The mainstream hypothesis that LDL cholesterol drives atherosclerosis may have been falsified by non-invasive imaging of coronary artery plaque burden and progression

Med Hypotheses. 2009 Oct;73(4):596-600. doi: 10.1016/j.mehy.2009.05.030. Epub 2009 Jun 26.


That LDL cholesterol drives atherosclerosis is a widely if not almost universally held belief, and this belief strongly influences the mainstream approach to coronary heart disease. However heart disease has a number of stages, and in terms of primary prevention, the initiation and progression of silent or sub-clinical atherosclerosis is clearly fundamental. However, studies that address the efficacy of interventions and practices aimed at the primary prevention of heart disease almost always use event-based endpoints such as fatal or non-fatal myocardial infarction or unstable angina. These endpoints do not directly relate to the primary prevention of silent atherosclerosis and to apply these results to asymptomatic individuals in this context involves an extrapolation. The advent of non-invasive imaging techniques which allow the determination of coronary artery plaque burden and progression of plaque has provided a unique opportunity to examine the relationship between both traditional and emerging risk factors and the extent of sub-clinical coronary artery disease and in particular allow the testing of the hypothesis that LDL cholesterol drives coronary atherosclerosis. Consistent with earlier autopsy studies, the use of electron beam tomography and contrast enhanced CT angiography techniques have created a large body of evidence which appears to falsify this hypothesis. The large number of null results for the association between serum LDL cholesterol levels and the prevalence or progression of both calcified and non-calcified plaque in the appropriate vascular bed and involving large numbers of men and women over a wide range of age, ethnic background, plaque burden and cholesterol levels cannot be easily dismissed. If the hypothesis is false, this has a significant impact on currently held views regarding risk factors and therapeutic interventions in the case of individuals who are asymptomatic, that is, issues associated with primary prevention. Also, if the hypothesis is false, then the use of changes in LDL as a surrogate marker for judging the importance of various risk factors for silent atherosclerosis and thus coronary artery disease can be called into question.

MeSH terms

  • Cholesterol, LDL / blood*
  • Coronary Artery Disease / diagnosis*
  • Coronary Artery Disease / physiopathology*
  • Diagnostic Imaging / methods*
  • Endpoint Determination / methods*
  • Evidence-Based Medicine*
  • False Positive Reactions
  • Humans
  • Models, Cardiovascular*
  • Risk Assessment / methods
  • Risk Factors


  • Cholesterol, LDL