Is atherosclerosis caused by high cholesterol?

According to the low‐density‐lipoprotein (LDL) receptor hypothesis, development of atherosclerosis is caused by a high concentration of LDL‐cholesterol in the blood, and lowering LDL‐cholesterol reverses, or at least retards, atherosclerosis, thus preventing cardiovascular disease.¹ As a scientific hypothesis, it is open to falsification: if the concentration of LDL‐cholesterol or total cholesterol and the degree of atherosclerosis do not correlate, or if there is no exposure‐response, e.g. if there is no association between the cholesterol changes (ΔLDL‐cholesterol or Δtotal cholesterol) and atherosclerosis progression.

The successful statin trials, with their substantial reduction of LDL‐cholesterol seemed to confirm the LDL receptor hypothesis, but their outcome was independent of the initial cholesterol concentration and the degree of its lowering. For instance, the p values for the relationships between the outcome, and the percentage or the absolute change in LDL cholesterol, as calculated in one of the trial reports,² were 0.76 and 0.97, respectively. The lack of exposure‐response, together with the benefit of the treatment in disorders and age groups where LDL‐cholesterol concentration has little if any predictive value, suggests that statins must have more important effects on cardiovascular disease than a lowering of cholesterol.³ Indeed, there is evidence that the statins have anti‐thrombotic and anti‐inflammatory effects, and also a beneficial influence on endothelial dysfunction, LDL oxidation, re‐vascularization and smooth muscle cell proliferation.

Even if these effects were operating in the trials, the substantial lowering of LDL‐cholesterol should at least have contributed to the improvement if the LDL receptor hypothesis were correct. The lack of exposure‐response also questions whether atherosclerosis is truly caused by high LDL‐cholesterol.

However, the outcome in the clinical trials was cardiovascular disease, not atherosclerotic progression. To answer the question, we need to compare the cholesterol concentration and the degree of atherosclerosis, and in particular, to study the influence of ΔLDL‐cholesterol on atherosclerotic progression, rather than clinical outcome. Read the original article here...