Abstract-As the major regulator of vascular homeostasis, the endothelium exerts a number of vasoprotective effects, such as vasodilation, suppression of smooth muscle cell growth, and inhibition of inflammatory responses. Many of these effects are largely mediated by nitric oxide, the most potent endogenous vasodilator. Nitric oxide opposes the effects of endothelium-derived vasoconstrictors and inhibits oxidation of low-density lipoprotein. A defect in the production or activity of nitric oxide leads to endothelial dysfunction, signaled by impaired endothelium-dependent vasodilation. Accumulating evidence suggests that endothelial dysfunction is an early marker for atherosclerosis and can be detected before structural changes to the vessel wall are apparent on angiography or ultrasound. Many of the risk factors that predispose to atherosclerosis can also cause endothelial dysfunction, and the presence of multiple risk factors has been found to predict endothelial dysfunction.

For patients with acute coronary syndrome, lipid-lowering therapy with atorvastatin, 80 mg/d, reduces recurrent ischemic events in the first 16 weeks, mostly recurrent symptomatic ischemia requiring rehospitalization.

Abstract-Coronary artery calcification is increased in the presence of atherosclerosis. However, there is great variability in the calcification of individual coronary stenoses, and the clinical significance of this finding remains unknown. We tested the hypothesis that culprit lesions associated with myocardial infarction or unstable angina are less calcified than are stenoses associated with stable angina. The study consisted of 78 patients who underwent intravascular ultrasound imaging of culprit stenoses after the placement of a stent. Seventeen patients presented with stable angina; 43, with unstable angina; and 18, with myocardial infarction. The extent of coronary calcification was measured by the angle of its arc and was quantified with a computer-based protractor. The arc of calcium was measured in the stented area at the point of maximal calcification and also as an average of the calcification found at proximal, middle, and distal stent segments. The maximal arc of calcium decreased progressively from patients with stable angina (91Ϯ10°) to those with unstable angina (59Ϯ8°) and to those with myocardial infarction (49Ϯ11°, Pϭ0.014). Similarly, the average arc of calcium was greatest (32Ϯ7°) in patients with stable angina, less (15Ϯ4°) in patients with unstable angina, and least (10Ϯ5°) in patients with acute myocardial infarction (Pϭ0.014). These associations remained significant after adjustment for other factors that potentially affect arterial calcification. Acute coronary syndromes are associated with a relative lack of calcium in the culprit stenoses compared with stenoses of patients with stable angina. Key Words: calcinosis Ⅲ calcium Ⅲ coronary vessels Ⅲ ultrasonography, interventional Ⅲ myocardial infarction C oronary artery calcification is an active process that is commonly observed in the setting of atherosclerosis. 1-3 Previous reports have found that arterial calcification is proportional to the overall burden of the atherosclerotic plaque but not necessarily to the severity of luminal narrowing. 3-7 Acute coronary syndromes, including myocardial infarction and unstable angina, arise from rupture or erosion of atherosclerotic plaques. 4 The relationship of lesional calcium toward propensity to plaque rupture and, thus, to the pathogenesis of acute coronary syndromes remains uncertain. 5 See editorial, page 1561Furthermore, the association between coronary calcification and atherosclerosis has stimulated interest in using arterial calcification to detect coronary atherosclerosis. Noninvasive methods of quantifying coronary calcification, eg, electron beam CT (EBCT), have helped to define the relationship between coronary artery calcification and the atherosclerotic burden. Whether such calcium-based approaches can be useful in visualizing the most dangerous, ie, vulnerable plaques, is unknown.In the present study, we tested the hypothesis that calcification of culprit lesions responsible is reduced for acute coronary syndromes compared with lesions associated with stable angina. Accordingl...

