9.1 Cardiovascular diseases

9.1 Cardiovascular diseases
Oxford Textbook of Public Health

Cardiovascular diseases

Russell V. Luepker

Burden of cardiovascular diseases



Disease trends
Coronary heart disease

Risk factors
Congestive heart failure
Rheumatic fever and heart disease
Congenital heart disease
Cardiomyopathy and myocarditis
Chapter References

Cardiovascular diseases are the leading cause of death and disability in many industrialized countries and they are increasing in the developing world. The principal cardiovascular diseases are related to atherosclerosis: coronary heart disease, stroke, and peripheral vascular disease. Hypertension, congestive heart failure, rheumatic heart disease, cardiomyopathy, and congenital heart disease are also prevalent. The patterns on distributions of these diseases vary in different regions, however, coronary heart disease is assuming pre-eminence in many areas.
The rise of the cardiovascular diseases is attributed to a number of factors. The gradual reduction and elimination of infectious diseases affecting the young and middle-aged has led to longer lives. The major cardiovascular diseases are chronic conditions which are progressive and affect mainly older populations. Longer life expectancy with increased proportions of older individuals in society has brought chronic diseases, particularly cardiovascular disease, to the forefront. Additionally, atherosclerotic related diseases are associated with affluent lifestyles. The widespread availability of foods containing high-fat animal products in many societies leads directly to elevated blood lipids. Surplus food plus reduction in habitual physical activity results in obesity, which also encourages hyperlipidaemia and hypertension. In countries where affluence is growing, these diseases are found first among the wealthy. However, cardiovascular disease gradually affects all segments of the population as better living conditions prevail.
These shifts have led to changing patterns of cardiovascular diseases worldwide. In many industrialized countries, the rates of cardiovascular disease are rising. In other countries, they are falling. In most developing countries, the rates are rising with greater affluence and less infectious disease.
The substantial prevalence of cardiovascular diseases resulted in widespread application of medical treatments to confront this epidemic. In some countries, 20 to 30 per cent of the adult population is currently under treatment for cardiovascular disease or increased risk of cardiovascular disease. There is a rapid development of high-technology procedures for disease treatment and amelioration. The widespread application of these advanced technologies has led to growing costs of health care, in many cases exceeding the ability of many national health budgets to supply these treatments.
The rise in cardiovascular diseases is a phenomenon of the twentieth century. It threatens to be the leading cause of death and disability worldwide in the twenty-first century. Public health can and does play a leading role in the prevention of these diseases. Because risk factors for these diseases are identifiable and readily modified in healthy individuals at the population level, the sources of this epidemic can be confronted. The elimination of these diseases is possible and is a major public health challenge of the coming period.
Burden of cardiovascular diseases
Cardiovascular disease is the leading cause of death in many countries and rising in many others. Figure 1 depicts mortality for cardiovascular disease and all causes in 1995 for men and women aged 35 to 74 in selected countries. Cardiovascular diseases account for more than 50 per cent of the deaths in many countries (American Heart Association 1999). A number of different cardiovascular diseases are commonly implicated (Fig. 2). In the United States, as in many industrialized countries, coronary heart disease accounts for approximately half of the deaths while stroke and other cardiovascular causes provide the remainder. In Sweden, coronary heart disease and stroke are about equal. In Japan, stroke is more common as are other hypertension-related diseases, such as congestive heart failure. In Egypt, infectious cardiac diseases are important causes, however, atherosclerotic diseases are increasing (WHO 1995, 1996; American Heart Association 1999). These differences in distributions of cardiovascular disease mortality are associated with different circumstances in those countries and differing methods of classifying death. They also reflect age distributions of the populations, as the most common cardiovascular diseases are strongly associated with increasing age (Fig. 3).

Fig. 1 Death rates per 100 000 population for cardiovascular diseases (CVD) and all causes in selected countries, 1995 (or most recent year available). (Source: American Heart Association 1999.)

Fig. 2 Cardiovascular disease mortality. (Source: WHO 1995, 1996.)

Fig. 3 Death rates per 100 000 population for heart disease by age, race, and sex in the United States, 1996. (Source: NHLBI 1998.)

Although rarely appreciated by clinicians, the majority of cardiovascular disease mortality occurs outside of hospitals as ‘sudden’ cardiac death (McGovern et al. 1996; Tunstall-Pedoe et al. 1996). It may occur at home, in a public place, during ambulance transport, or in the hospital emergency room. Even those who reach the hospital alive have high rates of mortality which may approach 100 per cent in some categories (for example myocardial rupture, cardiogenic shock). This mortality is commonly associated with coronary heart disease, but also with congestive heart failure and rheumatic heart disease, as lethal cardiac arrhythmias of sudden onset precede death in these conditions.
While cardiac death is a common outcome of cardiovascular disease, non-fatal disease is also prevalent. As shown in Table 1, cardiovascular disease accounted for 5.8 million hospital admissions with an average length of stay of 5.8 days in the United States in 1995. It also accounts for 52 million visits to the general practitioner. Many of the visits are due to underlying cardiovascular disease, such as angina pectoris or congestive heart failure, or to treatment of risk factors such as hypertension and hyperlipidaemia.

Table 1 Cardiovascular diseases: number of hospital admissions, general practitioner visits, and deaths from cardiovascular diseases in the United States, 1995

The magnitude of this problem is also shown in Fig. 4 which describes trends in non-fatal and fatal coronary heart disease hospital admissions over time in south-eastern New England in the United States. The rates reflect the age and sex differences in coronary heart disease (Derby et al. 2000).

Fig. 4 Total discharges and deaths with International Classification of Diseases Ninth Revision code 410 to 414 in men and women, by age, in southeastern New England, United States, 1980 to 1991. (Adapted from Derby et al. 2000.)

These common diseases now have many high-technology procedures designed to ameliorate the conditions and reduce symptomatology. Some can prolong life. These medical procedures and treatments include cardiac surgery, angioplasty, angiography, pacemakers, implanted defibrillators, sophisticated diagnostic testing, and pharmaceuticals. Between the cost of this care and the lost productivity resulting from morbidity and mortality, cardiovascular disease represents an enormous economic burden, as shown in Fig. 5, for the United States in 1998 (American Heart Association 1999).

Fig. 5 Estimated direct and indirect costs of cardiovascular diseases (CVD) and stroke in the United States, 1998. (Source: American Heart Association 1999.)

Disease trends
The epidemic of cardiovascular disease is largely a phenomenon of the twentieth century, and trends within this century are apparent. The Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) study demonstrated that coronary heart disease was rising and falling in different nations during the 1980s and 1990s (Fig. 6) (Tunstall-Pedoe et al. 1999). A downward trend was noted in the United States with coronary heart disease rates peaking in the mid-1960s and falling substantially since that time (Table 2) (NHLBI 1998). Stroke peaked earlier, declined slowly, and then began a precipitous age-adjusted decline in the 1970s. Non-cardiovascular disease declined somewhat, but accounted for only a small fraction of the lower age-adjusted population mortality. With age-adjusted mortality falling, driven by a decline in cardiovascular disease, the result has been increased longevity in many populations. However, absolute mortality (not adjusted for age) has not fallen significantly, as the disease is pushed into older age groups (Luepker 1994).

Table 2 Age-adjusted death ratesa and percentage change for all causes of death and cardiovascular disease in the United States (1950 and 1996)

Fig. 6 Trends for coronary events in women (MONICA). (Source: Tunstall-Pedoe et al. 1999.)

Coronary heart disease
A vast body of research enhances the understanding of the aetiology, prevention, and treatment of coronary heart disease (WHO 1982). Important observations are summarized below:

Population-based studies show wide differences between countries and groups within those countries (Fig. 1).

The differences between populations are strongly related to population levels of established risk factors. These, in turn, are associated with differences in cultural, behavioural, and individual characteristics (Keys 1980).

Within populations, lipids, blood pressure, cigarette smoking, and other characteristics are highly predictive of coronary heart disease events in individuals (Dawber et al. 1957; Keys 1980; WHO 1982). These risk factors are first evidenced in youth and track into adulthood. That is, high-risk youth are likely to become high-risk adults (Luepker et al. 1999).

Studies of large-scale migrations from one culture to another demonstrate that an increase in risk factors and coronary heart disease is observed when individuals migrate from a low- to high-risk culture and assume the lifestyle of that new culture (Kagan et al. 1974).

Population patterns in coronary heart disease are changing rapidly within countries as some rise and some fall (Fig. 6).

Changes in coronary heart disease patterns are associated with a reduction in risk characteristics leading to decreased incidence and to improved medical care, leading to increased survival after an initial clinical event (Higgins and Luepker 1989).

Clinical trials demonstrate conclusively that a reduction in coronary heart disease mortality and morbidity results from the lowering of traditional risk factors (cholesterol, blood pressure, cigarette smoking) by either behavioural and/or pharmacological methods.

