The Rise and Fall “ing” of the HDL Hypothesis

Earlier epidemiological studies have shown an inverse correlation between high-density lipoprotein cholesterol (HDLc) and coronary heart disease (CHD). This observation along with the finding that reverse cholesterol transport is mediated by HDL, supported the hypothesis that the HDL molecule has a cardioprotective role. More recently, epidemiological data suggest a U-shaped curve correlating HDLc and CHD. In addition, randomized clinical trials of drugs that significantly increase plasma HDLc levels, such as nicotinic acid and cholesterol ester transfer protein (CETP) inhibitors failed to show a reduction in major adverse cardiovascular events. These observations challenge the hypothesis that HDL has a cardioprotective role. It is possible that HDL quality and function is optimal only when de novo synthesis of apo A-I occurs. Inhibition of turnover of HDL with currently available agents yields HDL molecules that are ineffective in reverse cholesterol transport. To test this hypothesis, newer therapeutic drugs that increase de novo production of HDL and apo A-I should be tested in clinical trials.