Lipid Ratios and the Prediction of Atherothrombotic Risk

To help answer the question of Mary Ellen Lewis, PA-C, about her patient with a low-density lipoprotein (LDL) cholesterol level of 120 mg/dL and a high-density lipoprotein (HDL) cholesterol level of 100 mg/dL (CONSULTANT, June 2007), I would like to describe my approach to the treatment of dyslipidemia. Like Dr Kannel, I use lipid ratios and a multifactorial approach; however, I use the cholesterol retention fraction (CRF), or (LDL-HDL)/LDL. Specifically, I use a graph with the CRF on the ordinate and systolic blood pressure (SBP) on the abscissa (Figure). A threshold line is defined by the points whose coordinates (SBP, CRF) are (100, 0.74) and (140, 0.49). In my experience, 85% of patients with some form of atherothrombotic disease (eg, acute myocardial infarction, acute cerebral infarction, abdominal aortic aneurysm) have SBP-CRF plots that lie above the threshold line.

Of those patients with atherosclerotic disease whose SBP-CRF plots are below the line, most are current or former cigarette smokers. In only 6% of all patients in whom atherothrombotic disease develops is their disease not predicted by SBP-CRF plot position above the threshold line or cigarette smoking status. Moreover, patients with atherothrombotic disease who do not smoke and have plot positions below the threshold are typically elderly at the time of atherothrombosis onset (average age, 78 years for men and 75 years for women) and do not die until much later (on average, 94 years for men and 84 years for women).¹ Using this graph and its threshold line as a guide for treating dyslipidemia and/or hypertension, with the goal of bringing the SBP-CRF plot below the line, results in angiographic stabilization/regression of coronary atherosclerotic plaque in a minimum average of 75% of patients.²

In my experience, high HDL cholesterol levels can compensate for LDL levels of up to 169 mg/dL. However, at LDL cholesterol levels of 170 mg/dL and higher, the preventive effect of HDL cholesterol is progressively more impaired, until at LDL levels of 250 mg/dL, no protection is afforded by HDL cholesterol.

Ms Lewis's patient has a CRF of 0.17 and an LDL cholesterol level much lower than 170 mg/dL. Assuming that her patient has normal blood pressure, the SBP-CRF plot will be below the threshold line. If this patient has never smoked cigarettes, he or she would have virtually no risk of an atherothrombotic event until the eighth decade of life. Thus, no treatment is necessary-other than help with smoking cessation, if warranted.

In a relatively few cases, HDL cholesterol may be dysfunctional. Markedly elevated HDL levels resulting from phenytoin therapy or alcoholism may not be anti-atherogenic-and, of course, the markedly high levels of HDL cholesterol caused by cholesteryl ester transfer protein inhibitors are not protective either.³ Finally, there is a syndrome in which markedly elevated HDL levels are actually pre-inflammatory and pro-atherogenic, as Dr Kannel noted. However, none of these conditions, except possibly alcoholism, is common and thus should not influence therapy discussions in the vast majority of cases.

---- William E. Feeman, Jr, MD
Bowling Green, Ohio

I applaud you for your efforts to promote the cholesterol retention fraction. The concept is sound, because it more completely reflects atherogenic dyslipidemia than does the LDL cholesterol level alone. The CRF is highly correlated with the non-HDL/HDL ratio (r = .68). Framingham Study data have shown that the non-HDL cholesterol level substantially influences risk at any LDL cholesterol level, after adjusting for all associated risk factors.¹ Thus, it is likely that the CRF performs similarly. I am not sure whether it is a more robust predictor than the non-HDL/ HDL ratio. Guidelines recommend a non-HDL goal of less than 130 mg/dL if the triglyceride level is 200 mg/dL or greater or if coronary disease, diabetes, or a 20% multivariable risk of coronary heart disease (or presumably cardiovascular disease in general) is present.² The CRF or non-HDL/HDL ratio would appear particularly relevant for assessing the risk of cardiovascular disease in patients who are insulin resistant.

We both agree that it is very important to take associated risk factors into account. An isolated lipid level elevation is rare; instead, these elevations tend to occur in clusters and in conjunction with other standard risk factors. Clusters of 3 or more additional risk factors accompany dyslipidemia in about 40% of patients. The risk associated with any blood lipid level varies widely depending on the number of accompanying risk factors.

---- William B. Kannel, MD, MPH
Professor of Medicine and Public Health
Boston University School of Medicine

References:

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Feeman WE Jr. Prediction of the population at risk of atherothrombotic disease.

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Nissen S, Tardif MD, Nicholls S, et al. Effect of torcetrapib on the progression of coronary atherosclerosis.

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Liu C, Sempos R, Donahue J, et al. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease.

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