The population and trial data are congruent with laboratory and animal studies of atherosclerosis.
Coronary heart disease is the leading cause of adult mortality and a common cause of chronic disability in many countries. Research in coronary heart disease has been comprehensive and diverse including laboratory studies, animal models, clinical studies, population studies, and clinical trials. The evidence from these studies is convergent and implicates population-wide causes for this epidemic. It is apparent that strong cultural and individual factors in the setting of widespread affluence results in elevated risk of the underlying disease atherosclerosis. These influences and risk factors are safely modifiable in individuals and entire populations (WHO 1982; Stone et al. 1997; Wood et al. 1998b; Grundy 1999).
The rationale for disease prevention is found in many observations. Environmental factors encourage population-wide changes in behaviour resulting in mass elevations of risk. As populations live longer, this chronic disease is manifest following prolonged and sustained exposure to risk factors. Widespread genetic susceptibility also plays an important role in the setting of an unfavourable environment. Prevention of coronary heart disease is well founded based on these scientific observations. It begins with primary prevention or prevention of risk factor elevation in the first place (Luepker 1999). It includes identification and reduction of risk in high-risk individuals without manifest disease signs or symptoms. Finally, it rests on the identification of those who continue to be at high risk after coronary heart disease occurs. Well-established population and medical strategies are tested to implement prevention and the epidemic could be controlled with widespread and effective implementation of current knowledge.
Atherosclerosis is the underlying pathology in coronary heart disease. It is a process that affects medium-sized muscular arteries including the coronary, cerebral, and lower extremity vessels. The abdominal and thoracic aorta can also be involved. The lesions of atherosclerosis affecting the internal walls of blood vessels are commonly known as plaques. Plaques are an accumulation of lipids, principally cholesterol esters and free cholesterol, smooth muscle cells, macrophages, T lymphocytes, and connective tissue matrix (Fuster et al. 1992b; Ross and Fuster 1996). These lesions, when found in the coronary arteries, gradually obstruct blood flow over years of accumulation. They may also act acutely, obstruct blood flow as plaques rupture, and a clot is formed further obstructing blood flow (Fuster et al. 1992a).
Early lesions of atherosclerosis can be found among youth and young adults when fatty streaks are observed in the intima of coronary arteries (Stary et al. 1994, 1995). These fatty streaks may regress, but in populations where coronary heart disease is common, they tend to progress to diffuse intimal thickening and more developed fibrous and calcified plaques (Stary et al. 1994, 1995).
Many hypotheses have been advanced to explain the pathogenesis of atherosclerosis (Virchow 1856). The leading hypothesis is the ‘response to injury’ theory where local factors including hyperlipidaemia, infection, rheological forces, cigarette smoking, diabetes, and others injure the intima of the artery. The response of the arteries to this injury is local plaque formation. Repeated injury increases the size of this lesion (Ross and Glomset 1973). Another theory suggests that a nidus for the lesions is based on aberrant cell growth which initiates the lesion (Benditt and Benditt 1973).
While the usual natural history of atherosclerosis is progression over time, plaques can also regress. In non-human primates, atherosclerotic lesions regress with the reduction of plasma cholesterol levels (Wissler and Vesselinovitch 1976; Clarkson et al. 1984). Similarly, humans are observed to have regression in atherosclerotic lesions with lipid lowering by diet, drugs or surgery (Ornish et al. 1990; Buchwald et al. 1992; Watts et al. 1992). Atherosclerotic lesions, while complex and well organized, can regress.
Lesions of coronary atherosclerosis lead to many clinical outcomes, usually in the sixth decade of life or later. Atherosclerosis results in obstruction of blood flow in the coronary arteries with myocardial ischaemia and/or infarction. Angina pectoris or chest pain is related to an imbalance between blood supply and myocardial demands due to narrowed coronary arteries. Other common manifestations include sudden death and heart failure.
Risk factors
There are numerous known risk factors which play a role in the development of atherosclerosis. Risk factors are characteristics discovered initially in prospective epidemiological studies. The aetiological role of risk factors is supported by laboratory experimental data and confirmed with clinical trials in humans. They are characteristics which predict later disease and may play a causal role in the pathological process. These include diet, lipids, obesity, physical inactivity, diabetes, hypertension, tobacco smoking, and others.
There is substantial evidence to support a causal association of habitual dietary intake with coronary heart disease. Much of that evidence is found in studies comparing populations. However, there is also considerable evidence within populations to suggest the role of individual dietary intake in coronary heart disease morbidity and mortality. Human feeding experiments add evidence as do animal studies. A number of components of habitual diet have been considered. These include fat, dietary cholesterol, carbohydrates, fibre, alcohol, protein, and caloric excess. Information regarding diet and coronary heart disease is summarized here.

Habitual food intake varies greatly between populations. These differences are related to population prevalence of coronary heart disease (Keys 1980).

While more difficult to study, individual eating patterns are also associated with coronary heart disease (Keys et al. 1965; Keys 1980).

When all components of diet including fats, protein, carbohydrates, minerals, alcohol, and dietary supplements are considered, the type and amount of fat intake is the most important component in preventing coronary heart disease.

The association of dietary fat with coronary heart disease is predominantly through the effects of saturated fats and cholesterol on blood lipids.

Eating patterns are changing in many cultures, leading to improving coronary heart disease rates in some and worsening in others.

Clinical trials of secondary prevention find diet change effective in lowering coronary heart disease.

Laboratory animal studies of non-human primates are congruent with these human diet–disease relationships.
The evidence is strong for the effect of diet between populations. The best known is the Seven Countries Study which compared habitual food intake in samples from among seven national populations (Keys 1980). This study demonstrated great variability in habitual food intake and a clear association of fatty acids and dietary cholesterol with blood cholesterol levels. Those blood cholesterol levels were a strong predictor of coronary heart disease in initially healthy populations followed more than 25 years (Blackburn and Jacobs 1984).
So central is the association of diet with blood cholesterol level, that many investigators suggest a cholesterol-raising diet is essential for mass expression of coronary heart disease (Blackburn and Jacobs 1984). These conclusions rest on data showing a diet with increased animal fats, specifically saturated fat and cholesterol, is found in populations where disease rates are high. Conversely, populations where these dietary components are low show a decreased incidence of coronary heart disease. Changes in diet seem to precede rising or falling coronary heart disease rates. Such is the case in the United States where diet is changing associated with falling blood cholesterol and coronary heart disease (Table 3). Additional evidence comes from observations in other international studies, where countries such as Japan have elevated levels of blood pressure and cigarette smoking, important coronary heart disease risk factors, but fail to manifest high rates of coronary heart disease. The Japanese have lower population levels of blood cholesterol (Keys 1980).

Table 3 Nutrient intake in the United States (1978 and 1990)

Additional observations on migrating populations show the same conclusions. The Japanese living in Japan have low cholesterol levels and low rates of coronary heart disease. As they move to Hawaii and the United States, they progressively assume the lifestyle of those Westernized cultures and experience elevations in blood cholesterol, obesity, and coronary heart disease rates similar to the local population (Kagan et al. 1974). Similar observations have been made among Irish migrants (Kushi et al. 1985). Again, the assumption of a high-fat Western diet is associated with increased coronary heart disease.
While the associations between diet and coronary heart disease are very strong in between population comparisons, the data are more conflicting in studies within populations. Here, studies of food intake or eating patterns of individuals modestly predict subsequent disease, if at all. There are several well-recognized reasons for this apparent paradox.
Supportive evidence comes from metabolic ward feeding studies. Here, individuals fed controlled diets of known composition for prolonged periods, show a clear relationship between type and quantity of fat intake and blood cholesterol levels. This relationship is best described by the Keys’ formula which relates the intake of saturated fats, polyunsaturated fats, and dietary cholesterol to blood cholesterol levels (Keys et al. 1974). The Keys formula is calculated using the formula: 1.35 (2S – P) + 1.5Z where S is the percentage of dietary calories from saturated fatty acids, P is the percentage of dietary calories from polyunsaturated fatty acids, and Z is the square root of dietary cholesterol in mg/1000 kcal (Keys et al. 1965). A slight variant of this formula was given by Anderson et al. (1979).
Similar associations are described by Hegstad et al. (1965). More recent studies have provided increased detail including information on monounsaturated fats, and specific fatty acids including trans-fatty acids (Mattson and Grundy 1985; Ascherio et al. 1994; Ginsberg et al. 1998).
Given clear and consistent associations in between population studies and feeding experiments involving fat, why has such an association not emerged in free living populations? There are several reasons postulated. Among these is the difficulty of measurement of habitual food intake in individuals. While this measure is relatively simple in societies which have little variation in foods, it is particularly difficult in societies where unlimited foods are available and composition is highly variable on a daily basis. Individual data collection, such as 24-h recalls, fail to characterize usual intake adequately (Munger et al. 1992). Food frequency approaches which characterize longer periods of time are susceptible to recall bias and difficulty in determining ‘average intake’ (Feskanich et al. 1993).
There are also individual factors in the response to dietary intake. Even when food intake is carefully controlled, the digestion and absorption process may vary between individuals. Thus, two individuals eating the same diet may have a different cholesterol response. Similarly, genetic factors in lipid metabolism may result in differing responses to the same food intake (Jacobs et al. 1979).
It is generally acknowledged that a large-scale trial of dietary fat for the primary prevention of coronary heart disease is unlikely to be performed (Gordon 1988). Although coronary heart disease is common in populations, the enormous numbers of individuals needed for randomization, the challenges to effective control of food intake in a free living population, the number of years necessary to accumulate adequate endpoint events, and the cost, precludes such a study. However, there are numerous congruent sources of information that lend strength to the validity of dietary fat recommendations through reduced blood cholesterol and coronary heart disease. Prominent are clinical trials of secondary prevention using diet. Among those are the studies of Ornish et al., who found a beneficial effect of a stringent low-fat diet in patients with known coronary heart disease (Ornish et al. 1990). Similar findings were observed by Brown and Page (1958). Supportive evidence may also be found in the consistent observation of the beneficial effects of cholesterol lowering regardless of method. This is widely recognized in trials of secondary prevention of coronary heart disease through lipid lowering (Lipid Research Clinics Program 1984; Buchwald et al. 1990; Scandinavian Simvastatin Survival Study 1994; Sacks et al. 1996; LIPID Study Group 1998), but also in recent studies of primary prevention with lipid-lowering medications (Shepherd et al. 1995; Downs et al. 1998).
The recognition that usual food intake is a behaviour strongly related to culture and food availability has resulted in community-based public health strategies to improve dietary intake. The North Karelia and Stanford Three Town Studies were among the first to use public and health professional education about dietary fat to reduce blood cholesterol (Farquhar et al. 1977; Puska et al. 1995). In both studies, an improved eating pattern with reduced animal fats (saturated fats and cholesterol) resulted in reduced average blood cholesterols in these small communities. Larger studies in medium-sized cities in Europe and the United States showed similar results. Strong favourable secular trends in control communities resulted in modest differences in blood cholesterol levels (GCP Research Group 1988; Farquhar et al. 1990; Luepker et al. 1994; Carleton et al. 1995).
Comparisons between populations in countries show an ecological correlation between dietary proteins, particularly animal protein and mortality from coronary heart disease. However, there is little evidence that this association is causal. Metabolic ward experiments of men under isocholoric condition, with fat intake held constant while protein intake varied between 5 and 20 per cent of daily calories, found no change in blood cholesterol levels (University of Minnesota, unpublished data). Anitschkow (1983) found that dietary lipids rather than protein resulted in hyperlipidaemia and atherosclerosis in experimental rabbits.
These observations and others suggest that associations observed between populations are the result of animal fat associated with animal protein, rather than the effect of the protein itself. Specifically, consumption of fat from animals and high-fat milk products result in elevated blood cholesterol, rather than their high protein content. In coronary heart disease, it is generally agreed that dietary protein is not a factor in coronary heart disease.
A positive association is found between population intake of refined sugars and coronary heart disease. This relationship is confounded by many other dietary components and, importantly, the association of high levels of refined sugars with the usual diet of Westernized industrial countries. In the absence of a plausible biological connection between refined sugars and atherosclerosis, the association may actually be that of the high animal fat intake also found in those societies. However, refined sugars may have other deleterious effects such as dental disease.
Complex carbohydrates are negatively associated with coronary heart disease. Higher intake is found with low coronary heart disease mortality. These are also confounded by fat intake and other dietary factors. There is a plausible biological mechanism by which complex carbohydrates may affect coronary heart disease. Foods which have high levels of carbohydrates, such as fruits and vegetables, also contain fibre including pectins in fruit, bran fibre, and guar gum. These play a role in the absorption of fat and cholesterol in the intestines. Observational studies and clinical trials have demonstrated that increased fibre intake is associated with lower cholesterol levels (Ripsin et al. 1992; Jenkins et al. 1993). It is important to note that increased fibre intake is best attained by consumption of healthy fruits and vegetables, rather than dietary supplements.
There is a continuing debate regarding the effects of alcohol consumption on cardiovascular disease including coronary heart disease. Several associations are relevant to this issue as follows:

