Background Endothelial dysfunction is a key step in the initiation and progression of atherosclerosis and subsequent cardiovascular complications. We examined whether peripheral endothelial function, as assessed by fingertip reactive hyperemia-peripheral arterial tonometry (RH-PAT) can provide additional clinical value to traditional risk factors for cardiovascular diseases in predicting coronary artery disease (CAD). Methods We included 118 stable patients who were referred for coronary angiography for chest pain evaluation or abnormal stress test. A natural logarithmic value of RH-PAT index (Ln_RHI) was obtained before cardiac catheterization by an independent operator. Significant CAD was defined as luminal stenosis ≥70% (≥50% at left main) and/or fractional flow reserve ≤0.80 in one or more major coronary arteries or their major branches. Results Levels of Ln_RHI were significantly lower in patients with CAD (n=60) compared to patients without CAD (n=58) (0.69±0.29 vs. 0.88±0.27, p<0.001). Ln_RHI was significantly associated with CAD independent from traditional risk factors (odds ratio [OR] for 0.1 decrease in Ln_RHI 1.25, 95% confidence interval [CI] 1.04 to 1.52, p=0.01). The net reclassification index was improved when Ln_RHI was added to traditional risk factors (0.62, 95% CI: 0.27 to 0.97, p=0.001). Conclusions Peripheral endothelial function, as assessed by RH-PAT, improved risk stratification when added to traditional risk factors. RH-PAT is potentially useful for identifying patients at high risk for CAD.

Objectives This study tests the hypothesis that circulating mononuclear cells expressing osteocalcin (OCN) and bone alkaline phosphatase (BAP) are associated with distinct plaque tissue components in patients with early coronary atherosclerosis. Background Plaque characteristics implying vulnerability develop at the earliest stage of coronary atherosclerosis. Increasing evidence indicates that cells from the myeloid lineage might serve as important mediators of destabilization. Plaque burden and its components were assessed regarding their relationship to monocytes carrying both pro-inflammatory (CD14) and osteogenic surface markers OCN and BAP. Methods Twenty-three patients with angiographically non-obstructive coronary artery disease underwent coronary endothelial function assessment and virtual histology-intravascular ultrasound of the left coronary artery. Plaque composition was characterized in the total segment (TS) and in the target lesion (TL) containing the highest amount of plaque burden. Blood samples were collected simultaneously from the aorta and the coronary sinus. Circulating cell counts were then identified from each sample and a gradient across the coronary circulation was determined. Results Circulating CD14+/BAP+/OCN+ monocytes correlate with the extent of necrotic core and calcification (r=0.53, p=0.010; r=0.55, p=0.006, respectively). Importantly, coronary retention of CD14+/OCN+ cells also correlate with the amount of necrotic core and calcification (r=0.61, p=0.003; r=0.61, p=0.003) respectively. Conclusions Our study links CD14+/BAP+/OCN+ monocytes to the pathologic remodeling of the coronary circulation and therefore associates these cells with plaque destabilization in patients with early coronary atherosclerosis.

BackgroundEndothelial dysfunction is an early stage of atherosclerosis. Single‐nucleotide polymorphisms (SNPs) have been associated with vascular dysfunction, cardiac events, and coronary artery remodeling. We aimed to detect SNPs associated with endothelial dysfunction and determine whether these associations are sex specific.Methods and ResultsSix hundred forty‐three subjects without significant obstructive coronary artery disease underwent invasive coronary endothelial function assessment. We collected data from 1536 SNPs that had previously been associated with vasoreactivity, angiogenesis, inflammation, artery calcification, atherosclerotic risk factors, insulin resistance, hormone levels, blood coagulability, or with coronary heart disease. Coronary vascular reactivity was assessed by the percent change in coronary artery diameter ≤ −20% after an intracoronary bolus injection of acetylcholine on invasive coronary physiology study. SNPs significantly associated with coronary epicardial endothelial dysfunction were ADORA1,KCNQ1, and DNAJC4 in the whole cohort, LPA, MYBPH, ADORA3, and PON1 in women and KIF6 and NFKB1 in men (P<0.01).ConclusionsWe have identified several significant SNPs that are associated with an increased risk of coronary endothelial dysfunction. These associations appear to be sex specific and may explain gender‐related differences in development of atherosclerosis.

Background Single nucleotide polymorphisms (SNPs) are the most common source of genetic variation. Although microvascular pathology is associated with cardiovascular events, genetic phenotypes causing microvascular disease remain largely unknown. This study identifies gender specific SNPs associated with coronary microvascular dysfunction. Methods and Results Six-hundred and forty-three patients without significant obstructive coronary heart disease (CHD) were enrolled, referred for cardiac catheterization, and underwent invasive coronary microcirculatory assessment. Patient data was collected from 1529 autosomal SNPs and 7 X chromosome SNPs which were selected to represent the variability from 76 candidate genes having published associations with coronary vasoreactivity, angiogenesis, inflammation, vascular calcification, atherosclerosis risk factors, female hormones, blood coagulation, or CHD. Coronary flow reserve (CFR) was assessed by intracoronary injection of adenosine. Patients were categorized according to a CFR above or below 2.5 and were stratified by sex. After adjusting for age, sex, and BMI, this study demonstrates that SNPs within VEGFA and CDKN2B-AS1 are associated with abnormal CFR (P<0.005). SNPs within MYH15, VEGFA and NT5E are associated with abnormal CFR in men. No SNPs were associated with abnormal CFR in women. Conclusions Genetic variation within defined regions of VEGFA and CDKN2B-AS1 genes are associated with coronary microvascular dysfunction. Furthermore, sex-specific allelic variants within MYH15, VEGFA and NT5E are associated with an increased risk of coronary microvascular dysfunction in men.

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