bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-Wide Association Study of Genetic Predictors of Overall Survival for Non–Small Cell Lung Cancer in Never Smokers
Authors: Wu Xifeng , Wang Liang , Ye Yuanqing , Aakre Jeremiah A. , Pu Xia , Chang Gee-Chen , Yang Pan-Chyr , Roth Jack A. , Marks Randolph S. , Lippman Scott M. , Chang Joe Y. , Lu Charles , Deschamps Claude , Su Wu-Chou , Wang Wen-Chang , Huang Ming-Shyan , Chang David W. , Li Yan , Pankratz V. Shane , Minna John D. , Hong Waun Ki , Hildebrandt Michelle A.T. , Hsiung Chao Agnes , Yang Ping
Published: May 2013

To identify the genetic factors that influence overall survival in never smokers who have non–small cell lung carcinoma (NSCLC), we conducted a consistency meta-analysis study using genome-wide association approaches for overall survival in 327 never smoker patients with NSCLC from The University of Texas MD Anderson Cancer Center (Houston, TX) and 293 cases from the Mayo Clinic (Rochester, MN). We then conducted a two-pronged validation of the top 25 variants that included additional validation in 1,256 patients with NSCLC from Taiwan and assessment of expression quantitative trait loci (eQTL) and differential expression of genes surrounding the top loci in 70 tumors and matched normal tissues. A total of 94 loci were significant for overall survival in both MD Anderson and Mayo studies in the consistency meta-analysis phase, with the top 25 variants reaching a P value of 10−6. Two variants of these 25 were also significant in the Taiwanese population: rs6901416 [HR, 1.44; 95% confidence interval (CI), 1.01–2.06] and rs10766739 (HR, 1.23; 95%CI, 1.00–1.51). These loci resulted in a reduction of median survival time of at least eight and five months in three populations, respectively. An additional six variants (rs4237904, rs7976914, rs4970833, rs954785, rs485411, and rs10906104) were validated through eQTL analysis that identified significant correlations with expression levels of six genes (LEMD3, TMBIM, ATXN7L2, SHE, ITIH2, and NUDT5, respectively) in normal lung tissue. These genes were also significantly differentially expressed between the tumor and normal lung tissue. These findings identify several novel, candidate prognostic markers for NSCLC in never smokers, with eQTL analysis suggesting a potential biologic mechanism for a subset of these observed associations. Cancer Res; 73(13); 4028–38. ©2013 AACR.
Membrane versus Soluble Isoforms of TNF-α Exert Opposing Effects on Tumor Growth and Survival of Tumor-Associated Myeloid Cells
Authors: Ardestani Shidrokh , Li Bin , Deskins Desirae L. , Wu Huiyun , Massion Pierre P. , Young Pampee P.
Published: May 2013

TNF-α, produced by most malignant cells, orchestrates the interplay between malignant cells and myeloid cells, which have been linked to tumor growth and metastasis. Although TNF-α can exist as one of two isoforms, a 26-kDa membrane tethered form (mTNF-α) or a soluble 17-kDa cytokine (sTNF-α), the vast majority of published studies have only investigated the biologic effects of the soluble form. We show for the first time that membrane and soluble isoforms have diametrically opposing effects on both tumor growth and myeloid content. Mouse lung and melanoma tumor lines expressing mTNF-α generated small tumors devoid of monocytes versus respective control lines or lines expressing sTNF-α. The lack of myeloid cells was due to a direct effect of mTNF-α on myeloid survival via induction of cell necrosis by increasing reactive oxygen species. Human non–small cell lung carcinoma expressed varying levels of both soluble and membrane TNF-α, and gene expression patterns favoring mTNF-α were predictive of improved lung cancer survival. These data suggest that there are significant differences in the role of different TNF-α isoforms in tumor progression and the bioavailability of each isoform may distinctly regulate tumor progression. This insight is critical for effective intervention in cancer therapy with the available TNF-α inhibitors, which can block both TNF-α isoforms. Cancer Res; 73(13); 3938–50. ©2013 AACR.
Erythrocyte Membrane Phospholipid Fatty Acid Concentrations and Risk of Colorectal Adenomas: A Case–Control Nested in the French E3N-EPIC Cohort Study
Authors: Cottet Vanessa , Collin Mélanie , Gross Anne-Sophie , Boutron-Ruault Marie-Christine , Morois Sophie , Clavel-Chapelon Françoise , Chajès Véronique
Published: May 2013

Background: Although dietary fatty acids may influence colorectal carcinogenesis, few studies have examined the association with adenoma risk. We assessed the association between biomarkers of dietary fatty acids or metabolism of fatty acids and the risk of colorectal adenomas in a nested case–control study from the French E3N-EPIC cohort.

Methods: Among 13,106 women without prevalent cancer who completed the diet history questionnaire and who provided blood samples, 328 cases of adenomatous polyp were identified during an average of 6.6-year follow-up and randomly matched to 619 polyp-free colonoscopy controls. Erythrocyte membrane phospholipid fatty acid concentrations were determined by gas chromatography. Adjusted ORs for risk of colorectal adenomas with increasing concentrations of fatty acids were calculated using conditional logistic regression, separately for advanced and nonadvanced adenomas.

Results: Associations were stronger with advanced than nonadvanced adenomas. High concentration of pentadecanoate plus heptadecanoate acids were inversely associated with the risk of advanced adenomas [highest vs. lowest tertile: ORT3vsT1 = 0.40 (95% confidence interval (CI) 0.20–0.79); Ptrend = 0.009]. Oleic acid was associated with an increased risk of advanced adenomas [ORT3vsT1 = 2.32 (1.16–4.64); Ptrend = 0.018]. Some polyunsaturated fatty acids were associated with the risk of advanced adenomas, either positively for di-homo-γ-linolenate [ORT3vsT1 = 2.07 (1.15–3.72); Ptrend = 0.013], or negatively for eicosapentaenoic and docosahexaenoic acids [ORT3vsT1 = 0.50 (0.27–0.93); Ptrend = 0.044 and ORT3vsT1 = 0.50 (0.26–0.96); Ptrend = 0.028, respectively].

