Plasma Ceramide Levels Are Elevated in Patients With Early Coronary Atherosclerosis and Endothelial Dysfunction

Abstract

Background Elevated plasma ceramides are independent predictors of cardiovascular disease and mortality in patients with advanced epicardial coronary artery disease. Our understanding of plasma ceramides in early epicardial coronary artery disease, however, remains limited. We examined the role of plasma ceramides in early coronary atherosclerosis characterized by coronary endothelial dysfunction. Methods and Results Participants presenting with chest pain and nonobstructive epicardial coronary artery disease underwent coronary endothelial function. Patients (n=90) demonstrated abnormal coronary endothelial function with acetylcholine (≥20% decrease in coronary artery diameter or ≤50% increase in coronary blood flow). A total of 30 controls had normal coronary endothelial function. Concentrations of plasma ceramide 18:0 ( P =0.038), 16:0 ( P =0.021), and 24:0 ( P =0.019) differed between participants with normal and abnormal coronary endothelial function. Ceramide 24:0 (odds ratio [OR], 2.23 [95% CI, 1.07–4.66]; P =0.033) and 16:0 (OR, 1.91×10 6 [95% CI, 11.93–3.07×10 11 ]; P =0.018) were independently associated with coronary endothelial dysfunction. Among participants with endothelium‐dependent coronary dysfunction (n=78), ceramides 16:0 (OR, 5.17×10 5 [95% CI, 2.83–9.44×10 10 ]; P =0.033), 24:0 (OR, 2.98 [95% CI, 1.27–7.00]; P =0.012), and 24:1/24:0 (OR, 4.39×10 −4 [95% CI, 4×10 −7 –0.48]; P =0.030) were more likely to be elevated. Conclusions The current study demonstrated an association between increased circulating ceramide levels and coronary endothelial dysfunction in the absence of epicardial coronary artery disease. This study supports the role of plasma ceramides as a potential biomarker or a therapeutic target for early coronary atherosclerosis in humans.

Clonal Hematopoiesis of Indeterminate Potential Is Associated With Coronary Microvascular Dysfunction In Early Nonobstructive Coronary Artery Disease

“…The study protocol has been described in detail elsewhere. 8,16–18 Patients presenting to the catheterization laboratory with nonobstructive coronary artery (<40% angiographic stenosis in major vessels) underwent invasive coronary functional testing using an intracoronary Doppler guidewire. A Doppler guidewire (0.014-inch FloWire; Philips/Volcano, Inc) was advanced 2 to 3 mm distal to the tip of 2.2F coronary infusion catheter (Ultrafuse; SciMed Life System) positioned into the mid-portion of the left anterior descending artery.…”

“…CFR ≤2 was consistent with a clinical diagnosis of CMD associated with cardiovascular disease and MACE as described previously. 8,13,18–20…”

“…The study protocol has been described in detail elsewhere. 8,[16][17][18] Patients presenting to the catheterization laboratory with nonobstructive coronary artery (<40% angiographic stenosis in major vessels) underwent invasive coronary functional testing using an intracoronary Doppler guidewire. A Highlights…”

Role of ceramides in diabetic foot ulcers (Review)

“…Exogenous c16 ceramide-mediated endothelial NO synthase (NOS) uncoupling and dysregulated protein phosphatase 2 (PP2A) were found to damage human aortic endothelial cells in a study of atherosclerotic patients (70). Another study in patients with coronary arteries also found that ceramides were associated with coronary endothelial dysfunction (71). However, more mechanistic studies are needed to confirm the findings.…”

“…Sphingolipids are bioactive lipids found in atherosclerotic plaques, which have been linked to both the development and progression of atherosclerosis. Although their specific effects in human atherosclerotic plaques are still unclear, ceramides are an important component in sphingolipids that are also associated with atherosclerosis ( 71 ). By promoting their aggregation through ceramide-ceramide interactions, SM may be converted to ceramides by aSMase on low-density lipoprotein (LDL) surfaces, thus accelerating the onset of atherosclerosis.…”