Aging Clin. Exp. Res. 8: 75-89, 1996

REVIEW ARTICLE

Coronary heart disease risk factors in older persons M-C. Corti1, J.M. Guralnik1, and C. Bilato2 1Epidemiology, Demography, Biometry Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, 2Vascular Biology Unit, Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, U.S.A. (Aging Clin. Exp. Res. 8: 75-89, 1996) ABSTRACT. In most Western nations, coronary heart disease (CHD) is the leading cause of death and one of the most important causes of physical disability in persons over 65 years of age. The importance of traditional CHD risk factors has been well documented in middle-aged populations, whereas their role in older populations is still under debate. This paper reviews the epidemiologic evidence from observational studies and randomized clinical trials that established risk factors for CHD predict level of risk of CHD, and identify high risk individuals among older men and women. Hypertension and cigarette smoking have been clearly associated with an increased risk of CHD events, and their modification has been proven to be highly effective in the primary and secondary prevention of CHD in older persons. For other highly prevalent risk factors, such as lipid abnormalities, obesity and physical inactivity, evidence of an independent association with CHD risk has been demonstrated by the majority of observational studies. However, definitive proof from controlled clinical trials of the beneficial effects of their modification is still lacking in the older population. The role of estrogen replacement therapy in the primary and secondary prevention of CHD in older women is still an open question. In evaluating the impact of these risk factors in older persons, elements such as comorbidity, frailty, and age-related changes in risk profile should also be taken into consideration. Given the complexity of the relationship between risk factors and multiple disease statuses, other important outcomes, such as osteoporosis, cancer, falls and physical disability, should be considered when evaluating the risks and benefits of risk factor modifications in older persons.

INTRODUCTION Coronary heart disease (CHD) is the leading cause of death among men and women 65 years and older. Of all deaths from CHD, more than 75% occur in those aged 65 years and older (1). CHD death rates increase with age, even among persons with low levels of known risk factors, and age remains an important determinant of CHD mortality within the older population, even after adjusting for other risk factors. The roles of other, potentially modifiable risk factors for CHD in older persons have been the subject of much debate, although recent research, to be highlighted in this review, has provided clearer insight into these issues. In addition to being the leading cause of death, CHD and other cardiovascular diseases represent one of the most important causes of disability in older men and women. In a recent study that asked older participants to assess the condition causing their disability, heart disease ranked second after musculoskeletal disorders (2). Thus, efforts aimed at preventing CHD and cardiovascular disease morbidity in the elderly population have the potential to reduce the impact of physical disability in terms of personal burden and social costs. In this review, the roles of risk factors that are established in middle-aged populations will be individually assessed considering the totality of evidence collected from observational studies and intervention trials of older persons. The goal is to examine the ability of risk factors to predict CHD in the elderly, and consider the implications for prevention in the aged. For the most important CHD risk factors, this review will: 1) evaluate the prevalence of the risk fac-

Key words: Aged, atherosclerosis, cardiovascular disease, coronary heart disease, risk factors. Correspondence: M-C. Corti, M.D., M.H.S., Epidemiology, Demography, Biometry Program, National Institute on Aging, National Institutes of Health, 7201 Wisconsin Avenue, RM 3C309, Bethesda, MD, 20892, U.S.A. Received and accepted February 8, 1996.

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tors in the older population; 2) present the evidence from observational studies of older persons that this risk factor has an independent association with CHD outcomes; and 3) examine, if available, the effects of risk factor modification from primary and secondary prevention trials targeted to older populations. CIGARETTE SMOKING Among persons aged 65 years and older in the U.S., 14% of men and 11% of women were current smokers in 1993 (3). The prevalence of cigarette smoking diminishes with age, and declines to less than 10% for men and less than 5% for women aged 85 years and older (4). This decrease with age has been confirmed in longitudinal studies and in populations with different smoking habits (5, 6), and might be explained by both selective mortality and increasing incidence of age-related diseases that induce affected people to quit smoking. Despite the large body of evidence relating cigarette smoking to fatal CHD and other atherosclerosisrelated conditions in middle-aged populations (7), controversy has surrounded the role of cigarette smoking as a predictor of cardiovascular diseases in older adults. For example, no significant relation between cigarette smoking and CHD incidence and mortality was found in the Framingham Heart Study population (8-10), but the negative results of these studies could be partially explained by the inclusion of former smokers in the group of nonsmokers. In contrast, several prospective studies of older persons have shown a relation between current smoking and morbidity and mortality from coronary heart disease. Smoking was associated with an increased risk of CHD that persisted from middle to older age in a cohort of men of Japanese ancestry in the Honolulu Heart Program (11, 12). Another longitudinal study of 2500 people, age 65 to 74 years, showed that current smokers had a 50% increased risk of death from heart disease compared to nonsmokers, even after controlling for other risk factors (13). Several other studies confirmed the relation between current smoking and morbidity and mortality from coronary disease (14, 15). When the effects of smoking cessation were evaluated in a cohort of older men and women, improved survival was demonstrated in both those with and without CHD (16). In addition, when other manifestations of cardiovascular disease are considered, cigarette smoking has been consistently shown to be a significant predictor of intermittent claudication and stroke (17, 18). More definitive conclusions from populations that include very old individuals can be drawn from the

