Unlinking sudden death from coronary artery disease - a systematic scoping review of the association of low-density lipoprotein cholesterol and sudden death

Background Sudden death (SD) is a common first manifestation of cardiovascular disease (CVD) and accounts for more than 350 000 deaths per year in the U.S. (1) Coronary artery disease is held accounted for up to 80% of SD cases. (2) Whilst low-density lipoprotein (LDL-c) is a major modifiable risk factor for atherosclerosis and CVD, (3) it is still unclear whether elevated LDL-c is associated with SD. Recent studies found conflicting results, (4,5) challenging our understanding of the pathogenesis of SD. Purpose To address this apparent paradox for the association of LDL-c with sudden death and to investigate the role of this risk factor in SD, we performed a systematic scoping review of the literature reporting on LDL-c and SD. Methods Our review followed PRISMA-Scr guidelines. A comprehensive search string was developed at the guidance of an experienced librarian. Two independent reviewers screened PubMed and EMBASE for peer-reviewed case-control and cohort studies with LDL-c as an exposure variable, and SD as outcome variable. Articles were reviewed in a two-step process of (a) title and abstract screening and (b) full-text screening. Disagreements were resolved through consensus. Results Of 1835 articles retrieved, 570 met screening eligibility criteria. Studies that did not include LDL-c as exposure and SD as outcome or did not provide effect sizes were removed. We identified 9 relevant studies from 1982 to 2015, conducted in the U.S., Europe, and Asia, with a total of 9,639 SD cases. Two studies found an increased risk of SD with higher LDL-c and 2 studies found the contrary. 4 studies did not identify LDL-c as an independent associate of SD. One cohort study found a U-shaped relationship where both higher and lower levels led to higher risk for SD. Spectrum of included study type was broad, and definition of sudden death varied among studies. Results are displayed in Table 1. Conclusion Unlike other risk factors for coronary artery disease, LDL-cholesterol does not show a consistent association with sudden death. Focusing solely on lipid reduction may have limited impact on sudden death incidence. This suggests that sudden death may be of more multifactorial nature and require comprehensive strategies for effective prevention.