the association of alcohol consumption with increased blood pressure and the risk of stroke (Criqui 1987)

the association of alcohol consumption with increased high-density lipoprotein cholesterol and levels of triglycerides (Baraona and Lieber 1979; Gordon et al. 1981), both may affect coronary heart disease

the effect of alcohol on haemostatic factors including fibrinogen, platelet aggregation, and fibrinolysis (Meade et al. 1987)

large doses of alcohol lead to addiction and other severe diseases (Kramer et al. 1968). These include cardiovascular diseases such as congestive cardiomyopathy, cardiac arrhythmias, and sudden death (Kuller et al. 1989; Regan 1990).
Given these findings, why is there controversy about alcohol intake? It principally stems from epidemiological research which shows moderate intake of alcohol is associated with lower risk of coronary heart disease when compared to non-drinkers (Ferrence et al. 1986). Numerous studies support this observation after adjusting for other risk factors and confounders, which stimulates this debate. One controversy focuses on the type of alcoholic beverage containing this benefit. Some have suggested wine is the essential form (Ferrence et al. 1986), while others find that other alcoholic beverages such as beer and spirits are equally implicated (Colditz 1990). It is still not certain whether it is the ethanol or some other component in the beverage which has a beneficial effect. Studies of alcohol consumption are also fraught with difficulties. In many, report of consumption is inaccurate with long-term consumption as difficult to ascertain as for other foods. There is also a suggestion that people who are ill eliminate their alcohol consumption as the result of their illness, confusing cause and effect. Finally, there are social factors associated with the intake of certain beverages, particularly the use of wine among the more affluent.
In summary, while there are observational studies associating alcohol intake with lower coronary heart disease rates and plausible biological mechanisms are available, there are also concerns regarding the recommendation of alcoholic beverages as a preventive strategy for coronary heart disease. These rest in the potential for addiction, vehicular accidents, and negative effects on a number of organ systems, including the cardiovascular system.
Vitamins, minerals, and food supplements
Coronary heart disease has many advocates of oral supplements for treatment and prevention. Vitamins, minerals, and other food supplements are promoted as a simple easy way to avoid disease. There are numerous manufacturers who are willing to fulfil this ‘need’. However, most of these substances are untested in a rigorous and controlled manner. Among those considered are vitamins C and E, b-carotene, copper, iron, selenium, fish oil, and fibre.
Observational studies show benefit or harm for some (Milner et al. 1989; Rimm et al. 1993; Stampfer et al. 1993; Ascherio and Hunter 1994; Kritchevsky et al. 1995; Stampfer and Rimm 1995; Ascherio et al. 1999). Very few have been submitted to clinical trials. When this has occurred, either in healthy subjects or those with coronary heart disease, the results have been mixed and the need for more research is recognized (Hennekens et al. 1996; Heart Outcomes Prevention Evaluation Study Investigators 2000).
Homocysteine has been evaluated as a risk factor for coronary heart disease. It is a product of methionine metabolism and observational studies consistently show elevated blood homocysteine in association with coronary heart disease (Boushey et al. 1995). The exact mechanism for this association is uncertain. Fortunately, supplementation with vitamins B6, B12, and folate appears to lower homocysteine levels (Osganian et al. 1999). The clinical and therapeutic effects of these changes is unknown; recently in the United States, however, folate supplementation was added to many grain products which should result in lower population levels of homocysteine (Boushey et al. 1995; Osganian et al. 1999).
Blood lipids
The preponderance of population, clinical, and experimental data indicate that blood lipids play a causal role in atherosclerosis and resulting coronary heart disease. Mass elevations in blood lipids appear to be a necessary factor for mass coronary heart disease. The research underlying these statements is summarized below.

Mean levels and distributions of blood lipids which vary widely between populations (Pooling Project Research Group 1978; Keys 1980; Stamler et al. 1986; Wallace and Anderson 1987) demonstrate a strong graded relationship between levels of total serum or plasma cholesterol and coronary heart disease. The low-density lipoprotein fraction of cholesterol is most atherogenic.

High-density lipoprotein cholesterol is inversely related to coronary heart disease. Higher levels are associated with less disease. High-density lipoprotein cholesterol is strongest as a predictor of coronary heart disease in populations where total cholesterol and disease risk is high (Gordon et al. 1977; NIH 1993a).

Although the mechanisms are poorly understood, there is a growing consensus that serum triglycerides, as measured in the fasting state, are associated with coronary heart disease (NIH 1993a).

Blood cholesterol levels among youth after puberty parallel those of the adult population (Luepker 1999). Those levels among youth track into adulthood (Webber et al. 1986).

Migration studies demonstrate that blood cholesterol levels rise to the level of the new culture when migrating from a low to a high cholesterol environment (Kagan et al. 1974).

Blood cholesterol levels continue to be predictive among adults over the age of 65 years, although the relative risk is reduced (Rubin et al. 1990; Abbott et al. 1997; Aronow and Ahn 1998).

Blood cholesterol can be lowered among adults with moderate changes in diet and loss of weight.

Clinical trials with lipid-lowering agents among those with moderate to severe blood cholesterol elevations demonstrate reduced coronary heart disease associated with lower cholesterol levels. This occurs both in individuals with coronary heart disease and those without evidence of clinical disease. It is particularly true of the newer statin drugs, but also with other methods (Lipid Research Clinics Program 1984; Buchwald et al. 1990; Scandinavian Simvastatin Survival Study 1994; Shepherd et al. 1995; Multiple Risk Factor Intervention Trial Research Group 1996; Sacks et al. 1996; Downs et al. 1998; LIPID Study Group 1998).

A progressive fall in blood cholesterol in the United States is associated with changes in the habitual diet during the last 25 years (Johnson et al. 1993a).
Population studies of blood lipids consistently show a positive association of mean blood cholesterol with coronary heart disease. As shown in Fig. 7, comparisons between different national groups show a significant association between blood cholesterol levels in health and coronary heart disease events among middle-aged men (Keys 1980). Similarly, data from the Multiple Risk Factor Intervention Trial, where over 356 000 healthy middle-aged men were followed over time, blood cholesterol predicted coronary heart disease outcomes in a progressive and continuous way as shown in Fig. 8 (Stamler et al. 1986). This continued gradation of blood cholesterol levels and disease suggest that lower blood cholesterol is better but there is no discrete point at which relative risk is sharply higher. The distributions imply the need for strategies to lower blood cholesterol at the population level, because cholesterol is normally distributed, and most disease events will come from the middle of the distribution, not the high extreme (Blackburn and Jacobs 1984).

Fig. 7 Coronary heart disease related deaths and cholesterol. Coronary heart disease age-standardized 10-year death rates of the cohorts versus the median serum cholesterol levels (mg/dl) of the cohorts. All men judged free of coronary heart disease at entry. B, Belgrade, Yugoslavia; C, Crevalcore, Italy; D, Dalmatia; E, East Finland; G, Corfu; I, Italian railroad; K, Crete; M, Montegiorgio, Italy; N, Zutphen, The Netherlands; R, American railroad; S, Slavonia; T, Tanushimaru, Japan; U, Ushibuka; V, Velika Krsna, Yugoslavia; W, West Finland; Z, Zrenjanin, Yugoslavia.

Fig. 8 Coronary heart disease (CHD) related deaths and cholesterol. (Source: Neaton et al. 1992.)

Lipids are insoluble in a water medium, namely blood. They are carried as lipoprotein particles in combination with proteins. Total cholesterol is the most widely used blood measure. It represents that chemical entity regardless of the carrier protein. Total cholesterol is commonly divided into three major components based on the density of the particles: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol. Each of these fractions is associated with specific protein carrier molecules. Low-density lipoprotein is the largest component of total cholesterol and is the atherogenic fraction. High-density lipoprotein comprises a smaller fraction and is inversely related to coronary heart disease, with higher levels of high-density lipoprotein associated with less disease. The very low-density lipoprotein contains modest amounts of cholesterol, but is the main carrier for triglycerides. Triglycerides are the major entity by which fat is transported and stored in the body.
There is considerable research on subfractions of these lipoproteins and the protein carriers which transport them. While important in research, these subfractions—including lipoprotein A, apolipoprotein E, high-density lipoprotein 2, and high-density lipoprotein 3—and many others are not established measures for clinical use nor are they relevant for public health strategies at this time.
There have been numerous trials designed to lower blood cholesterol or its subfractions. Dietary trials are noted above. However, the majority of trials have been in high-risk individuals by virtue of elevated blood cholesterol or known coronary heart disease. The trials take many years and are costly; however, the results are consistent and clear. The Coronary Drug Project enrolled men between 30 and 64 years old who had a previous myocardial infarction. The nicotinic acid treatment group showed significant lower mortality compared to those on placebo at 15 years after the study began (Canner et al. 1986). Similarly, the Lipid Research Clinic Coronary Primary Prevention Trial randomized men with elevated blood cholesterol aged 30 to 59 years to cholestyramine or placebo (Lipid Research Clinics Program 1984). These participants, followed for 7 to 10 years, showed significantly lower cardiovascular disease in the treatment group associated with cholesterol lowering. These and other early trials occurred before the more powerful cholesterol-lowering drugs—the statins. The effects of the early generation of drugs on cholesterol was modest and it is not surprising to find modest effects. Recently, with the use of statins, much larger effects of cholesterol reduction are observed with accompanying greater reductions in coronary heart disease events. In primary prevention, the West of Scotland Coronary Prevention Study is of particular interest (Shepherd et al. 1995). Randomizing 6595 men with moderately elevated cholesterol to placebo or pravastin, investigators observed significant reductions in serum total cholesterol and low-density lipoprotein cholesterol concentrations. Significantly fewer major coronary events were observed with lower total mortality in the treatment group compared to the controls. Similarly, the Airforce/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TXAPS) studied healthy subjects with modest increases in blood cholesterol. With lovastatin, significant reductions in cholesterol, coronary events, and all causes of mortality were also observed (Downs et al. 1998).
A number of large secondary prevention trials using statin therapy to lower cholesterol have also been completed, including the Scandinavian Simvastatin Survival Study (Scandinavian Simvastatin Survival Study 1994). It demonstrated a significant reduction in all causes of mortality, coronary heart disease mortality, coronary events, and revascularization procedures in patients with known coronary heart disease. The Cholesterol and Recurrent Events trial and the Long-Term Intervention with Fibrostatin in Ischemic Disease trial also demonstrated lipid reductions associated with fewer major coronary events (Sacks et al. 1996; LIPID Study Group 1998).
There have also been two important secondary prevention trials with gemfibrozil, a fibric acid derivative. A Finnish trial among men with known coronary heart disease resulted in a significant reduction of coronary events associated with changes in high-density lipoprotein cholesterol and triglycerides. Total cholesterol results were variable (Frick et al. 1987). A more recent treatment study of men with average total and low-density lipoprotein cholesterol but low high-density lipoprotein cholesterol with gemfibrozil also produced positive results. High-density lipoprotein cholesterol increased significantly in the treatment group compared to placebo. Coronary events were reduced. Interestingly, serum triglycerides also fell significantly, raising questions about the relative importance of the two lipid effects (Rubins et al. 1999).
There is consistent evidence from clinical trials of the benefits of lower total cholesterol and low-density lipoprotein cholesterol. There is also a suggestion that raising high-density lipoprotein cholesterol and lowering triglycerides add to these beneficial effects.
While recognizing that population-wide reductions in blood cholesterol would have great benefits, there are also clinical indicators of elevated blood cholesterol requiring aggressive and pharmacological management. This includes both high-risk individuals who are disease free, as well as in the case of secondary prevention for those who have known coronary heart disease. The Adult Treatment Panel of the United States National Cholesterol Education Program has suggested levels appropriate for further diagnosis and treatment (NIH 1993a). These are seen in Table 4. More recently, the European Society of Cardiology made similar recommendations for prevention; however, these recommendations integrate other risk factors (Wood et al. 1998a).

