tbuckley/cabot-search huggingface dataset:
Abstract 5167: Neutrophil Infiltration of Human Carotid Plaques Correlates With the Characteristics of Rupture-prone Lesions
Authors: Mihaela G Ionita, Aryan Vink, Pleunie van den Borne, Petra van der Kraak, JP de Vries, Frans Moll, Gerard Pasterkamp, Dominique de Kleijn
Journal: Circulation (2009)

Aim : Atherosclerosis is a chronic, complex inflammatory process and is the underlying cause of stroke and myocardial infarction due to rupture of the atherosclerotic plaque leading to acute occlusion of the artery in the brain or heart. Little is known about neutrophil infiltration in human carotid atherosclerotic plaques and its association with plaque morhology has not been described yet. This, despite accumulating evidence suggesting a link between systemic inflammation and atherosclerosis. To study this, we scored the number of plaque neutrophils and related this to plaque morphology and inflammatory status. Methods and Results : Carotid atherectomy specimens were obtained from 340 patients and stained for the neutrophil marker CD66b. CD66b-positive neutrophils were counted and expressed as number per square millimeter of tissue. Higher neutrophil numbers were found in plaques with a high lipid core, high macrophage numbers and low collagen and smooth muscle cell numbers. Plaques with high neutrophil numbers contained significant higher interleukin-8 (p=0.001), matrix metalloprotease (MMP)-8 (p=0.039) and MMP-9 (p=0.002) concentrations. The number of new capillaries within plaques was significantly (p=0.045) correlated with high neutrophil numbers. Conclusion : This shows for the first time that Neutrophil-numbers are strongly associated with the histopathological features and the inflammatory status of rupture-prone atherosclerotic lesions, suggesting a possible role for neutrophils in plaque destabilization.
Abstract 595: Cardioprotective Effects of Recombinant Human Erythropoietin in Rats with Experimental Autoimmune Myocarditis
Authors: Wataru Mitsuma, Masahiro Ito, Makoto Kodama, Koumei Tanaka, Koichi Fuse, Kazuki Okamura, Haruo Hanawa, Mikio Nakazawa, Yoshifusa Aizawa
Journal: Circulation (2006)

Background and Purpose: Erythropoietin (EPO) has been known to have cytoprotective effects on several tissues, presumably through modulation of apoptosis and inflammation. The effect of EPO on myocardial inflammation, however, has not been yet clarified. We investigated the cardioprotective effects of EPO in rats with experimental autoimmune myocarditis (EAM). Methods and Results: Seven-week-old Lewis rats immunized with cardiac myosin were treated with either EPO (500 IU/day intraperitoneally once a day from day 0 to day 21, n=9) or vehicle (n=8), and were examined on day 22. In EPO treated group, the myocarditis area, which was determined with a color image analyzer, was significantly attenuated compared with in vehicle group (26.6 ± 4.1 % versus 40.5 ± 4.1 %; p &lt; 0.01). Echocardiogram demonstrated significant improvement of left ventricular fractional shortening in EPO treated group than in vehicle group (48 ± 3.2% versus 33.4 ± 2.5%; p &lt; 0.01). These improvements in EPO treated group were along with suppression of mRNAs of tumor necrosis factor- α and interleukin -6 in the hearts (p &lt; 0.05 versus vehicle) by assessing quantitative RT-PCR. EPO also decreased myocyte apoptosis, as assessed by TUNEL staining, significantly (p &lt; 0.05 versus vehicle). Furthermore, immunohistochemical staining for EPO receptor revealed that cardiomyocytes were faintly stained in healthy age-matched rats, while strongly stained in rats with EAM. Conclusions: EPO, which is widely used in the clinical field, ameliorated the progression of EAM by modulating myocardial inflammation and myocyte apoptosis. The present study may suggest the beneficial effects of EPO for patients with inflammation-related cardiac diseases.
Abstract 5201: Low-dose Tetrahydrobiopterin Supplementation Reduces Atherosclerosis Progression in Apolipoprotein E-Knockout Mice via Effects on Vascular T cell Infiltration
Authors: Tim S Schmidt, Eileen McNeill, Gillian Douglas, Mark J Crabtree, Ashley B Hale, Charles A O’Neill, Keith M Channon, Nicholas J Alp
Journal: Circulation (2009)

