A Century of Cholesterol and Coronaries: From Plaques to Genes to Statins

One-fourth of all deaths in industrialized countries result from coronary heart disease. A century of research has revealed the essential causative agent – cholesterol-carrying low density lipoprotein (LDL). LDL is controlled by specific receptors (LDLRs) in liver that remove it from blood. Mutations that eliminate LDLRs raise LDL and cause heart attacks in childhood, whereas mutations that raise LDLRs reduce LDL and diminish heart attacks. If we are to eliminate coronary disease, lowering LDL should be the primary goal. Effective means to achieve this goal are currently available. The key questions are: Who to Treat, When to Treat, and How Long to Treat.

The data reviewed here focus on LDL as the sine qua non of atherosclerosis. However, LDL does not act alone. Evidence from genetically-manipulated mice indicates that the atherogenic effect of LDL requires macrophages and inflammatory cytokines (Glass and Witztum, 2001; Libby et al., 2011). In humans, at any given level of LDL the probability of a myocardial infarction is increased by well-documented risk factors that include cigarette smoking, hypertension, diabetes, and low HDL. Although these contributory factors are important, they all require LDL to instigate the lesion. The epidemiologic data in China and Japan, the genetic data with PCSK9 and NPC1L1 deficiency, and the therapeutic data with statins demonstrate that myocardial infarctions can be markedly diminished by LDL-lowering even when macrophages, cytokines, and risk factors are present. Fortunately, we now have the ability to lower LDL with diet and with drugs.

The Next Century

The past 100 years have witnessed the crest of the coronary disease epidemic in Western countries and its beginning recession. Scientists have made dramatic advances in understanding cholesterol, the lipoproteins that carry it in plasma, and the manner in which genes and diets alter lipoprotein levels. The century of cholesterol research produced four lines of evidence – experimental, genetic, epidemiologic, and therapeutic – that converge upon LDL as the primary cause of atherosclerosis. Few, if any, chronic diseases have been subjected to such intensive scrutiny, and rarely has the cause and the approach to prevention been documented so convincingly.

It does not seem an exaggeration to state that targeted application of an LDL-lowering regimen may eventually curtail one of the major killers of the last century. The key questions for the 21st century are: Who to target? and When? Ideally, LDL-lowering therapy should be initiated before atherosclerotic plaques develop, or at least before they develop their most threatening features. Currently, we base our decisions for LDL lowering on factors such as the absolute level of LDL, the presence of other risk factors, and a family history of early coronary disease. In the future, we may be able to use genetic polymorphisms that render arteries susceptible or resistant to LDL entry and susceptible or resistant to the ensuing inflammation. Such genetic polymorphisms may increase our assessment of risk, but they are unlikely to be absolute. Our decisions would be greatly helped if someone develops a noninvasive method to detect the earliest atherosclerotic plaques in the coronary arteries, to monitor their growth, and to detect the earliest signs of the inflammation and instability that lead to thrombosis. Given such a method for early detection and given our powerful methods to lower LDL, we should surely be able to end the epidemic of heart attacks that killed so many over the last century.

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