The Best Lipid Fraction for the Prediction of the Population at Risk of Atherothrombotic Disease. William E. Feeman, Jr., M.D.

Transcription

1 The Best Lipid Fraction for the Prediction of the Population at Risk of Atherothrombotic Disease William E. Feeman, Jr., M.D. 640 South Wintergarden Road Bowling Green, Ohio Phone Fax BGS No conflict of Interest No publication elsewhere No financial contracts No sources of support No Disclosures Word Count: 2525

2 Introduction Dyslipidemia is an important cause of atherothrombotic disease (ATD, or atherosclerotic disease with emphasis on the thrombosis that so often precipitates the acute clinical event, such as acute myocardial infarction, acute cerebral infarction, abdominal aortic aneurysm, etc.) (1-6) Four lipid fractions are widely available for screening: total serum cholesterol (CT), low-density lipoprotein (LDL) cholesterol, a ratio between CT and high-density lipoprotein (HDL) cholesterol (hereafter termed the Framingham Fraction, or FF), and a ratio between LDL-cholesterol and HDL-cholesterol. A newer lipid ratio between LDL-cholesterol and HDL-cholesterol, specifically the cholesterol retention fraction (CRF, or [LDL-HDL]/LDL) has been advocated (7). The CRF has been shown to be of value in predicting the population at risk of ATD (7) and in guiding therapy to maximally stabilize/regress coronary plaque angiographically (8). The purpose of this article is to compare the ability of these five lipid fractors to predict the population at risk of ATD.

3 Materials and Methods The author began his practice of family medicine in Bowling Green, the county seat of Wood County, in northwest Ohio on 4 Nov Details of the author s practice here been published elsewhere. (7, 9-10) Briefly, the author s practice, for purposes of this paper, consists of patients typically seen in family practice: members of both sexes and all age groups, from newborns to people in their tenth decade of life. During the 4 Nov Nov 2003 time frame, 6763 male and 6635 female patients (total 13,398 people) were seen in the author s office and entered into the general population data base of the Bowling Green Study (BGS) of the Primary and Secondary Prevention of Atherothrombotic Disease (ATD). These patients were mainly European-Americans, with Mexican-Americans being the chief minority. Asian-Americans and African- Americans were present only in small numbers. Bowling Green is a small city in the midst of the farmlands of Northwest Ohio. It numbers about 16,000 people, but is also the home of Bowling Green State University, which adds an additional 12,000 individuals to the populace. The University is also the city s chief employer. Multiple small industries are also present, but in the environs of Bowling Green, agriculture is the chief form of employment. Wood County, of which Bowling Green is the county seat, has an overall population of about 110,000 people. Many of these people seek their medical care in Bowling Green. The populations of Bowling Green and Wood County in general do not differ much. All of the author s patients have been entered into an age-sex database. Thus, blood pressures are known for 6579 male and 6620 female patients. Body mass index

4 determinations are known for 6688 male and 6631 female patients. Cigarette smoking status was not routinely until 1984; hence this data is known only for 4136 male and 3884 female patients. Total serum cholesterol (CT) is known for 2039 male and 2202 female patients and triglycerides (TG) are known for 1881 male and 2056 female patients. Since LDL- and HDL-cholesterol data were not available in Bowling Green until 1978, complete lipid profiles are available for only 1340 male and 1482 female patients. Twohour postprandial blood glucose levels are known for 1506 male and 1646 female patients. Initially, the author s practice was incorporated into a general population database, as described above. Over time, however, a number of the author s patients (1009 patients during the 4 November November 2003 timeframe) developed ATD events. These events included all ATD events in all vascular beds, and hence included such events as acute myocardial infarction, acute cerebral infarctions, abdominal aortic aneurysm, etc. All ATD patients were subsequently incorporated into an ATD database. In discussion of this database, it must be noted that the populace of Bowling Green and its environs is a fluid population. Thus complete follow-up of all patients to ascertain ATD status is not possible. However, there is only one hospital in Wood County (Wood County Hospital) and when patients who have left the author s practice enter into the hospital, the author is often able to interview them to ascertain ATD status. Also, the author s patients know of his interest in preventive cardiology, and at times inform him of what has happened to their relatives whom he formerly treated. Finally,