Table 4 Initial classification based on total cholesterol and high-density lipoprotein cholesterol levels

Blood pressure
Considerable epidemiological, clinical, and experimental data show high blood pressure or hypertension to be a major risk factor for coronary heart disease. Hypertension is also strongly predictive of other diseases including cerebrovascular disease, renal failure, and congestive heart failure. It is also widely recognized that treatment of hypertension to lower blood pressure reduces cardiovascular disease. The problem is common and large portions of the population are exposed or currently under treatment with medication. The important observations about hypertension are as follows.

Population studies find a modest relationship between hypertension and coronary heart disease mortality between countries (Keys 1980).

Within populations, coronary heart disease is strongly related to both systolic and diastolic blood pressures.

Levels of blood pressure among youth track into adulthood (Clarke and Lauer 1985).

The primary prevention of hypertension through lifestyle modifications including weight reduction, regular physical activity, decreased sodium intake, and other factors have the potential to reduce the disease burden.

For those with fixed hypertension, clinical trials demonstrate that treatment to reduce blood pressure reduces stroke, coronary heart disease, congestive heart failure, cardiovascular disease, and total mortality.

Treatment for hypertension is widely available; however, many individuals are neither diagnosed nor effectively treated (Sheps 1997).
Elevated blood pressure plays an important role in a number of diseases. The effect of sustained mechanical forces associated with elevations in blood pressure leads to target organ damage in the heart, brain, kidneys, and other organs. The origins of high blood pressure are not well understood, however, associations with obesity, physical inactivity, salt intake, and alcohol intake suggest these behavioural factors play an important role. Genetic factors are also apparent, but the considerable prevalence of hypertension suggests that these hereditary characteristics are very common in most populations.
As shown in Fig. 9, systolic blood pressure predicts coronary heart disease outcomes between populations in a modest but linear fashion. Many populations worldwide have substantial prevalences of hypertension including the Japanese, Chinese, Africans, and others (over 50 per cent in some adult groups). However, as noted above, the presence of elevated blood cholesterol seem essential for the manifestation of coronary heart disease. For stroke and other sequelae of hypertension, blood lipid elevations do not appear necessary. This is apparent in the Japanese population where stroke is quite common, but coronary heart disease is not.

Fig. 9 Coronary heart disease related deaths and systolic blood pressure. The 10-year age-standardized coronary death rates, men without evidence of cardiovascular disease at entry, of the 16 cohorts versus the median systolic blood pressures of those cohorts at entry. B, Belgrade; C, Crevalcore; D, Dalmatia; E, east Finland; G, Corfu; I, Italian railroad; K, Crete; M, Montegiorgio; N, Zutphen; R, American railroad; S, Slavonia; T, Tanushimaru; U, Ushibuka; V, Velika Krsna; W, west Finland; Z, Zrenjanin.

Within populations, blood pressure is predictive of cardiovascular disease outcomes including coronary heart disease (Kannel et al. 1986; Sheps 1997) (Fig. 10). Early studies focused on diastolic blood pressure, but more recently systolic blood pressure, which appears to be more reliably measured, has assumed increasing importance for diagnosis and treatment.

Fig. 10 Coronary heart disease (CHD) and blood pressure. DBP, diastolic blood pressure; SBP, systolic blood pressure. (Source: Neaton et al. 1992.)

The prevalence of hypertension, regardless of the definition, is substantial. In the United States, between 15 and 20 per cent of adults have high blood pressure by the definition of the National High Blood Pressure Education Program (Sheps 1997). The prevalence of hypertension rises progressively with age and in older age groups, it can affect the majority of the population. In certain racial groups, the prevalence is even higher. Hypertension is a worldwide epidemic.
While hypertension is common, its prevalence has not changed significantly in recent years (McGovern et al. 1996). However, in the past 20 years, detection, treatment, and control of high blood pressure has progressively improved. As shown in Table 5, awareness, treatment, and control of blood pressure have substantially increased. In the 1990s, however, there was an apparent levelling of effect in the United States with many still unaware and ineffectively treated (Sheps 1997).

Table 5 Trends in the awareness, treatment, and control of high blood pressure in adults in the United States (1976–1994)a

Lifestyle modifications including weight, exercise, and diet offer the potential for preventing hypertension. They have also been found to be effective at lowering moderate hypertension with little risk and minimal cost. Even though lifestyle factors alone may not control high blood pressure, they can reduce the amount of antihypertensive drugs deemed necessary (Neaton et al. 1993; Singer et al. 1995). Excess body weight is associated with elevation in blood pressure. Weight reduction can reduce blood pressure in obese individuals with hypertension (Trials of Hypertension Prevention Collaborative Research Group 1992). Therefore, it is widely recommended that weight reduction is an important part of hypertension control. Weight loss medications, recently discovered to be associated with heart valve damage and pulmonary hypertension, are not recommended (Connolly et al. 1997). Physical inactivity also plays a role in hypertension with unfit individuals having up to 50 per cent increased risk of developing high blood pressure (Blair et al. 1984). Moderate physical activity aids in controlling weight and may actually lower blood pressure (NIH 1996). Dietary factors may also play a role in precipitating or reducing hypertension. Alcohol use raises blood pressure. The National High Blood Pressure Education Program recommends no more than 30 ml of ethanol as beer, wine, or whisky per day for men and 15 ml per day for women (Sheps 1997).
Salting of food as a method of preservation is well established over many centuries. However, modern food preservation methods do not require salt and it is mainly an acquired taste. Unfortunately, the human kidney was developed in the setting of low sodium and high potassium diets. Hence, the body is well designed to retain, but not excrete sodium, which it effectively does. The need for sodium is quite small and many times the amount required is consumed in processed food (Blackburn and Prineas 1983).
Salt intake is particularly relevant to hypertension. Population surveys demonstrate strong associations between population blood pressure and salt intake (Gleiberman 1973; Freis 1976; INTERSALT Cooperative Research Group 1988). Migration studies where salt intake is greatly increased among people who migrate from low to high salt cultures is associated with increasing prevalence of hypertension (Joseph et al. 1983). Within cultures where associations are more difficult to find, careful measurement results in individual correlations between salt intake and blood pressure (Kesteloot et al. 1980).
Clinical studies have found that restriction in salt results in lower blood pressure. Marked sodium depletion, as practised in an earlier era, can even reduce blood pressure among severe hypertensives (Blackburn and Prineas 1983), and sodium restriction enables high blood pressure to be controlled with lower doses of antihypertensive drugs. In some patients, salt restriction may control mild to moderate hypertension without resorting to drugs. Potassium also plays an important role, as increased potassium appears to reduce the blood pressure, enhancing the effects of sodium reduction (Meneely and Battarbee 1976).
Despite widespread information about the role of salt, considerable debate remains. The American National Dietary Goals recommend no more than 6.0 g of sodium chloride daily (Sheps 1997). This remains significantly more than humans need, but well below the average intake. As the use of processed foods increases, salt may play an undiminished or even increasing role in hypertension.
The decision to initiate pharmacological treatment of high blood pressure depends on a variety of factors, including the absolute level of blood pressure, the presence of cardiovascular disease, target organ damage, and the presence of other coronary heart disease risk factors. The benefits of pharmacological treatment have been demonstrated for coronary heart disease, stroke, heart failure, renal disease, and all causes of mortality (Moser and Hebert 1996; Psaty et al. 1997). There has been debate over the generalizability of hypertension trials to older adults and other groups; it is generally believed that all populations will benefit from blood pressure lowering. There are many medications currently available for hypertension treatment, however, b-blockers and diuretics are recommended for initiating treatment as they have the longest clinical trial experience and a proven record of reducing morbidity and mortality in clinical trials (Sheps 1997; Psaty et al. 1997). Other agents may be required in special circumstances.
There is some debate regarding what constitutes a normal blood pressure and, hence, what requires pharmacological treatment. Most agree that 120/80 represents a normal blood pressure in an adult. The recommendations for blood pressure classification among adults over the age of 18 years of the United States National High Blood Pressure Education Program are shown in Table 6 (Sheps 1997). The European recommendations are somewhat different, but in a similar range (Wood et al. 1998a).