Tetrahydrobiopterin (BH4) supplementation improves endothelial function in models of vascular disease by maintaining endothelial nitric oxide synthase coupling and nitric oxide bioavailability. Recent studies using pharmacological and transgenic endothelial-specific BH4 supplementation highlighted the therapeutic potential of BH4 in native atherosclerosis and vascular injury and suggested a potential role for BH4 as regulator of inflammation and vascular remodeling. However, the cellular mechanisms through which this leads to reduced atherosclerosis remain unclear. We have used a pharmaceutical BH4 formulation to address the hypothesis that improved endothelial function resulting from exogenous BH4 supplementation leads to reduced atherosclerosis through effects on vascular inflammation. Single oral dose pharmacokinetic studies revealed rapid BH4 uptake from the gastrointestinal tract into plasma and organs. While in most organs BH4 levels returned to baseline by 8 hours after dosing, BH4 levels in aorta remained markedly increased at 24 hours, suggesting an active mechanism for BH4 retention. Daily oral BH4 supplementation in 8 week old chow-fed ApoE-KO mice for 8 or 12 weeks had no effect on plasma lipids or hemodynamic parameters, but resulted in a significant 45% relative reduction in aortic root atherosclerosis only at 10 mg/kg BH4, compared with placebo controls (0.049 vs. 0.088 mm2, P&lt;0.05 after 8 weeks; 0.142 vs. 0.259 mm2, P&lt;0.05 after 12 weeks). BH4 treatment led to a striking reduction in T cell infiltration, both within plaques (0.001886 vs. 0.006653 mm2; P&lt;0.05) and in the surrounding adventitia (0.007741 vs. 0.020133 mm2; P&lt;0.05). Importantly, BH4 treatment had no effect on circulating leukocyte numbers, and furthermore no evidence for BH4 uptake by peripheral blood mononuclear cells from plasma after single oral supplementation was found. Experiments using endothelium-targeted GTP-cyclohydrolase 1 transgenic mice, with a specific increase in endothelial BH4 levels, revealed a similar reduction in vascular T cell infiltration, suggesting that BH4 supplementation reduces atherosclerosis through a reduction in vascular T cell infiltration mediated by salutary effects on endothelial nitric oxide bioavailability.
2006 George L. Duff Memorial Lecture—Familial Hypobetalipoproteinemia, a Unique Form of Fatty Liver
Authors: Gustav Schonfeld, Pin Yue, Maurizio Averna, Zhouji Chen
Journal: Circulation (2006)

Several genetic forms of familial hypobetalipoproteinemia (FHBL) exist: (a) those due to premature stop-codon–specifying mutations or missense mutations of APOB; (b) those due to nonsense or missense mutations of PCSK9; (c) those due to certain mutations of MTP; and (d) those linked to none of the above-mentioned genes. “Knock-in” mouse models of apoB truncations (apoB38.9 and apoB27.6) resemble human FHBL phenotypes. In heterozygous crosses of apoB38.9 or apoB27.6 mice, homozygotes are born at &lt;10% of expected frequencies, suggesting that homozygosity is lethal. In heterozygous apoB-defective FHBL, even the product of the normal allele, apoB100, is produced at only ~25% of the normal rate as a result of increased intracellular degradation. Furthermore, the lipid-ferrying capacities of the abnormal truncated apoBs are reduced. The net result is an impaired hepatic lipid export system via VLDL particles, resulting in increases of hepatic fat despite adaptive decreased synthesis of hepatic fatty acids and cholesterol. To assess the role of genetic factors in the fatty livers of mice, a 10-strain survey was performed. Six-fold differences in hepatic triglyceride levels were found, demonstrating the importance of genetic factors. Breeding of the apoB38.9 defect into low, medium, and high hepatic triglyceride strains yielded 3 congenic strains: the SWR/J-apoB +/38.9 , C57BL/J-apoB +38.9 , and BALBcByJ-apoB +/38.9 , respectively. Significant effects on hepatic triglyceride levels were found by mouse strain, by the apoB38.9 gene, and there were strain–gene interactions. Thus, modifying genes affect the expression of the apoB38.9 defect.
Abstract 5258: Insulin Stabilizes Coronary Microvascular Endothelial Barrier via PI3K/Rac1-mediated Stabilization of cell-cell adhesions
Authors: Muhammad Aslam, Johannes Thom, Imran Hussain, Frauke V Haertel, Mathias Grebe, Ali E Erdogan, Hans M Piper, Harald Tillmanns, Thomas Noll, Dursun Guenduez
Journal: Circulation (2009)