5 during the study timeframe, death certificates were in the public domain and the author was able to view the death certificates of his ex-patients and determine the cause of death. A brief discussion about the Cholesterol Retention Fraction (CRF, or [LDL- HDL]/LDL) is in order. The BGS devised the CRF as a means of estimating the amount of cholesterol accumulating in the artery wall. The CRF takes into account the amount of cholesterol entering the artery wall (LDL), and the amount of cholesterol being removed from the artery wall by reverse cholesterol transport (HDL). This difference was than expressed as a fraction of the cholesterol entering the artery wall. The concept was essentially this: of the cholesterol entering the artery wall, what percentage stays there. Initially, the simple LDL:HDL ratio was used, but was abandoned because the CRF predicts ATD patients better than the LDL:HDL ratio by 5% (Feeman, unpublished data). Incidentally, inspection of the author s database indicates that if LDL levels are excessively high, then even high levels of HDL cannot prevent the accumulation of LDLcholesterol within the artery wall and the consequent onset of clinical ATD events. In the BGS, the LDL level at which HDL s protective powers begin to fail is 170 mg/dl (4.4 moles/l). Even so, the lower the CRF, the later in life is the onset of ATD. The scenario of CRF > 0.70 and/or LDL > 170 mg/dl (4.4 mmoles/l) is termed the Cholesterol Threshold (CThr). For purposes of this analysis, the four lipid predicators have been divided into sextiles. (See Table I) The LDL:HDL ratio is not included in this table because CRF is a better lipid predictor.

6 Results Table I gives the breakdown of each lipid predictor into sextiles. In the first analysis, the four lipid predictors have been compared with respect to the incidences of each of the sextiles in the general population (of the BGS database) and the portion of ATD patients in each sextile. See tables II-III. It will be noted that for each lipid predictor, the higher the sextile ranking, the greater the proportion of ATD patients in that sextile. (Table II) However, the FF, LDL, and CT lipid predictors have progressively fewer general population patients in the higher sextiles of the predictors. (Table III) In other words, the FF, LDL, and CT lipid predictors predict the population of ATD patients better and better in fewer and fewer patients. Only with the CRF does the number of patients rise as the sextile rank increases, such that the CRF predicts the population of ATD patients better and better in more and more patients. In the second analysis, the four lipid predictors are compared as to the frequency of each sextile in the general population and the frequency of each sextile in the ATD population. (Tables III and IV) For the FF, LDL, and CT lipid predictors, the sextiles in the general population have many more patients in the lower ranking sextiles than in the higher-ranking sextiles, and the same is true in the ATD population. Only with the CRF do numbers of ATD population patients increase as the number of general population patients increase. In the third analysis, which is limited to the ATD population, the sextiles of each lipid predictors (FF, LDL, and CT) are compared with similar sextiles of the CRF. (See Table V for LDL; Tables for FF and CT are not shown but follow the same pattern) It will be noted that, in general, at any level of each of the three lipid predictors (FF, LDL,

7 and CT) the higher the CRF, the younger is the average age of ATD onset and the lower the CRF, the older is the average age of ATD onset. The tables permit the opposite analysis and in general the age of ATD onset is less clearly demonstrated when the CRF is held constant and the values of other lipid predictors are increased or decreased.

