VLDL–Associated Apolipoproteins Predict CVD Events

Study Questions:

Does measurement of each of the known apolipoproteins directly by mass spectrometry have a better association with incident cardiovascular disease (CVD) than the standard available apoA-I and apoB associated with high-density lipoprotein (HDL) particles and non-HDL particles, respectively?

Methods:

The Bruneck Study is a prospective, population-based survey of the epidemiology and pathogenesis of atherosclerosis and CVD. Associations of 13 apolipoproteins, lipid species, and other plasma proteins with incident CVD (91 events), defined as stroke, myocardial infarction (MI), or sudden cardiac death (SCD), were assessed prospectively over a 10-year period in 688 participants using mass spectrometry. Changes in apolipoprotein and lipid levels following treatment with volanesorsen, an antisense drug targeting apoC-III, were determined in two intervention trials, one of which was randomized. Associations with incident endpoints were examined using Cox regression adjusted for classic lipid and nonlipid risk factors and statin therapy.

Results:

Subjects were on average 66 years old, 52% were female, 6.4% reported prior CVD, and 9% were prescribed statins. The apolipoproteins most significantly associated with incident CVD were apoC-II (hazard ratio per 1 standard deviation [HR/SD]: 1.40, apoC-III 1.38; and apoE 1.31; each p < 0.001). Associations were independent of HDL and non-HDL cholesterol, diabetes, systolic blood pressure, and smoking as well as prior CVD and statins. The association of triglycerides with CVD (p < 0.001) lost significance after adjustment for HDL and non-HDL cholesterol. ApoC-III inhibition by volanesorsen reduced plasma levels of apoC-II, apoC-III, triacylglycerols, and diacylglycerols, and increased apoA-I, apoA-II, and apoM (all p < 0.05 vs. placebo) without affecting apoB-100 (p = 0.73).

Conclusions:

The strong associations of very-low-density lipoprotein (VLDL)-associated apolipoproteins with incident CVD in the general community support the concept of targeting triacylglycerol-rich lipoproteins to reduce risk of CVD.

Perspective:

Petar Alaupovic, an internationally renowned biochemist and lipidologist, died in 2014, at the age of 91 years. He was a founder of the modern field of lipoproteins and demonstrated the importance of apoC-III, which inhibits lipoprotein lipase, and apoC-II is an activator that requires insulin as a cofactor. That the novel antisense to apoC-III reduces the number of proatherogenic VLDL triglyceride-rich particles and modestly increases apoA-I and II without a change in apoB, makes it a perfect agent to complement statins and LDL cholesterol lowering agents for the prevention and treatment of atherosclerosis. Volanesorsen may have other benefits considering the associated apolipoproteins were implicated in de novo lipogenesis, glucose metabolism, complement activation, blood coagulation, and inflammation.


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