Evidence that Low Density Lipoprotein Is the Primary Cause of Atherosclerotic Cardiovascular Disease: A Bradford-Hill Approach

Cardiovascular disease is the leading cause of death in the Westernized world. The costs in productive lives lost to individuals, families, and society are staggering. The epidemiology, pathogenesis, and preventative treatment are all clearly described. Why then, has this epidemic not been eradicated? One reason is the uncertainty about the primary cause of atherosclerotic cardiovascular disease. Low density lipoprotein (LDL) is a circulating lipid particle that deposits cholesterol into the arterial wall which subsequently evolves into an atherosclerotic plaque and a life-threatening arterial thrombosis. The reason that LDL is not universally accepted as the cause of atherosclerosisis that there are no randomized controlled trials (RCT’s) providing this evidence. For ethical, financial, and scientific reasons, an RCT of sufficient duration to prove or disprove this hypothesis may never be initiated. We propose a unique approach to support the critical role of LDL in the pathogenesis of cardiovascular disease. Employing criteria based on those proposed by Sir Austin Bradford Hill, we describe the large body of scientific evidence supporting LDL as the primary cause of atherosclerosis. Sir Austin Bradford Hill was a British epidemiologist/statistician who lived in the 20th century. He acknowledged that the cause of a disease could not always be established by a randomized clinical trial. Therefore, he outlined nine criteria (now known as the Bradford-Hill criteria) that should be met if an etiological factor was likely the cause of a disease. The data in this manuscript are organized according to these nine criteria. These data strongly suggest that LDL is the primary cause of atherosclerotic cardiovascular disease and that sufficient LDL reduction (i.e., to mmol/L) will lead to atherosclerotic cardiovascular disease becoming a rare event.