Remnant cholesterol and risk of myocardial infarction in patients with coronary artery disease undergoing revascularization

Extensive evidence from epidemiologic, genetic and clinical intervention studies have established low-density lipoprotein cholesterol (LDL-C) as a causal factor and a primary treatment target in atherosclerotic cardiovascular disease (ASCVD)1. However, significant residual risk has been reported among statin-treated individuals, that even with combined lipid-lowering therapies and despite substantial reduction in LDL-C continue to experience recurrent cardiovascular events2. Although LDL is considered the main atherogenic cholesterol-rich particle, other apo B-containing lipoproteins such as triglyceride (TG) rich lipoproteins and lipoprotein(a) also contribute to intimal cholesterol deposition and activation of proinflammatory pathways3,4. Remnant cholesterol (RC), describes the cholesterol content of a subset of triglyceride-rich lipoproteins, particularly very-low and intermediate density lipoproteins (VLDL and IDL) in the fasting state and additionally chylomicron remnants in the non-fasting state5. Biology support cholesterol rather than TG content of remnant lipoproteins as the main driver for atherosclerosis, and both epidemiologic and genetic evidence suggest that RC is a causal factor associated with ASCVD6,7. Nevertheless, although RC instigate cardiovascular disease development and progression, it is relatively unexplored in research studies and is not included as part of risk stratification models3,7. Moreover, the importance of RC to cardiovascular disease prevention in clinical practice is underappreciated, possibly due to insufficient data on the role of RC as a therapeutic target in ASCVD patients with residual risk8.

Direct measurement of RC requires specialization and is not broadly applied for routine clinical use. However, RC can be simply estimated from a standard lipid profile as total cholesterol minus LDL-C minus high-density lipoprotein cholesterol (HDL-C), without any additional cost5. Such estimation may be less accurate in hypertriglyceridemic individuals due to the inaccuracy of LDL-C estimation by the Friedewald equation when TGs are elevated9. The use of alternative formulas for LDL-C calculation, such as the Martin-Hopkins equation, enables to estimate LDL-C without assuming a fixed ratio between TGs and VLDL-cholesterol (VLDL-C), resulting in a more variable distribution of RC levels10. Using LDL-C by the Martin-Hopkins equation (referred hereinafter as LDL-CM) was reported to provide a more accurate estimate of RC than using LDL-C estimated by the Friedewald equation11.

RC was shown in large cohorts of individuals free of cardiovascular disease to improve risk prediction of ASCVD and to be associated with future development of cardiovascular events independent of traditional risk factors12, 13, 14, 15, 16. However, data on the association of RC with adverse cardiovascular events in patients with known coronary artery disease is less robust, particularly in the acute setting, and was investigated mostly in cohorts of small sample size17, 18, 19, 20, 21. Moreover, as the main literature on RC and cardiovascular risk stem from few research cohorts, there is a place for more diverse, real-world data13, 14, 15, 16, 17,21. In the current analysis, our aim was to investigate the association between RC (as calculated with the use of Martin-Hopkins formula for LDL-CM estimation) and the risk for future myocardial infarction (MI) in patients with evidence of coronary artery disease undergoing revascularization. Furthermore, we wished to examine whether the predictive value of RC is retained in patients treated with lipid-lowering therapies and after adjustment for non-HDL-C or LDL-CM levels.

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