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data of the Established Populations for Epidemiological Studies of the Elderly (EPESE) (19). In this study, the relationship between cigarette-smoking and allcause, cardiovascular disease and cancer mortality was prospectively examined among 7178 persons aged 65 years and older without a history of myocardial infarction, stroke or cancer. After adjustment for cardiovascular risk factors, current smokers, compared to those who had never smoked, had a significantly higher risk of all-cause and cardiovascular mortality (Fig. 1). In age-stratified analyses, however, the relative risk of all-cause mortality tended to decline among men and women 75 years and older. In both sexes, former smokers had rates of cardiovascular disease mortality similar to those who never smoked, regardless of age at cessation and number of years since last smoked. This observation, described also in other studies (13, 16), suggests that the biological effect of smoking on cardiovascular mortality is related to cur-

Figure 1 - Relation of cigarette smoking with the risk of allcause and cardiovascular disease mortality in three cohorts of the Established Populations for the Epidemiologic Study in the Elderly (EPESE). Relative risks are adjusted for age, community, and cardiovascular disease risk factors. Adapted from LaCroix A.Z. et al., 1991 (19).

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rent use, and the risk falls rapidly after cessation. However, the cumulative smoking history is strongly related to smoking-related cancer mortality (19), and to angiographically documented coronary artery disease (20). In conclusion, the deleterious effects of cigarette smoking extend well into later life, and there is evidence that the benefits of smoking cessation persist at advanced age. Older persons should be strongly encouraged to quit smoking at all ages. HIGH BLOOD PRESSURE The mean systolic blood pressure (SBP) of most Western populations increases with age in both men and women, while the mean diastolic blood pressure (DBP) tends to decline after gradually rising until the age of 55 (17, 21). The average systolic pressure in men and women over 65 is between 140 and 150 mmHg, and the mean diastolic pressure between 70 and 80 mmHg (21, 22). The increase in SBP as well as pulse pressure (22) with aging may be, at least in part, the result of progressive vascular stiffness and decreased compliance of the tunica media of the aorta, and changes in the extracellular matrix of the vessel wall (23, 24). It is unclear whether these changes and the resultant increase in SBP reflect normal aging or a distinct pathological process, since the blood pressure of remote and primitive populations shows no tendency to increase with age (25). Among persons aged 65 years and older, the prevalence of hypertension (defined as a SBP r160 and/or DBP r90) is about 50% in women and more than 30% in men. In men, hypertension prevalence increases to above 40% by the age of 75 (17, 26, 27). This large proportion of hypertensive persons in old age is not just the result of the number of hypertensive patients that survive to age 65, but also of the increasing incidence of new cases of high blood pressure observed with advancing age (28). In fact, data from the Framingham Heart Study (28) demonstrated that the incidence of newly identified hypertension in men was 28 per 1000 person-years from age 60 to 69 years and 31.1 per 1000 person-years from age 70 to 79 years, while in women, incidence rates rose, in the same decades, from 34.7 per 1000 person-years to 42.8 per 1000 person-years. Besides changes in the vascular tree that occur with aging, other determinants might play a role in the increase of hypertension with age, such as changes in body mass index (29-31), hormonal status (32), sodium (33-35) and potassium (36) intake and physical activity (37). Many epidemiological studies in middle-aged pop-

