the U.S. population, have some form of cardiovascular disease. Each year, approximately 6 million hospitalizations

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1 Cardioprotection: What is it? Who needs it? William B. Kannel, MD, MPH From the Department of Preventive Medicine and Epidemiology, Evans Department of Clinical Research, Boston University School of Medicine, Boston William B. Kannel, MD Cardioprotection can take several forms. During an acute cardiovascular event, protective measures can limit damage and enhance survival. In those who have had a previous cardiovascular event, cardioprotective measures can prevent recurrence and long-term cardiovascular related damage. Protective measures can also prevent initial cardiovascular events in the general population and in people who are at high risk due to an adverse cardiovascular risk profile. Magnitude of the problem Despite monumental gains in the knowledge of cardiovascular and its prevention, it remains the major cause of death among adults (Figure 1). Worldwide, 12 million deaths occur from cardiovascular each year, according to the third monitoring report of the World Health Organization ( ). In the United States, more than 960,000 individuals die of cardiovascular each year, accounting for more than 40% of all deaths. Although the death rate from coronary heart (CHD) declined by more than 50% from 1968 to 1990, that decline has leveled off. 1 Societal costs of the are enormous (Figure 2). A staggering 58 million Americans, about 25% of the U.S. population, have some form of cardiovascular. Each year, approximately 6 million hospitalizations are related to cardiovascular, and the Centers for Disease Control and Prevention estimate that it costs the United States about $274 billion each year. Advanced atherosclerotic occlusive cardiovascular often exists without overt clinical manifestations and must be sought out by an exercise electrocardiogram (ECG), ambulatory ECG monitoring, or periodic routine ECG monitoring. Carotid artery ultrasonography, ankle-brachial pressure determination, or electron-beam computed tomography can also detect. Atherosclerotic cardiovascular is a diffuse process that involves the heart, brain, kidneys, and limbs. Its presence in one vascular territory heralds its presence elsewhere because of shared predisposing risk factors. Among Framingham study subjects who sustained an initial myocardial infarction (MI), about one fourth had antecedent angina, 10% had previous peripheral artery, 5% to 8% had a stroke, and 3% to 10% had heart failure. 2 Coronary is the most common and most lethal manifestation of atherosclerotic cardiovascular. In men younger than 65 years, the annual incidence of coronary (12 per 1,000) more than equals the rate of all other atherosclerotic events combined (7 per 1,000). 3 Disease-specific epidemiology Major cardiovascular events for which epidemiologic data are available include MI, sudden cardiac death, and heart failure. MI. Acute MI occurs in approximately 2 per 1,000 people each year. It is a major cause of sudden death in adults and remains the number one cause of death in the United States. Despite the decline in the mortality rates from cardiovascular, the incidence of first-time hospitalizations for MI is increasing slightly, especially among African Americans. Between 1987 and 1994, hospital admissions for MI increased by 7.4% per year among African American women and by 2.9% among African American men. 3 In the same period, the incidence of recurrent MI decreased by 18.8% in men (2.6% per year) and by 14.5% among women (1.9% per year). 4 Survival after MI has also improved. One in three MIs that occur in the general population go unrecognized and are detected only by routine ECG surveillance. These undetected MIs are more common in persons with hypertension and in men with diabetes. 5 The incidence of initial coronary events ascertained from 44- year follow-up data from the original Framingham study cohort and 20-year surveillance of their offspring indicates that, for 40-yearolds, the lifetime risk of a coronary event (including recognized and unrecognized MI, angina, and sudden and nonsudden coronary deaths) is 49% for men and 32% for 5

2 Cardiovascular Risk Protection FIGURE 1 Leading causes of death for all males and females, United States, 1999 Deaths in thousands A B C D E Source: CDC/NCHs and the American Heart Association. FIGURE 2 445, ,832 63,535 62,415 31,150 A Total cardiovascular B Cancer C Accidents 512, ,006 Males Females 61,766 37,249 36,012 A B D E F D Chronic lower respiratory s E Diabetes mellitus F Influenza and pneumonia women. 6 Comparing age groups 35 to 64 years and 65 to 94 years, incidence doubles with age in men and triples with age in women. Women lag behind men in death by 20 years, but the sex ratio of incidence narrows with advancing age. The incidence abruptly increases threefold in women during menopause. 7 Sudden cardiac death. Sudden cardiac death accounts for about one half of all cardiovascular deaths in Estimated direct and indirect costs (in billions of dollars) of cardiovascular s and stroke, United States, 2002 Billions of dollars Heart Coronary heart Stroke CVD = Cardiovascular Source: CDC/NCHs and the American Heart Association. Hypertensive 23.2 Congestive heart failure Total CVD the United States and other developed countries; up to 80% of all persons who die suddenly have CHD. 8 Sudden cardiac death is the initial coronary event in about 16% of CHD patients. 