Conclusion: A specific erythrocyte membrane phospholipid fatty acid profile, presumably reflecting both a complex dietary pattern and altered fatty acid metabolism, is associated with advanced colorectal adenoma risk.

Impact: Adenomas could be a target for primary prevention of colorectal cancer, using interventional strategy based on lipidomic profile of patients. Cancer Epidemiol Biomarkers Prev; 22(8); 1417–27. ©2013 AACR.
Gastric Reflux Is an Independent Risk Factor for Laryngopharyngeal Carcinoma
Authors: Langevin Scott M. , Michaud Dominique S. , Marsit Carmen J. , Nelson Heather H. , Birnbaum Ariel E. , Eliot Melissa , Christensen Brock C. , McClean Michael D. , Kelsey Karl T.
Published: May 2013

Background: Gastric reflux can reach into the upper airway, inducing cellular damage in the epithelial lining. This condition is believed to be a risk factor for development of laryngopharyngeal squamous cell carcinoma (LPSCC), although the literature is conflicting.

Methods: To better clarify this relationship, we assessed the association of self-reported heartburn history and medication use among 631 patients with LPSCCs and 1234 control subjects (frequency-matched on age, gender, and town of residence) enrolled as part of a population-based case–control study of head and neck squamous cell carcinoma in the greater Boston area.

Results: After adjusting for age, gender, race, smoking, alcohol consumption, HPV16 seropositivity, education, and body mass index, subjects reporting a history of frequent heartburn and who were neither a heavy smoker nor heavy drinker had a significantly elevated risk of LPSCCs [OR, 1.78; 95% confidence interval (CI), 1.00–3.16]. Among those with a history of heartburn, there was an inverse association between antacid use and LPSCCs relative to those never taking heartburn medication (OR, 0.59; 95% CI, 0.38–0.93) that remained consistent when analyzed by smoking/drinking status, HPV16 status, or by primary tumor site.

Conclusions: Our data show that gastric reflux is an independent risk factor for squamous cancers of the pharynx and larynx. Further studies are needed to clarify the possible chemopreventive role of antacid use for patients with gastric reflux.

Impact: Elucidation of additional risk factors for head and neck cancer can allow for risk stratification and inform surveillance of high-risk patients. Cancer Epidemiol Biomarkers Prev; 22(6); 1061–8. ©2013 AACR.
Heart Rate Variability and Extubation Readiness in Extremely Preterm Infants
Authors: Kaczmarek Jennifer , Chawla Sanjay , Marchica Cinzia , Dwaihy Meghan , Grundy Linda , Sant'Anna Guilherme Mendes
Published: May 2013

Background: Mechanical ventilation (MV) is associated with changes in autonomic nervous system activity in preterm infants, which can be assessed by measurements of heart rate variability (HRV). Decreased HRV has been described in adults undergoing disconnection from MV; such information is not available in preterm infants. Objective: To compare differences in HRV between infants successfully extubated and those who failed, and to evaluate the accuracy of HRV as a predictor of extubation readiness. Methods: This is a prospective, observational study of infants with a birth weight ≤1,250 g undergoing their first extubation attempt. Heart rate was measured during a 60-min period immediately prior to extubation and HRV was calculated using the frequency domain analysis. Results: A total of 47 infants were studied; 36 were successfully extubated and 11 reintubated. There were no differences in patient demographics, ventilator settings, blood gases or postextubation management between the groups. All components of the HRV analysis were significantly decreased in infants who failed, generating high areas under the receiver operating characteristic curve. The specificity and positive predictive values were 100, but with limited sensitivity and negative predictive values. Conclusions: Infants considered ‘ready to be extubated' but who subsequently failed their first extubation attempt had decreased HRV prior to extubation. Though promising, the value of HRV as a predictor of extubation readiness requires further evaluation.
QRS Prolongation in the Prediction of Clinical Cardiac Events in Patients with Acute Heart Failure: Analysis of Data from the Korean Acute Heart Failure Registry
Authors: Park Hyoung-Seob , Kim Hyungseop , Park Jae-Hyeong , Han Seongwoo , Yoo Byung-Su , Shin Mi-Seung , Seong In-Whan , Ahn Youngkeun , Kang Seok-Min , Kim Jae-Joong , Jeon Eun-Seok , Cho Myeong-Chan , Choi Dong-Ju , Chae Shung Chull , Kim Yung-Jo , Seo Hong-Seog , Oh Byung-Hee , Lee Myung-Mook , Ryu Kyu-Hyung ,   on behalf of the Korean Acute Heart Failure Registry
Published: May 2013

Objectives: A prolonged QRS duration has been associated with an unfavorable prognosis in chronic compensated heart failure (HF). However, its predictive value during an admission for acute HF is limited, even in HF with a preserved ejection fraction (EF). The purpose of this study was to evaluate the prognostic utility of the QRS duration in acute HF. Methods: Analyses were performed using data from 1,489 patients with a 2-year follow-up. The patients were selected from the Korean Acute Heart Failure Registry and were divided into three groups according to QRS duration (≤80, 81-119 or ≥120 ms). The all-cause mortality and readmission for HF were assessed. Results: During the study period, 774 primary events occurred (359 deaths and 415 HF). The event frequencies were higher in patients with a prolonged QRS duration. The increased risk associated with the QRS duration was also demonstrated after adjustment for cardiac outcome variables. The prognostic significance of the QRS duration was demonstrated in patients with reduced EF but not in those with a preserved EF. Conclusions: A prolonged QRS duration could be a significant predictor of the 2-year cardiac outcome in patients with acute HF, particularly in those with a reduced EF.
Secondary Mitral Regurgitation in Heart Failure with Reduced or Preserved Left Ventricular Ejection Fraction
Authors: Ennezat Pierre Vladimir , Maréchaux Sylvestre , Pibarot Philippe , Le Jemtel Thierry H.
Published: May 2013