ulations have documented a strong and independent association between high blood pressure and clinically relevant outcomes, such as coronary heart disease, stroke, congestive heart failure and renal insufficiency (38). In virtually every study, both SBP and DBP have been independent predictors of risk, but for years physicians have tended to focus more on treating elevations of DBP than on SBP, particularly when patients were elderly (39). The first Joint National Commission report (40), based on the results of the Veteran Affairs Cooperative Study, indicated that treatment strategies for high blood pressure should primarily focus on lowering DBP. The Hypertension Detection and Follow-up Program, a randomized controlled trial of treatment of diastolic hypertension in persons aged 45 to 69, demonstrated a decreased incidence of CHD endpoints in the treated group. The intervention was successful also in the subgroup aged 60 to 69 years, but persons 70 years and older were not studied (41). More recent studies have shown that for persons above 45 years, elevated SBP is a more potent risk factor for subsequent cardiovascular morbidity and mortality than elevated DBP (42, 43). In middle-aged and older persons, the importance of isolated systolic hypertension (ISH, a SBP r160 mmHg with DBP b90 mmHg) has been clearly demonstrated, and those with ISH may have a greater risk of cardiovascular disease morbidity and mortality than persons with only elevated DBP (44). Despite strong observational evidence for the association of ISH with stroke and total cardiovascular disease mortality, its association with CHD outcomes has not always been so consistent (45, 46). However, the Systolic Hypertension in the Elderly Program (SHEP) clinical trial, designed to assess the effects of ISH treatment in the elderly, unequivocally showed that benefits of the pharmacologic intervention in persons aged 60 and older with ISH are not limited to stroke incidence and mortality, but extend to CHD incidence (47). The SHEP trial, a large, five-year, multicenter clinical trial (47), demonstrated that antihypertensive stepped-care drug treatment significantly reduced the incidence of stroke by 37%, and the incidence of non-fatal myocardial infarctions by 33%. Trials in the elderly have also confirmed the benefits of pharmacologic treatment of combined systolic and diastolic hypertension (48-50) in reducing cerebrovascular events and fatal and non-fatal CHD events. The STOP study (Swedish Trial in Old Persons with Hypertension) confirmed that treatment of systolic and/or diastolic hypertension in 1627 men and women aged 70-84 years significantly decreased

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the risk of cardiovascular disease morbidity and mortality (50). The European Working Party on Hypertension in the Elderly study demonstrated significant benefits of antihypertensive therapy on cardiovascular and CHD mortality (-27% and -38%, respectively), and a non-significant reduction in all-cause mortality (-9%) (51). Similarly, a reduction, although non-significant, in all-cause and cardiovascular mortality was found in the treated subgroup aged 60 to 69 in the Australian Therapeutic Trial in Mild Hypertension (52). Finally, analyses of data from 4396 patients aged 65 to 74 enrolled in the Medical Research Council trial showed reduction in risks in the treated group of stroke (31%), coronary events (35%) and all cardiovascular events (35%) (49). In several epidemiologic studies of older persons, the relationship between blood pressure and mortality appears to be U-shaped, i.e., rates of mortality at both low and high levels of blood pressure exceed the rate at intermediate levels (14, 48, 53, 54). In fact, U- or J-shaped associations have been documented for at least three major cardiovascular risk factors: blood pressure, total cholesterol and weight (55). Recently, results from the East Boston cohort of the EPESE study provided new insights in elucidating the associations of systolic and diastolic blood pressure with mortality (56). In this cohort, the highest rates of mortality were seen in those with high and low blood pressure in unadjusted analyses. However, after adjustment for confounding variables and exclusion of deaths within the first 3 years of follow-up, the study demonstrated a linear relationship between higher SBP and cardiovascular (p for linear trend <0.0001) and total mortality (p for linear trend <0.0007) (Fig. 2). A similar association was observed between DBP and cardiovascular mortality. These data support the hypothesis that the high death rates in elderly individuals with low blood pressure (resulting in U- or J-shaped curves) are a short-term phenomenon attributable to co-morbidity and low blood pressure in people approaching death. In conclusion, observational studies have provided evidence that high blood pressure levels are associated with an increase in the risk of cardiovascular morbidity, mortality and all-cause mortality; clinical trials have demonstrated that treating high blood pressure can significantly reduce cardiovascular morbidity and mortality in older persons. The totality of evidence strongly supports recommendations to treat high blood pressure, one of the most prevalent and important modifiable risk factors in elderly people. LIPIDS AND LIPOPROTEINS

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Figure 2 - Relation of systolic and diastolic blood pressure with the ten-year risk of cardiovascular disease mortality in the East Boston cohort of the Established Populations for the Epidemiologic Study in the Elderly (EPESE). Relative risks were calculated after adjustment for health related factors, comorbidity, and exclusion of those dying in the first three years. Adapted from Glynn R.J. et al., 1995 (56).

