The Mainstream Hypothesis That LDL Cholesterol Drives Atherosclerosis May Have Been Falsified By Non-Invasive Imaging of the Coronary Plaque Burden and Progression
William R. Ware, Ph.D., Faculty of Science (Emeritus), University of Western Ontario, London, ON, Canada
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The following commentary is based on and summarizes my paper “The mainstream hypothesis that LDL cholesterol drives atherosclerosis may have been falsified by non-invasive imaging of the coronary plaque burden and progression” .
Progress in science depends not only on hypothesis generation but also on hypothesis falsification. Cholesterol, and in particular LDL, has been called the driving force of atherosclerosis . But this widely held view is based almost entirely on studies with cardiac event endpoints rather than a direct measure of coronary plaque burden and progression. Extensive data continues to accumulate indicating that, contrary to the conventional wisdom, total cholesterol (TC) and LDL cholesterol in asymptomatic individuals are not associated with either the extent or progression of coronary plaque, as quantified either by electron beam tomography (EBT) or coronary CT angiography. Since conventional lipid risk factors fail to identify significant numbers of individuals with extensive plaque burden and also fail to identify many with zero or low plaque burden, non-invasive imaging can lead to reassignment of risk categories and can identify individuals who by traditional assessment qualify for therapy when none is in fact indicated . When enhanced risk is identified by high coronary calcium scores, it appears to be almost universally an indication for lipid lowering. If the hypothesis is false, this brings into question the proposed approach, in the context of primary prevention, that calls for LDL targets as the central and in many cases the only therapeutic response to the enhanced risk [4,5].
Some Inconvenient Questions
If the hypothesis is true that LDL is the driving force of atherosclerosis, then in the context of coronary heart disease, one would expect to find statistically and clinically meaningful correlations between LDL cholesterol levels and the extent and progression of atherosclerosis as directly measured by coronary artery plaque. The same would be expected for TC, an adequate surrogate for LDL. Extensive evidence suggests otherwise. Thus arise the following rather inconvenient questions:
- Why do autopsy studies of the correlation between the extent of coronary atherosclerosis and serum cholesterol yield null results? The answer that the blood samples, mostly from accident or suicide victims, were obtained too long after death has been discredited .
- Why did Hecht et al.  find that total TC, LDL, and HDL cholesterol did not correlate with either the extent or prematurely of calcified plaque burden in 1,105 consecutive, asymptomatic individuals self-referred for EBT?
- Why did Hecht et al.  fail to find a correlation between LDL and the coronary calcium percentile (correlation coefficient 0.06 with a scatter plot showing no visible correlation) for 304 asymptomatic women? In fact, no correlation was found between either the calcium percentile or score and any lipid measurement.
- Why, when 1,653 men and women without a history of CHD were subjected to coronary CT angiography using contrast media, did Johnson et al.  fail to find a correlation between total plaque burden (calcified, mixed, and non-calcified) and total serum cholesterol (Spearman’s rho = -0.04), a result the authors indicate agreed with other studies?
- Why in a study of the impact of psychosocial factors on coronary calcification in a large group of male and female asymptomatic individuals (n = 780), was there no correlation between TC or LDL and the calcium score with Spearman correlation coefficients near zero? Multivariate analysis gave an odds ratio of 1.005 for LDL .
- Why did Arad et al.  in the St. Francis Heart Study find no correlation (r = 0.03, p = 0.15) between LDL levels and coronary calcium scores in 4,903 asymptomatic individuals?
- Why for adults with familial hypercholesterolemia, did Jensen et al.  find that age-adjusted coronary calcium scores were not associated with cholesterol levels?
- Why did Kronmal et al.  find among approximately 2,900 individuals that the relative risk of incident coronary artery calcium associated with LDL was only 1.03 per 10 mg/dL and barely reached statistical significance (lower CI 1.01) whereas both HDL and triglycerides exhibited much stronger associations?