Recent findings, both in animal and clinical studies show that insulin, besides its metabolic effects, has protective effects under inflammatory conditions as well as in reducing major cardiovascular events in patients undergoing vascular surgery. Loss of endothelial barrier is one of the earliest manifestations of inflammation and atherosclerosis. The role of insulin in the regulation of endothelial barrier function is not well described. The integrity of the endothelial barrier is highly dependent on acto-myosin based endothelial contractile machinery and adherens junctions. Rho-GTPases (Rac1 and RhoA) are well described as important regulators of actin cytoskeleton and adherens junctions and maintain integrity of endothelial barrier. Here the hypothesis was tested whether insulin stabilizes endothelial barrier via Rac1-mediated stabilization of adherens junctions. Methods and Results: In cultured coronary microvascular endothelial cells from rat heart (RCEC) insulin reduced the macromolecular permeability (albumin flux) from 4.9±0.2 × 10 −6 cm 2 /s to 3.4±0.3 × 10 −6 cm 2 /s (n5, P&lt;0.05 for all further parameters) in a concentration-dependent manner with a maximum effect with 1U/ml and caused 3-fold increase in Akt phosphorylation (Western blot). This protective effect on permeability could be blocked by HNMP(AM)3 (1 μ M, a specific insulin receptor inhibitor), and Wortmannin (1 μ M; PI3K inhibitor), suggesting that insulin reduces permeability via receptor-mediated activation of Akt. Furthermore, insulin induced a 3-fold activation of Rac1 (pull down assay), increased cortical actin and VE-cadherin at cell-cell adhesions (confocal microscopy). These insulin effects could be blocked by HNMP(AM)3, and wortmannin. Furthermore, inhibition of Rac1 with NSC23766 (100 μ M; pharmacological inhibitor of Rac1) abrogated insulin mediated barrier stabilization. Conclusion: We show here for the first time that insulin enhances endothelial barrier function in RCEC monolayers via PI3K/Akt-mediated activation of Rac1, which stabilizes endothelial cell adherens junctions. Further understanding of this mechanism could be beneficial in the development of therapeutic strategies for vessel protection during pathological conditions.
Abstract 5452: Consistency of Detection of Abnormal Late Enhancement in Left Ventricular Myocardium by Multislice CT in Myocardial Disease in Comparison With Cardiac Magnetic Resonance Using Segment by Segment Analysis
Authors: Hiroyuki Takaoka, Nobusada Funabashi, Masae Uehara, Michiko Daimon, Marehiko Ueda, Taichi Murayama, Issei Komuro
Journal: Circulation (2009)

