Journal of the American College of Nutrition, Vol. 27, No. 1, 1-5 (2008)
Published by the American College of Nutrition
The LDL to HDL Cholesterol Ratio as a Valuable Tool to Evaluate Coronary Heart Disease Risk
Maria Luz Fernandez, PhD and
Densie Webb, PhD, RD
Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut (M.L.F.)
Health and Nutrition Communications, Austin, Texas (D.W.)
Address reprint requests to: Maria Luz Fernandez, PhD, University of Connecticut, Dept. Nutritional Sciences, 3624 Horsebarn Road Ext., U-17, Storrs, CT 06269. E-mail: maria-luz.fernandez{at}uconn.edu
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ABSTRACT
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The current National Cholesterol Education Program Adult Treatment Panel III guidelines recommend specific target levels of LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) for determining cardiovascular disease (CVD) risk and evaluating the effectiveness of lipid-lowering therapies. While there is a growing consensus that levels of apolipoprotein (apo) B and the ratio of apo B/apo A-I are more accurate predictors of CVD risk, the question has been raised as to whether it is realistic to expect patients and health professionals to switch from cholesterol-based guidelines to apolipoprotein-based guidelines. Because it will take time before apolipoprotein terminology is recognized by the general public and recommended by the NCEP Adult Treatment panel to evaluate risk, it may be more efficacious to continue adhering to the already familiar and proven measurements of the LDL-C/HDL-C ratio. The following review provides evidence that the LDL-C/HDL-C ratio continues to be a valuable and standard tool to evaluate CVD risk in all populations.
Key words: LDL cholesterol, HDL cholesterol LDL-C/HDL-C ratio, cardiovascular disease risk, apolipoprotein B, apolipoprotein A-I
Abbreviations: Apo = apolipoprotein • CRP = C reactive protein • CVD = cardiovascular disease • HDL-C = HDL cholesterol • LDL-C = LDL cholesterol • MI = myocardial infarction • NCPE = National Cholesterol Education Program
Key teaching points:
•The NCEP recommends target levels for both LDL cholesterol and HDL cholesterol to assess risk for heart disease
•The LDL-C/HDL-C ratio provides key information regarding coronary heart disease risk
•Several epidemiological and clinical studies have found that the LDL-C/HDL-C ratio is an excellent monitor for effectiveness of lipid lowering therapies
•The LDL-C/HDL-C is a better predictor for risk of heart disease than LDL-C alone
•The LDL-C/HDL-C reflects the two way traffic of cholesterol entering and leaving the arterial intima
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Introduction
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Controversy exists regarding what is the best method for identifying those who are at increased risk for coronary heart disease. Some experts have proposed C-reactive protein (CRP), a marker for inflammation, as a screening tool for prediction of cardiovascular disease (CVD). Several epidemiological studies have shown positive associations between CRP levels and the incidence of cardiovascular disease [1–5] although recent studies have questioned the validity of the connection [6,7]. However, The current National Cholesterol Education Program (NCEP) guidelines recommend specific target levels of LDL and HDL cholesterol for determining CVD risk and evaluating effectiveness of lipid-lowering therapies [8]. It is interesting to note that recent studies have found the level of apolipoprotein (apo) B and the ratio of the lipoproteins apo B/apol A-I to be the most accurate predictors of risk and the best measurements for evaluating treatment [9–13]. Because each atherogenic particle contains one molecule of apoB, levels of apo B are a direct measurement of the number of potentially atherogenic particles including very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and LDL [14]. Similarly, the concentration of apo A-I reflects the number of antiatherogenic HDL particles and not just the concentration of cholesterol carried by this lipoprotein. In other words the number of atherogenic versus non-atherogenic lipoproteins transported in blood provides a more comprehensive evaluation of cardiovascular disease risk.
Traditional cholesterol measurements tend to be most accurate at predicting risk for those at the lower and higher ends of the risk spectrum. These measurements are less helpful for the majority of people whose risk falls somewhere in between [15]. The Thirty-Person/Ten-Country Panel recently concluded that the apo B/apo A1 ratio is superior to conventional cholesterol measurements in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease [12]. The panel also recommended that apo B be included in all guidelines as an indicator of cardiovascular risk. Both the INTERHEART [10] and the AMORIS [16] studies, show a strong, direct relation between a high apoB/apoA-1 ratio and an increased risk for fatal and acute myocardial infarction (MI).