9 It is also the most frequent mode of death, accounting for 30% to 50% of coronary deaths. 10,11 The incidence of these precipitant deaths is the same with Q-wave and non Q-wave MI 12 and with silent and symptomatic infarctions. 13 MI confers twice the risk of sudden death compared with angina. 11,13 About 80% of sudden deaths occur in asymptomatic patients without a history of coronary. 14 Sudden deaths are also common in patients with heart failure. Heart failure. Since 1980, the prevalence of heart failure in the United States has doubled 4.8 million patients are currently living with heart failure. Since 1970, hospitalizations for heart failure have tripled, and office visits have skyrocketed from 1.7 million to 2.9 million in the past decade. 15 In persons older than 65 years, the incidence of heart failure is 12 per 1,000 in men and 9 per 1,000 in women. Lifetime risk of heart failure is 20% for persons 40 years of age. Who is at major risk for CHD? A substantial proportion of coronary progresses from inapparent to MI and death. Much of the accelerated atherogenesis leading to this premature morbidity and mortality occurs in a subset of the population with modifiable predisposing risk factors. Data from the Framingham study reveal the following major risk factors for CHD: Cigarette smoking Hypertension Dyslipidemia characterized by increased total or low-density lipoprotein (LDL) cholesterol and a low level of high-density lipoprotein (HDL) cholesterol 6

3 Diabetes Increasing age With the exception of age, all of these factors are modifiable with demonstrated benefit. Other factors that increase the risk for developing CHD include obesity, physical inactivity, family history of premature CHD, hypertriglyceridemia, a lipid profile that includes small, dense LDL particles, increased levels of lipoprotein(a), increased levels of serum homocysteine, and abnormal coagulation factors. Patients at particularly high risk for CHD events include those who have had a previous MI and those with heart failure or high risk for heart failure, diabetes, and hypertension. Diabetes. In the Third Adult Treatment Panel (ATP III) report of the National Cholesterol Education Program (NCEP), diabetes is considered a CHD risk equivalent because it carries a high risk of developing CHD within 10 years, partly as a result of its association with multiple risk factors. ATP III defines a CHD risk equivalent as a risk of a major coronary event above 20% over the next 10 years, which is equivalent to the risk of major coronary events in persons with established CHD (Table 1). 16 Blood lipid levels. Blood lipids play a pivotal role in the genesis of CHD. Three fourths of patients with CHD or MI have some form of lipid abnormality. According to the Framingham Heart Study, 27% of CHD events in men and 34% of those in women are associated with total cholesterol levels of 200 mg/dl or above after adjusting for other risk factor variables. 17 The Framingham study has shown that efficient selection of dyslipidemic candidates for the development of CHD requires the use of the total-to-hdl or total-to-ldl cholesterol ratio, which reflects the joint effect of the two-way cholesterol traffic entering and being removed from the arterial intima. These ratios more efficiently predict coronary than these lipids by themselves. 18 The ratio efficiently determines the risk conferred by a total cholesterol level above and below 240 mg/dl and an LDL cholesterol level above and below 130 mg/dl. Elevated total and LDL cholesterol levels tend to cluster with other major risk factors, occurring in isolation only about 20% of the time. Because the risk associated with dyslipidemia is markedly affected by frequently accompanying risk factors, it is important to consider blood lipids as components of a cardiovascular risk profile. According to data from the Atherosclerosis Risk in Communities (ARIC) study, the lowest incidence of CHD events occurs in persons in the lowest quintile of LDL cholesterol (a median of 88 mg/dl in women and 95 mg/dl in men). 19 The ARIC authors concluded that optimal LDL cholesterol values are below 100 mg/dl for both men and women. Independent predictors of CHD were LDL cholesterol, HDL cholesterol, lipoprotein(a), and triglycerides (in women, not men). Metabolic syndrome. Metabolic syndrome has recently been recognized by ATP III as a secondary target of risk reduction therapy. Individuals affected by this syndrome have an increased risk for CHD, independent of their LDL cholesterol levels. Insulin resistance plays an important role in metabolic syndrome, which is characterized by several major risk factors coupled with lifestyle risk factors and emerging risk factors. These individuals characteristically have abdominal obesity, atherogenic dyslipidemia (as heralded by elevated triglyceride levels, small, dense LDL particles, and low HDL cholesterol), elevated blood pressure, insulin resistance, and prothrombotic and proinflammatory states. Management of both the lipid and nonlipid risk factors that constitute metabolic syndrome is necessary. Not only should underlying causes, such as obesity and physical inactivity, be addressed, but treatment for nonlipid and lipid risk factors should also be initiated. Because one fourth of individuals who experience MI have no previous symptoms, clinicians should be proactive in risk assessment and primary prevention in asymptomatic individuals. 