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.
Highlights
In the United States, 500,000 individuals die from atherosclerotic cardiovascular disease (ASCD) each year (Figure 1) [1]
In individuals with a lifetime nonsense mutations in PCSK9 resulting in a reduction of low density lipoprotein cholesterol (LDL-c) by 38 mg/dl compared to a similar population of middle aged individuals, cardiovascular disease was reduced by 88% [44]
It should be noted that the average LDL-c for patients entering the hospital with an acute coronary event is below 100 mg/dl and their HDL-c is above 40 mg/dl [62]
Summary
In the United States, 500,000 individuals die from atherosclerotic cardiovascular disease (ASCD) each year (Figure 1) [1]. This number equates to approximately one death per minute. Based on the LDL-c Principle (for each reduction in LDL-c, there is a corresponding reduction in ASCD), the death rate should decline to ~250,000 over 10 years with an LDL-c of 70 mg/dl [46] At this LDL-c level, coronary artery disease may be reversible in some individuals with minimal risk factors [52]. These opposing forces continue throughout life beginning in the teenage years with LDL-c slowly predominating with atherosclerotic plaque deposition in many individuals [18]
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