Secondary mitral regurgitation (MR) has been extensively studied in heart failure due to reduced ejection fraction. In contrast, the occurrence and the pathogenesis of secondary MR are much less known in heart failure with preserved ejection fraction (HFpEF). The present review aimed at describing this common but ignored feature of HFpEF.
Short-Term Neonatal Outcome among Term Infants after in utero Exposure to Serotonin Reuptake Inhibitors
Authors: Leibovitch Leah , Rymer-Haskel Noa , Schushan-Eisen Irit , Kuint Jacob , Strauss Tzipora , Maayan-Metzger Ayala
Published: May 2013

Background: Serotonin reuptake inhibitor (SRI) medications are commonly in use during pregnancy. Objectives: To evaluate short-term neonatal clinical signs among infants exposed to intrauterine SRI medications, in order to estimate the need for postnatal monitoring and observation. Methods: Retrospective review of clinical data in medical files of term infants born to mothers who reported treatment with SRIs during pregnancy. Results: Out of 401 infants in the study group, 165 (41%) were reported to have at least 1 clinical symptom, including respiratory distress, jitteriness, restlessness, feeding difficulties, regurgitations, fever ≥38°C, a short cyanotic event and convulsions. In the symptomatic group, 70% exhibited mild symptoms, among them restlessness, jitteriness or feeding difficulties, while around 30% exhibited significant symptoms. Overall, 12% of the total cohort, mostly males (70%), presented significant clinical symptoms, but none had an urgent or life-threatening condition. Infants in the study group were shorter in length and had a higher rate of Apgar score <7 at 1 min, meconium-stained amniotic fluid and respiratory distress. Conclusions: Despite the high incidence of clinical signs among infants born to SRI-treated mothers, most of their symptoms were mild and self-limited. These infants should be observed while they are close to their mothers on the maternity ward for 48 h after birth.
Repeated Intrauterine Exposures to Inflammatory Stimuli Attenuated Transforming Growth Factor-β Signaling in the Ovine Fetal Lung
Authors: Collins Jennifer J.P. , Kallapur Suhas G. , Knox Christine L. , Kemp Matthew W. , Kuypers Elke , Zimmermann Luc J.I. , Newnham John P. , Jobe Alan H. , Kramer Boris W.
Published: May 2013

Background: Bronchopulmonary dysplasia (BPD) is one of the most common complications after preterm birth and is associated with intrauterine exposure to bacteria. Transforming growth factor-β (TGFβ) is implicated in the development of BPD. Objectives: We hypothesized that different and/or multiple bacterial signals could elicit divergent TGFβ signaling responses in the developing lung. Methods: Time-mated pregnant Merino ewes received an intra-amniotic injection of lipopolysaccharide (LPS) and/or Ureaplasma parvum serovar 3 (UP) at 117 days' and/or 121/122 days' gestational age (GA). Controls received an equivalent injection of saline and or media. Lambs were euthanized at 124 days' GA (term = 150 days' GA). TGFβ1, TGFβ2, TGFβ3, TGFβ receptor (R)1 and TGFβR2 protein levels, Smad2 phosphorylation and elastin deposition were evaluated in lung tissue. Results: Total TGFβ1 and TGFβ2 decreased by 24 and 51% after combined UP+LPS exposure, whereas total TGFβ1 increased by 31% after 7 days' LPS exposure but not after double exposures. Alveolar expression of TGFβR2 decreased 75% after UP, but remained unaltered after double exposures. Decreased focal elastin deposition after single LPS exposure was prevented by double exposures. Conclusions: TGFβ signaling components and elastin responded differently to intrauterine LPS and UP exposure. Multiple bacterial exposures attenuated TGFβ signaling and normalized elastin deposition.
Menopausal Symptoms after the Discontinuation of Long-Term Hormone Replacement Therapy in Women under 60: A 3-Year Follow-Up
Authors: Perrone Giuseppina , Capri Oriana , Galoppi Paola , Patacchioli Francesca R. , Bevilacqua Elisa , de Stefano Maria G. , Brunelli Roberto
Published: May 2013

Background: Prescriptions for hormone replacement therapy (HRT) declined following the publication of the Women's Health Initiative study. The number of women who experience recurrence of menopausal symptoms after discontinuation of long-term HRT (LT-HRT), the length of time these symptoms last and the preferred alternative treatments remain unknown. Methods: This prospective 3-year follow-up study analyses the prevalence and intensity of menopausal symptoms that occur in young postmenopausal women who discontinued LT-HRT. Symptoms were evaluated using the Menopause Rating Scale. Results: Women (254) who discontinued LT-HRT (mean use: 6.9 ± 2.3 years) were recruited. Mean age at menopause was 48.1 ± 3.4 years. Mean age at discontinuation was 56.8 ± 3.7 years. 23% of the women were lost to follow-up. Of the remaining 196 women, 93% experienced a recurrence of menopausal symptoms within the first year, 25% resumed low-dose HRT, 62% used vaginal estrogens, 54% used phytoestrogens, and 2% used alternative therapies. A decrease in symptom prevalence and intensity was observed during the 3-year follow-up. Conclusions: Symptoms re-appeared in a significant proportion of patients within the first year after discontinuation of LT-HRT. However, after 3 years, the majority of these women were asymptomatic. Patients who discontinue LT-HRT may require a more detailed follow-up immediately after the discontinuation of treatment.
Which Social Network or Support Factors are Associated with Cognitive Abilities in Old Age?
Authors: Gow Alan J. , Corley Janie , Starr John M. , Deary Ian J.
Published: May 2013