Purpose: To evaluate the capability of multislice CT (MSCT) to detect abnormal late enhancement (LE) in the left ventricular (LV) myocardium in myocardial disease, we compared MSCT with cardiac magnetic resonance (CMR) using segment by segment analysis and summarized the merit of performing late phase acquisition of MSCT. Materials and Methods: 79 subjects (61 male, 56.9±15.6 years) with suspected LV myocardial abnormalities (24 hypertrophic cardiomyopathy, 13 dilated cardiomyopathy, 5 cardiac sarcoidosis, 4 cardiac amyloidosis, 3 arrhythmogenic right ventricular cardiomyopathy, and 1 Fabry disease, et al) underwent enhanced MSCT (Aquilion One, or Light Speed Ultra 16) and CMR (Intera Achieva). Images were divided into 8 segments: 6 in the LV and each one in the right ventricle and either right or left atrium for each subject. Results: Among the 632 segments, LE was detected in 127 segments in MSCT, 137 segments in CMR, and 100 segments in both MSCT and CMR. LE was detected in 27 segments in only MSCT, and in 37 segments in only CMR. LE was not detected in 468 segments in either MSCT or CMR. In comparing CT with CMR for detecting LE, the sensitivity, specificity, positive and negative predictive values, and consistency were 73.0, 94.5, 78.7, 92.7 and 89.9%, respectively. Conclusions: The consistency of detection of LE in LV myocardium by MSCT in myocardial disease compared with CMR was 89.9% in spite of poor contrast resolution of CT. MSCT should be used to evaluate LV myocardium in subjects with suspected LV myocardial abnormalities by adding late phase acquisition despite increments of radiation exposure, and even though late phase acquisition is more desirable than pre enhanced scanning.
2006 Lewis K. Dahl Memorial Lecture—Nitric Oxide Deficiency in Renal Disease
Authors: Christine Baylis
Journal: Circulation (2006)

Nitric oxide (NO) production is reduced in renal disease, in part because of decreased endothelial production. Evidence indicates that NO deficiency contributes to cardiovascular events and progression of kidney damage. Two possible causes of NO deficiency are substrate (L-arginine) limitation and increased levels of circulating endogenous inhibitors of NO synthase (particularly asymmetric dimethylarginine [ADMA]). Decreased L-arginine availability in chronic kidney disease (CKD) is due to perturbed renal biosynthesis of this amino acid. In addition, inhibition of transport of L-arginine into endothelial cells and shunting of L-arginine into other metabolic pathways (eg, involving arginase) might also decrease availability. Elevated plasma and tissue levels of ADMA in CKD are functions of both reduced renal excretion and reduced catabolism by dimethylarginine dimethylamino-hydrolase (DDAH). The latter might be associated with loss-of-function polymorphisms of a DDAH gene and/or functional inhibition of the enzyme by oxidative stress in CKD and end-stage renal disease. An increase in ADMA has emerged as a major independent risk factor in end-stage renal disease (and probably CKD). Raising endogenous L-arginine and/or lowering ADMA concentration is a major therapeutic goal to reduce endothelial dysfunction, cardiovascular risk, and possibly progression in renal disease.
Abstract 4853: Spironolactone Therapy is Associated With Rapid Improvements in Blood Pressure Control and Cardiac Remodeling in Patients With Resistant Hypertension
Authors: Mustafa I Ahmed, Krishna K Gaddam, James D Gladden, Ravi V Desai, Steven G Lloyd, Himanshu Gupta, Thomas S Denney, Suzanne Oparil, Louis J Dell’Italia, David A Calhoun
Journal: Circulation (2009)