20 Hypertension as a risk factor. Hypertension is a strong risk factor for CHD. Even moderate elevations in blood pressure are associated with increased risk, especially in women. The Framingham study recently investigated the risk of cardiovascular in participants with high-normal blood pressure ( / mm Hg) who were initially free of hypertension and cardiovascular. Compared with optimal blood pressure, highnormal blood pressure was associated with a risk factor adjusted hazard ratio for cardiovascular of 2.5 for women and 1.6 for men. 21 These findings indicate the need to determine whether lower- TABLE 1 What are CHD risk equivalents? Other clinical forms of atherosclerotic - Peripheral arterial - Abdominal aortic aneurysm - Symptomatic carotid artery Diabetes Multiple (single or total) risk factors that confer a 10-year risk for CHD > 20% CHD = coronary heart. Source: Executive summary of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 16 7

4 Cardiovascular Risk Protection Metabolic syndrome According to ATP III, metabolic syndrome is a constellation of risk factors that, in aggregate, confer a high risk of CHD at any given level of LDL cholesterol. The syndrome is closely linked to a generalized metabolic disorder called insulin resistance, in which the normal actions of insulin are impaired. Metabolic syndrome is a secondary target of risk reduction therapy after LDL cholesterol, which is the primary target. A diagnosis of metabolic syndrome is made when three or more of the following risk determinations are present: Abdominal obesity: waist circumference > 102 cm in men and > 88 cm in women Triglycerides > 150 mg/dl HDL cholesterol < 40 mg/dl in men and < 50 mg/dl in women Blood pressure 130/85 mm Hg Fasting glucose 110 mg/dl ATP = Adult Treatment Panel; CHD = coronary heart ; LDL = low-density lipoprotein; HDL = highdensity lipoprotein. ing high-normal blood pressure can reduce the risk of cardiovascular. About 50% of the cardiovascular events that occurred in Framingham study participants occurred in persons with stage 1 or 2 hypertension. 22 Despite the 1.5-fold to twofold increase in risk imposed by this degree of hypertension, the absolute risk is modest, making it necessary to treat many to prevent one case unless risk stratification is used to target candidates for treatment. Optimal therapy must address the many other risk factors that accompany hypertension 80% of the time. 23 In the Cardiovascular Health Study (CHS), a recent prospective trial of 5,888 men and women, researchers sought to determine risk factors for CHD and stroke in patients ages 65 years and older. 24 Systolic and diastolic blood pressure and pulse pressure (the difference between systolic and diastolic blood pressures) were directly associated with the risk of MI and stroke. Systolic blood pressure was the best predictor of cardiovascular events. There was no evidence of a J-curve relationship between blood pressure level and cardiovascular risk. The Framingham study investigated whether pulse pressure is useful for predicting coronary. 25 Considered individually, systolic pressure, diastolic pressure, and pulse pressure were each positively associated with risk of coronary over 20 years of follow-up after adjusting for age, sex, and other risk factors. Of these risk factors, pulse pressure yielded the strongest impact. When systolic and diastolic blood pressure were jointly considered in a multivariable model, the association was positive for systolic pressure and negative for diastolic pressure. In middle-aged and elderly participants (ages 50 to 79 years), coronary risk increased with decreasing diastolic pressure at any level of systolic pressure above 120 mm Hg. This suggests that pulse pressure is an important component of blood pressure risk. Additional risk factors. Several risk factors that were not included in ATP III have received considerable attention and merit mention. Among these are plasma homocysteine, C-reactive protein (an inflammatory marker), and the angiotensin-converting enzyme genotype (ACE DD). Homocysteine levels, when high, may be markers for abnormal endothelial function and could promote procoagulant changes in clotting factors. Several studies tentatively place normal homocysteine levels at below 10 µmol/l, and each 5-µmol/L increase has been shown to increase CHD risk by 60% in men and 80% in women. 