Background: Social networks and support have been proposed as cognitively protective in old age. As studies often consider these social factors in isolation the question of which characteristics of the social environment are beneficial remains. Objective: The current study examined associations between measures of social networks (including contact with friends/family, marital status and living arrangement), feelings of loneliness and social support, and a range of cognitive outcomes. Methods: Social network, loneliness and support data were available in the Lothian Birth Cohort 1936 (LBC1936, n = 1,091) at age 70. Participants completed a battery of cognitive tests, and factor scores were available for general cognitive ability, and the cognitive domains of processing speed and memory. Childhood cognitive ability data from age 11 were also available. Results: When examined in separate ANCOVAs, lower loneliness and more social support were significantly associated with better cognitive abilities at age 70, though not memory (independently of age, sex, childhood cognitive ability and social class), accounting for about 0.5-1.5% of the variance. When the social factors were considered simultaneously, higher loneliness remained associated with lower general cognitive ability (ηp2 = 0.005, p = 0.046), and those living alone (ηp2 = 0.007, p = 0.014) or with less social support (ηp2 = 0.007, p = 0.016) had slower processing speed. When these final models were repeated including a depression symptoms score as a covariate, the associations between loneliness and general cognitive ability, and social support and processing speed, were no longer significant. However, the association between living alone and processing speed remained (ηp2 = 0.006, p = 0.031). Conclusions: Of the social factors considered, loneliness, social support and living arrangement were most consistently associated with aspects of cognitive ability in older people, and these associations appeared to be partly, though not wholly, accounted for by symptoms of depression. Although longitudinal follow-up is required to examine the causal direction of the effects more definitively, it may be beneficial to promote the development of interventions to reduce loneliness and social isolation, and to increase social support.
Genetic variation of platelet function and pharmacology: An update of current knowledge
Authors: Schaeffeler Elke , Schaeffeler Elke , Gawaz Meinrad , Schwab Matthias , Geisler Tobias
Published: May 2013

Platelets are critically involved in atherosclerosis and acute thrombosis. The platelet phenotype shows a wide variability documented by the inherited difference of platelet reactivity, platelet volume and count and function of platelet surface receptors. Several candidate genes have been put into focus and investigated for their functional and prognostic role in healthy individuals and patients with cardiovascular (CV) disease treated with antiplatelet agents. In addition to genetic variation, other clinical, disease-related and demographic factors are important so-called non-genetic factors. Due to the small effect sizes of single nucleotide polymorphisms (SNP) in candidate genes and due to the low allele frequencies of functional relevant candidate SNPs, the identification of genetic risk factors with high predictive values generally depends on the sample size of study cohorts. In the post-genome era new array and bioinformatic technologies facilitate high throughput genome-wide association studies (GWAS) for the identification of novel candidate genes in large cardiovascular cohorts. One of the crucial aspects of platelet genomic studies is the precise definition of a specific clinical phenotype (e.g. stent thrombosis) as this will impact importantly the findings of genomic studies like GWAS. Here, we provide an update on genetic variation of platelet receptors and drug metabolising enzymes under specific consideration of data derived by GWAS. The potential impact of this information and the role in personalised therapeutic concepts will be discussed.
Circulating Blood Endothelial Nitric Oxide Synthase Contributes to the Regulation of Systemic Blood Pressure and Nitrite Homeostasis
Authors: Wood Katherine C. , Cortese-Krott Miriam M. , Kovacic Jason C. , Noguchi Audrey , Liu Virginia B. , Wang Xunde , Raghavachari Nalini , Boehm Manfred , Kato Gregory J. , Kelm Malte , Gladwin Mark T.
Published: May 2013

Objective—

Mice genetically deficient in endothelial nitric oxide synthase (eNOS
−/−
) are hypertensive with lower circulating nitrite levels, indicating the importance of constitutively produced nitric oxide (NO•) to blood pressure regulation and vascular homeostasis. Although the current paradigm holds that this bioactivity derives specifically from the expression of eNOS in endothelium, circulating blood cells also express eNOS protein. A functional red cell eNOS that modulates vascular NO• signaling has been proposed.

Approach and Results—

To test the hypothesis that blood cells contribute to mammalian blood pressure regulation via eNOS-dependent NO• generation, we cross-transplanted wild-type and eNOS
−/−
mice, producing chimeras competent or deficient for eNOS expression in circulating blood cells. Surprisingly, we observed a significant contribution of both endothelial and circulating blood cell eNOS to blood pressure and systemic nitrite levels, the latter being a major component of the circulating NO• reservoir. These effects were abolished by the NOS inhibitor L-NG-nitroarginine methyl ester and repristinated by the NOS substrate
l
-arginine and were independent of platelet or leukocyte depletion. Mouse erythrocytes were also found to carry an eNOS protein and convert
14
C-arginine into
14
C-citrulline in NOS-dependent fashion.

