Abstract Body (Do not enter title and authors here): Introduction: Endothelial dysfunction is a precursor for the development of atherosclerotic coronary artery disease (CAD). Arterial flow-mediated vasodilation (FMD) is a correlate of Nitric Oxide mediated endothelial-dependent vascular relaxation. The prognostic impact of progressive endothelial dysfunction, measured as FMD decline, is unclear among patients with CAD. We hypothesized that the progression of endothelium dysfunction in conduit arteries, as assessed by delta FMD, is an independent predictor for adverse cardiovascular outcomes. We investigated whether CAD polygenic risk score (PRS) and traditional risk factors impact the progression of endothelial dysfunction.
Methods: Among a sample of 620 outpatients with stable CAD (age 63±9 years, 25% women), FMD was measured at rest and during follow-up (at 1 to 2 years) and expressed as % hyperemic dilation. Participants were followed up to 6 years for incident adverse events including myocardial infarction, heart failure and cardiovascular mortality. Linear regression models were utilized to investigate the impact of PRS and risk factors on delta FMD (follow-up minus baseline). Cox-proportional hazards models were performed to investigate the prognostic impact of FMD decline after adjustment for sociodemographic attributes, clinical factors and medications.
Results: During a median follow-up of 5 years, 101 patients had at least one adverse cardiovascular event. Participants with a higher PRS and lower baseline FMD had a greater decline in endothelial function (r= - 0.12, P <0.01) and (r= +0.51, P< 0.01), respectively. In contrast, traditional risk factors and medications did not correlate with delta FMD. A 1% decrease in delta FMD during follow-up was associated with a 9% increase in the hazard of adverse events (95%CI, 3-16). The results remained consistent despite adjustment for baseline FMD, follow-up duration as well as sociodemographic, clinical risk factors and medications.,
Conclusions: In individuals with CAD, progressive endothelial dysfunction is associated with a worse cardiovascular prognosis. However, changes in endothelial function correlates with CAD PRS. These findings suggest that atherosclerotic progression is driven by the interplay of intrinsic genetic and biological factors. Future secondary prevention efforts should focus on the development of novel biomarkers to monitor disease progression.