Background: The addition of spironolactone to a multidrug regimen is emerging as an effective antihypertensive strategy in patients with resistant hypertension independent of underlying aldosterone status. The effect of spironolactone on cardiac remodeling in these patients is not clear however. Aims: In the current prospective study we used 3D-magnetic resonance imaging (MRI) to accurately evaluate the effects of spironolactone therapy on cardiac remodeling in patients with resistant hypertension. Methods and Results: Twenty-two resistant hypertension patients were evaluated by MRI, prior to, and then 3 and 6 months following addition of spironolactone to a multidrug regime (all were taking at least 3 antihypertensives including a diuretic). Patients had a mean age of 54±2 years, 27% were female, 27% were African American and mean left ventricular (LV) ejection fraction was 70±1%. At three-months following spironolactone therapy, systolic and diastolic blood pressures were significantly improved (141±3 vs. 122±2, p&lt;0.001 and 85±3 vs. 77±2, p=0.002, respectively). Furthermore significant reductions were noted in LV mass index (86±3 vs. 72±3, p&lt;0.001), LA volume index (46±3 vs. 39±2, p=0.003) and BNP levels (44±9 vs. 17±5, p=0.009). Reductions in blood pressures, LV mass index and LA volumes remained significant independent of underlying aldosterone status. At six-months, there were no significant further reductions in any of these parameters. Conclusions: In addition to a marked antihypertensive effect, addition of spironolactone to a multidrug regimen is associated with rapid regression of LV hypertrophy and reductions in LA volumes and BNP, all of which are important prognostic indicators. These findings demonstrate the broad cardiovascular benefits associated with spironolactone therapy in patients with resistant hypertension.
Abstract 4758: Multiple Inter-strut Hollow, a Unique Finding of Optical Coherence Tomography After Sirolimus Eluting Stent Implantation: The Prevalence and Clinical Characteristics
Authors: Shingo Hosogi, Hayato Shimizu, Hiroyuki Tanaka, Yasushi Fuku, Hiroyuki Yamamoto, Tsuyoshi Goto, Kazushige Kadota, Kazuaki Mitsudo
Journal: Circulation (2009)

Background: It has been reported that Optical Coherence Tomography (OCT) revealed cavities formation between and outside of the stent strut, Multiple Inter-strut Hollow (MIH) after Sirorimus eluting stent (SES) implantation. However, the incidence and the clinical characteristics of MIH are unknown. Methods: We analyzed the findings of OCT, in 60 cases with in-stent restenosis (ISR) after SES (n=52) and bare metal stent (BMS) (n=8) implantation. MIH was defined as multiple cavity formation which maximum depth was over 0.3mm between and outside of the stent strut in OCT. Furthermore, we examined the relation between the maximum depth of MIH and the clinical characteristics of the lesions with MIH, such as, original lesion type (AMI/UAP, stable AP, CTO or ISR) and period to restenosis (more than 1 year or less than 1 year). Results: The incidence of MIH was significantly higher in SES group compared with BMS group (42.3% v.s. 0.0%; p&lt;0.05) and also showed the tendency to increase in the group which original lesion type was CTO. Regarding the maximum depth of MIH, there was no significant difference between more and less than 1 year groups (0.62+−0.24mm v.s. 0.53+−0.12mm; p=0.34), however, the depth of MIH tended to increase in CTO group. Conclusions: MIH is peculiar phenomenon after SES implantation on OCT findings. Further careful follow-up is needed to reveal the clinical implication of MIH. Incidence of MIH
Abstract 5269: Asymmetric Dimethylarginine Triggers Vasculo-Renal Interaction in CKD Mice
Authors: Hidemi Kajimoto, Hisashi Kai, Suguru Yasuoka, Takahiro Anegawa, Hiroki Aoki, Tsutomu Imaizumi
Journal: Circulation (2009)