Conclusions—

These are the first studies to definitively establish a role for a blood-borne eNOS, using cross-transplant chimera models, that contributes to the regulation of blood pressure and nitrite homeostasis. This work provides evidence suggesting that erythrocyte eNOS may mediate this effect.
Risk Stratification and Transplant Benefit in Children Listed for Heart Transplant in the United States
Authors: Singh Tajinder P. , Almond Christopher S. , Piercey Gary , Gauvreau Kimberlee
Published: May 2013

Background—

The sickest children among those listed for heart transplant (HT) are also at higher risk of post-transplant mortality. We hypothesized that transplant benefit, defined as percentage reduction in risk of 1-year mortality on receiving HT, increases with higher risk of wait-list mortality.

Methods and Results—

We analyzed all children aged <18 years listed for first HT in the United States between July 2004 and December 2010. We developed a model for 90-day wait-list mortality (or removal because of deterioration) and stratified listed children into deciles based on their risk of wait-list mortality. Listed children were followed up for 1 year to assess cumulative 1-year wait-list mortality among the 10 risk groups. We developed a model for 1-year post-transplant mortality to estimate the risk of post-transplant mortality for children in each risk group. Of 2979 listed children, 15% reached the wait-list end point within 90 days and 18% within 1 year. Of 2034 HT recipients, 6.8% died within 90 days and 10.8% within 1 year. The risk of 90-day wait-list mortality increased progressively from 2.4% to 51.6% from the first to the tenth risk decile. Transplant benefit increased progressively across the wait-list risk groups (
P
<0.001 for trend). However, transplant benefit for children in the top 5% of risk (7.4%) was lower than that for children in the 91st to 95th percentile of risk (10.3%).

Conclusions—

Sicker children on the wait-list benefit more from HT unless the post-transplant mortality is predicted to be very high. Whether consideration of transplant benefit in allocation policy can improve overall survival among listed children requires further analysis.
South Asians Have Elevated Postexercise Blood Pressure and Myocardial Oxygen Consumption Compared to Europeans Despite Equivalent Resting Pressure
Authors: Chaturvedi Nish , Bathula Rajaram , Shore Angela C. , Panerai Ronney , Potter John , Kooner Jaspal , Chambers John , Hughes Alun D.
Published: May 2013

Background

Stroke mortality rate is higher in South Asians than in Europeans, despite equivalent or lower resting blood pressure (BP). Elevated recovery BP after exercise predicts stroke, independently of resting values. We hypothesized that South Asians would have adverse postexercise hemodynamics and sought explanations for this.

Methods and Results

A population‐based sample of 147 European and 145 South Asian middle‐aged men and women performed the Dundee 3‐minute step test. Cardiovascular risk factors were measured. BP, heart rate, and rate–pressure product, a measure of myocardial oxygen consumption, were compared. With 90% power and 5% significance, we could detect a difference of 0.38 of a standard deviation in any outcome measure. Resting systolic BP was similar in South Asians (144 mm Hg) and Europeans (142 mm Hg) (
P
=0.2), as was exercise BP (
P
=0.4). However, recovery systolic BP at 3 minutes after exercise was higher in South Asians by 4.3 mm Hg (95% confidence interval [CI], 0.2 to 8.3 mm Hg;
P
=0.04). This effect persisted when adjusted for exercise BP and work effort (5.4 mm Hg [95% CI, 2.2 to 8.7 mm Hg;
P
=0.001]). Adjustment for baroreflex insensitivity and greater aortic stiffness in South Asians contributes greatly to attenuating this ethnic difference (1.9 mm Hg [95% CI, −0.9 to 4.6 mm Hg;
P
=0.4]). Similarly, rate–pressure product recovery after exercise was impaired in South Asians by 735 mm Hg/min (95% CI, 137 to 1334 mm Hg/min;
P
=0.02); again, adjustment for baroreflex insensitivity and aortic stiffness attenuated this difference (261 mm Hg/min [95% CI, −39 to 561 mm Hg/min;
P
=0.3]).

Conclusion

Postexercise recovery of BP and rate–pressure product is impaired in South Asians compared to Europeans even though resting and exercise BP are similar. This is associated with the autonomic dysfunction and aortic stiffness in South Asians.

(
J Am Heart Assoc
. 2012;1:e000281 doi

:
10.1161/JAHA.111.000281
.)
Aldosterone Increases Early Atherosclerosis and Promotes Plaque Inflammation Through a Placental Growth Factor‐Dependent Mechanism
Authors: McGraw Adam P. , Bagley Jessamyn , Chen Wei‐Sheng , Galayda Carol , Nickerson Heather , Armani Andrea , Caprio Massimiliano , Carmeliet Peter , Jaffe Iris Z.
Published: May 2013

Background

Aldosterone levels correlate with the incidence of myocardial infarction and mortality in cardiovascular patients. Aldosterone promotes atherosclerosis in animal models, but the mechanisms are poorly understood.

Methods and Results

Aldosterone was infused to achieve pathologically relevant levels that did not increase blood pressure in the atherosclerosis‐prone apolipoprotein E–knockout mouse (ApoE−/−). Aldosterone increased atherosclerosis in the aortic root 1.8±0.1‐fold after 4 weeks and in the aortic arch 3.7±0.2‐fold after 8 weeks, without significantly affecting plaque size in the abdominal aorta or traditional cardiac risk factors. Aldosterone treatment increased lipid content of plaques (2.1±0.2‐fold) and inflammatory cell content (2.2±0.3‐fold), induced early T‐cell (2.9±0.3‐fold) and monocyte (2.3±0.3‐fold) infiltration into atherosclerosis‐prone vascular regions, and enhanced systemic inflammation with increased spleen weight (1.52±0.06‐fold) and the circulating cytokine
RANTES
(regulated and normal T cell secreted; 1.6±0.1‐fold). To explore the mechanism, 7 genes were examined for aldosterone regulation in the ApoE−/− aorta. Further studies focused on the proinflammatory placental growth factor (Pl
GF
), which was released from aldosterone‐treated ApoE−/− vessels. Activation of the mineralocorticoid receptor by aldosterone in human coronary artery smooth muscle cells (
SMC
s) caused the release of factors that promote monocyte chemotaxis, which was inhibited by blocking monocyte Pl
GF
receptors. Furthermore, Pl
GF
‐deficient ApoE−/− mice were resistant to early aldosterone‐induced increases in plaque burden and inflammation.

