Plasma Sphingomyelin Level as a Risk Factor for Coronary Artery Disease

Abstract

Abstract-Only a fraction of the clinical complications of atherosclerosis are explained by known risk factors. Animal studies have shown that plasma sphingomyelin (SM) levels are closely related to the development of atherosclerosis. SM carried into the arterial wall on atherogenic lipoproteins may be locally hydrolyzed by sphingomyelinase, promoting lipoprotein aggregation and macrophage foam cell formation. A novel, high-throughput, enzymatic method to measure plasma SM levels has been developed. Plasma SM levels were related to the presence of coronary artery disease (CAD) in a biethnic angiographic case-control study (279 cases and 277 controls). Plasma SM levels were higher in CAD patients than in control subjects (60Ϯ29 versus 49Ϯ21 mg/dL, respectively; PϽ0.0001). Moreover, the ratio of SM to SMϩphosphatidylcholine (PC) was also significantly higher in cases than in controls (0.33Ϯ0.13 versus 0.29Ϯ0.10, respectively; PϽ0.0001). Similar relationships were observed in African Americans and whites. Plasma SM levels showed a significant correlation with remnant cholesterol levels (rϭ0. 51, PϽ0.0001). By use of multivariate logistic regression analysis, plasma SM levels and the SM/(SMϩPC) ratio were found to have independent predictive value for CAD after adjusting for other risk factors, including remnants. The odds ratio (OR) for CAD was significantly higher for the third and fourth quartiles of plasma SM levels (OR T he association of lipid abnormalities and coronary atherosclerosis is well established. Case-control and prospective epidemiological studies have shown a direct correlation between coronary artery disease (CAD) and serum levels of total cholesterol and LDL cholesterol (LDL-C) and an inverse relationship between CAD and HDL cholesterol (HDL-C) levels. 1 However, compared with plasma cholesterol measurements, very little attention has been given to the relationship between phospholipids and CAD. 2,3 Atherogenesis is initiated by the interaction of cholesterol-rich lipoproteins, such as LDL, with the arterial wall. 4,5 The uptake of lipoprotein cholesterol by macrophages, leading to foam cell formation, is a central event in the initiation and progression of atherosclerosis. 6 However, native LDL is incapable of generating foam cells from macrophages. Thus, it is thought that LDL is modified in the arterial wall by processes such as oxidation, leading to macrophage chemotaxis and the uptake of modified LDL by macrophage foam cells. 7 Retention of lipoproteins on the subendothelial matrix, followed by aggregation, has also emerged as a central pathogenic process in macrophage foam cell formation and atherogenesis. 8 Lipoprotein aggregation in the vessel wall may result from enzymatic modification of LDL, induced by locally produced sphingomyelinase (SMase). 9 It has long been known that sphingomyelin (SM) accumulates in human and animal atheroma and that the major source is plasma lipoproteins. 10 Plasma SM levels are increased in human familial hyperlipidemias, especially in familial hypercholester...

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

“…Furthermore, serum sphingomyelin decreased in recovery from exercise with a similar response in most species. Total serum sphingomyelin relates to risk of cardiovascular disease (CVD) (18,29), so the decrease in recovery could reflect a common pathway by which exercise is cardioprotective and promotes insulin sensitivity.…”

“…Serum ceramides are increased in obesity and type 2 diabetes (13,17) and are associated with the development of ath- erosclerosis (18). Serum ceramides are thought to promote insulin resistance by activating intracellular inflammatory cascades and increasing macrophage cytokine production via Toll-like receptor 4 signaling (6).…”

Circulating ceramides are inversely associated with cardiorespiratory fitness in participants aged 54–96 years from the Baltimore Longitudinal Study of Aging

“…Perhaps through these same mechanisms, ceramides may contribute to the early stages of atherosclerosis (Ichi et al ., 2006; Bismuth et al ., 2008) and the accumulation of ceramide in the myocardium may cause cardiac dysfunction in obese and diabetic individuals, even in the absence of hypertension and myocardial ischemia (Park & Goldberg, 2012). It is noteworthy that Jiang and colleagues found that plasma levels of sphingolipids are an independent risk factor for coronary heart disease (Jiang et al ., 2000). In animal models, the ceramide accumulation within the myocardium is responsible for a direct toxic effect on myocardial fibrils, cardiomyocytes apoptosis, and altered cardiac metabolism (Park & Goldberg, 2012).…”

Ceramide: A common pathway for atherosclerosis?

“…Evidence has also shown a probable implication of sphingolipids in atherosclerosis. Jiang et al have shown that plasma sphingomyelin concentration is correlated with the development of atherosclerosis and furthermore was also shown to be an independent predictor of coronary artery disease [1]. The accumulation of sphingolipids noted in atherosclerosis appears to influence the atherogenic process by affecting lipoprotein metabolism and lipid efflux and by acting as a key signaling molecule.…”