Table 6 Classification of blood pressure for adults aged 18 years and oldera

Cigarette smoking
Tobacco use is a worldwide problem associated with many diseases. While best known for causing lung cancer, cigarette use has a larger effect on mortality and morbidity from coronary heart disease. Some of the salient observations on tobacco use are as follows.

Cigarette smoking addicts 20 to 80 per cent of adult men worldwide with a somewhat lower proportion of adult women addicted.

Comparisons between populations often find no association between coronary heart disease and the prevalence of cigarette smoking. However, the individual association of cigarette smoking to coronary heart disease is strong.

Cigarette smoking is falling in some countries but rising in most, and is a growing epidemic in developing nations.

Cigarette smoking begins in youth and gradually increases until it becomes nicotine addiction.

The main mechanisms by which cigarette smoking affects coronary heart disease are as a chronic promoter of atherosclerotic lesions and as an acute risk factor increasing sympathetic stimulation and enhancing clotting.

While randomized population trials of cigarette use have not been performed, cigarette cessation reduces levels of coronary heart disease mortality.

Coronary heart disease is directly related to exposure to tobacco smoke.

There is a growing awareness that environmental tobacco smoke or second-hand smoke has a deleterious effect on exposed non-smokers.
Tobacco use through cigarette smoking is one of the major causes of disease and disability in the world. In the United States, there are approximately 47 million adult smokers and it is estimated that 430 000 deaths annually are associated with cigarette smoking (USDHHS 1998b). These victims are replaced by the teenagers who begin the smoking habit. In the United States, the direct medical costs of smoking are estimated to be $50 billion/year with similar indirect costs.
Cigarette smoking is linked to the major cardiovascular diseases including myocardial infarction, sudden death, stroke, and peripheral vascular disease (USDHHS 1983, 1997). These associations are found across age, gender, and ethnic groups (USDHHS 1983, 1997; Neaton and Wentworth 1992). The relationship of coronary heart disease mortality to smoking status is shown in Fig. 11. One of the most important findings is the association of cigarette smoking with sudden unexpected death among younger individuals. Similarly, acute myocardial infarction in younger individuals (less than 50 years of age) is very strongly associated with tobacco use (Rosenberg et al. 1983; Kannel et al. 1984). The interaction of cigarette smoking with other risk factors such as cholesterol, diet, obesity, hypertension, lipids, diabetes, and ECG abnormalities is also well demonstrated (Pooling Project Research Group 1978; Suarez and Barrett-Connor 1984; Williams et al. 1986; Multiple Risk Factor Intervention Trial Research Group 1996). Among the strongest pieces of evidence is the observation that continued cigarette smoking after myocardial infarction is predictive of recurrent events and death (Rosenberg et al. 1985; Hermanson et al. 1988), and those who quit smoking dramatically reduce their chance of a second event or death (Rosenberg et al. 1985; Hermanson et al. 1988; USDHHS 1990; Kawachi et al. 1994).

Fig. 11 Cigarette smoking and coronary heart disease (CHD). (Source: Neaton et al. 1992.)

The mechanisms by which tobacco and the constituents of tobacco smoke affect cardiovascular disease are still debated. Both acute and chronic mechanisms probably contribute. Firstly, there is evidence that smoking plays a direct role in the atherosclerotic process. This is shown by the Pathological Determinants of Atherosclerosis in Youth Study of 1443 autopsies of men and women aged 15 to 34 years who died of trauma (McGill et al. 1997). Fatty abdominal and aortic streaks and raised lesions were associated with cigarette use in this otherwise healthy population. This may be the result of injury to the arterial endothelium from smoking (McGill et al. 1997; Zimmerman and McGeachie 1987). More acutely, the immediate pharmacological effects of nicotine and carbon monoxide are well known. Platelet adhesion, acute coronary constriction, and tachycardia are commonly cited (Maouad et al. 1984; Meade et al. 1987). Finally, there is the rapid improvement in patients observed after smoking cessation.
In recent years, the focus has shifted to environmental tobacco smoke which affects non-smokers in public and private settings. A number of recent studies suggest consistent and increased relative risk of cardiovascular disease among those exposed to environmental tobacco smoke (Table 7). While it is difficult to measure exposure to environmental tobacco smoke, the consistency of these studies is suggestive and reinforces the effort to control cigarette smoking in public settings (Garland et al. 1985; Svendsen et al. 1987; Helsing et al. 1988; Hole et al. 1989; Layard 1995; Tunstall-Pedoe et al. 1995; Steenland et al. 1996; Kawachi et al. 1997).

Table 7 Cohort studies of environmental tobacco smoke and coronary heart disease

Trends in cigarette smoking vary by country. While certain countries, such as the United States, have seen significant declines over the past several decades, smoking is static in some countries and rising in others. Of particular concern is the increased marketing of tobacco to countries in the developing world. Similarly, tobacco companies have become more effective at advertising to youth, the source of future smokers.
Programmes to control tobacco use have focused on prevention and cessation. Smoking prevention programmes in the schools have received considerable attention and met some success (Perry et al. 1992). Smoking cessation programmes for older teens are in the testing phase and new programmes are emerging (Sussman et al. 1999). Cessation interventions among adults have emphasized behavioural and pharmacological strategies (Fiore et al. 1996). These have included nicotine replacement therapy, social support, and skills training/problem solving. In addition, widespread restriction of smoking reduces the societal support for the behaviour.
In summary, cigarette smoking is an addictive behaviour which leads to many health-impairing effects including coronary heart disease. Elimination of cigarette smoking would significantly improve the health of any population.
Overweight and obesity
Excess body weight as fat is increasingly recognized for its importance in the development of cardiovascular diseases. On a population level, overweight and obesity have become common among adults in industrialized countries and the affluent in developing countries. Several important observations include the following.

Overweight and obesity are associated with increased mortality.

Severe obesity is recognized as an independent risk factor for mortality. Less severe obesity may also be an independent risk factor.

Obesity is associated with elevated blood pressure, hyperlipidaemia, diabetes mellitus, and insulin resistance. Reduction in body fat diminishes the level of each of these risk factors.

Increasing body weight is a worldwide problem and is the result of excess food in the setting of reduced physical activity.
Obesity is commonly described as excess body fat, however, the exact proportion of fat rendering one overweight or obese is debated. Body mass index, which is weight in kilograms divided by height in meters squared, is a commonly used standard. Expert panels suggest a body mass index above 25 is classified as overweight and above 30 as obese (Eckel and Krauss 1998; USDHHS 1998a). More recently, visceral adiposity has been proposed as a better marker for obesity as a predictor of cardiac risk (Freedman 1995). Visceral adiposity is simply measured by the waist to hip ratio, using the circumference of these two sites. Other more complex methods to determine body fat are available but require sophisticated instruments.
Overweight and obesity are an increasing problem in much of the world. As shown in Table 8, both overweight and obesity measured in national surveys have substantially increased in recent years in the United States. Men are more likely to be overweight (body mass index greater than 25 kg/m2) but women are more likely to be obese (body mass index greater than 30 mg/m2). Ethnic minorities, such as African Americans and Mexican Americans living in the United States, have similar, if not greater, adiposity.

Table 8 Prevalence of overweight and body mass index levels in the American population (age 20–74 years)

The association of obesity with mortality is well established. For the severe or morbidly obese, lifespan is significantly reduced (Sjostrom 1992). For the less severely obese, the debate is that of obesity as an independent risk factor for cardiovascular disease or as one which operates through other known risk factors (Harris et al. 1993, 1997; Solomon and Manson 1997). The question is a scientific one rather than one of public health.
Obesity and overweight affects lipoprotein metabolism through higher low-density lipoprotein cholesterol, increased triglycerides, and lower levels of high-density lipoprotein cholesterol. Weight reduction accomplished through diet is associated with significant improvement in lipids (Dattilo and Kris-Etherton 1992). The association of weight and blood pressure is also well established. In the Nurses Health Study, one unit in body mass index was associated with a 12 per cent increase in the risk of hypertension (Huang et al. 1998). Other observational studies consistently show this relationship (Dyer and Elliott 1989). Weight loss is well demonstrated to reduce blood pressure. This includes even modest reductions in weight (Stamler et al. 1987; Hypertension Prevention Trial Research Group 1990; Wassertheil-Smoller et al. 1992; Trials of Hypertension Prevention Collaborative Research Group 1997). In addition, recent research suggests that a diet lower in fat and higher in fruits and vegetables also results in lower blood pressure among the mildly hypertensive (Krauss et al. 1998). In each of these studies, weight reduction via diet allows the reduction of antihypertensive medications.
Insulin resistance is the underlying condition associated with adult-onset or type II diabetes. Obesity is a crucial factor in the development of insulin insensitivity and increased interabdominal fat is implicated (Krauss et al. 1998). Many suggest that the current epidemic of diabetes is a direct function of increasing obesity. Weight loss can be critical to the control of adult-onset diabetes. Both insulin resistance and hyperglycaemia are significantly reduced when patients lose weight (Paisey et al. 1998). This may result in the ability to reduce diabetic therapy.
Clinicians are well aware of the difficulty of obtaining significant and sustained weight loss among patients. Many now suggest that obesity prevention is the best strategy. By reducing the increased adiposity that occurs with age, many of the sequelae and difficulty of losing weight as an adult would be avoided (National Task Force on Prevention and Treatment of Obesity 1994). For those who are obese, both control of calorie intake and increase in calorie expenditure through physical activity is essential. Pharmacological means and starvation diets are still unproven and may be dangerous (Connolly et al. 1997).
Diabetes, hyperglycaemia, and hyperinsulinaemia
The insulin era has revealed a strong association between diabetes and cardiovascular diseases, particularly those caused by atherosclerosis. Large vessel disease associated with diabetes results in myocardial infarction, stroke, and peripheral vascular disease. Microvascular disease is associated with retinopathy, renal disease, and cardiomyopathy. In addition to strong associations with known cardiovascular risk factors, diabetes is an independent predictor of disease (Kannel and McGee 1979; Stamler et al. 1993). Salient observations regarding diabetes are as follows.

Diabetes and hyperglycaemia are strongly related to atherosclerosis.

Diabetes and hyperglycaemia are associated with obesity and abnormal lipid patterns.

Diabetes is increasing along with obesity in susceptible populations.

Control of associated risk factors can reduce the atherosclerotic complications of diabetes.

