Introduction
Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality worldwide. The role of low-density lipoproteins (LDLs) in the development of ASCVD has been a subject of intense research and debate. This article aims to evaluate the comprehensive clinical and genetic evidence establishing the causal relationship between LDLs and ASCVD. We delve into a range of studies, from genetic analyses to randomized controlled trials, to solidify our understanding of LDL’s definitive role in this critical disease process.
Genetic Insights into LDL and ASCVD
Genetic studies provide a powerful lens through which to examine causality. Rare genetic mutations affecting the LDL receptor, a key protein responsible for clearing LDL from the bloodstream, offer compelling evidence. Individuals with mutations that impair LDL receptor function exhibit markedly elevated levels of LDL cholesterol (LDL-C). These genetically determined high LDL-C levels are directly associated with a dose-dependent increase in the risk of ASCVD. Conversely, genetic variants that lead to lower LDL-C levels are linked to a correspondingly reduced risk of ASCVD. This natural genetic experiment underscores the intrinsic link between LDL-C burden and ASCVD risk.
Epidemiological and Mendelian Randomization Studies
Prospective epidemiologic cohort studies, encompassing vast populations and long follow-up periods, consistently demonstrate a strong association between LDL-C levels and ASCVD. Furthermore, Mendelian randomization studies, which leverage naturally occurring genetic variations as proxies for modifiable risk factors, reinforce this association and strengthen the inference of causality. These studies minimize confounding and reverse causation, common limitations in observational epidemiology. Meta-analyses synthesizing data from over 200 prospective cohort studies and Mendelian randomization studies, involving over 2 million participants and 20 million person-years of follow-up, reveal a striking log-linear relationship. This relationship highlights that the longer and greater the exposure of the vasculature to elevated LDL-C, the higher the risk of ASCVD.
Randomized Trials of LDL-Lowering Therapies
The most definitive evidence for causality comes from randomized controlled trials evaluating LDL-lowering therapies. These trials, including over 150,000 cardiovascular events, consistently show that reducing LDL-C levels through various pharmacological interventions leads to a proportional reduction in ASCVD events. The benefit observed is directly related to the absolute reduction in LDL-C and the duration of exposure to lower LDL-C. Importantly, both genetic studies and intervention trials converge on the same conclusion: lowering plasma LDL particle concentration, irrespective of the mechanism, reduces ASCVD risk in proportion to the absolute decrease in LDL-C. This effect is contingent on the reduction in LDL-C being concordant with the reduction in LDL particle number and the absence of detrimental off-target effects from the interventions.
Conclusion
The totality of evidence, derived from diverse and robust scientific methodologies including genetic studies, prospective epidemiologic cohorts, Mendelian randomization analyses, and randomized clinical trials, unequivocally establishes a causal relationship between LDL and ASCVD. These consistent findings across multiple lines of investigation solidify the understanding that LDL is not merely associated with, but directly causes, atherosclerotic cardiovascular disease. This robust evidence base is critical for guiding clinical practice and public health strategies aimed at preventing and managing this pervasive and life-threatening condition, as often discussed and published in leading journals such as the European Heart Journal (Eur Heart J).