While the apo B/apo A I ratio is rapidly gaining favor as the most accurate measurement the question remains if the improved ability to predict risk, justifies the increased cost of widespread apolipoprotein screening and whether the substitution of apolipoprotein-centered measurements to cholesterol-centered measurements would serve to help or simply to confuse both patients and health professionals.
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Problems in Changing from Lipoprotein Cholesterol to Apolipoproteins
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From a practical standpoint, questions have been raised as to how readily a change in standards for assessing risk would be accepted by patients as well as physicians in general practice including cardiology, diabetology, neurology and other specialties [17]. The measurement of LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) is part of the standard blood lipid profile while determination of circulating apolipoproteins is not. Additional testing must be ordered by the physician and the additional cost carried by the patient. Major insurance carriers consider that testing for apoB is experimental and not a routine measurement and therefore will not reimburse the expense [18]. Insurance companies are unlikely to cover costs of apo B and apo A1 testing as long as it is not part of the NCEP guidelines, but the guidelines are unlikely to focus on apolipoproteins until testing and reimbursement are readily available and affordable for patients.
Aside from the added expense, the implementation of apolipoprotein testing presents some general public education problems. While cholesterol is a household word, apo B and apo A-I are not. Dr. Ole Faergeman of the National Heart and Lung Institute in London has argued that it would be difficult to educate the public in "apolipoproteinology" [17] and supports the idea that the wisest action should be to maintain cholesterol measurements as the focus for patients. Dr. Margo Denke from the University of Texas Health Science Center in San Antonio, who coauthored the latest US NCEP guidelines also argues against moving to apolipoprotein measurements. Her rationale is based on the enormous amount of time, effort and money that have been spent educating health professionals and the public regarding cholesterol terminology. Replacing cholesterol with apo B or a ratio of apo B/apo A-I, would result in further confusion [19]. Moreover, substituting apo B for LDL-C would be difficult at this point, since the central principle of the NCEP guidelines is to use new knowledge to build on existing guidelines, not to replace them with guidelines based on new concepts. However, the path of least resistance in terms of cholesterol education may not be the best path to take in terms of improving detection and treatment of cardiovascular disease.
A more tenable option that has been proven to be an accurate predictor of cardiovascular risk is the LDL-C/HDL-C ratio, which can be obtained from a standard lipid profile and is more accurate than LDL-C or HDL-C alone [20]. Changes in ratios have been shown to be better indicators of successful CHD risk reduction than changes in absolute levels of lipids or lipoproteins [21,22]. Moreover, while not perfect, measurements of apo B and apo A-I tend to reflect the levels of LDL-C and HDL-C [23].
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Evidence for the Predictive Value of LDL-C/HDL-C Ratios
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Several large epidemiological and clinical studies have found the LDL-C/HDL-C ratio to be an excellent predictor of CHD risk and an excellent monitor for the effectiveness of lipid-lowering therapies [20,22,24–26].
In the Helsinki Study, a 5-year clinical trial of more than 4,000 middle-aged men with elevated lipids, the LDL-C/HDL-C ratio had more prognostic value than LDL-C or HDL-C alone [20]. The ratio was especially accurate at predicting risk among those who also had elevated triglyceride levels. It was found that by using the LDL-C/HDL-C ratio along with fasting triglyceride concentration, it was possible to identify a subgroup that was able to achieve over 70% reduction in CHD risk with gemfibrozil (a lipid-lowering agent). The findings suggest that relatively simple laboratory measurements can be used to identify a small group of people that is most likely to benefit from long-term drug intervention.
The PROSPER trial, a retrospective analysis of 6,000 patients, found that the ratio of LDL-C/HDL-C was the most powerful measure of cardiovascular disease risk in elderly people [27]. The researchers also concluded that changes in LDL-C/HDL-C ratio as a result of statin treatment appeared to account for the beneficial effects of therapy and suggested that statin therapy could usefully be targeted to those with an LDL-C/HDL-C ratio >3.3.