Control of blood glucose in type I diabetics reduces microvascular complications. There is a suggestion of a similar effect among type II diabetes.
The association of clinical diabetes mellitus with coronary heart disease and other atherosclerotic conditions is well documented (West 1978; Pyorala et al. 1987) with relative risks at two or three times that for diabetics compared to non-diabetics (Kannel and McGee 1979; Stamler et al. 1993). In Fig. 12, the Multiple Risk Factor Intervention Trial data compares diabetics and non-diabetics. It is apparent that diabetes alone in the absence of hypercholesterolaemia, cigarette smoking, and elevated systolic blood pressure results in increased relative risk of cardiovascular disease mortality. The effect of diabetes is magnified when associated with these other risk characteristics.

Fig. 12 Cardiovascular disease (CVD) mortality and diabetes. (Source: Stamler et al. 1993.)

It was believed that diabetes combined with the use of a high-fat, low-carbohydrate, and low-fibre diet increased vascular complications. It is now clear that the deleterious effects of the disease itself on the endothelium and coagulation abnormality play an important direct role (Carmassi et al. 1992; Sowers et al. 1994). It was also observed that diabetes is strongly associated with classical risk factors. Diabetics have elevated levels of triglycerides and low-density lipoprotein cholesterol with decreased levels of high-density lipoprotein cholesterol. There is also a high prevalence of obesity and hypertension among diabetics (Knowler et al. 1978; Winocour 1992; Schaefer et al. 1994; Clarkson et al. 1996; Lehto et al. 1997).
Cross-cultural comparisons present a more complicated picture. They indicate that factors other than the glucose insulin disorder itself result in atherosclerosis. Evidence is presented in the apparently low rates of atherosclerosis in diabetic Eastern Jews, Chinese, and south-west American Indians (West 1978; Pyorala et al. 1987). The Pima Indians are a classical example of a population exposed to calorie abundance, excessive obesity, and the diabetic phenotype but with little evidence of cardiovascular disease (Knowler et al. 1978).
In healthy people, glucose intolerance alone is weak and inconsistently associated with cardiovascular disease risk (Stamler et al. 1979; Pyorala et al. 1987). However, increased insulin levels were found to predict coronary heart disease in Australia, France, and Finland (Pyorala et al. 1987) and it is postulated to be the cause of excess coronary heart disease among Asian immigrants to the United Kingdom (Hughes 1990).
The treatment of diabetes is based on control of blood glucose and treatment of associated risk factors. Lifestyle strategies, weight loss, and physical activity can be effective at reducing blood glucose and controlling the associated risk factors. This is particularly true for type II diabetics. For type I diabetics, insulin for glucose control and control of associated risk factors can reduce diabetic complications.
Pharmacological control of type II diabetes has produced mixed results. The original University Group Diabetes Program reported an increased rate of myocardial infarction with the use of first-generation sulphonylureas in the setting of effective blood glucose control (UGDP 1975). More recent trials with newer oral agents did not observe this complication (UKPDS 1995). The more recent Diabetes Control and Complication Trial studied glucose control in insulin-dependent diabetics. Microvascular complications were significantly reduced (DCCT Research Group 1993). Large vessel disease was also reduced, but the differences were not significant.
The relationship between diabetes, atherosclerosis, and coronary heart disease is well established in people with clinical diabetes living in affluent industrialized cultures. Data from other cultures suggest that other factors are at work. The use of lifestyle strategies, control of other risk factors, and pharmacological measures in diabetes is the standard of care and may reduce cardiovascular complications of this disease.
Physical activity
Physical activity and its opposite, physical inactivity, have assumed increasing importance as risk factors for cardiovascular disease. As society has become more mechanized, a sedentary lifestyle has become the norm. Operating both through other risk factors such as obesity, hypertension, hyperlipidaemia, and diabetes, physical inactivity is associated with cardiovascular disease. However, it is also thought to be independently associated as well. Several important observations regarding physical inactivity include the following.

Physical inactivity is associated with acute myocardial infarction and sudden death both for the initial event and recurrent events. Regular activity is associated with reduced events.

Physical activity at work is declining.

Physical activity in leisure time, while increasing, is still not widespread.

Physical inactivity begins with declining exercise among youth as they reach teenage years.

Physical inactivity is associated with known risk factors including hyperlipidaemia, hypertension, diabetes mellitus, and obesity. In addition, physical activity is proposed by some to be an independent risk factor.

Systemic and cardiac mechanisms are postulated to explain the observed exercise benefits.
Two of the primary activities of human beings are obtaining and consuming food. Historically, this took considerable physical energy in hunting or farming activities, only a few very affluent were spared from activity. The past two centuries have witnessed a dramatic transition as farming has become more efficient. Mechanized transportation has eliminated the use of physical activity to move from place to place. The workplace has become increasingly mechanized as machines do most or all heavy labour. The result has been a rising tide of physical inactivity (Blackburn and Jacobs 1988).
Much of the information on physical inactivity comes from observational studies. These are hampered by the difficulties of measuring habitual physical activity and the interplay of other risk characteristics in cardiovascular disease outcomes. Meta-analysis by Powell et al. of observational studies selected for quality, measurement, and follow-up showed a significant and graded relationship between physical inactivity and the risk of first coronary heart disease event. They calculated a relative risk of 1.9 compared with sedentary individuals (Powell et al. 1987). The Multiple Risk Factor Intervention Trial of over 12 000 men demonstrated similar relationships with those with regular leisure time physical activity having lower risk of coronary heart disease and death (Leon et al. 1987) (Table 9). Similarly, Paffenbarger et al. showed that physical activity after university was more protective than participation in sporting activities during school (Paffenbarger et al. 1984). While there are many observational studies, there is general agreement that a primary prevention trial of physical activity is unlikely to be feasible and public health recommendations must come from available data.

Table 9 Mortality and leisure-time physical activity in men

There are more data for secondary prevention. Observational studies find that individuals who continue with regular physical activity after myocardial infarction have lower relative risk than those who are sedentary (NIH 1996). These studies are confounded by severity of disease which is associated both with physical inactivity and mortality. Those who are very ill are less likely to exercise and more likely to have increased recurrent events and mortality. For this reason, a number of randomized clinical trials of cardiac rehabilitation after myocardial infarction have been performed. These demonstrate lower mortality associated with exercise, but most studies have been small and underpowered (Wilhelmsen et al. 1975; Shaw 1981; Benson et al. 1983). A meta-analysis by Oldridge et al. of 10 randomized trials found significant improvement associated with cardiac rehabilitation programmes lasting at least 6 weeks (Oldridge et al. 1988). The preponderance of published evidence appears to support the benefit of a physical activity programme following acute myocardial infarction (O’Connor et al. 1989).
Both observational studies and clinical trials of physical activity have suffered from the lack of well-validated instruments to characterize habitual activity in free living populations. While survey instruments for work and leisure time physical activity are available, they are not ideal.
Physical activity is believed to function through a number of biological and physiological mechanisms. It operates through other cardiovascular risk factors including lipoproteins, carbohydrate metabolism, clotting factors, and obesity. It may result in lower blood pressure and aid in smoking cessation. In addition to its effects on other risk characteristics, physical activity is thought to increase epicardial artery diameter, increase coronary blood flow, and decrease myocardial work and oxygen demand. The heart may work more efficiently and be better able to function under stressful circumstances.
There is considerable debate over public health recommendations for physical activity. Some of the issues include the amount, type, and duration of physical activity needed to obtain beneficial cardiovascular effects. There is also the issue of fitness as an independent factor. Finally, the association of vigorous physical activity with sudden death has increased concerns regarding advice. Considering these factors, several recommendations have emerged in recent years (NIH 1996). These suggest that moderate physical activity such as brisk walking for 30 min on most days of the week is adequate to produce significant benefit in a sedentary society. More vigorous physical activity can be recommended; however, only moderate cardiovascular gains accrue from this addition (NIH 1996). The activity should be of sufficient vigour to increase the heart rate and breathing rate. Regular physical activity will lead to increased fitness; however, much of the association with fitness may be genetically determined rather than the result of training (Blair et al. 1989). Nonetheless, observational studies do show that physical fitness is associated with lower rates of cardiovascular disease (Blair et al. 1989).
Finally, safety is a crucial consideration in advising physical activity for individuals or public health recommendations. Research has shown an excess risk of sudden death during and shortly after strenuous exercise (Siscovick et al. 1984; Mittleman et al. 1993). This is a particular issue in those habitually inactive, but there is still excess risk among those who exercise regularly. However, the overall benefit of regular exercise far outweighs the acute excess risk.
Physical inactivity is epidemic in most industrialized societies and becoming more so in the developing world. It is associated with cardiovascular disease through myocardial infarction and sudden death. Regular physical activity involving daily exertion is an important public health recommendation. The type of physical activity recommended is that which involves large muscle groups for sustained periods of at least 30 min.
Psychosocial factors
Psychosocial factors including personality characteristics and the social environment are popularly believed to play an important role in cardiovascular disease. There are also many professionals who also believe that these factors influence the major diseases of modern life. Despite this widespread belief, it has been difficult to demonstrate causal connections to coronary heart disease or other diseases. This may be due to difficulties in measurement, confounders, or less than convincing biological mechanisms. Nonetheless, emotional states of anger, aggression, fear, anxiety, and depression are associated with physiological changes, which may affect cardiovascular disease. Certain personality types may precipitate or aggravate these factors. There are three major areas that have received the most attention and will be briefly discussed here. They are type A behaviour, hostility, and social support.
Type A behaviour
Type A behaviour is characterized by aggressiveness, competitive drive, preoccupation with deadlines, and time urgency. Historically, it is measured by a structured interview (Friedman and Rosenman 1959). There are also other methods including self-reported inventories and questionnaires. Data in the 1980s found type A behaviour to be associated with coronary heart disease in the Western Collaborative Group Study and the Framingham Study (Rosenman et al. 1975; Haynes et al. 1980). In the Western Collaborative Group Study a prospective cohort of 3000 men was assessed by the structured interview. The relative risk of fatal and non-fatal coronary heart disease was approximately 2 for type A men. The Framingham Study used a self-administered questionnaire to evaluate type A behaviour. Relative risk for coronary heart disease was similar to that found in the Western Collaborative Group Study (Haynes et al. 1980).
Following these initial observations, a number of other studies attempted to replicate these results. A summary of 14 angiography studies found an equal balance of positive and null associations (Dimsdale et al. 1981). Several larger prospective studies done in the 1980s failed to confirm earlier findings using either self-administered instruments or the structured interview (Case et al. 1985; Cohen and Reed 1985; Shekelle et al. 1985a, 1985b). A reanalysis of the original Western Collaborative Group data also questioned the original results (Ragland and Brand 1988a, 1988b). Finally, an intervention study was performed to look at behaviour patterns and recurrent coronary heart disease. In this study, performed by the originators of the type A behaviour interview, coronary heart disease outcomes were reduced, but this study has not been replicated (Friedman et al. 1984).
Current evidence for type A behaviour is mixed and while there continues to be widespread belief about its importance, there is inadequate evidence to make public health or clinical recommendations regarding its detection and treatment.
Initial enthusiasm concerning the findings about type A behaviour led to an attempt to find critical elements accounting for the observed coronary heart disease differences. Early studies in selected groups found an association between hostility and coronary heart disease (Matthews et al. 1977; Barefoot et al. 1983; Hecker et al. 1988). Many studies used parts of the type A behaviour construct. Others used the Minnesota Multi-Phasic Personality Index and its ‘Cook Medley Hostility Subscore’. Six prospective studies using the Cook Medley instrument have been published with three positive and three negative findings (Shekelle et al. 1983; McCranie et al. 1986; Hecker et al. 1988; Hearn et al. 1988; Leon et al. 1988; Barefoot et al. 1989).
Recent research suggests that anger or hostility is an acute rather than a chronic risk factor and associated with plaque rupture (Muller et al. 1997). This research may provide further insights into this characteristic.
Social support
A number of observational studies find social support or a supportive environment associated with lower coronary heart disease risk. Two Scandinavian studies found a strong relationship between social support and mortality in men (Orth-Gomer and Johnson 1987; Kaplan et al. 1988). Disentangling the role of social support from prevalent illness, economic factors, and personality types is difficult. It is apparent that those with a substantial support network, including a supportive spouse, have better coronary heart disease outcomes.
Associated with support, there is increased exploration of environmental factors particularly work situations. Here a number of studies have shown that jobs with high demand and low control of the work environment have a relative risk of about 2 for acute myocardial infarction after controlling for other risk characteristics (Alfredsson et al. 1982; Schnall et al. 1990). Again, the complex interactions associated with these environments and the response of the individual are likely to play a role, but are difficult to evaluate. Not all humans react similarly to an identical environment.
Acute coronary heart disease risk factors
Most of the risk factors discussed are associated with the underlying disease process, atherosclerosis. If atherosclerosis is prevented, then coronary heart disease as a clinical event is extremely rare. However, since many individuals have atherosclerosis by middle-age or older years, there has been an increasing search for factors which lead to the transition from chronic atherosclerotic disease to acute ischaemia, myocardial infarction, and sudden death. These are sometimes called acute risk factors or triggers.
There were two initial observations leading to these insights. The first related to the pathophysiology of the aortic plaque. While large and obstructing plaques are clearly related to disease, it was also found that small non-obstructive lesions could rupture, form a nidus for clot, and ultimately obstruct the coronary artery. This phenomenon was more likely to result in death than traditional obstructive lesions which were more likely to cause chronic ischaemia and angina pectoris (Fuster et al. 1992a). The second observation was that of a morning peak in acute myocardial infarction, sudden death, and even stroke. This suggested there were identifiable circumstances associated with disease manifestation (Muller et al. 1987; Ridker et al. 1990). Further work in this field suggested that sympathetic stimulation with activation of clotting as a potential underlying mechanism. A number of factors were implicated. They included heavy exertion, sexual activity, anger, and other factors (Mittleman et al. 1993). Some of the characteristics are modified with aspirin use or b-blockers (Willich et al. 1993).
In summary, it is likely that more will be learned about acute risk factors and treatment found to prevent events in individuals with established atherosclerotic disease. This should not be confused with true primary prevention where the atherosclerotic process is prevented.
Other risk factors
In addition to the risk factors described above, there is ongoing research looking for other markers of risk. While classical risk factors explain much or most of the disease relationships, there is still much to learn. Among the most promising areas is that of genetics where markers of coronary heart disease and protential mechanisms will be found.
Congestive heart failure
Congestive heart failure is increasing in prevalence in many areas of the world. Congestive heart failure is a clinical constellation of signs and symptoms resulting from circulatory and neural responses to cardiac dysfunction (Poole-Wilson 1989). This dysfunction usually manifests as inadequate pumping ability by the heart. It can have multiple underlying aetiologies including ischaemic heart disease, hypertension, non-ischaemic cardiomyopathy, infection, diabetes mellitus, and others. Several observations about the population patterns of congestive heart failure are as follows.