According to the U.S. National Cholesterol Education Program (NCEP) guidelines, “high-risk elderly patients who are otherwise in good health are candidates for cholesterol-lowering therapy”, and “the physician should maintain a positive attitude toward the potential benefit of cholesterol reduction in older persons” (57). These statements reflect the concept that high levels of total serum cholesterol (TC) and LDL-cholesterol (LDL-C), as well as low concentrations of HDL-cholesterol (HDL-C), continue to predict CHD in the population aged 65 years and older. Yet, despite considerable evidence that hypercholesterolemia is an important risk factor for atherosclerosis-related diseases in middle age persons (58-60), the association between high levels of cholesterol and CHD in older individuals remains controversial (61, 62). The prevalence of lipid abnormalities is substantial in the elderly population (63). One-third of older men

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and one-half of older women have elevated TC (r240 mg/dL), and LDL-C levels above the high risk threshold of 160 mg/dL (64, 65). Low HDL-C levels are more prevalent among older men than women (63). There are gender differences in age-related changes in total cholesterol levels (66), and these differences might explain the higher prevalence of lipid abnormalities in older women as compared to men. Around the age when women are going through menopause, TC levels in men begin to decline with age. In women, however, TC continues to rise for several years after menopause, resulting in more women than men in the high cholesterol category. After the age of 65, TC and LDL-C tend to decline in both men and women. Therefore, TC levels in women over 65 years of age better reflect the degree of cholesterol elevation over the past decades than do TC levels in older men, in whom a steeper drop has been going on longer (67). These gender-related differences have been consistently reported across several studies (17, 63, 68, 69), although different lipid and lipoprotein distributions have been reported in the elderly population by different authors. The common finding of a progressive decrease in TC into the oldest ages might reflect the selective survival of individuals with a less atherogenic lipid profile or, alternatively, the effect that poor health, changes in dietary habits and decreased body weight have on reducing cholesterol level (64, 65). Thus, single recent measures of cholesterol at old age likely underestimate the lifetime exposure level, and have the potential to misclassify older persons with a heavy burden of disease and consequent low cholesterol as low-risk individuals. In fact, in middle-aged populations, total cholesterol shows a direct relationship with CHD and all-cause mortality, but this relationship is far less clear in older people. It remains an open question whether total cholesterol simply does not have the same relationship to CHD in older compared to younger persons, or whether other factors, such as frailty and other health-related conditions, may modify the relationship between risk factor and outcome. In the last few years, many conflicting results have been published on the relationship between TC and CHD. In some studies of older people, this relationship has been shown to be either U- or J-shaped (59), while in others TC has been found to be not related at all with the mortality risk (62). In contrast, several observational studies have reported a direct relationship between TC and cardiovascular disease in the elderly, when individuals with preexisting CHD were excluded from analyses (70-72). In the Honolulu Heart Program (71), TC levels measured in old

age predicted subsequent CHD as well as TC measured in middle age. Among 250 men aged 75 to 97 years in the Baltimore Longitudinal Study on Aging, a linear relationship between TC and risk for CHD was observed (72). In the Rancho Bernardo Study, hypercholesterolemia predicted early death from CHD in men but not in women, aged 65-89, in a three-year follow-up period (73). In the Framingham Heart Study, on the contrary, TC was significantly associated with CHD risk only in older women with cholesterol concentration above the 90th percentile (306 mg/dL), while in other subgroups (older men, women with TC between 200 and 239 mg/dL or 240 mg/dL and 306 mg/dL) the relative risks had confidence intervals that overlapped 1.0 (9). Similarly, in the three cohorts of the EPESE study, a TC level r240 mg/dL was associated with a significant 80% increase in the CHD mortality risk in women, but in men, elevated TC was associated with a modest, non-significant increase in risk (74). Studies in limited samples of subjects aged 65 and older have generally not provided strong evidence that HDL-C is significantly associated with CHD (71). Among 350 persons aged 75 to 85 years participating in the Bronx Health study, a significant relationship between HDL-C and cardiovascular events was found only in men (75), while in the Rancho Bernardo Study, high HDL-C levels had a protective effect on CHD mortality only in women (73). A recent study from the New Haven, Connecticut, cohort of the EPESE study showed a lack of association between elevated TC level, low HDL-C levels, high TC/HDL-C ratio and risk of all-cause and CHD mortality, and hospitalization for myocardial infarction or unstable angina (62). The analysis of all three EPESE communities which included 2527 women and 1377 men, however, has provided convincing evidence that even in persons aged 71 years and older, HDL-C has a strong relationship with CHD mortality, and that this risk is still present in both men and women aged 80 years and older (Fig. 3). In this longitudinal study, the relative risk of death from CHD for those with low HDL-C (<35 mg/dL) compared to those with HDL-C >60 mg/dL was 2.5 (95% CI=1.6-4.0), and for each unit increase in the TC/HDL-C ratio there was a 17% increase in the risk of CHD death (74). The study provided convincing evidence that the CHD risk estimation in the elderly can be improved by adding HDL-C to the total cholesterol measurement, and that high risk elderly patients can therefore be identified and, if indicated, treated for lipid abnormalities. Less information is available on the impact of serum triglycerides (TG) on CHD or other atherosclero-

