Prebeta-1 HDL

Dear Dr Malloy,

I have just read your article on prebeta-1 HDL in the American Journal of Cardiology. I have found that the population at risk of atherothrombotic disease (ATD) is best predicted by the balance between LDL and HDL, and I use the Cholesterol Retention Fraction (CRF, or [LDL-HDL]/LDL) as the lipid predictor. (1, 2) In the latter publication, I presented a table that gives the incidence of ATD per age group and CRF sextile. (ATD includes AMI, AP, AAA, CVA, etc.) The incidence of ATD increases with age and higher CRF sextile, being highest with CRF of 0.80 or higher and least with CRF of 0.59 or lower. Cigarette smokers have their ATD events a decade or so earlier than do ex-smokers or never smokers. When the CRF is combined with systolic blood pressure (SBP), a graph can be created with the CRF on the ordinate and SBP on the abscissa. If one graphs the CRF-SBP plots of all ATD patients on this graph, then the vast majority of such plots form a cluster, separated from a few outliers. A threshold line can be generated that separates these main sequence ATD patient CRF-SBP plots from the outliers. The co-ordinates of this line are (0.74,100) and (0.49,140). [These co-ordinates are based on lipid values obtained when the indirect method of HDL measurement is used; if the direct method of HDL measurement is utilized, then the co-ordinates need to be adjusted to (0.62,100) and (0.40,140).] In my practice, and in the validation studies that I have been able to obtain (3), 85% of all ATD patients have CRF-SBP plots above the threshold line. (The validation studies tend to use younger patients with worse lipid abnormalities, and 95% of those ATD patients have CRF-SBP plots above the threshold line.)

Cigarette smokers, I had thought, had their ATD events earlier than ex-smokers and never smokers because cigarette smoking causes an inflammatory response in the fibrous cap of the ATD plaque and because smoking enhances clot formation, especially when combined with high TG. Now, I believe that you have pointed out that cigarette smoking may render HDL at least somewhat dysfunctional by interfering with the ability of prebeta-1 HDL to pick up free cholesterol from the macrophage/smooth muscle cell, thus enhancing cholesterol accumulation within the artery wall. This would be most obvious, if I understand your paper correctly, in people with CRF values not normally associated with early-onset ATD ( i.e., where HDL , LDL, and CRF levels appear to be normal). Cigarette smokers, with such lipid levels, should have their ATD events earlier in your study and ex-smokers/never smokers later. There may, however, be a lower limit on the ability of cigarette smoking to lead to ATD since some patients who smoke, but have ideal lipid levels, do not suffer their ATD events until their ninth decade of life.

Incidentally, in the absence of cigarette smoking, and in the presence of an optimal CRF (0.59 or less), TG elevations do not appear to be associated with early onset ATD. Moreover, the prediction of the population at risk of ATD is independent of the two hour postprandial blood sugar level (2 hr pp BSL), requiring only the graph previously described and cigarette smoking for accurate prediction. This suggests that cigarette smoking is the culprit at the base of prebeta-1 HDL dysfunction in younger patients, and that TG and the 2 hr pp BSL may promote ATD events in older patients via prebeta-1 HDL dysfunction. Interestingly, I have found that lipid levels are identical in AMI and AP patients, but the presence of cigarette smoking and/or diabetes will favor AMI as the presenting scenario, whereas the presence of hypertension favors AP as the presenting scenario.

I wonder if I might prevail upon you to plot the CRF-SBP plots of your ATD patients on my graph. You could then examine those ATD patients whose CRF-SBP plots lie below the threshold line. This is where the role of prebeta-1 HDL should be most obvious. Cigarette smokers should have their ATD events at an earlier age than ex-smokers, who should have their ATD events somewhat earlier than never-smokers. Also prebeta-1 HDL levels should be correspondingly higher in smokers than in ex-smokers—and even higher (?) than in never-smokers.

I hope that you perform this analysis and let me know the results. In any event, your article has opened up a new insight into ATD for me, and I thank you for that. Incidentally, if you want to see any of the publications/presentations that I cited, you can visit my website at


W.E. Feeman,Jr,MD

PS Can you send me some reprints of your article.


1. Feeman W.E, Jr., The Best Lipid Predictor. Journal of Clinical Lipidology. 2007; 1 (5): 421.
2. Feeman W.E. Jr. Prediction of the Population at Risk of Atherothrombotic Disease. Experimental and Clinical Cardiology. Winter 2004. 9: (4); 235-241.
3. Predicting the Population at Risk of Atherothrombotic Disease
Using a Lipid Ratio. Presented at the National Lipid Assoc. Scientific Sessions. May 2010.

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