Fig. 10.9 PrognosticvalueofC-reactiveprotein(CRP)incoronaryarterydisease.Relativerisk(y-axis)reflectstheriskforacardiovascularevent(e.g.,myocardialinfarction).Thex-axisshowsthe10-yearriskforacardiovasculareventcalculatedfromthetraditionalriskfactorsidentifiedintheFraminghamStudy.Ineachriskgroup,CRPlevelsfurtherstratifythepatients.(Data from Ridker PM, et al: Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. NEnglJMed347:1557, 2002.) significant atherosclerotic lesions with associated inflammation. Thus elevated CRP levels may be a marker of underlying asymptomatic atherosclerosis. Furthermore, there is no direct evidence that lowering CRP diminishes cardiovascular risk or that CRP is involved in the formation of atheromas. It is of interest that CRP is reduced by smoking cessation, weight loss, and exercise, all of which could reduce the risk of atherosclerosis independently. Thus, whether elevated CRP is a marker of or a consequence of plaque inflammation remains to be resolved.
Hyperhomocysteinemia. Serum homocysteine levels correlate with coronary atherosclerosis, peripheral vascular disease, stroke, and venous thrombosis. Homocystinuria, due to rare inborn errors of metabolism, causes elevated circulating homocysteine (greater than 100 µmol/L) and is associated with early-onset vascular disease. Although low folate and vitamin B12 levels can increase homocysteine levels, supplemental vitamin ingestion does not affect the incidence of cardiovascular disease.
Metabolic syndrome. Associated with central obesity (Chapter 8), this clinical entity is characterized by insulin resistance, hypertension, dyslipidemia (elevated triglycerides and depressed HDL), hypercoagulability, and a pro-inflammatory state, which may be triggered by cytokines released from adipocytes. The dyslipidemia, hyperglycemia, and hypertension are all cardiac risk factors, while the systemic hypercoagulabgramle and pro-inflammatory state may contribute to endothelial dysfunction and/or thrombosis.
Lipoprotein(a) levels. Lipoprotein(a) is an LDL-like particle that contains apolipoprotein B-100 linked to apolipoprotein(a). Lipoprotein(a) levels are correlated with risk of coronary and cerebrovascular disease, independent of total cholesterol or LDL levels.
Apolipoprotein(a) is homologous to plasminogen, suggesting a potential link between thrombogenesis and circulating molecules that can drive atherosclerosis.
Elevated levels of procoagulants are potent predictors of risk for major cardiovascular events including myocardial infarction and stroke. Excessive activation of thrombin, which you may recall can initiate inflammation through cleavage of protease-activated receptors (PARs; Chapter 4) on leukocytes, endothelium, and other cells, may be particularly atherogenic.
Clonal hematopoiesis. It is now recognized that a surprisingly high fraction of older individuals have clonal hematopoiesis (Chapter 12), defined by the presence of a major clone of cells in the bone marrow that have acquired somatic driver mutations in one or more well-characterized oncogenes or tumor suppressor genes. Despite the presence of these mutations, such patients typically have normal blood counts. Unexpectedly, epidemiologic studies have found that clonal hematopoiesis is strongly associated with an increased risk of death from cardiovascular disease, possibly because of alterations in the function of innate immune cells derived from mutated hematopoietic stem cells. Work is ongoing to further confirm this association and determine its mechanistic basis.