The PROCAM Study, which included almost 11,000 men aged 36 to 65 years who were studied for 4 to 14 years, found a continuous and graded relationship between the LDL-C/HDL-C ratio and CVD mortality [24]. Coronary deaths spiked when the LDL-C/HDL-C ratio reached between 3.7 and 4.3. In the Physicians’ Health Study, which involved almost 15,000 men ages 40 to 84 years, a 1-unit increase in the LDL-C/HDL-C ratio was associated with a 53% increase in risk of MI [25]. In the Boston Area Health Study, which analyzed a group of men and women less than 76 years of age with no prior history of CVD but who had experienced a first MI, a 1-unit increase in the LDL-C/HDL-C ratio was associated with a 75% increase in risk of MI [28]. In addition, comparison of individual LDL-C/HDL-C ratios from subjects in the Framingham Study clearly indicates that the ratios are significantly more robust predictors of CVD than the individual levels of LDL-C or HDL-C [22].
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The Effect of Dietary Cholesterol on the LDL-C/HDL-C Ratio
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The effects of dietary cholesterol on blood lipid can be used as an example to illustrate why LDL-C/HDL-C is a better predictor of CVD than LDL-C alone. Numerous studies have shown that the LDL-C/HDL-C ratio is not affected by dietary cholesterol [29,30]. However, earlier studies evaluating the impact of dietary cholesterol on serum cholesterol focused on total cholesterol as the primary marker for risk, and dietary cholesterol was, at the time, believed to have an impact on this marker. Subsequent studies focused on plasma LDL-C concentrations as is reflected in the ATP III Guidelines, and limitations on dietary cholesterol are a part of the recommendations for diet and lifestyle changes designed to reduce risk [8].
Feeding studies have demonstrated that dietary cholesterol increases both LDL and HDL cholesterol, with little change in the LDL-C/HDL-C ratio. On average, the LDL-C/HDL-C ratio is predicted to increase 0.01 unit per 100 milligrams/day increase in dietary cholesterol, an amount unlikely to impact cardiovascular disease risk [31]. In fact, studies have found that including as many as 3 eggs per day (about 640 milligrams of cholesterol) raised both LDL-C and HDL-C in those individuals classified as hyper-responders. In addition, no significant increases in cholesterol carried by these lipoproteins was observed in hypo-responders resulting in all cases in a non-significant effect on the LDL-C/HDL-C ratio [29,30]. Moreover, studies show that when LDL-C increases as a result of eating eggs, the LDL particles are generally large and less atherogenic [32,33]. A significant decrease in the small LDL particles, associated with increased risk for CVD [34], has also been observed [35].
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Conclusions
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Though apo B levels and apo B/apo A1 ratios appear to be the most accurate predictors of CHD, the question remains whether the potential improvement in risk prediction over that provided by currently available lipid measurements justifies the additional costs of substituting apolipoprotein determinations for the current measurements of lipoprotein cholesterol [36]. Another issue is whether the difference is enough to warrant major changes in the framework of existing cholesterol guidelines for assessing risk determining the best treatment plan and monitoring progress. Existing guidelines (ATP III) for detecting cardiovascular disease risk and treating patients focus on plasma LDL-C concentrations as the primary clinical target and these guidelines are followed by most physicians in patient care. While the current literature supports the use of apoB/apo A-I ratio as the most accurate predictor of CVD risk, it may not be the most practical. In contrast, numerous reports show LDL-C/HDL-C to be a more accurate predictor of risk than LDL-C alone and currently is the most practical approach available.
An LDL-C/HDL-C ratio point for initiating lipid-lowering therapy should be determined. The current NCEP guidelines recommend levels of LDL and HDL that represent a ratio of about 2.5 [8]. Current research suggests risk of death from cardiovascular disease begins to increase significantly around a ratio of 3.3–3.7 [24].
Until questions regarding the practicality of utilizing apoliprotein measurements as predictors of CVD risk can be answered, guidelines should incorporate LDL-C/HDL-C ratios for determining whether to initiate therapy and for monitoring progress. The existing focus on LDL-C as the primary culprit in atherogenesis may divert attention from the more efficient lipid profile of LDL-C/HDL-C. The LDL-C/HDL-C ratio reflects the two-way traffic of cholesterol entering and leaving the arterial intima in a way that the individual levels of LDL-C and HDL-C do not [22].
Received January 2, 2007.
Accepted March 2, 2007.
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ABSTRACT
Introduction