- Why did Sung et al.  in a recent study of coronary calcium scores and estimated coronary risk find negligible correlation between LDL or TC and calcium scores in 1,653 asymptomatic individuals judged free of CHD (Spearman’s coefficient = 0.07 and 0.08 respectively). Even the correlation coefficient of 0.26 found for the log calcium score versus 10-year absolute risk estimate yielded a scatter plot suggesting that this magnitude of correlation, which was 3 to 4 times greater than that found for LDL and TC, still had no clinical utility.
- Why in a study of 177 asymptomatic patients of intermediate risk of CHD did Ramadan et al.  find a null result (OR = 1.022, p = 0.361) for the odds of positive coronary calcification and LDL in a multivariate model?
- Why were Takamiya et al.  unable to find any association whatsoever between LDL and coronary calcium in three multiple logistic regression models when 100 asymptomatic individuals underwent EBT.
- Finally and perhaps the most important question, why is there no association between TC or LDL and the progression of atherosclerosis [13,17-25]? All 10 studies cited involved EBT. Most studies examined the correlation with LDL as well as TC.
These questions directly address coronary plaque and thus do not involve arguments based on studies involving other vascular beds. Furthermore, the correlation between carotid artery intima-media thickness and coronary atherosclerosis is modest, especially in asymptomatic individuals or those merely suspected of CHD, where correlation coefficients range mostly between 0.2 and 0.3 .
It might be argued that total plaque rather than calcified plaque should be the basis for judging the hypothesis, although one study cited in the above questions did indeed look at total plaque . Also, eight studies involving over 27,000 asymptomatic patients found that those with zero calcium score had an extremely low average annual coronary event rate (6.6 per 10,000) , and as the calcium score increases, so does the risk of adverse coronary events .
LDL As A Surrogate Endpoint For CHD Risk
The above results do not support the widely held view that a diet high in saturated fat is atherogenic because it raises LDL and thus stimulates atherosclerosis. The fat-cholesterol hypothesis was the basis of the original objections to both dietary fat and carbohydrate-restricted diets, and it is also part of the justification for standard guideline recommendation to limit fat intake and saturated fat in particular. Also, increased saturated fat intake leads to a decrease in small dense LDL, and in a recent study greater intake in saturated fat was found to be associated with reduced progression of coronary arthrosclerosis . The role of saturated fat in CHD was already challenged in 1998 .
Determinants of Plaque Progression
In ten coronary plaque progression studies cited above [13,17-25], the prior existence of calcified plaque and hypertension were the most frequently found statistically significant positive risk factors, followed by diabetes, lipoprotein(a), triglycerides, smoking, the Framingham risk score, and HDL (negative association), but these latter factors were not consistently identified. In terms of modifiable factors, the only strong association consistently found was with hypertension, which was also found in a study that started with individuals having a zero calcium score .
Plaques and Lipid Lowering
The null results from the 19 trials cited above suggest that lowering LDL would have no impact on the prevalence or progression of coronary plaque and calls into question the proposed approach which targets LDL for asymptomatic persons of intermediate traditional risk of CHD who exhibit elevated coronary calcium [4,5]. Several randomized clinical trials employing statins and enrolling asymptomatic individuals support this inference. The placebo controlled studies found that statin therapy had no effect on the progression of coronary calcification as measured by the calcium score [30,31]. In trials comparing doses or different statins, atherosclerosis progression as measured by calcified plaque showed no relationship with on-treatment LDL levels and intensive therapy was unable to attenuate coronary artery calcium progression [31-33].
It is interesting in view of the JUPITER lipid lowering and CRP trial  that three recent studies directly examined the correlation between the coronary calcium score and high-sensitivity CRP (hsCRP) levels and found that there was no association [18,35,36]. These results are consistent with JUPITER’S event-based endpoints, and suggest that the JUPITER protocol may not be impacting silent atherosclerosis.
Clearly in the context of true primary prevention of CHD the goal is to address coronary plaque by preventing its formation or limiting its extent or inducing regression to a degree which is clinically significant, not just a few percent reduction in a somewhat arbitrarily chosen target atheroma. The literature cited and discussed above suggests that a new approach is needed. There has already been one study that goes beyond LDL and reported significant regression in coronary plaque .
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