Conclusions

Aldosterone increases early atherosclerosis in regions of turbulent blood flow and promotes an inflammatory plaque phenotype that is associated with rupture in humans. The mechanism may involve
SMC
release of soluble factors that recruit activated leukocytes to the vessel wall via Pl
GF
signaling. These findings identify a novel mechanism and potential treatment target for aldosterone‐induced ischemia in humans.
Elevated PCSK9 Levels in Untreated Patients With Heterozygous or Homozygous Familial Hypercholesterolemia and the Response to High‐Dose Statin Therapy
Authors: Raal Frederick , Panz Vanessa , Immelman Andrew , Pilcher Gillian
Published: May 2013

Background

Proprotein convertase subtilisin kexin type 9 (
PCSK
9) is an enzyme that impairs low‐density lipoprotein cholesterol (
LDL
‐C) clearance from the plasma by promoting
LDL
receptor degradation. Patients with familial hypercholesterolemia (
FH
) have reduced or absent
LDL
receptors and should therefore have elevated
PCSK
9 levels.

Methods and Results

Fasting lipograms and
PCSK
9 levels were measured 51 homozygous
FH
(
HoFH
), 20 heterozygous
FH
(
HeFH
), and 20 normocholesterolemic control subjects. Levels were repeated following high‐dose statin therapy.
LDL
‐C levels were significantly higher in untreated
HoFH
(13.4±0.7 mmol/L) and
HeFH
patients (7.0±0.2 mmol/L) compared with controls (2.6±0.1 mmol/L) (
P
<0.01). Statin therapy decreased
LDL
‐C levels from 13.4±0.7 to 11.1±0.7 mmol/L in
HoFH
and from 7.0±0.2 to 3.6±0.2 mmol/L in
HeFH
patients (
P
<0.01).
PCSK
9 levels were higher in untreated
HoFH
(279±27 ng/mL) and
HeFH
(202±14 ng/mL) than in controls (132±10 ng/mL) (both
P
<0.01). High‐dose statin therapy increased
PCSK
9 levels from 279±27 to 338±50 ng/mL in
HoFH
, and significantly so in the
HeFH
patients from 202±14 to 278±20 ng/mL (
P
<0.01). Linear regression analysis showed a correlation between
PCSK
9 and
LDL
‐C (r=0.6769;
P
<0.0001); however, this was eliminated following statin therapy (r=0.2972;
P
=0.0625).

Conclusions

PCSK
9 levels are elevated in untreated
FH
patients, particularly in those with
HoFH
. High‐dose statin therapy further increases
PCSK
9 levels.
PCSK
9 inhibitors might be a beneficial therapy for
FH
patients, even in those with
HoFH
.
Impact of Global Geographic Region on Time in Therapeutic Range on Warfarin Anticoagulant Therapy: Data From the ROCKET AF Clinical Trial
Authors: Singer Daniel E. , Hellkamp Anne S. , Piccini Jonathan P. , Mahaffey Kenneth W. , Lokhnygina Yuliya , Pan Guohua , Halperin Jonathan L. , Becker Richard C. , Breithardt Günter , Hankey Graeme J. , Hacke Werner , Nessel Christopher C. , Patel Manesh R. , Califf Robert M. , Fox Keith A. A. ,   ROCKET AF Investigators
Published: May 2013

Background

Vitamin K antagonist (
VKA
) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (
TTR
) is a widely cited measure of the quality of
VKA
therapy. We sought to identify factors associated with
TTR
in a large, international clinical trial.

Methods and Results

TTR
(international normalized ratio [
INR
] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the
ROCKET AF
trial. Factors associated with
TTR
at the individual patient level (i‐
TTR
) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i‐
TTR
was 55.2% (SD 21.3%) and the median i‐
TTR
was 57.9% (interquartile range 43.0% to 70.6%). The mean time with
INR
<2 was 29.1% and the mean time with an
INR
>3 was 15.7%. While multiple clinical features were associated with i‐
TTR
, dominant determinants were previous warfarin use (mean i‐
TTR
of 61.1% for warfarin‐experienced versus 47.4% in
VKA
‐naïve patients) and geographic region where patients were managed (mean i‐
TTR
varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i‐
TTR
s had
INR
distributions shifted toward lower
INR
values and had longer inter‐
INR
test intervals.

Conclusions

Independent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i‐
TTR
in global studies of warfarin. Regional differences in mean i‐
TTR
are heavily influenced by subtherapeutic
INR
values and are associated with reduced frequency of
INR
testing.

Clinical Trial Registration

URL:
ClinicalTrials.gov
. Unique identifier:
NCT
00403767.
Joint Commission Primary Stroke Centers Utilize More rt‐PA in the Nationwide Inpatient Sample
Authors: Mullen Michael T. , Kasner Scott E. , Kallan Michael J. , Kleindorfer Dawn O. , Albright Karen C. , Carr Brendan G.
Published: May 2013

Background

The Joint Commission began certifying primary stroke centers (
PSC
s) in December 2003 and provides a standardized definition of stroke center care. It is unknown if
PSC
s outperform noncertified hospitals. We hypothesized that
PSC
s would use more recombinant tissue plasminogen activator (rt‐
PA
) for ischemic stroke than would non‐
PSC
s.

