The Application of the LDL Principle

Abstract

The LDL Principle has recently been invoked to describe the observation that lowering the LDL cholesterol (by whatever means) results in a lowering of atherosclerotic cardiovascular events. The scientific basis of the LDL Principle dates back to the discovery that the LDL receptor is the prime determinant of the circulating LDL-c concentration. Since that time, major advances have been made at both the basic and clinical science level in our understanding of the pathogenesis and reversal of atherosclerosis. The incorporation of atherogenic lipoproteins plus inflammatory mediators into plaque formation permits the targeted intervention into preventing plaque rupture. In addition, genetic studies identifying individuals with unique phenotypes of either abnormally high or low LDL-c concentrations have provided insight into possible therapeutic modalities that have recently provided the physician with the tools necessary to apply the LDL Principle to achieve reversal of atherosclerosis. The epidemic of atherosclerotic cardiovascular disease has resulted in numerous randomized controlled intervention trials in an attempt to identify approaches to reduce ASCD morbidity and mortality. Recently published data indicate that circulating LDL-c levels of 50 mg/dl or less are not only physiologic at birth but also effective in greatly reducing cardiovascular disease. In addition, the recent availability of two PCSK9 inhibitors provides the primary care physician with the possibility of achieving this low level of LDL-c even in statin intolerant patients. The widespread availability of the coronary artery calcium scan plus the inclusion of traditional cardiovascular risk factors in risk assessment has enabled the physician to readily identify asymptomatic individuals at high risk for cardiovascular events. Aggressively applying the LDL Principle to these individuals has the potential of greatly reducing cardiovascular mortality. This review will document the scientific basis for this principle and provide the arguments in favor of its aggressive application.

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

“…Since this burden is expressed as multiple atherosclerotic plaques, clinical cardiovascular events become manifested in the mature adult. If the adult subsequently reduces his/her LDL below 70 mg/dl (1.81 mmol/L) via diet and/or medication, the atherosclerotic burden can be reduced and atherosclerosis can be reversed [6] [48].…”

“…The LDL concentration determines the increase or decrease in atherosclerotic burden ( Figure 2) [6]. Furthermore, for optimal clinical outcomes, extensive genetic, pathophysiological, and experimental evidence support maintaining an LDL cholesterol concentration of <50 mg/dl (1.3 mmol/L).…”

“…Furthermore, for optimal clinical outcomes, extensive genetic, pathophysiological, and experimental evidence support maintaining an LDL cholesterol concentration of <50 mg/dl (1.3 mmol/L). Based on these published data, significantly reducing the number one cause of death in the Western world would be expected [6]. However, this expectation has not materialized because of doubts that LDL is the primary cause of atherosclerosis.…”

“…Furthermore, studies that result in volunteers obtaining LDL cholesterol concentrations below 70 mg/dl (1.81 mmol/L) have shown additional benefit [17]. Thus, the lower the LDL cholesterol, the greater the reduction in atherosclerosis in a dose response fashion [6].…”

“…Alternatively, when circulating LDL cholesterol is elevated, increased cardiovascular risk rises in proportion to the LDL cholesterol elevation [6]. non-esterified fatty acids [4].…”