A family history of premature CHD—in a first-degree relative before age 55 years in men and before age 65 years in women—is a well-recognized predictor of CHD risk. Its use in major risk-stratification scoring systems has been limited due to inconsistent availability of the data; nonetheless, many clinicians routinely inquire about it. When collected systematically in randomized trial and added to the Framingham score, such family history reclassified 4.8% of patients from intermediate to high risk, supporting the view that the effort should be considered in CHD risk stratification. Compared to the cost of detecting other genetically identified CHD risk factors (see later discussion), systematic use of family history is likely to be much less expensive and potentially more cost-effective.

Interest in the CRP as a risk-factor determinant derives from the growing appreciation for the role chronic inflammation plays in the pathophysiology of atherosclerosis. Being a wellestablished marker of inflammation, CRP measurement has attracted considerable interest as an adjunct to the Framingham score. Using a highly sensitive CRP assay (hs-CRP), a level greater than 3.0 mg/L independently confers a relative CHD risk of 1.58 compared to persons with a level less than 3.0 mg/L. Levels less than 1 have been termed “low,” 1-3 “intermediate,” and greater than 3 “high.” Although meta-analytic study finds that hs-CRP measurement does not meet the criteria for routine use in CHD risk determination, its selective application in persons already deemed intermediate risk can improve risk stratification and identify persons in need of more intensive lipid-lowering therapy; however, the degree of benefit may be modest. In meta-analytic study, use of the hs-CRP yielded a net reclassification improvement of 1.52%, estimated to prevent one additional CHD event over 10 years for every 400 to 500 intermediate-risk persons screened. This benefit is considerably more modest than that initially suspected when hs-CRP was first identified as an independent risk factor. So far, there are insufficient data to indicate that lowering the CRP reduces coronary event risk.

The observation that some persons with otherwise unexplained atherosclerotic disease had elevated serum homocysteine concentrations triggered a period of intense interest in its detection and treatment, especially among persons with coronary artery disease (see Chapter 30). High levels of homocysteine are thought to be injurious to arterial walls, and initial epidemiologic study suggested a strong independent relationship, perhaps accounting for risk in persons with otherwise unexplained coronary events. However, subsequent investigations found the increase in relative risk to be more modest (on the order of 9% to 18%). Moreover, although treatment (e.g., with pharmacologic doses of vitamins B₆ and B₁₂ and folic acid) significantly reduces homocysteine elevations, it has failed to demonstrate reduction in coronary event rates and might even exacerbate risk (see Chapters 18, 30 and 31). Consequently, enthusiasm for routine homocysteine measurement and treatment has waned, and these are not recommended for primary prevention.

Arterial calcification is thought to be an active consequence of the atherosclerotic process rather than a passive result of aging. Mediators of atherogenesis appear capable of transforming vascular smooth muscle cells into osteoblast-like cells. The degree of coronary artery calcification, as determined by multidetector computed tomography, appears to correlate with degree of atherosclerotic burden, stimulating interest in this measure as a useful determinant of coronary event risk. However, lack of standardization of results, scarcity of population-based data, and little evidence for impact on reclassification of CHD risk (except perhaps in persons at intermediate risk) limit any conclusions about its usefulness as a risk assessment tool. Its role as a risk-stratification tool is the subject of ongoing study and some debate (see Chapter 36).

Some, but not all, epidemiologic and observational studies show an inverse relation between low 25-hydroxyvitamin D levels and CHD events. In those that do show a relationship, risk appears to diminish as serum levels approach low normal levels (20 to 30 ng/mL) and increase again at high vitamin D levels (>50 ng/mL). Evidence remains spotty for any CHD preventive benefit associated with vitamin D supplementation (except perhaps in persons with end-stage renal disease on dialysis). These inconsistent findings cause most experts to conclude that existing evidence is insufficient to prove a causal relationship between CHD events and vitamin D levels. Despite much interest in vitamin D, the absence of a well-defined causal relationship and a firmly established therapeutic benefit argue against measurement of 25-hydroxyvitamin D for CHD risk determination.

Associations between incidence of cardiovascular disease and other traditional markers of mineral metabolism (e.g., parathyroid hormone, phosphorus, and calcium-phosphorus product) have also been noted in epidemiologic studies. Newly discovered markers of mineral metabolism (e.g., fibroblast growth factor 23, fetuin-A, uncarboxylated matrix Gla protein) show promise in predicting risk of cardiovascular events in persons with end-stage renal disease and those with known cardiovascular disease.

Whether any of the markers of mineral metabolism will add predictive power for determining risk of primary coronary events and influence preventive efforts remains to be determined.

Lp(a) lipoprotein (also referred to as lipoprotein[a]) consists of an LDL particle bound to apolipoprotein(a). It is thought to transport proinflammatory oxidized phospholipids that contribute to atherosclerotic plaque formation. Serum levels appear to be genetically determined and correlate with coronary disease risk. Measurement does not require fasting, making its determination a potentially attractive alternative to standard lipid profiling for coronary risk determination. However, its use as a risk determinant remains uncertain at this time because of inadequate standardization of measurement, uncertain contribution to risk stratification, and limited data on efficacy of treatment.