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1.6 1.1 0.6 0.1

Figure 3 - Relation of HDL-cholesterol (HDL-C) and total cholesterol (TC) with five-year risk of coronary heart disease (CHD) mortality by age group. Results are from the three cohorts of the Established Populations for the Epidemiologic Study in the Elderly (EPESE) and are adjusted for CHD risk factors and gender. Deaths during the first year were excluded. Adapted from Corti M-C. et al., 1995 (74).

sis-related outcomes in the elderly. Overall, it appears that TG levels are not an independent predictor of CHD in older persons (71). It should be remembered, however, that high levels of TG are often associated with obesity, glucose intolerance and low HDL-C concentrations, all of which confer an increased risk of CHD, even in individuals above 65 years. In recent years, the important role of Lp(a) as a risk factor for atherosclerosis has been recognized. Elevated plasma levels of Lp(a) (>30 mg/dL) are, indeed, associated with myocardial infarction, stroke and other atherosclerotic cardiovascular diseases (7678). Most of these studies, however, were performed in populations less than 60 years old, and recent cross-sectional observations suggested that the clinical relevance of Lp(a) as a risk factor for cardiovascular diseases is less marked in the elderly (79). However, another recent study reported a strong relationship between Lp(a) levels and atherothrombotic disease in a Japanese population older than 75 years (80). Definitive conclusions on the impact of Lp(a) on atherosclerosis-related diseases in the elderly will require further investigations. To date, no specific clinical trial for the treatment

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of dyslipidemic older persons without CHD has been reported, while convincing evidence has recently been provided that the drug pravastatin is effective in reducing all-cause and CHD mortality in a primary prevention trial in middle-aged healthy men with elevated cholesterol (81). A secondary prevention clinical trial among persons aged 35-70 with preexisting CHD demonstrated that treatment with the cholesterol lowering drug simvastatin significantly decreased all-cause and CHD mortality, as well as major coronary events, even in the subgroup aged 60-70 years (82). Therefore, evidence indicates that drug treatment of lipid abnormalities is beneficial in persons up to 70 years of age with pre-existing CHD. Further randomized controlled trials are needed to evaluate the benefits of pharmacologic interventions for secondary prevention in those over age 70, and for primary prevention in the entire older population. BODY WEIGHT The relationship between CHD and body weight is complex. Body weight co-varies with other coronary

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risk factors that play a major role in the pathogenesis of atherosclerosis, such as glucose intolerance, hyperinsulinemia, diabetes, high blood pressure, high TC/ HDL-C ratio, smoking and physical inactivity. In the younger population, overweight is strongly and independently associated with CHD (83, 84), and women who maintain their ideal body weight have a 35 to 60 percent lower risk of myocardial infarction than women who become obese (85). Across the full spectrum of body mass index (BMI), however, BMI and CHD have shown a positive linear association, a U- or Jshaped relation, or no association at all (86). The role of obesity in CHD morbidity and mortality is more controversial, and less studied in the elderly population. Some studies have found no independent association between BMI and risk of CHD (12, 13, 15), in others, BMI predicted myocardial infarction incidence in men, but not in women (87, 88), and in others the risk of cardiovascular disease mortality was increased at the high and low extremes of BMI (89). Age-related weight change may be responsible for the complexity of the BMI-CHD mortality association in older persons. Current weight in older persons may not represent the most accurate measure of life-time risk exposure. This is suggested by the results of two studies among older men and women in the Framingham Heart Study (9, 89). A higher metropolitan relative weight at the time of entry into the study, but not current BMI at age 65, was associated with a 30% increase in the risk of CHD incidence (9). Similarly, persons who remained above the 70th percentile at both ages of 55 and 65 years had a relative risk of all-cause and cardiovascular mortality significantly higher than the reference group (BMI = 23.0-25.2 for men; 24.1-26.1 for women). Those who were overweight only at age 65 had a small increase in risk of mortality, while those losing 10% of BMI from ages 55 to 65years were at increased risk of death, suggesting that the relationship between thinness and increased mortality observed in older persons may be explained by weight loss associated with concurrent illness (89). Other methodologic biases, such as the failure to accurately control for cigarette smoking or weight loss due to pre-existing illness, may explain differences found in various studies (85). In addition, these conflicting results might be partially explained by the fact that obesity is biologically linked, in the causal pathway to mortality, with factors such as hypertension, diabetes and lipid abnormalities (84, 90). If these factors are simultaneously considered in multivariate analyses, the effect of obesity is likely to be attenuated or eliminated (90). In older persons, the effects of voluntary weight