8 Discussion Epidemiologically, to be a good lipid predictor, the predictor should do three things very well. First, it should predict the ATD incidence progressively better as its value is progressively higher, but conversely, it should also have a reasonable number of people in its upper ranges. FF, LDL, CT, and CRF all predict a greater incidence of ATD as the upper ranges of each predictor are approached. However, there are progressively fewer patients in the higher sextiles of the FF, LDL, and CT predictors. Only with the CRF do the numbers of people in the higher CRF sextiles not only not drop sharply, but also actually rise. This is clearly important since there are more people who are targets for intervention in the upper CRF sextiles than in the upper FF, LDL, and CT sextiles. This in turn implies that more ATD events can be prevented using the CRF as the prime lipid predictor. Second, the best lipid predictor should have most of its ATD patients at the higher end of its range and only a few at the lower end of its range. This is clearly true for the CRF, but the sextiles in which the most ATD events occur in the other predictors range between Sextiles II and IV. This is important because, ideally, only those people at moderate or high risk of an ATD event should be treated. Such a targeted approach prevents treatment of those not at risk for the lipid portion of the ATD risk profile, and as a result allows limited health care resources to be allocated more prudently. As a result, one would treat CRF Sextiles V and VI. (See below for comment about treatment of Sextile IV in women) and not treat lower sextiles. For LDL, one would have to treat at Sextile III and higher; for CT, one would have to treat at Sextile IV and higher. For FF, it

9 is difficult to make a treatment decision, but perhaps treatment should begin at Sextile II or III and higher. Another way to approach this matter is to advise treatment whenever the lipid predictor incidence in the ATD population exceeds that in the general population. Hence, using the CRF predictor, one would treat at Sextile V and higher in men and Sextile IV in higher in women. Using FF, one would treat at Sextile III and higher and the same is true for LDL. Using CT, one would treat at Sextile IV and higher. Sextile IV in the CRF predictor for women deserves explanation. Most women who develop ATD in this group are elderly hypertensive patients in their eight and ninth decades of life. Moreover if one separates this sextile into halves ( and ), then the risk is higher in the latter cohort than former cohort Since this group of women is at risk mainly latter in life, this author's practice is to treat the associated hypertension first and then treat the lipids if needed. Third, at any level of FF, LDL, and CT, stratification by CRF produces a gradient in ATD risk, as measured by the average age of ATD onset. The ability of the CRF to, in general, stratify ATD risk (as measured by average of ATD onset) at any given level of the other three predictors implies its superiority over the other three predictors. The findings of this study should not come as a surprise to lipidologists. CT is the sum of LDL, HDL, and very-low density lipoprotein cholesterol (VLDL). Hence, CT may be elevated if any of these components are elevated. Elevated LDL clearly constitutes a risk of ATD; however, elevated HDL does not and neither does an isolated VLDL, (11). Unfortunately an elevated CT does not tell the physician which combination of the components are elevated. For example, given a CT of 250 mg/dl (6.48 mmoles/l), is the

10 ATD risk the same if LDL=125mg/dl (3.24 mmoles/l) HDL=100mg/dl (2.59 mmoles/l), and VLDL=25 mg/dl (0.28 mmoles/l) or if LDL=170mg/dl (4.40 mmoles/l), HDL=20mg/dl (0.52 mmoles/l) and VLDL= 60 mg/dl (0.68 mmoles/l)? The former patient is at little risk of ATD, whereas the latter patient is at extremely high risk of ATD- --yet both have the same CT. A similar scenario holds for LDL. The average LDL for an ATD event in a male in the BGS is 145 mg/dl (3.78 moles/l). (Feeman unpublished data) If a lipid profile of a male discloses a LDL level of 145 mg/dl (3.78 mmoles/l), should his physician panic and prescribe a statin immediately? This author believes that a further investigation is necessary first. Suppose that patient has a HDL of 100mg/dl (2.59 mmoles/l) and a VLDL of 25 mg/dl (0.28 mmoles/l), or alternately suppose that the patient has a HDL of 20 mg/dl (0.52 mmoles/l) and a VLDL of 60 mg/dl (0.68 mmoles/l). The former patient is at little risk of an ATD event if he has never smoked cigarettes, is not hypertensive, and is not diabetic. The latter patient is at very high risk, and if he is also a cigarette smoker who is also a diabetic hypertensive, he is at extremely high risk. The former patient might well be followed on diet and exercise, whereas the latter patient requires medication at the onset and both have the same LDL level. As for FF, the ratio may be high if LDL is high, if HDL is low, or if VLDL is high. The average FF for a male with ATD in the BGS is 5.9. (Feeman, unpublished data) If a male patient has HDL=40 mg/dl (1.04 mmoles/l), LDL=60 mg/dl (1.55 mmoles/l), and VLDL=136 mg/dl (1.54 mmoles/l), or if he has HDL=80 mg/dl (2.07 mmoles/l), LDL=380 mg/dl (9.84 mmoles/l), and VLDL=10 mg/dl (0.11 mmoles/l), in either case FF=5.9, but would the treatment scenario be the same? Certainly, the therapeutic

11 regimen would be vastly different in these two men with the same FF (5.9) and certainly the goals of treatment would be different. The former patient would be treated to prevent pancreatitis, the latter to prevent ATD.