Methods and Results

Data were obtained from the Nationwide Inpatient Sample from 2004 to 2009. The analysis was limited to states that publicly reported hospital identity. All patients ≥18 years with a primary diagnosis of acute ischemic stroke were included. Subjects were excluded if the treating hospital was not identified, if it was not possible to determine the temporal relationship between certification and admission, and/or if admitted as a transfer. Rt‐
PA
was defined by
ICD
9 procedure code 99.10. All eligibility criteria were met by 323 228 discharges from 26 states. There were 63 145 (19.5%) at certified
PSC
s. Intravenous rt‐
PA
was administered to 3.1% overall: 2.2% at non‐
PSC
s and 6.7% at
PSC
s. Between 2004 and 2009, rt‐
PA
administration increased from 1.4% to 3.3% at non‐
PSC
s and from 6.0% to 7.6% at
PSC
s. In a multivariable model incorporating year, age, sex, race, insurance, income, comorbidities,
DRG
‐based disease severity, and hospital characteristics, evaluation at a
PSC
was significantly associated with rt‐
PA
utilization (
OR
, 1.87; 95%
CI
, 1.61 to 2.16).

Conclusions

Subjects evaluated at
PSC
s were more likely to receive rt‐
PA
than those evaluated at non‐
PSC
s. This association was significant after adjustment for patient and hospital‐level variables. Systems of care are necessary to ensure stroke patients have rapid access to
PSC
s throughout the United States.
Daily Ischemic Preconditioning Provides Sustained Protection From Ischemia–Reperfusion Induced Endothelial Dysfunction: A Human Study
Authors: Luca Mary Clare , Liuni Andrew , McLaughlin Kelsey , Gori Tommaso , Parker John D.
Published: May 2013

Background

It is well established that acute ischemic preconditioning (
IPC
) protects against ischemia–reperfusion (
IR
) injury; however, the effectiveness of repeated
IPC
exposure has not been extensively investigated. We aimed to determine whether daily
IPC
episodes provide continued protection from
IR
injury in a human forearm model, and the role of cyclooxygenase‐2 in these responses.

Methods and Results

Thirty healthy volunteers were randomized to participate in 2 of 3 protocols (
IR
alone, 1‐day
IPC
, 7‐day
IPC
) in an operator‐blinded, crossover design. Subjects in the
IR
alone protocol underwent flow‐mediated dilation (
FMD
) measurements pre‐ and post‐
IR
(15′ upper‐arm ischemia and 15′ reperfusion). The 1‐day
IPC
protocol involved
FMD
measurements before and after 1 episode of
IPC
(3 cycles of 5′ upper‐arm ischemia and 5′ reperfusion) and
IR
. Day 7 of the 7‐day
IPC
protocol was identical to the 1‐day
IPC
protocol but was preceded by single daily episodes of
IPC
for 6 days prior. During each protocol, subjects received a 7‐day treatment of either the cyclooxygenase‐2 inhibitor celecoxib or placebo. Pre‐
IR FMD
was similar between groups.
IR
alone reduced
FMD
post‐
IR
(placebo, Δ
FMD
: −4.4±0.7%; celecoxib, Δ
FMD
: −5.0±0.5%). One‐day
IPC
completely prevented this effect (placebo, Δ
FMD
: −1.1±0.6%; celecoxib, Δ
FMD
: 0.0±0.7%;
P
<0.0001). Similarly, 7‐day
IPC
demonstrated persistent endothelial protection post‐
IR
(placebo, Δ
FMD
: −0.9±0.9%; celecoxib, Δ
FMD
: 0.0±0.8%;
P
<0.0001,
P
<0.0001 for
ANOVA
effect of
IPC
protocol). Celecoxib did not alter responses to
IR
in any protocol.

Conclusions

Daily episodes of
IPC
provide sustained protection from
IR
‐induced endothelial dysfunction in humans through a mechanism that appears cyclooxygenase‐2‐independent.
Hemoglobin A
1c
Is Associated With Increased Risk of Incident Coronary Heart Disease Among Apparently Healthy, Nondiabetic Men and Women
Authors: Pai Jennifer K. , Cahill Leah E. , Hu Frank B. , Rexrode Kathryn M. , Manson JoAnn E. , Rimm Eric B.
Published: May 2013

Background

Hemoglobin A1c (HbA
1c
), a time‐integrated marker of glycemic control, predicts risk of coronary heart disease (
CHD
) among diabetics. Few studies have examined HbA
1c
and risk of
CHD
among women and men without clinically elevated levels or previously diagnosed diabetes.

Methods and Results

We conducted parallel nested case–control studies among women (
N
urses'
H
ealth
S
tudy) and men (
H
ealth
P
rofessionals
F
ollow‐up
S
tudy). During 14 and 10 years of follow‐up, 468 women and 454 men developed incident nonfatal myocardial infarction (
MI
) and fatal
CHD
. Controls were matched 2:1 based on age, smoking, and date of blood draw. For these analyses, participants with a history of diabetes or HbA
1c
levels ≥6.5% at baseline were excluded. Compared with HbA
1c
of 5.0% to <5.5%, those with an HbA
1c
of 6.0% to <6.5% had a multivariable‐adjusted relative risk (
RR
) of
CHD
of 1.90 (95%
CI
1.11 to 3.25) in women and 1.81 (95%
CI
1.09 to 3.03) in men. The pooled
RR
of
CHD
was 1.29 (95%
CI
1.11 to 1.50) for every 0.5%‐increment increase in HbA
1c
levels and 1.67 (95%
CI
1.23 to 2.25) for every 1%‐increment increase, with the risk plateauing around 5.0%. Furthermore, participants with HbA
1c
levels between 6.0% and <6.5% and
C
‐reactive protein levels >3.0 mg/L had a 2.5‐fold higher risk of
CHD
compared with participants in the lowest categories of both biomarkers.