26 Niacin can elevate homocysteine, whereas folic acid and vitamins B 6 and B 12 can decrease homocysteine concentrations. Currently, several clinical trials are in progress to assess the effects of lowered homocysteine on the risk of cardiovascular or stroke. In individuals with elevated cholesterol levels, the presence of C- reactive protein, a marker of vascular inflammation, identifies those at highest risk for cardiovascular events. In patients with only moderately elevated cholesterol levels, it seems to be less of a risk factor for vascular events. HMG- CoA reductase inhibitors and aspirin have been shown to reduce levels of C-reactive protein. Researchers are also studying how antibiotics affect vascular inflammation and C-reactive protein levels, because it is believed that the inflammation may be associated with infection. Clinical data are lacking, however, to show that lowering C-reactive protein improves outcomes. The ACE DD genotype is associated with higher levels of plasma ACE, and has been linked to a higher risk of CHD in patients with no other CHD risk factors. According to a recent study of 213 patients with familial hypercholesterolemia, the odds ratio for MI was 2.57 in men who had the ACE DD genotype, compared with those with the ACE DI or II genotype. 27 Risk assessment Guidelines from ATP III; the American College of Cardiology 8

5 (ACC); the American Heart Association (AHA); the sixth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI); and a task force comprising the European Society of Cardiology, the European Atherosclerosis Society, and the European Society of Hypertension all recommend CHD risk factor assessment in asymptomatic individuals. According to ATP III, all persons 20 years of age or older should undergo a fasting lipoprotein profile every 5 years. Framingham Risk Score. According to both the ACC and AHA, multifactorial statistical models, such as the Framingham Risk Score, are helpful determinants of global risk. A CHD prediction score sheet has been derived from data from the Framingham study. This model was based on 5,300 men and women ages 30 to 74 years at baseline who were followed up over 12 years for CHD. It incorporates age, sex, blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, diabetes, and smoking status. These variables are entered into a risk calculation model to determine an individual s relative and the absolute risk of a cardiac event in the next 5 to 10 years (Figure 3). 28 A point value is assigned to each risk factor; these are then added to calculate an individual s 10-year risk for CHD. For example, a 55-year-old nonsmoking man with diabetes and a total cholesterol level of 250 mg/dl, an HDL level of 39 mg/dl, and a blood pressure of 146/88 mm Hg would accrue the following points: 4 points for his age 2 points for his total cholesterol level 1 point for his HDL cholesterol level 2 points for his blood pressure 2 points for his diabetes His total points would therefore be 11, a score that translates to a 31% risk of CHD over the next 10 years. This is almost twice that of the average risk for a 55-year-old man. ATP III. ATP III developed its own 10-year risk assessment calculations. The variables included age, total cholesterol level, smoking status, HDL cholesterol level, and systolic blood pressure. Joint European Task Force on CHD Prevention. As a result of accumulating clinical evidence in support of primary and secondary coronary prevention, a task force was convened in 1998 by the European Society of Cardiology, the European Atherosclerosis Society, and the European Society of Hypertension to develop a multifactorial risk assessment. The task force revised its initial 1994 recommendations, paying close attention to new data on lowering lipid levels. FIGURE 3 The task force recommended that clinicians concentrate efforts on individuals with overt CHD or other atherosclerotic conditions and those considered to be at high risk for. High-risk individuals are those with a combination of risk factors, which include: Smoking Dyslipidemia (elevated total and LDL cholesterol levels, low HDL cholesterol levels, and elevated triglycerides) Family history of premature coronary Hypertension Diabetes Once an assessment of absolute risk is made, lifestyle intervention and drug therapies are recommended for those who have the highest multifactorial risk. Furthermore, the task force recommended that absolute CHD risk should always be Estimated 10-year CHD risk in 55-year-old adults according to levels of various risk factors Framingham Heart Study, United States Estimated 10-year rate (%) Males Females 5 A B C D A B C D Blood pressure (mm Hg) 120/80 140/90 140/90 140/90 Total cholesterol (mg/dl) HDL cholesterol (mg/dl) Diabetes No No Yes Yes Cigarettes No No No Yes CHD = coronary heart ; HDL = high-density lipoprotein. Source: Wilson PWF, D Agostino RB, Levy D, et al

6 Cardiovascular Risk Protection considered in the decision for pharmacologic intervention for hypertension and elevated lipid levels. An absolute CHD risk above 20% over the next 10 years or CHD risk above 20% when projected to 60 years of age that remains despite professional lifestyle interventions calls for the selective use of proven drug therapies. Other classifications of risk. Apart from the standard classifications of risk derived from Framingham data, other methods to assess a patient s risk of cardiovascular have been developed and studied. Recently, the AHA s Prevention V conference proposed an approach to office-based testing depending on a patient s global risk assessment. 