12 Conclusion The CRF is a better predictor of the lipid portion of ATD risk because as CRF sextiles increase in rank, the CRF predicts that risk better in more patients, whereas FF, LDL, and CT predict risk better in fewer patients. The CRF is a better lipid predictor, moreover because only the patients in the Sextiles V and VI need treatment, whereas with the other lipid predictors (FF, LDL, and CT) ATD risk is higher in the middle sextiles. Furthermore, CRF is a better lipid predictor because at, in general, any given Sextile of the other lipid predictors (FF, LDL, and CT), ATD risk is stratified (when measured by the average age of ATD onset) by CRF, being younger when CRF is higher, and older when the CRF is lower. Finally, the case scenarios described at the end of Discussion clearly show the ambiguities in treatment of dyslipidemia using FF, LDL, and CT. Since the CRF is purely a disorder of the cholesterol entering the artery wall and the cholesterol being removed from the artery wall, it is not subject to those ambiguities.

13 Table I Lipid Predictor Sextiles Lipid I II III IV V VI Predictor CT < 99 mg/dl mg/dl mg/dl mg/dl mg/dl > 300 mg/dl < 2.56 mmoles/l mmoles/l mmoles/l mmoles/l mmoles/l > 7.77 mmoles/l LDL < 99 mg/dl mg/dl mg/dl mg/dl mg/dl > 200 mg/dl < 2.56 mmoles/l mmoles/l mmoles/l mmoles/l mmoles/l > 5.18 mmoles/l FF < > 8.0 CRF < > 0.80 CT means total cholesterol LDL means low-density-lipoprotein cholesterol HDL means high-density-lipoprotein cholesterol FF means Framingham Fraction, or the ratio of total cholesterol to high-density-lipoprotein cholesterol (CT: HDL) CRF means Cholesterol Retention Fraction, or (LDL-HDL)/LDL

14 Table II ATD Incidence Per Lipid Sextile in General Population Sex Lipid Predictors I II III IV V VI Male No. ATD pts per sextile CRF No. pts. per sextile % 11% 15% 18% 28% 39% No. ATD pts per sextile LDL No. pts. per sextile % 14% 26% 30% 38% 42% No. ATD pts per sextile FF No. pts. per sextile % 21% 22% 34% 28% 46% No. ATD pts per sextile CT No. pts. per sextile % 3% 13% 27% 34% 44% Female No. ATD pts per sextile CRF No. pts. per sextile % 12% 11% 21% 28% 44% No. ATD pts per sextile LDL No. pts. per sextile % 10% 21% 26% 38% 54% No. ATD pts per sextile FF No. pts. per sextile % 18% 29% 34% 44% 45% No. ATD pts per sextile CT No. pts. per sextile % 3% 7% 21% 40% 51% See Table I for sextile parameters and definition of lipid predictors

15 Table III Frequency Distribution of Sextiles per Lipid Predictor in General Population Sex Lipid Predictors I II III IV V VI Male No. pts per sextile CRF Total pts. per sextile % 7% 16% 26% 32% 11% No. pts per sextile FF Total pts. per sextile % 25% 19% 12% 6% 7% No. pts per sextile LDL Total pts. per sextile % 25% 24% 17% 7% 5% No. pts per sextile CT Total pts. per sextile ~0% 11% 43% 32% 11% 3% Female No. pts per sextile CRF Total pts. per sextile % 14% 20% 24% 20% 5% No. pts per sextile FF Total pts. per sextile % 22% 14% 6% 3% 3% No. pts per sextile LDL Total pts. per sextile % 28% 21% 13% 7% 6% No. pts per sextile CT Total pts. per sextile ~0% 11% 43% 32% 11% 4% See Table I for sextile parameters and definition of lipid predictors