Population prevalence of congestive heart failure is directly related to the prevalence and types of underlying cardiovascular conditions.

Population rates of congestive heart failure vary widely because of the differing definitions and classification systems used to describe cases.

Population levels of congestive heart failure are rising as more individuals survive acute myocardial infarction and chronic hypertension.

Congestive heart failure is predominantly a disease of older adults and the mortality is substantial.

Treatment of congestive heart failure has improved as randomized clinical trials have demonstrated the utility of certain drugs.
Research into congestive heart failure has been hampered by variability in case definition. Symptoms, signs, radiological studies, tests of ventricular performance, and tests of exercise capacity have all been utilized. All methods have limitations and are particularly poor in the classification of mild congestive heart failure (Hlatky et al. 1986; Chakko and Gheorghiade 1992). The diagnosis may be commonly confused with obesity-related dyspnoea, poor physical condition, myocardial ischaemia, pulmonary disease, or other conditions.
There are several studies of congestive heart failure incidence. The Framingham Study and the Gothenberg Study are examples of the cohort approach (Eriksson et al. 1989; Ho et al. 1993). These were able to identify incident cases prospectively and characterize them at the time of diagnosis. Studies in Finland, Holland, and Rochester, Minnesota, are examples of a population approach (Van de Lisdonk et al. 1990; Remes et al. 1992; Rodeheffer et al. 1993). These study types find significant differences in incidence, which ranges from 100 to 500 per 100 000 population per year, and that incidence increases sharply with age.
There are more data available on congestive heart failure prevalence. Rates also vary widely due to differences in methodology and case definition. Observed prevalence in industrialized societies ranges from 300 to 2000 individuals per 100 000 population (unadjusted for age) and 3000 to 13 000 per 100 000 population for those over the age of 65 years (Cowie et al. 1997). Of particular interest are the data from the American National Health and Nutrition Examination Survey which show a self-report prevalence of 1.1 per cent for adults aged 25 to 74 years while clinical examination results in a prevalence of approximately 2 per cent (Schocken et al. 1992). Congestive heart failure prevalence appears to be rising, largely attributed to increased survival from acute myocardial infarction (Ranofsky 1974; Graves and Gillum 1996).
Mortality from congestive heart failure is substantial with the Framingham Study reporting 5-year survival of 25 per cent for men and 38 per cent for women in an early analysis (Ho et al. 1993b). Improved survival was observed in the later National Health and Nutrition Examination Survey. Among individuals with congestive heart failure (age greater than 55 years), 61 per cent of women and 28 per cent of men were still alive 15 years later (Schocken et al. 1992). However, the validity of congestive heart failure diagnosis on death certificates has been questioned (Cowie et al. 1997). Because congestive heart failure is a constellation of science, symptoms, and physiological changes, it is often not considered among the underlying causes of death. For example, in the United Kingdom, congestive heart failure is never used as an underlying cause of death (Cowie et al. 1997). In the United States, congestive heart failure is categorized as a cause of death and rose from 10 000 in 1968 to 42 000 deaths in 1993 (USDHHS 1996). It is also a contributing cause of death in many other fatalities (Yusuf et al. 1989; Kannel et al. 1994).
There are numerous causes of the myocardial dysfunction which underlies congestive heart failure. Hypertensive cardiovascular disease with left ventricular hypertrophy results in a 15-fold greater risk of developing congestive heart failure (Kannel et al. 1994). Coronary heart disease, particularly when manifested as myocardial infarction, also leads to increased congestive heart failure with damaged and dysfunctional myocardial muscle. In the Framingham Study, approximately 20 per cent of those who survived myocardial infarction developed heart failure within 5 to 6 years (Kannel 1987). Previously, hypertension was the most common underlying cause of congestive heart failure, but there has been a shift to coronary heart disease as a more common aetiology. Diabetes mellitus with congestive heart failure also increased in prevalence (Ho et al. 1993a; Levy et al. 1996; Davis et al. 1997). While these are the major causes of congestive heart failure in industrialized societies, in many nations other diseases play an important role including rheumatic heart disease, cardiomyopathy, and pulmonary heart disease.
As most congestive heart failure is a late consequence of an underlying cardiovascular disease, primary treatment should consist of prevention of that underlying disease whether it is hypertension, coronary heart disease, rheumatic heart disease, or other conditions. If these conditions are adequately controlled, congestive heart failure is uncommon. However, there are currently many individuals with these diseases who have congestive heart failure as the primary cause of their limitation and disability. Traditional treatment with diuretics and digitalis are widely used, however, these have recently been questioned (Cohn 1996). In recent clinical trials, congestive heart failure treated with vasodilators and angiotensin-converting enzyme inhibitors has reduced mortality and increased function, leading to optimism for long-term therapy for congestive heart failure (Cohn et al. 1986; SOLVD Investigators 1991, 1992; Swedberg et al. 1992; Johnson et al. 1993b; Cohn 1996).
Rheumatic fever and heart disease
For centuries, rheumatic fever with resulting rheumatic heart disease was the leading cause of cardiovascular morbidity and mortality worldwide. It continues as an important problem in areas where poverty, overcrowding, malnutrition, and lack of medical care are found (WHO 1984b; WHO 1988). Although much less common than previously, it is still a problem even in industrialized countries where outbreaks occur.
Some of the salient observations about rheumatic fever and rheumatic heart disease include the following.

Rheumatic heart disease is still common in many developing countries.

Outbreaks are observed in developed countries.

The origins of rheumatic heart disease are well understood. Throat infections with group A Streptococcus can result in acute rheumatic fever with carditis, which may lead to chronic rheumatic heart disease.

Primary prevention of rheumatic fever rests in appropriate antibiotic treatment of streptococcal infections.