Symptomatic peripheral vascular insufficiency is considered a marker of high risk for a CHD event, but evidence remains insufficient to indicate that the ABI (the systolic blood pressure at the dorsalis pedis pulse divided by the systolic blood pressure in the arm) confers independent predictive value for a CHD event or that it is useful in reclassification of intermediate-risk persons. The ABI does serve as a useful means of
detecting peripheral artery disease. A ratio of 0.9 or less suggests its presence; however, other major CHD risk factors (e.g., smoking, hypertension, hypercholesterolemia, diabetes) predict peripheral vascular disease with nearly equal accuracy.

Ultrasound measurements of the intima-media thickness (IMT) in the common and internal carotid arteries commonly serve as surrogate indicators of atherosclerotic disease in research studies and have been examined as independent predictors of CHD events. The maximum thickness in the internal carotid is used as an indicator of plaque; the median thickness in the common carotid is viewed as an indicator of generalized atherosclerotic disease. While both have been found to be independent predictors of CHD events, only the maximum IMT of the internal carotid artery significantly improves the risk stratification provided by the Framingham score and does so only modestly (about 7% reclassified). Factors limiting its application are the modest contribution to reclassification, few data on the impact of such reclassification, and issues of standardization and technical difficulty of measurement.

Abnormal resting ECG findings (LVH, ST- and T-wave abnormalities) and abnormal exercise ECG findings (ST-segment depression, abnormal heart rate recovery, limited exercise tolerance) are associated with increased CHD risk (pooled hazard ratio estimates, 1.4 to 2.1) in asymptomatic persons; however, there are no data on improvement in outcomes or improvement in risk stratification over that provided by the Framingham score. Angiography rates were increased as a consequence of stress testing asymptomatic persons, with upward of 2.6% undergoing invasive investigation after exercise ECG.

An independent relationship between resting heart rate and risk of a CHD event has long been observed in epidemiologic studies as has a change in resting heart rate over time in a healthy population. In one large population study, a change in heart rate over 10 years from less than 70 beats/min to greater than 85 beats/min nearly doubled the CHD event risk compared to those whose rates never exceed 70 beats/min. As interesting as such findings are, there are no data on the efficacy of lowering the neither resting heart rate nor evidence that using the resting heart rate or change in resting heart rate over time enhances risk stratification.

Although many psychosocial and sociodemographic factors are associated with increased risk of CHD events, few have been formally studied for their ability to improve risk stratification and outcomes. Limitations include difficulty quantifying psychosocial factors, studying them in prospective systematic fashion, determining impact on risk stratification, and ability to successfully modify them. Among the psychosocial factors most rigorously studied are long working hours (>11 hours/day), which have been found to be additive to the predictive power of the Framingham score, but only modestly (4.7%); the measure improved risk stratification, but only for low-risk patients; no data are available on the impact of reducing work hours. Among other potentially important risk factors under intense study is access to health insurance.

Estimates of the relative risk associated with subclinical hypothyroidism (as determined by TSH and thyroid hormone indices) range from 1.08 to 1.20, slightly higher for persons less

than 65 years of age. Similar degrees of risk have been noted with subclinical hyperthyroidism. There are no data on use of thyroid indices for CHD risk stratification and few randomized prospective data on treatment of asymptomatic persons with regard to effect on CHD event rates.

A host of biomarkers have been examined in addition to those noted earlier (e.g., hsCRP). These include chromosome 9p21 genomic markers, constellations of single nucleotide polymorphisms, B-type natriuretic peptide, and cystatin C. Gains in predictive power appear minimal at most, infrequently resulting in reclassification.

Direct-to-consumer programs for assessment of cardiovascular risk are increasingly common and unregulated. They include carotid artery ultrasound, ABI, abdominal ultrasound for aortic aneurysm, CT for coronary calcium scoring, lipid profiling, and measurement of CRP. The above-noted limitations of many of these potentially useful studies, not to mention poor quality control and lack of standardization, make such screening outside the context of a comprehensive professional medical evaluation fraught with risks for false alarms and false reassurances. Even more egregious and potentially harmful are offerings of studies that lack any evidence base, such as use of an ultrasound ejection fraction determination for assessment of cardiac sudden death risk, or use of a “brachial artery elasticity” measurement for calculation of cardiovascular event risk. Patients and the public should be warned against making use of such testing absent standards setting, regulatory oversight, and consumer education regarding the limitations and potential harms of such testing.

Simply maintaining a physically active lifestyle can be expected to reduce the cardiovascular risk by as much as 35% to 70%. Light to moderate exercise (defined below) can reduce all-cause mortality by 45%, even after adjusting for potential confounders; gardening for more than 60 minutes a week is associated with a 68% lower risk of primary cardiac arrests. Whereas exercise is most effective when commenced early in life, physical activity also confers benefit if initiated later in life. The elderly benefit in terms of survival despite the small risk associated with sudden physical or sexual activity, a risk markedly blunted by habitual physical activity. Among elderly men, walking more than 2 miles a day reduces the mortality rate by nearly 50% compared with those who walk less than 1 mile a day; similar benefits are found among elderly women, though the benefit appears more limited in those older than 75 years, especially those with poor health status. Exercise-related CHD risk reduction from exercise applies in high-risk persons as well as those with lesser degrees of risk. Patients with established CHD (secondary prevention; see 31) experience a 20% to 25% decrease in overall mortality, with reductions in fatal reinfarction and total cardiovascular deaths, but interestingly, not in nonfatal reinfarctions. Risk of sudden death from arrhythmias decreases.