Only a fraction of the clinical complications of atherosclerosis are explai
ned by known risk factors. Animal studies have shown that plasma sphingomye
lin (SM) levels are closely related to the development of atherosclerosis.
SM carried into the arterial wall on atherogenic lipoproteins may be locall
y hydrolyzed by sphingomyelinase, promoting lipoprotein aggregation and mac
rophage 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 hig
her in CAD patients than in control subjects (60+/-29 versus 49+/-21 mg/dL,
respectively; P<0.0001). Moreover, the ratio of SM to SM+phosphatidylcholi
ne (PC) was also significantly higher in cases than in controls (0.33+/-0.1
3 versus 0.29+/-0.10, respectively; P<0.0001), Similar relationships were o
bserved in African Americans and whites. Plasma SM levels showed a signific
ant correlation with remnant cholesterol levels (r=0.51, P<0.0001). By use
of multivariate logistic regression analysis, plasma SM levels and the SM/(
SM+PC) ratio were found to have independent predictive value for CAD after
adjusting for other risk factors, including remnants. The odds ratio (OR) f
or CAD was significantly higher for the third and fourth quartiles of plasm
a SM levels (OR 2.81 [95% CI 1.66 to 4.80] and OR 2.33 [95% CI 1.38 to 3.92
], respectively) as well as the SM/(SM+PC) ratio (OR 1.95 [95% CI 1.10 to 3
.45] and OR 2.33 [95% CI 1.34 to 4.05], respectively). The findings indicat
e that human plasma SM levels are positively and independently related to C
AD. Plasma SM levels could be a marker for atherogenic remnant lipoprotein
accumulation and may predict lipoprotein susceptibility to arterial wall sp
hingomyelinase.