Background Shear stress gradients and inflammation have been causally associated with atherosclerosis development in carotid bifurcation regions. The mechanism underlying higher levels of carotid intima‐media thickness observed among HIV‐infected individuals remains unknown. Methods and Results We measured carotid intima‐media thickness progression and development of plaque in the common carotid, bifurcation region, and internal carotid artery in 300 HIV‐infected persons and 47 controls. The median duration of follow‐up was 2.4 years. When all segments were included, the rate of intima‐media thickness progression was greater in HIV‐infected subjects compared with controls after adjustment for traditional risk factors (0.055 vs. 0.024 mm/year, P=0.016). Rate of progression was also greater in the bifurcation region (0.067 vs. 0.025 mm/year, P=0.042) whereas differences were smaller in the common and internal regions. HIV‐infected individuals had a greater incidence of plaque compared with controls in the internal (23% vs. 6.4%, P=0.0037) and bifurcation regions (34% vs. 17%, P=0.014). Among HIV‐infected individuals, the rate of progression in the bifurcation region was more rapid compared with the common carotid, internal, or mean intima‐media thickness; in contrast, progression rates among controls were similar at all sites. Baseline hsCRP was elevated in HIV‐infected persons and was a predictor of progression in the bifurcation region. Conclusions Atherosclerosis progresses preferentially in the carotid bifurcation region in HIV‐infected individuals. hsCRP, a marker of inflammation, is elevated in HIV and is associated with progression in the bifurcation region. These data are consistent with a model in which the interplay between hemodynamic shear stresses and HIV‐associated inflammation contribute to accelerated atherosclerosis. (J Am Heart Assoc. 2012;1:jah3‐e000422 doi: .) Clinical Trial Registration URL: http://clinicaltrials.gov. Unique identifier: NCT01519141

Background: There is growing interest in the use of multiplexed aptamer-based assays for large-scale proteomic studies. However, the analytic, short- and long-term variation of the measured proteins is largely uncharacterized. Methods: We quantified 4001 plasma protein analytes from 42 participants in the Atherosclerosis Risk in Communities (ARIC) Study in split samples and at multiple visits using a multiplexed modified aptamer assay. We calculated the CV, Spearman correlation, and intraclass correlation (ICC) between split samples and evaluated the short-term (4–9 weeks) and long-term (approximately 20 years) variability using paired t-tests with log-transformed protein concentrations and Bonferroni-corrected significance thresholds. We performed principal component (PC) analysis of protein analyte concentrations and evaluated their associations with age, sex, race, and estimated glomerular filtration rate (eGFR). Results: The mean baseline age was 57 years at the first visit, 43% of participants were male and 57% were white. Among 3693 protein analytes that passed quality control, half (n = 1846) had CVs < 5.0%, Spearman correlations > 0.89, and ICCs > 0.96 among the split samples. Over the short term, only 1 analyte had a statistically significant difference between the 2 time points, whereas, over approximately 20 years, 866 analytes (23.4%) had statistically significant differences (P < 1.4 × 10−5, 681 increased, 185 decreased). PC1 had high correlations with age (−0.73) and eGFR (0.60). PC2 had moderate correlation with male sex (0.18) and white race (0.31). Conclusions: Multiplexed modified aptamer technology can assay thousands of proteins with excellent precision. Our results support the potential for large-scale studies of the plasma proteome over the lifespan.

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Objective To assess the effects of empagliflozin, a selective SGLT2 inhibitor, on broad biological systems through proteomics. Research Design and Methods 3,713 proteins were quantified using aptamer-based proteomics in 144 paired plasma samples obtained from 72 participants across the spectrum of glucose tolerance, before and after 4 weeks of empagliflozin 25 mg/day. Biology of the plasma proteins significantly changed by empagliflozin (at false discovery rate-corrected p<0.05) was discerned through Ingenuity Pathway Analysis. Results Empagliflozin significantly affected levels of 43 proteins, 6 related to cardiomyocyte function (fatty acid binding protein 3 and 4 (FABPA), neurotrophic receptor tyrosine kinase (NTRK2), renin, thrombospondin-4, and leptin receptor), 5 to iron handling (ferritin heavy chain 1, transferrin receptor protein 1 (TFRC), neogenin, growth differentiation factor 2 (GDF-2), and ß2microglobulin) and 1 to spingosine/ceramide metabolism (neutral ceramidase), a known pathway of cardiovascular disease. Among the protein changes achieving the strongest statistical significance, insulin-like binding factor protein-1 (IGFBP-1), transgelin-2, FABPA, growth differentiation factor-15 (GDF15), and sulphydryl oxidase 2 precursor (QSOX2) were increased, while ferritin, thrombospondin-3, and REarranged during Transfection (RET) were decreased by empagliflozin administration Conclusion SGLT2 inhibition is associated, directly or indirectly, with multiple biological effects, including changes in markers of cardiomyocyte contraction/relaxation, iron handling, and other metabolic and renal targets. The most significant differences were detected in protein species (GDF15, ferritin, IGFBP-1 and FABP) potentially related to the clinical and metabolic changes that were actually measured in the same patients. These novel results may inform further studies, using targeted proteomics and a prospective design.