reduction on the risk of CHD are still uncertain because of the paucity of data from longitudinal studies, or intervention trials addressing this issue. Despite these uncertainties, however, the well-recognized effects of obesity on established coronary risk factors, and other important outcomes, such as osteoarticular diseases and physical function (91), reinforce the concept that maintaining an ideal body weight over the entire life span may have beneficial results measured not just in terms of years of life gained, but also in terms of better quality of life (89). DIABETES Glucose metabolism tends to become progressively impaired with advancing age (92, 93), and aging in itself is characterized by a postreceptor defect in insulin action (94) and peripheral hyperinsulinemia (95). According to the currently accepted National Diabetes Data Group criteria, the prevalence of diabetes increases from 2% in the 20- to 44-year-old age group, to nearly 18% in those aged 65 to 74 years (96). In the elderly, diabetes mellitus is an important risk factor for CHD, as it is in younger persons (97, 98). Data from the Framingham Heart Study demonstrate that, after adjusting for other risk factors, older persons with fasting blood glucose levels >175 mg/dL had twice the risk for incident CHD than those with blood glucose levels below 90 mg/dL (9). When individuals with intermediate fasting blood glucose (125-174 mg/dL) were considered, however, sex differences were noted. The female population still had a significant 1.8-fold increase in the risk of CHD, while among men the relative risk was 0.9 (95% CI=0.6-1.6). Sex-differences have also been observed in other studies of middle-aged and older populations (87, 88, 99, 100), suggesting that there may be different risk profiles for older men and women. Like obesity, the association of diabetes and glucose intolerance with CHD is complex. Impaired glucose metabolism, in fact, is often present in individuals with other coronary risk factors such as hypertension (85), and is pathophysiologically related to obesity, dyslipoproteinemias and other metabolic disorders that significantly accentuate the individual atherogenic risk profile. For example, glucose intolerance and diabetes are often preceded by weight gain (101), and diabetes has been found to be a positive predictor of SBP among 5201 men and women aged 65 to 101 years (102). Evidence that optimal glycemic control is associated with a lower overall rate of long-term complications, including vascular complications, exists only for

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young and middle-aged type I diabetics (103). In addition, tight glycemic control is associated with an increased risk of hypoglycemia; among older adults, hypoglycemia may have serious consequences, such as falls and injuries, or may precipitate events such as myocardial infarction or stroke (104). Therefore, the prevention of long-term complications among older persons should be balanced with the risks of short-term and acute complications secondary to pharmacologic treatment. Although it is not yet clear whether optimal glycemic control reduces the risk of CHD in middle aged and old adults with type II diabetes, there is evidence that diabetes acts synergistically with hypertension, obesity and smoking in exacerbating the risk of CHD, especially among women (105). Therefore, screening for impaired glucose metabolism should be considered in persons over the age of 65 and, if other risk factors are present, control of these exacerbating factors could yield greater reductions in the risk of CHD in diabetic compared to non-diabetic older persons. POSTMENOPAUSE AND HORMONE REPLACEMENT THERAPY It has been established that the postmenopausal estrogen-deficient state is a risk factor for cardiovascular disease in women. In the Framingham Heart Study, natural or surgical menopause is associated with a doubling of the risk of a CHD event (106). By age 75, the incidence of cardiovascular disease in women is essentially equal to the incidence in men (107), suggesting that circulating estrogen has an important impact on the progression of atherogenesis, and that the estrogen-deficient state after menopause underlies the steep increase in CHD risk in older women. Several observational studies support the hypothesis that estrogen replacement therapy (ERT) exerts a protective effect on CHD morbidity and mortality in postmenopausal women, but data on women 65 years and older are limited (108-111). Observational, non-randomized studies suggest that the expected reduction in risk of developing cardiovascular disease among postmenopausal women treated with ERT is about 50% (112, 113). Unfortunately, data from large randomized clinical trials are still lacking, and conclusive answers to these questions must wait for several more years, when results from the Women’s Health Initiative (114), a large-scale multicenter, randomized trial will be available. The protective effect of circulating estrogens is biologically plausible, since estrogens influence several metabolic risk factors: they reduce TC and