20 Low-risk patients are those who have no elevated risk factors (about 35% of adults fall into this category). Intermediate-risk patients, about 40% of adults, have one or more elevated risk factor levels, but they are not candidates for intensive risk reduction interventions. These individuals should be further studied using noninvasive tests to determine their risks. These tests TABLE 2 Predisposing conditions for heart failure can include ankle-brachial index, ultrasonographic examination of the carotid artery, electron-beam computed tomography, and exercise stress testing. High-risk patients, about 25% of the adult population, are those with established CHD, atherosclerotic, or type 2 diabetes or they are older patients with multiple risk factors. The risk of an event in these patients is considered to be the same as in patients who have CHD or a previous MI. Intensive risk reduction strategies are recommended for persons in this high-risk category. Hazard Prevalence Population ratio* (%) at risk (%) Condition Men Women Men Women Men Women High blood pressure (> 140/90 mm Hg) MI Angina Diabetes Left ventricular hypertrophy on ECG Valve *Adjusted for age and risk factors. MI = myocardial infarction; ECG = electrocardiogram. Source: Levy D, Larson MG, Vasan RS, et al. 31 Emerging trends in heart failure Epidemiology. Heart failure is the only cardiovascular disorder that seems to be increasing in prevalence. Since 1980, the prevalence of heart failure has doubled, with more than 400,000 new cases diagnosed annually. Mortality from heart failure has also doubled since 1968, and is now 219,000 annually. Increasing age is perhaps the most notable risk factor for heart failure. In those younger than 65 years, the incidence is 3 per 1,000 persons in men, and this increases to 12 per 1,000 in men older than 65 years. In women, the risk is 2 per 1,000 in those younger than 65 years and 9 per 1,000 in those age 65 or older. Risk factors. Left ventricular function is an important marker for increased risk of heart failure. Clinical indicators that warrant further investigation for deteriorating left ventricular function include ECG evidence of left ventricular hypertrophy or a rapid resting heart rate, a low or decreased vital capacity, and radiographic evidence of an enlarged heart. The risks for heart failure increase steeply when multiple markers are present. Left ventricular hypertrophy by itself increases the risk of heart failure twofold to threefold. 29 One half of the subjects in the Framingham study who developed heart failure had normal systolic function; approximately 50% of all clinical heart failure occurs in individuals with ejection fractions above 55%. In women, about 65% of heart failure cases occur in those with normal ventricular function. In contrast, 75% of heart failure cases in men are associated with reduced left ventricular function. 30 Other risk factors for heart failure include elevated systolic blood pressure, increased pulse pressure, angina, a history of MI, diabetes, and valvular heart (Table 2). 31 MIs (including silent and unrecognized infarctions) increase the risk for heart failure fivefold to sixfold, diabetes increases the risk by two to three times, and valvular heart is associated with a doubling of risk. Five-year mortality for patients with heart failure is 60% to 75%. The mortality rates are higher in African American men and women than in whites. Patients with heart failure also have an increased risk of CHD, with the 10-year risk estimated to be 40% to 50%. The risk of stroke in 10

7 these individuals is two to five times greater than in the general population, with a 10-year risk of 30% to 40%. Risk assessment. Those at high risk for heart failure need to be identified early so that preventive measures can be implemented. Multivariable risk profiles that include age, sex, ECG record, vital capacity, systolic blood pressure, heart rate, diabetic status, radiographic evidence of cardiomegaly, and the presence of CHD or murmurs can be used in global risk assessment. The Framingham study devised a risk appraisal model to assess the multivariable hazard of heart failure in persons predisposed by virtue of the presence of hypertension or coronary or valve. 32 With this multivariable risk formulation, it is possible to identify highrisk candidates for heart failure who are vulnerable because of multiple marginal risk factor abnormalities who might otherwise be overlooked. It also helps identify persons likely to have impaired left ventricular systolic function, who require further evaluation and preventive measures. Conclusion The risk of CHD and heart failure can be predicted by routine assessment of cardiac risk factors. Several approaches to risk assessment using multiple CHD risk factors are available. In most cases, office-based risk assessment is adequate to predict and quantify risk. Persons presenting with any particular risk factor need a global multivariable risk assessment to determine the necessary urgency and vigor of therapy. The goal of therapy is to reduce global cardiovascular risk. REFERENCES 1. Daviglus ML, Stamler J. Major risk factors and coronary heart : Much has been achieved but crucial challenges remain. J Am Coll Cardiol 2001; 38: Cupples LA, Gagnon DR, Wong ND, et al. Preexisting cardiovascular conditions and long-term prognosis after initial myocardial infarction: The Framingham study. 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