Background: Patients with chronic kidney disease (CKD) also suffer increased morbidity and mortality from cardiovascular diseases (CVD). Endothelial dysfunction is a major factor underlying the pathogenesis of CVD. Asymmetric dimethylarginine (ADMA), an endogenous endothelial nitric oxide synthase (eNOS) inhibitor, is elevated in CKD. We hypothesized that ADMA has a role in endothelial dysfunction in CKD. Methods and Results: We created a CKD model by performing 5/6 nephrectomy (Nx) in mice. Blood and 24-hour urine were collected for measurements of renal function and ADMA, and NOx levels at 4 weeks after Nx. Nx induced renal failure (serum blood urea nitrogen, controls: 26.9±1.6 mg/dL, Nx mice: 61.0±3.8 mg/dL, p &lt;0.001; serum creatinine, controls: 0.19±0.01 mg/dl, Nx mice: 0.31±0.03 mg/dL, p &lt;0.01) without changing blood pressure. The serum ADMA level was higher (p &lt;0.01) in Nx mice (1.20±0.05 nmol/mL) than in controls (1.00±0.05 nmol/mL). Urinary NOx was lower in Nx mice (controls: 2153±189 nmol/L, Nx mice: 706±335 nmol/L, p &lt;0.05). Isometric tension study using aortic rings showed that endothelium-mediated relaxation induced by acetylcholine was impaired in Nx mice. Furthermore, pretreatment with exogenously administered ADMA at a serum concentration comparable to that in Nx mice reduced acetylcholine-induced relaxation in the aorta of controls. Western blotting showed the phosphorylated eNOS level of the aorta was lower in Nx mice than in controls, whereas eNOS levels were similar. The expression level of dimethylarginine dimethylaminohydrolase-1 (DDAH-1), a degradation enzyme of ADMA, was reduced in the kidney, but not in the aorta of Nx mice. In an ex vivo experiment using cultured human umbilical vein endothelial cells, ADMA treatment with a concentration corresponding to the serum level in Nx mice reduced the eNOS phosphorylation level. Conclusions: Elevated levels of circulating ADMA, probably resulting from decreased DDAH-1 expression in the kidney, appear to impair endothelial function by inhibiting eNOS activity in CKD. ADMA may thus have a triggering role in the vasculo-renal interaction in CKD.
Abstract 5089: Impaired Calf Skeletal Muscle Glucose Uptake in Subjects With Peripheral Artery Disease and Intermittent Claudication
Authors: Reena L Pande, Mi-Ae Park, Todd S Perlstein, Akshay S Desai, Jeanne Doyle, Robert S Copeland-Halperin, Whitney M Redline, Marcelo F Di Carli, Mark A Creager
Journal: Circulation (2009)

Objectives : Severity of claudication symptoms does not correlate well with ankle brachial index (ABI) in patients with peripheral artery disease (PAD), suggesting that non-hemodynamic mechanisms may play an important role. Given the association of PAD with insulin resistance, we hypothesized that local calf muscle glucose uptake is impaired in PAD, and therefore that local insulin resistance may contribute to the pathophysiology of claudication. Methods: We studied 37 subjects with PAD (ABI ≤ 0.9) and stable claudication and 11 healthy controls who underwent dynamic positron emission tomography (PET) imaging of the legs with 18-FDG during a hyperinsulinemic-euglycemic clamp (insulin @ 2 mU/kg/min). Using fused PET/CT images, regions of interest were drawn in the primary muscle groups of the lower leg. Average glucose uptake was quantified using the graphical Patlak analysis. Whole body insulin sensitivity was assessed as the glucose disposal rate (M) from the insulin clamp. Data are presented as median [interquartile range, IQR] or mean± standard error (SE). Results: Compared to healthy, age-matched controls, PAD subjects were insulin resistant (M = 3.4 mg/kg/min [IQR 2.7– 4.8] vs. 5.0 [3.7– 6.6], p=0.019) even after excluding those with diabetes (24% of PAD subjects), p=0.04. Average calf muscle glucose uptake was significantly lower in PAD subjects (48.6±2.6 mmol/kg/min) compared with healthy controls (62.9±6.5 mmol/kg/min), p=0.009. Similar impairments were observed in the subgroup of PAD subjects without diabetes (49.5±3.1, p=0.04 vs. healthy controls). Whole body insulin sensitivity explained 10% of the variability in local calf muscle glucose uptake (r 2 =0.10, p=0.04). Conclusions: We demonstrate that subjects with claudication are insulin resistant and have reduced calf muscle glucose uptake, independent of coexistent diabetes. The poor correlation between whole body insulin sensitivity and lower extremity glucose uptake suggests unique determinants of leg glucose uptake in PAD. These findings support our underlying hypothesis that impaired calf muscle substrate utilization due to local insulin resistance may be a novel mechanism underlying the pathophysiology of intermittent claudication.