Conclusions

Our findings suggest that HbA
1c
is associated with
CHD
risk among apparently healthy, nondiabetic women and men and may be an important early clinical marker of disease risk.
Prospective Observational Study of Implantable Cardioverter‐Defibrillators in Primary Prevention of Sudden Cardiac Death: Study Design and Cohort Description
Authors: Cheng Alan , Dalal Darshan , Butcher Barbara , Norgard Sanaz , Zhang Yiyi , Dickfeld Timm , Eldadah Zayd A. , Ellenbogen Kenneth A. , Guallar Eliseo , Tomaselli Gordon F.
Published: May 2013

Background

Primary‐prevention implantable cardioverter‐defibrillators (
ICDs
) reduce total mortality in patients with severe left ventricular systolic function. However, only a minority of patients benefit from these devices. We designed the Prospective Observational Study of Implantable Cardioverter‐Defibrillators (
PROSE
‐
ICD
) to identify risk factors and enhance our understanding of the biological mechanisms that predispose to arrhythmic death in patients undergoing
ICD
implantation for primary prevention of sudden death.

Methods and Results

This is a multicenter prospective cohort study with a target enrollment of 1200 patients. The primary end point is
ICD
shocks for adjudicated ventricular tachyarrhythmias. The secondary end point is total mortality. All patients undergo a comprehensive evaluation including history and physical examination, signal‐averaged electrocardiograms, and blood sampling for genomic, proteomic, and metabolomic analyses. Patients are evaluated every 6 months and after every known
ICD
shock for additional electrocardiographic and blood sampling. As of December 2011, a total of 1177 patients have been enrolled with more nonwhite and female patients compared to previous randomized trials. A total of 143 patients have reached the primary end point, whereas a total of 260 patients died over an average follow‐up of 59 months. The
PROSE
‐
ICD
study represents a real‐world cohort of individuals with systolic heart failure receiving primary‐prevention
ICDs
.

Conclusions

Extensive electrophysiological and structural phenotyping as well as the availability of serial
DNA
and serum samples will be important resources for evaluating novel metrics for risk stratification and identifying patients at risk for arrhythmic sudden death.

Clinical Trial Registration

URL
:
http://clinicaltrials.gov/
Unique Identifier:
NCT
00733590.
Beta and Angiotensin Blockades Are Associated With Improved 10‐Year Survival in Renal Transplant Recipients
Authors: Aftab Waqas , Varadarajan Padmini , Rasool Shuja , Kore Arputharaj , Pai Ramdas G.
Published: May 2013

Background

Mortality in allograft kidney transplant recipients is high, and cardiovascular disease is the leading cause of death in these patients. They have heightened activity of sympathetic and renin–angiotensin systems. We tested the hypothesis that blockade of sympathetic and renin–angiotensin systems in these patients may offer a survival benefit using a large cohort of patients with long‐term follow up.

Methods and Results

Medical records of 321 consecutive patients from our institution who had received renal transplantation between 1995 and 2003 were abstracted. Survival was analyzed as a function of pharmacological therapies adjusted for age, sex, and comorbidities. The characteristics of the 321 patients were as follows: age at transplant, 44±13 years; 40% male; 89% with hypertension; 36% with diabetes, and mean left ventricular ejection fraction of 60%. Over a follow‐up of 10±4 years, there were 119 deaths. Adjusted for age, sex, diabetes, and coronary artery disease, use of a beta‐blocker therapy (
P
=0.04) and angiotensin‐converting enzyme inhibitor or receptor blocker (
P
=0.03) was associated with better survival. This treatment effect was seen across all major clinical subgroups and was supported by propensity score analysis. The propensity score–adjusted 10‐year survival was 95% in those taking both groups of medications, 72% in those taking either of them, and 64% in those taking neither (
P
=0.004).

Conclusions

Use of beta‐blocker and angiotensin blocking therapies is associated with higher survival after renal transplantation, indicating their potential protective role in this high‐risk population.
Periaortic Adipose Tissue and Aortic Dimensions in the Framingham Heart Study
Authors: Thanassoulis George , Massaro Joseph M. , Corsini Erin , Rogers Ian , Schlett Christopher L. , Meigs James B. , Hoffmann Udo , O'Donnell Christopher J. , Fox Caroline S.
Published: May 2013

Background

Periaortic fat, because of its contiguity with the aorta, may promote vascular remodeling and aortic dilatation. However, the relations between perioartic fat depots and aortic dimensions have not been previously described.

Methods and Results

A total of 3001 individuals (mean age 50±10 years, 49% women) from the
F
ramingham
O
ffspring and
T
hird
G
eneration cohorts underwent computed tomography for quantification of periaortic fat and aortic dimensions. We estimated the association between quantitative periaortic and visceral adipose tissue volumes (per standard deviation [
SD
] increment of volume) with aortic dimensions in both the thorax and abdomen. Thoracic periaortic fat was associated with higher thoracic aortic dimensions (β coefficient per SD of fat volume 0.67 mm, 95% confidence interval 0.58 to 0.76 mm;
P
<0.001). The association persisted after adjustment for age, sex, and cardiovascular risk factors including body mass index and visceral adipose tissue volume. Results for the association of periaortic fat and abdominal aortic dimensions were similar. Further adjustment for adipokines (resistin and adiponectin) had no significant impact on these associations.

Conclusions

Periaortic fat volume was associated with aortic dimensions in both the thorax and abdomen, supporting the notion that local fat depots may contribute to aortic remodeling. Further work to understand the mechanisms underlying this association is warranted.