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LDL-C levels, increase HDL-C concentration (115), and modulate carbohydrate metabolism, blood pressure and the coagulation system (113). In middleaged women age 45 to 64 years, strong evidence of a positive influence of ERT on metabolic risk factors for CHD has been provided by the results of a recently concluded clinical trial, the Postmenopausal Estrogen/Progestin Interventions trial (PEPI) (116). The use of unopposed estrogen and of three combined estrogen-progestin regimens significantly increased HDL-C levels, decreased LDL-C levels, and lowered fibrinogen levels, with little effects on insulin levels or blood pressure. Observational studies suggest that the beneficial effects of ERT on lipoproteins and other metabolic parameters might be also expected in women over age 65 (117). In the Cardiovascular Health Study, 2955 women aged 65 to 100 years were examined. Estrogen use was strongly associated (p<0.0001) with lower LDL-C, fibrinogen, glucose and insulin levels, higher HDL-C and reduced BMI. Furthermore, estrogen users had decreased carotid wall thickness and less carotid stenosis (118). Despite the fact that no clinical trials have been designed specifically for women over 65 years, all these findings suggest the potential for important benefits from estrogen alone or combined with progestin, particularly among older women, known to be at higher risk for CHD than younger postmenopausal women. However, the actual decision to continue ERT from menopause through old age, or to begin ERT in women over age 65 remains a difficult one. In addition to the potential benefits in reducing CHD, other aspects to be considered in making this decision include the potential for increased uterine and breast cancer risk, and the benefits related to the well-known protective effects of ERT in the prevention and treatment of osteoporosis. PHYSICAL EXERCISE Several studies have demonstrated reduced CHD incidence and mortality in middle aged men and women who engage in regular physical activity (119). However, comparable data relating physical activity to morbidity and mortality in older adults are limited, and most of these studies refer to men only (120, 121). In the Harvard alumni study of men aged 35 to 74, overall death rates were one-quarter to one-third lower among more active alumni than among less active men, and the largest difference between these two groups was in CHD mortality (121). By the age of 80, the increased longevity attributable to ade-

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quate exercise ranged from one to two years. In the Honolulu Heart Program, the rate of CHD in active men 64 years and older was less than half the rate experienced by the more sedentary men (RR, 0.43; 95% CI, 0.19-0.99). Results remained unchanged after controlling for several cardiovascular risk factors, suggesting that the beneficial effects of exercise may be independent from its influence on other established CHD risk factors, such as HDL-C levels, glucose intolerance, overweight and hypertension (120). A case-control study in a group of men and women aged 76 years or less (mean age 72 years) found similar results: men and women in the most active group, categorized by level of energy expenditure, had a 55 to 60% lower risk of myocardial infarction than those in the least active category, even after controlling for other risk factors (122). Results from more than 22 randomized trials of rehabilitation with exercise after myocardial infarction in middle-aged persons, mainly men, were summarized by O’Connor in a comprehensive meta-analysis (123). Aggregate estimates of the risk after 3 years of follow-up indicated a beneficial effect of rehabilitation on total mortality, cardiovascular mortality and fatal reinfarction. Although these results may be partially attributed to the non-exercise components of the rehabilitation programs, and cannot be directly applied to the older population, they support the potential benefits of physical activity in the secondary prevention of CHD. Even among persons r65 years without serious chronic disease or disabling conditions, physical inactivity is common; in a cohort of physically capable older adults, 20% of men and 32% of women never engaged in any vigorous or moderate exercise, including walking or gardening (124). In this cohort, physical inactivity was associated with an increased likelihood of mortality, and an increased risk of physical impairment over both 3 and 6 years of follow-up. However, no consistent association was found between activity and new myocardial infarction or angina during 6 years of follow-up. Although no randomized, controlled trial of exercise in the primary prevention of CHD in the elderly has ever been performed, data from observational studies suggest the possibility that modifying a sedentary life-style may reduce the risk of cardiovascular disease, all-cause mortality (125), falls (126) and functional decline in older persons (124, 127). OTHERS Several other parameters have been suggested as risk factors for atherosclerotic cardiovascular diseas-

es, such as elevated serum fibrinogen (128-131), increased uric acid (132-134), serum iron and ferritin levels (135-138), decreased serum albumin (139142) and increased homocysteine levels (143). Most of these findings, however, are from studies that were performed in middle-aged populations, and did not investigate people older than 65 years. For most of these proposed risk factors, unequivocal conclusions have not been reached, and it is possible that the increased risk associated with these parameters is largely mediated through their relation with established risk factors. Uric acid, for example, is correlated with blood pressure, anti-hypertensive therapy, body weight, serum cholesterol, and cigarette smoking (143); high levels of fibrinogen are often found in smokers and individuals with hypercholesterolemia, untreated hypertension, and obesity (144). Finally, homocysteine levels are positively associated with age, heavy smoking, and total cholesterol levels in subjects aged 40 to 67 years (146). SPECIAL CONSIDERATIONS IN THE OLDER POPULATION In recent years, the approaches to understanding CHD risk factors that have worked well in the middleaged population have been applied to the older population, and increased information on older people is now available. However, studying the older population brings with it complexities that are not present in middle-aged, generally healthy populations. A number of issues that are unique to the older population and have relevance for the study of CHD risk factors are reviewed here. Age Age per se is one of the most important determinants of CHD mortality in older persons. Age may well represent a surrogate measure of the longer exposure to established risk factors, and an indirect measure of the limited capability of the aged to cope with them. Furthermore, age can be considered an indirect measure of age-related clustering of multiple risk factors, and of the increased burden of comorbid chronic conditions. However, despite the age-associated increase in CHD incidence in both men and women, it should be remembered that CHD is not an inevitable consequence of the aging process. Autopsy studies have revealed that coronary arteries nearly free of atheroma are not uncommon findings among people dying of other causes when 90 years old (147). Gender differences