16 Table IV Frequency Distribution of Sextiles per Lipid Predictors in Atherothrombotic Disease Population Sex Lipid Predictors I II III IV V VI Male No. pts. per sextile CRF Total patients % 4% 10% 20% 39% 22% No. pts. per sextile FF Total patients % 21% 19% 20% 9% 16% No. pts. per sextile LDL Total patients % 18% 27% 21% 12% 9% No. pts. per sextile CT Total patients % 30% 41% 19% 6% Female No. pts. per sextile CRF Total patients % 8% 12% 30% 30% 13% No. pts. per sextile FF Total patients % 25% 22% 11% 8% 7% No. pts. per sextile LDL Total patients % 18% 25% 18% 14% 15% No. pts. per sextile CT Total patients % 22% 38% 27% 11% See Table I for sextile parameters and definition of lipid predictors

17 Table V CRF vs LDL Sextiles in Atherothrombotic Disease Population LDL Sextiles CRF Sextile 710 patients > < 0.39! > , < ! ,134 11, CRF means Cholesterol Retention Fraction ([LDL-HDL]/LDL) LDL means low density lipoprotein cholesterol

18 Table VI CRF vs FF in Atherothrombotic Disease Population: FF Sextiles CRF Sextiles 710 patients > < 0.39! > , < , ! ,134 11, CRF means Cholesterol Retention Fraction [(LDL-HDL]/LDL) FF means Framingham Fraction (CT/HDL)

19 Table VII CRF Sextiles vs CT Sextiles in Atherothrombotic Disease Population: CT Sextile CRF Sextiles 710 patients > < 0.39! > , , , < ! ,134 11, CRF means Cholesterol Retention Fraction ([LDL-HDL]/LDL) CT means total cholesterol

20 References: 1. Keys A, Aravanis C, Blackburn H, van Buchen FSP, et al. Probability of Middle- Aged Men Developing Coronary Heart Disease in Five Years. Circulation. 1972;45: Gordon T, Garcia-Palmier, Kagan A, et al. Differences in Coronary Heart Disease in Framingham, Honolulu, and Puerto Rico. J. Chron. Dis. 1974;27: The Expert Panel. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med. 1988;148: Greenland P, Knoll MD, Stamler J, et al. Major Risk Factors as Antecedents of Fatal and Nonfatal Coronary Heart Disease Events. JAMA. 2003;290: Khot UN, Khot MB, Bajzer CT, et al. Prevalence of Conventional Risk Factors in Patients with Coronary Heart Disease. JAMA. 2003;290: Nam BH, Kannel WB, D Agostino. Search for an Optimal Atherogenic Lipid Risk Profile: From the Framingham Study. Am J Cardio. 2006;97: Feeman W.E. Jr. Prediction of the Population at Risk of Atherothrombotic Disease. Experimental and Clinical Cardiology. Winter : (4); Feeman W.E. Jr. Prediction of Angiographic Stabilization/Regression of Coronary Atherosclerosis by a Risk Factor Graph. J. Cardio. Risk. 2000; 7:

21 9. Feeman W.E. Jr. The Bowling Green Study of the Primary and Secondary Prevention of Atherosclerosis: Descriptive Analysis, Findings, Applications and Conclusions. Ohio J. Sci. 92 (5): Feeman W.E. Jr. The Bowling Green Study of the Primary and Secondary Prevention of Atherosclerotic Disease: Update Ohio. J. Sci. 94 (4): Feeman W.E. Jr. Proposal for a New Lipid Disorder Classification presented at the 14 th International Symposium on Drugs Affecting Lipid Metabolism. September 2001 New York City, New York.

22 Addendum CRF vs Other Lipid Predictors Total ATD Population Average Age at ATD Onset Sextile Equivalent Line Above Line On Line Below Line FF LDL CT

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