To the Editor, I was delighted to read the lead article (in the Autumn issue of The Lipid Spin) by Maria Luz Fernandez, PhD, concerning the use of

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1 To the Editor, I was delighted to read the lead article (in the Autumn issue of The Lipid Spin) by Maria Luz Fernandez, PhD, concerning the use of the LDL: HDL ratio in the prediction of the population at risk of atherothrombotic disease (ATD). She also points out INTERHEART findings which propose that the aop-b:aopa-i ratio is superior to the LDL:HDL ratio. The problem with the apoprotein ratio is that apoproteins are not ready for widespread testing in the various clinical laboratories across the country. Moreover, TG contribute to apo-b, and it is well known that TG do not contribute materially to the ATD plaque. I have further shown that in patients with optimal LDL and HDL levels and no history of cigarette smoking, elevated TG do not impact ATD, at least in terms of average age of ATD onset. (1) But even more critically, there have been no published randomized clinical trials (RCT) to establish outcomes data, and hence goals of therapy, for apoproteins and their ratios. Thus, any proposed goals for apoproteins are at best speculative and must await the results of RCT s to define such goals. The above problems are not applicable to the use of lipid ratios. In 2000, I published a meta-analysis of eight published angiographic regression trials. (2) I discussed these findings in Phorum 5 in April, Briefly, I use a variation of the LDL:HDL ratio specifically, the Cholesterol Retention Fraction (CRF, or [LDL HDL]/ LDL), which is 5% more accurate than the LDL:HDL ratio in predicting the population at risk of ATD. I have combined the CRF with the systolic blood pressure (SBP) into a graph, which when combined with cigarette smoking status, creates a global risk tool that contains a threshold line. (See figure.) The threshold line is not a regression line, but rather a line of demarcation separating the mainstream of CRF-SBP plots of ATD patients from a few outliers, providing the greatest area under the line with the fewest CRF-SBP plots, using the principal of the fewest false negatives. Patients who develop ATD despite a CRF- SBP plot below the threshold line are usually cigarette smokers, current or past. Patients who develop ATD despite a CRF-SBP plot below the threshold line and who have never smoked cigarettes tend to be old at time of their clinical events, usually late in the eighth decade of life, with death usually occurring years later. I consider that such patients are virtually immune to ATD. In the meta-analysis, I showed that any therapy that brought the CRF-SBP plot below the threshold line resulted in angiographic stabilization/regression of coronary plaque in a minimum average of 75% of cases and had POSCH been structured to control blood pressure, that number would have exceeded 95% of cases. This finding was at least as good as substituting LDL for the graph. Thus, we do have angiographic evidence of outcomes for lipid ratios, and since plaque stabilization/regression is associated with a decrease in ATD clinical events (3), then by extension, clinical outcomes. One notes that at higher levels of SBP, even within the normal range, the CRF must be lower in order for the CRF-SBP plot to be below the threshold line. Hence, there is no fixed goal for the CRF, rather the goal is whatever it takes to get the CRF-SBP plot below the threshold line. Use of the CRF has problems at both ends of the spectrum. When LDL is very high, HDL is unable to compensate. This begins at LDL > 169 mg/dl (4.4 mmoles/l) and in my experience, the ability of HDL to compensate for LDL is virtually lost when LDL > 250 mg/dl (6.3 mmoles/l). Hence I always try to get LDL <170 mg/dl (4.4 mmoles/l). These limits also hold for the LDL:HDL ratio. Conversely, when HDL

2 is exceedingly low, the CRF will always be high. In such cases, I try to get LDL < 80 mg/dl (2.0 mmoles/l). (2) This is also true for the LDL:HDL ratio. Since the NCEP has never run a RCT to vet its goals, and since these goals are in virtual continual revision, I see no reason why the 2009 revision of NCEP goals could not utilize lipid rations. Why not? At any level of LDL, knowledge of the CRF provides additional risk stratification, at least in terms of average age of ATD onset and number of patients. (1) This data can be applied to Jupiter findings as well. (4) Briefly, Jupiter studied patients with lower levels of LDL and high hs-crp. Jupiter was stopped early because of fairly marked reductions in ATD events and mortality in the rosuvastatin group. May I suggest that since it has been established that patients who develop ATD with lower levels of LDL usually have low levels of HDL (5), then the high hs-crp is simply a surrogate for low HDL and that those who benefited from rosuvastatin were those with high CRF s and that placebo patients who suffered ATD events likewise were those with higher CRF s. The argument runs as follows: some LDL crosses the endothelium and enters the media when LDL> 100mg/dl (2.5 moles/l), but as long as HDL levels are sufficiently high, say 40 mg/dl (2.0 mmoles/l), the HDL is able to retrieve the LDL by reverse cholesterol transport; however, if HDL is deficient, the LDL accumulates and the lower the HDL, the faster LDL accumulates setting up an inflammatory response and resulting in an elevated hs-crp. It would be interesting to run the Jupiter analysis in terms of CRF instead of hs-crp. I believe that such an analysis would show that those Jupiter patients who had benefit from rosuvastatin and those who sustained ATD evens on placebo had higher CRF s, giving CRF-SBP plots above the threshold line, whereas those who had no benefit from rosuvastatin or suffered no harm on placebo were patients with CRF-SBP plots below the threshold line. Sincerely, W.E. Feeman, Jr, MD

3 References: 1. Feeman WE Jr. Best Lipid Predictor. National Lipid Association (NLA) Scientific Sessions, May 2008, Seattle, Washington. 2. Feeman WE Jr. Best Lipid Predictor. National Lipid Association (NLA) Scientific Sessions, May 2008, Seattle, Washington. 3. Gotto AM. Lipid Lowering, Regression, and Coronary Events. Circulation 1995; 92: Ridker PM, Danielson E, Fonesca FAH, Genest J, etal. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. N Engl J Med. 2008; 359 (21): Miller GJ, Miller NE. Plasma High-Density Lipoproteins Concentration and Development of Ischemic Heart Disease. Lancet. 1975; 1:

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