collateral blood flow in large vessel occlusions. Along with technological advances, these new imaging modalities are improving the diagnosis, workup, and management of acute ischemic stroke- roles that will continue to expand in the future.

title: Metabolic syndrome and cerebral vasomotor reactivity
abstract: Metabolic syndrome has been proposed as a risk factor for stroke and transient ischaemic attack. One pathophysiological mechanism could be impairment of endothelial function. Thus, we hypothesized that cerebral vasomotor reactivity would be decreased in patients with metabolic syndrome, compared to patients without metabolic syndrome.

title: Transcranial Doppler ultrasonography: From methodology to major clinical applications.
abstract: Non-invasive Doppler ultrasonographic study of cerebral arteries [transcranial Doppler (TCD)] has been extensively applied on both outpatient and inpatient settings. It is performed placing a low-frequency (≤ 2 MHz) transducer on the scalp of the patient over specific acoustic windows, in order to visualize the intracranial arterial vessels and to evaluate the cerebral blood flow velocity and its alteration in many different conditions. Nowadays the most widespread indication for TCD in outpatient setting is the research of right to left shunting, responsable of so called "paradoxical embolism", most often due to patency of foramen ovale which is responsable of the majority of cryptogenic strokes occuring in patients younger than 55 years old. TCD also allows to classify the grade of severity of such shunts using the so called "microembolic signal grading score". In addition TCD has found many useful applications in neurocritical care practice. It is useful on both adults and children for day-to-day bedside assessment of critical conditions including vasospasm in subarachnoidal haemorrhage (caused by aneurysm rupture or traumatic injury), traumatic brain injury, brain stem death. It is used also to evaluate cerebral hemodynamic changes after stroke. It also allows to investigate cerebral pressure autoregulation and for the clinical evaluation of cerebral autoregulatory reserve.

title: Lifestyle modification for metabolic syndrome: a systematic review.
abstract: All 5 components of metabolic syndrome have been shown to improve with lifestyle and diet modification. New strategies for achieving adherence to meaningful lifestyle change are needed to optimize atherosclerotic cardiovascular risk reduction. We performed a systematic literature review, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework (PRISMA), investigating optimal methods for achieving lifestyle change in metabolic syndrome.



We submitted standardized search terms to the PubMed Central, CINAHL, Web of Science, and Ovid databases. Within those results, we selected randomized controlled trials (RCTs) presenting unique methods of achieving lifestyle change in patients with one or more components of the metabolic syndrome. Data extraction using the population, intervention, comparator, outcome, and risk of bias framework (PICO) was used to compare the following endpoints: prevalence of metabolic syndrome, prevalence of individual metabolic syndrome components, mean number of metabolic syndrome components, and amount of weight loss achieved.



Twenty-eight RCTs (6372 patients) were included. Eight RCTs demonstrated improvement in metabolic syndrome risk factors after 1 year. Team-based, interactive approaches with high-frequency contact with patients who are motivated made the largest and most lasting impact. Technology was found to be a useful tool in achieving lifestyle change, but ineffective when compared with personal contact.



Patient motivation leading to improved lifestyle adherence is a key factor in achieving reduction in metabolic syndrome components. These elements can be enhanced via frequent encounters with the health care system. Use of technologies such as mobile and Internet-based communication can increase the effectiveness of lifestyle change in metabolic syndrome, but should not replace personal contact as the cornerstone of therapy. Our ability to derive quantitative conclusions is limited by inconsistent outcome measures across studies, low power and homogeneity of individual studies, largely motivated study populations, short follow-up periods, loss to follow-up, and lack of or incomplete blinding.

title: The Effects of Ezetimibe/Simvastatin versus Simvastatin Monotherapy on Platelet and Inflammatory Biomarkers in Patients with Metabolic Syndrome
abstract: In a randomized, double-blind, crossover study of 15 aspirin-naive patients (mean age 48.8 ± 10.2 years) with the metabolic syndrome, statin monotherapy (simvastatin 40 mg daily) was compared to combination therapy (simvastatin 40 mg and ezetimibe 10 mg daily) on biomarkers of inflammation and platelet activity. The addition of ezetimibe to simvastatin over a 4-week period was associated with reduced expression of CD141 (thrombomodulin; p = 0.02), platelet endothelial cell adhesion molecule (p < 0.0001) and CD51/61 (vitronectin receptor; p = 0.048) compared to statin monotherapy. Ezetimibe added to simvastatin improves several indices of platelet reactivity beyond statin monotherapy. However, the clinical relevance of these findings await results of the IMPROVE-IT trial (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