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Numerous studies, some of which have been reviewed here, have demonstrated that differential risk profiles according to gender are a common finding, especially among older persons. This could be an artifact of inadequate sample sizes in these studies, or a valid observation. There are a number of different possible explanations for these differences. For example, high CHD mortality rates in middle aged men may select out of the population those men at highest risk of CHD. Differences in the intensity of diagnostic and treatment approaches for CHD in men vs women may result in different manifestations of this disease in older surviving persons. Finally, a different biological effect of risk factors on atherosclerosis-related clinical end-points in postmenopausal, older women compared to older men can also be postulated as a possible explanation of observed gender differences. Relative risk versus absolute risk There has been a common notion that some of the usual cardiovascular risk factors no longer apply in older persons. This was considered to be the case when the first data from the Framingham Heart Study participants entering older age were analyzed (8, 148). Since then, however, as shown in this review, several other population-based studies have provided a more complete picture of the role of established CHD risk factors in the elderly, and established risk factors generally remain important in this age group. Relative risk estimates do tend to decline with advancing age (149, 150). However, absolute risks are substantially higher in the older population, and the absolute risk difference between those with and without a risk factor tends to be greater in the older population (151). Thus, the relative risk does not fully convey the potential public health impact of disease prevention in the elderly. Health status and comorbidity Another important consideration is that, with advancing age, the population becomes increasingly heterogeneous with regard to health status (152). With increasing comorbidity, there is a tendency to modify unhealthy habits, such as stopping smoking after a lifetime of smoking. Furthermore, poor health status per se can induce pathologic changes resulting in changes in several risk factors, such as blood pressure and serum cholesterol, toward levels usually associated with low risk status (153). It is, therefore, common to observe high risk individuals drifting toward low risk exposure levels, especially after clinically relevant events. The effect is that risk factors measured at old age, such as blood pressure, lipids,

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body weight and smoking, might not accurately represent the cumulative life-time exposure to a specific factor (152, 153). This observation suggests that epidemiological studies in older populations may require more rigor, and that the assessment of risk factors in the elderly must take into account the potential effects of differences in overall health status and previous risk factor level (153). Primary and secondary prevention in the elderly There is now convincing evidence that, after accounting for age- and health-related factors that modify the relationship between risk factors and outcomes, it is still possible to identify high risk older individuals. When risk factors are modifiable, there are indications that it is possible to prevent CHD events through life-style and pharmacologic interventions even late in the life. Unfortunately, elderly individuals have often been excluded from primary and secondary prevention trials and, therefore, only observational evidence or results from trials in middleaged adults may be available to support the need for screening and intervention in older high risk individuals. Future directions: screening for subclinical disease and risk factors modifications The prevalence of subclinical cardiovascular disease in older otherwise healthy persons is considerable. Among the 5201 Cardiovascular Health Study participants, 36% of women and 38.7% of men aged 65 years and older had unequivocal signs of subclinical cardiovascular disease, as compared to 26.4% of women and 37.5% of men with clinical disease (154). This study showed a direct association of blood glucose levels, systolic blood pressure, and LDL-C with subclinical atherosclerosis. As the authors hypothesize, risk factors for subclinical disease are similar to those for clinical disease at younger ages. Therefore, risk factor modifications especially targeted to those with subclinical disease could be a very cost-effective intervention, potentially preventing the onset of clinical disease in a considerable group of high risk older individuals. REFERENCES 1. National Center for Health Statistics: Vital statistics of the United States, 1989. Vol II. Mortality. Part A. Government Printing Office, Washington, D.C., (DHHS publication n. (PHS), 93-1101, 1993. 2. Ettinger W.H., Fried L.P., Harris T., Shemansky L., Schulz R., Robbins J.: Self-reported causes of physical disability in older people: the Cardiovascular Health Study. J. Am. Geriatr. Soc. 42: 1035-1044, 1994.

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