August 18, 2011

5 Min Read
Cardiovascular Disease Predictors and Biomarkers

by Joseph L. Evans, Ph.D.

The American Heart Association (AHA) estimates nearly 81 million Americans (one in three adults) have one or more types of cardiovascular disease (CVD) including high blood pressure, coronary heart disease (CHD), heart failure, stroke and congenital cardiovascular defects. CVD is the leading cause of morbidity and mortality in the United States and the world.

Over the past 30 years, several indices have emerged to help identify an individuals relative risk for developing CVD. These include quality of diet, degree of physical activity, body weight (especially visceral adiposity) and tobacco consumption, along with a host of metabolic and physiological parameters. (see Figure 1 below)

Figure 1. Major risk factors associated with cardiovascular disease (CVD). LDL-Chol, Low-density lipoprotein cholesterol; Total-Chol, Total cholesterol; HDL-Chol, High-density lipoprotein cholesterol.

The value of identifying risk factors for CVD and other diseases lies in the potential for nutritional, lifestyle, behavioral and pharmaceutical interventions to facilitate risk reduction. Ideally, this would result in prevention, decreased incidence, decreased severity or, at the very least, a delay in disease onset. A major challenge in this area is to distinguish between primary and secondary indicators.

Risk Factors, Biomarkers and Surrogate End Points

A risk factor is a characteristic, indicator, condition or behavior that increases ones possibility or probability of contracting a disease or injury (e.g., age, diet, smoking, occupation, etc.).1 Risk biomarkers are biological indicators that reflect a changed physiological state that is associated with risk of disease. Biomarkers can be either biochemical, physiological, anatomical or physical. Surrogate end points are risk biomarkers that have been validated as predictors of disease risk, and may be used in place of clinical measurement of the incidence of the disease.2 Very few risk biomarkers have been clinically validated to the status of surrogate endpoint. In the cardiovascular area, for example, FDAs Center for Food Safety and Applied Nutrition (CFSAN) recognizes three surrogate endpoints when evaluating the scientific evidence for a potential health claim and qualified health claim: blood pressure, (plasma and serum) total cholesterol and low-density lipoprotein (LDL) cholesterol. Nonetheless, the judicious use of a biomarker(s) with solid scientific and clinical support offers the potential for claim substantiation, and should be seriously considered for inclusion in the clinical protocol as an outcome measurement(s).

Emerging Biomarkers

Several biomarkers have received significant attention in the CVD area. These include high sensitivity C-reactive protein (hsCRP), homocysteine, apolipoprotein B, lipoprotein A and ADMA (asymmetric dimethyl arginine). Of these, hsCRP provides some additional predictive value to the Framingham Cardiovascular Risk Score, a widely used algorithm that estimates CVD risk.3 For each of these biomarkers, it is uncertain whether selectively lowering them, independent of affecting other risk factors, would result in a reduction of CVD. However, another biomarker, oxidized LDL (OxLDL), has been shown in clinical research to be a more sensitive indicator for discriminating between individuals with and without CVD than traditionally measured lipid biomarkers.4,5

Many subjects who suffer from CVD have laboratory values for LDL-cholesterol, a surrogate endpoint recognized by all major regulatory agencies, that fall within or below the normal range.6 This observation indicates other risk factors exist and await validation. In this regard, a major candidate is OxLDL. As is true for all major chronic diseases, CVD is associated with oxidative stress and inflammation. Since it was first proposed by Steinberg,7 the role of oxidatively modified LDL in atherosclerotic plaque formation and the progression of atherosclerosis has garnered extensive biochemical, cellular, animal and clinical support. In clinical trials, OxLDL is reported to be a more sensitive predictor of risk for developing CVD compared to total cholesterol and LDL-cholesterol, which are more widely accepted risk factors. Thus, nutritional interventions designed to reduce OxLDL, such as the Mediterranean diet, offer a scientifically sound approach for improving cardiovascular health, and perhaps delaying the development of atherogenesis.8

In conclusion, scientifically based biomarkers can: 1) aid in the early assessment of disease risk; 2) facilitate the generation of clinical data to support safety, efficacy, and product claims; and 3) once validated, can serve as surrogate endpoints to substantiate health claims.

Joseph L. Evans, Ph.D., is the manager, pharmacology, and Novus Research Fellow at Stratum Nut rition, St. Charles, MO.


1. U.S. Food and Drug Administration. Guidance for Industry: Evidence-Based Review System for the Scientific Evaluation of Health Claims. 2011. 7-14-2011. Accessed 7/14/2011.

2. Rasnake CM, Trumbo PR, Heinonen TM. Surrogate endpoints and emerging surrogate endpoints for risk reduction of cardiovascular disease. Nutr Rev. 2008;66:76-81.

3. Tsimikas S, Willerson JT, Ridker PM. C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J Am Coll Cardiol. 2006;47:C19-C31.

4. Huang H et al. The oxidation ratio of LDL: a predictor for coronary artery disease. Dis Markers. 2008;24:341-349.

5. Johnston N et al. Improved identification of patients with coronary artery disease by the use of new lipid and lipoprotein biomarkers. Am J Cardiol. 2006;97:640-645.

6. Sachdeva A et al. Lipid levels in patients hospitalized with coronary artery disease: An analysis of 136,905 hospitalizations in Get With The Guidelines. Am Heart J. 2009;157:111-117.

7. Steinberg D et al. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320:915-924.

8. Evans JL. Cardiovascular benefits of the Mediterranean diet: targeting oxidized LDL. AgroFood Hi-tech. 2011;22:40-42.


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