title: Combination therapy with statin and fibrate in patients with dyslipidemia associated with insulin resistance, metabolic syndrome and type 2 diabetes mellitus
abstract: People with insulin resistance/metabolic syndrome (IR/MS) and/or type 2 diabetes mellitus (T2DM) have increased rates of cardiovascular disease (CVD) even when low-density lipoprotein cholesterol levels are at or near target levels. Contributors to this problem are the high triglyceride (TG) levels and low levels of high-density lipoprotein cholesterol (HDLC) that are commonly present in this population, even with statin therapy.  This review focuses on the use of a combination of statins with fibrates, which lower TG and raise HDLC concentrations and, therefore, have the potential to further lower rates of CVD more in people with IR/MS and/or T2DM. Treatment with this combination is uncommon because doctors and patients are fearful of muscle, liver and renal complications and because the evidence that the combination will actually reduce risk has been lacking. In this review, the authors examine the efficacy and safety of the statin–fibrate combination, particularly fenofibrate and simvastatin, the combination used in the ACCORD trial.  The authors' opinion is that this combination of fenofibrate and statin is as safe as either drug alone and, in patients with significant dyslipidemia, is likely to reduce CVD. Concerns remain concerning fenofibrate-associated increases in serum creatinine levels and the significant heterogeneity in the reduction in CVD by the combination in women. A trial of statin + fenofibrate in people with IR/MS and/or T2DM who also have significant dyslipidemia is needed.

title: Angiotensin receptor blockade increases pancreatic insulin secretion and decreases glucose intolerance during glucose supplementation in a model of metabolic syndrome.
abstract: Renin-angiotensin system blockade improves glucose intolerance and insulin resistance, which contribute to the development of metabolic syndrome. However, the contribution of impaired insulin secretion to the pathogenesis of metabolic syndrome is not well defined. To assess the contributions of angiotensin receptor type 1 (AT₁) activation and high glucose intake on pancreatic function and their effects on insulin signaling in skeletal muscle and adipose tissue, an oral glucose tolerance test (oGTT) was performed in five groups (n = 10/group) of rats: 1) lean strain-control 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg/kg · d olmesartan for 6 wk; OLETF ARB), 4) OLETF + 5% glucose water (HG) for 6 wk (OLETF HG), and 5) OLETF + HG + ARB (OLETF HG/ARB). The glucose response to the oGTT increased 58% in OLETF compared with lean-strain control, whereas glucose supplementation increased it an additional 26%. Blockade of angiotensin receptor reduced the oGTT response 19% in the ARB-treated groups and increased pancreatic insulin secretion 64 and 113% in OLETF ARB and OLETF HG/ARB, respectively. ARB treatment in OLETF ARB and OLETF HG/ARB did not have an effect on insulin signaling proteins in skeletal muscle; however, it reduced pancreatic AT₁ protein expression 20 and 27%, increased pancreatic glucagon-like peptide-1 (GLP-1) receptor protein expression 41 and 88%, respectively, and increased fasting plasma GLP-1 approximately 2.5-fold in OLETF ARB. The results suggest that improvement of glucose intolerance is independent of an improvement in muscle insulin signaling, but rather by improved glucose-stimulated insulin secretion associated with decreased pancreatic AT₁ activation and increased GLP-1 signaling.

title: Effect of Renin-Angiotensin system inhibition on cardiovascular events in older hypertensive patients with metabolic syndrome.
abstract: Metabolic syndrome (MetS) is associated with cardiovascular disease (CVD). Insulin resistance has been hypothesized as the underlying feature of MetS. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are widely used antihypertensives that may improve insulin sensitivity. The aim of the study is to evaluate the effect of ACEI/ARB on incident CVD events in older hypertensive patients with MetS.



We used the Cardiovascular Health Study, a prospective cohort study of individuals>65years of age to evaluate ACEI/ARB use and time to CVD events (including coronary and cerebrovascular events). The study included 777 subjects who had hypertension and ATP III-defined MetS, but free of CVD and diabetes at baseline. Cox regression models were used to evaluate the effect of ACEI/ARB as compared to other antihypertensives on the time to the first CVD events.



ACEI/ARB use was associated with a decreased risk of CVD events (adjusted HR=0.658, 95 % C.I. [0.436-0.993]) compared to other antihypertensives. When CVD endpoints were evaluated separately, use of ACEI/ARB was associated with lower rates of angioplasty and coronary events (HR of 0.129 and 0.530 respectively, with 95 % CI [0.017-0.952] and [0.321-0.875]).



ACEI/ARB use was associated with a lower risk of CVD events in older hypertensive patients with MetS, primarily due to a reduction in coronary events. The potential protective effect of ACEI/ARB on CVD events in older individuals with MetS will need further confirmation from prospective studies.

title: Metabolic syndrome.
abstract: Metabolic syndrome is not a disease per se, but is a term that highlights traits that may have an increased risk of disease, approximately 2-fold for cardiovascular disease and 5-fold or more for type 2 diabetes mellitus. Obesity and insulin resistance are believed to be at the core of most cases of metabolic syndrome, although further research is required to truly understand the pathophysiology behind the syndrome and the gene-environment interactions that increase susceptibility. The mainstay of treatment remains lifestyle changes with exercise and diet to induce weight loss and pharmacologic intervention to treat atherogenic dyslipidemia, hypertension, and hyperglycemia.