The Role of Emerging Risk Factors in Cardiovascular Outcomes

Abstract

Purpose of review: This review discusses the recent evidence for a selection of blood-based emerging risk factors, with particular reference to their relation with coronary heart disease and stroke.

Recent findings: For lipid-related emerging risk factors, recent findings indicate that increasing high-density lipoprotein cholesterol is unlikely to reduce cardiovascular risk, whereas reducing triglyceride-rich lipoproteins and lipoprotein(a) may be beneficial. For inflammatory and hemostatic biomarkers, genetic studies suggest that IL-6 (a pro-inflammatory cytokine) and several coagulation factors are causal for cardiovascular disease, but such studies do not support a causal role for C-reactive protein and fibrinogen. Patients with chronic kidney disease are at high cardiovascular risk with some of this risk not mediated by blood pressure. Randomized evidence (trials or Mendelian) suggests homocysteine and uric acid are unlikely to be key causal mediators of chronic kidney disease-associated risk and sufficiently large trials of interventions which modify mineral bone disease biomarkers are unavailable. Despite not being causally related to cardiovascular disease, there is some evidence that cardiac biomarkers (e.g. troponin) may usefully improve cardiovascular risk scores. Many blood-based factors are strongly associated with cardiovascular risk. Evidence is accumulating, mainly from genetic studies and clinical trials, on which of these associations are causal. Non-causal risk factors may still have value, however, when added to cardiovascular risk scores. Although much of the burden of vascular disease can be explained by 'classic' risk factors (e.g. smoking and blood pressure), studies of blood-based emerging factors have contributed importantly to our understanding of pathophysiological mechanisms of vascular disease, and new targets for potential therapies have been identified.

Keywords: Atherosclerosis; Coronary heart disease; Epidemiology; Risk factors; Stroke; Vascular disease.

Fig. 1

Mendelian randomization and randomized controlled trial designs compared. Reproduced with permission from: Davey Smith G, Ebrahim S. Mendelian Randomization: Genetic Variants as Instruments for Strengthening Causal Inference in Observational Studies. In: Biosocial Surveys, National Research Council of the National Academy of Sciences, 2008. Courtesy of National Academies Press, Washington, D.C

Fig. 2

Association of the LPA Genotype Score with the Lp(a) Lipoprotein Level and the Risk of Coronary Disease in the PROCARDIS Cohort. The odds ratios (squares, with the size inversely proportional to the sampling variation) are for the association of the LPA genotype score (no variant alleles, one variant allele, or two variant alleles) with the risk of coronary disease, as measured with the use of ‘floating absolute risks’ which summarize the sampling variation for the three genotype scores without the selection of an arbitrary baseline genotype score. The vertical lines indicate 95% confidence intervals. Reproduced with permission from: Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361(26):2518–2528. Copyright © 2009 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society