Inflammation and ATD

To the Editor,

The comments of Paul Ridker, MD, in the Editor’s Roundtable: JUPITER follow-up (15 May 2011 issue of Amer J Cardiol, pgs 1549-1557), require comment. Ridker declares hsCRP to be a major risk factor for atherothrombotic disease (ATD). Dr Ridker is in error in this statement. If hsCRP were a major ATD risk factor, then people with the highest levels of hsCRP should have the highest risk for ATD and as Ridker himself has pointed out, natives of sub-Sahara Africa frequently have malaria, and those that do have malaria have extremely high levels of hsCRP, but do not have ATD events to any significant degree. This finding is consistent with Dr Roberts’ observation that people with rheumatoid arthritis and systemic lupus erythematosis have only a slight increase in atherosclerotic plaque. Moreover, it is common knowledge, as confirmed by Dr Friedewald, that nonsteroidal agents are excellent anti-inflammatory agents but actually increase the risk of ATD events. Finally, many conditions other than ATD cause rises in hsCRP, which is why repetitive testing is necessary to confirm the initial hsCRP. Hence, hsCRP can not be a major risk factor for ATD: risk factors actually cause ATD, but, on the other hand, markers of ATD simply denote the presence of ATD. Indeed, Ridker pointed out in the early days of hsCRP, that hsCRP is a marker for the inflammatory response to known ATD risk factors: cigarette smoking, dyslipidemia, and hypertension—and I might even add diabetes mellitus to this list.

Dr Ridker also states that an LDL level of <130 mg/dl is low. The average LDL at which an ATD event occurs in Wood County, Ohio, is 145 mg/dl in men and 154 mg/dl in women—so an LDL in the range of 130 mg/dl is not that low. The population at risk of ATD is easily and accurately predictable by a global risk factor graph, but only when a ratio between LDL and HDL is used (such as the Cholesterol Retention Fraction, or CRF, defined as [LDL-HDL]/LDL). (1) If only LDL is used, the accuracy of the predictive graph falls dramatically. (Feeman, unpublished data) This finding is illustrated by the case report by Dr Davidson: a woman with a strong family history of ATD, and LDL of 100 mg/dl, HDL of 20 mg/dl, and hsCRP of 6 mg/L. Her LDL probably would not usually be considered for treatment, but her CRF is 0.80, which is in the highest sextile and warrants therapy. In my experience, however, ATD events in patients with this type of dyslipidemia, in the absence of cigarette smoking, do not happen till very late in life—unless these lipids have been present since birth. (Incidentally, a hsCRP value of 6 mg/L is high enough to suggest a non-ATD etiology.) The global risk factor graph has been presented in this Journal. (2) I included it in this letter for illustrative purposes. (See Figure.) Finally, I have an age-sex database of full lipid panels for almost 3000 persons. People in this database are free-living in their own homes and are rarely receiving dyslipidemic medications. The average LDL levels of the patients aged 80 years or more are 134 mg/dl in men and 136 mg/dl in women. Respective CRF values are 0.63 and 0.55. Of the 27 men, only three have LDL levels below 100 mg/dl, and only one of those is anywhere near 70 mg/dl. Of the 42 women, only five have LDL levels below 100 mg/dl, and of those only one is anywhere near 70 mg/dl. Thus, a LDL level of 70 mg/dl is not necessary for a long life. In conclusion, I question the comments of Ridker. I would appreciate his response. Sincerely, W.E. Feeman, Jr, MD References: 1. Feeman W.E. Jr. Prediction of the Population at Risk of Atherothrombotic Disease. Experimental and Clinical Cardiology. Winter 2004. 9: (4); 235-241. 2. Feeman W.E. Jr. Treating Lipids in the General Population. American Journal of Cardiology. August 1, 2008; 372-373.

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