For individuals with a history of rheumatic fever and/or rheumatic heart disease, antibiotic prophylaxis is recommended.
During the 1960s, the incidence of acute rheumatic fever ranged from 23 to 55 per 100 000 urban children aged 2 to 14 years in the United States. Currently, it is less than 2 per 100 000 with a prevalence of rheumatic heart disease of less than 1 per 1000 school-aged children (Dajani 1991). In other parts of the industrialized world, such as Scandinavia, similar low rates are found (WHO 1988). However, in some areas of South America, the prevalence of acute rheumatic fever is significantly higher, ranging from 1 to 10 per cent of school-aged children (PAHO 1970). Similar high rates are seen in areas of Asia and Africa (WHO 1988). The mechanisms by which this infection produces the clinical syndrome of acute rheumatic fever and subsequent rheumatic heart disease is well studied (Catanzaro et al. 1954). A group A streptococcal infection of the throat (tonsillopharyngitis) can be followed, in approximately 3 weeks, by an episode of acute rheumatic fever. In outbreak situations, this occurs in up to 3 per cent of those with a throat infection; however, it is usually much lower (Siegel et al. 1961). The rheumatic fever attack results in an inflammatory reaction which involves the heart, joints, and/or the central nervous system. Of those with acute rheumatic fever, at least 50 per cent develop some manifestation of carditis, but this proportion rises when more sophisticated diagnostic methods are used (Dajani 1991). The diagnosis of acute rheumatic fever is made principally from the clinical findings using the revised Jones criteria. These include the major manifestations of carditis, polyarthritis, chorea, erythema marginatum, and/or subcutaneous nodules. Other manifestations include arthralgias and fever. Laboratory findings of acute phase reactants including elevated erythrocyte sedimentation rate and C-reactive proteins are common. A positive throat culture for streptococcal antigen and/or increased streptococcal antibody titre aid in making the diagnosis. These criteria may not be sufficiently sensitive in industrialized countries where clinical patterns have changed significantly so that arthritis may be the only presentation. In addition, a significant portion of individuals do not have a symptomatic preceding infection (Wannamaker 1973). Rheumatic fever is most common among youth from age 6 to 15 years with the syndrome rarely observed below the age of 5 years (Bland and Jones 1951).
Rapid antigen tests for the diagnosis of group A streptococcal throat infections are highly specific, but less sensitive. While a positive test suggests the need for treatment, a negative test indicates the need for a throat culture (Dajani et al. 1995). Antibody tests can confirm a recent group A streptococcal infection.
Primary prevention of acute rheumatic fever is the recommended approach. Throat cultures should be performed on all patients with tonsillopharyngitis and those with a positive culture for group A streptococcal infections treated (Dajani et al. 1995). Antibiotic treatment can effectively prevent acute rheumatic fever even when given up to 9 days from the onset of the infection (Denny et al. 1950). The recommended treatment schedule by the American Heart Association is found in Table 10. Treatment can be either oral or by injection.

Table 10 Primary prevention of rheumatic fever (treatment of streptococcal tonsillopharyngitis)

In individuals with a history of acute rheumatic fever, the likelihood of secondary attacks with additional damage is common, estimated to be approximately 50 per cent of those with streptococcal infections. For this reason, prophylaxis with an antibiotic is widely recommended (Dajani et al. 1995).
If group A streptococcal infections are appropriately detected and treated, rheumatic heart disease can be effectively prevented. In those where it is not prevented, life-long valvular heart disease results in diminishing function, and, if left untreated, premature mortality.
Congenital heart disease
Malformations of the heart and cardiovascular system present at birth are among the more common of congenital defects. They are the result of genetic and/or environmental factors. These malformations frequently have significant haemodynamic consequences and may result in severe illness and/or death (Friedman 1997).
Congenital heart disease includes a wide variety of malformations of the cardiovascular system including the septal, heart valve, and great vessels defects. The true incidence of congenital heart disease is difficult to determine but approximates 8 per 1000 live births in the United States (Fyfe and Kline 1990; Friedman 1997). This is probably an underestimate, as much congenital heart disease is not discovered until adulthood, is mild, or is fatal prior to birth. In addition, the 0.8 per cent incidence does not include mitral valve prolapse or non-obstructive bicuspid aortic valves, both of which are common. Males are more likely to have congenital heart disease than females, but the pattern differs by defect type (Samanck 1994).
Genetic transmission plays an important role in congenital heart disease. Family studies find that the offspring of parents with congenital heart disease have an increased malformation incidence ranging from 1.4 to 16.1 per cent (Ferencz 1986). Identical twins are both affected 25 to 30 per cent of the time. However, despite the known genetic clustering and the identification of disorders associated with single genes, it is estimated that only 10 per cent of congenital heart disease has an identifiable genetic origin (Noonan 1978).
Maternal infections are estimated to cause 10 per cent of all congenital heart disease. Rubella is commonly implicated when it occurs in the first 2 months of pregnancy with congenital malformations in about 80 per cent of live births. Subclinical Coxsackie and other virus infections are also implicated in congenital heart disease.
There are many exposures associated with increased incidence of congenital heart disease. Acute hypoxia, residence at high altitudes, high carboxyhaemoglobin levels, and cigarette smoking are among potential causes (Alberman and Goldstein 1971). External X-ray exposure is associated with Down’s syndrome and other congenital defects (Nora 1971). Metabolic defects including diabetes and phenylketonuria are associated with increases in congenital defects.
Diet- and drug-associated exposures are also implicated. They include the well-known examples of thalidomide and folic acid antagonists. Dextroamphetamines, anticonvulsants, lithium chloride, alcohol, and progesterone/oestrogen are suspected as teratogens acting in the first trimester of pregnancy. Certain pesticides and herbicides are similarly implicated (Zierler 1985).
The overall incidence of congenital heart disease appears to have remained stable although the distribution of defect types may be changing. There are unexplained increases in ventricular septal defect and patent ductus arteriosis. Rubella-related disease is declining, perhaps the result of widespread vaccination for that disease (NHLBI 1979).
The most effective strategy for congenital heart disease is prevention including genetic counselling for families with congenital heart disease, rubella immunization, and avoidance of exposure to known teratogens. Of particular importance are avoidance of alcohol abuse and cigarette smoking.
For many that were born with congenital heart disease, modern medical and surgical techniques can provide palliation, if not a cure. For the most severe cases, heart and heart–lung transplants are assuming increasing importance.
Cardiomyopathy and myocarditis
Cardiomyopathy and myocarditis are a diverse set of diseases that have, as a central feature, pathological involvement of the heart muscle. Congestive heart failure is the frequent outcome of this condition as the heart fails to pump effectively. Cardiomyopathies account for a substantial portion of cardiovascular disease related deaths in developing countries (WHO 1984a). However, they are becoming more common in industrialized nations with increasing rates of ischaemic cardiomyopathy.
There are numerous known causes of myopathy as detailed in a recent report by the WHO (Table 11). The WHO advocates that the term cardiomyopathy be reserved for myocardial dysfunction of unknown aetiology; however, it is commonly applied even when the aetiology is known (Richardson et al. 1996).

Table 11 Major international causes of cardiomyopathy and myocarditis

The natural history of cardiomyopathy varies according to the type. Many cases begin with an acute phase where inflammation of the myocardium is common (myocarditis). The widespread use of endomyocardial biopsy has been of some assistance in identifying and classifying myocarditis (Fowles 1985). In many cases, the initial myocarditis is probably undetected because it is mild. There are clinical courses ranging from minimal heart failure to a brief rapid course leading to death. Investigators at the Mayo Clinic in Olmsted County, Minnesota, found an incidence of idiopathic dilated cardiomyopathy of 6 per 100 000 person years (Shabeter 1983). Overall prevalence in the United States was 35.3 per 100 000 population (Gillum 1986).
The prevalence of cardiomyopathy appears to be increasing in the United States. However, it is uncertain whether this is an actual increase or improved diagnostic methods and greater clinical sensitivity. For most cases, a specific cause is not known.
Cardiomyopathy is grouped into three major types: (a) dilated, characterized by dilatation of the ventricles and contractual dysfunction with congestive heart failure; (b) hypertrophic, with left ventricular hypertrophy and well-preserved cardiac function; (c) restrictive, with impaired diastolic filling frequently due to scarring of the myocardium of the ventricle. The dilated cardiomyopathy pattern is most commonly observed, although there is considerable overlap between types (Keren and Popp 1992).
Alcohol abuse is the most important cause of cardiomyopathy in the United States accounting for approximately 8 per cent of all cases (Rubin 1979; Okada and Wakafuji 1985). This may operate through a direct toxic effect, thiamine deficiency, or additives such as cobalt in alcoholic beverages. Abstinence may halt or reverse this disease (Regan et al. 1977; Rubin 1979; Okada and Wakafuji 1985). Viral infections are a very commonly observed cause of cardiomyopathy. Coxsackie virus, echo virus, influenza, and polio are frequently implicated (Levine 1979). These diseases begin as acute myocarditis and then progress to a chronic condition which results in dilated cardiomyopathy.
Hypertrophic cardiomyopathy is detected by the use of echocardiographic techniques. This condition uncommonly causes difficulty for patients and is usually well managed with medication (Wigle 1988). Chagas’ disease is caused by the protozoan Trypanosoma cruzi. Beginning as a myocarditis, its clinical manifestations are manifest many years later. The disease is most prevalent in Central and South America with over 20 million thought to be infected with the parasite (Morris et al. 1990; Hagar and Rahimtoola 1995). This disease may also be found in non-endemic areas through migration, contaminated blood products, and tourism (Hagar and Rahimtoola 1991). Treatment is available for the acute parasitic infections; however, the cardiomyopathy cannot be directly treated.
Schistosomiasis is a parasitic infection epidemic in the Nile and Yangtze basins. It may involve a majority of the population in certain endemic areas. Chronic pulmonary embolization leads to pulmonary hypertension, right ventricular hypertrophy, and right ventricular heart failure. Direct involvement of the myocardium is rare. New medications can be of assistance in controlling the infection and prevention is the principal strategy employed.
Chapter References
Abbott, R.D., Sharp, D.S., Burchfiel, C.M., et al. (1997). Cross-sectional and longitudinal changes in total and high-density-lipoprotein cholesterol levels over a 20-year period in elderly men: the Honolulu Heart Program. Annals of Epidemiology, 7, 417–24.
Alberman, E.D. and Goldstein, H. (1971). Possible teratogenic effect of cigarette smoking. Nature, 231, 529–30.
Alfredsson, L., Karasek, R., and Theorell, T. (1982). Myocardial infarction risk and psychosocial work environment: an analysis of the male Swedish working force. Social Science and Medicine, 16, 463–7.
American Heart Association (1999). Heart and stroke statistical update (1998). American Heart Association, Dallas, TX.
Anderson, J.T., Jacobs, D.R., Jr, Foster, N., et al. (1979). Scoring systems for evaluating dietary pattern effect on serum cholesterol. Preventive Medicine, 8, 525–37.
Anitschkow, N. (1983). Experimental atherosclerosis in animals (ed. E.V. Cowdry), p. 271. Macmillan, New York.
Aronow, W.S. and Ahn, C. (1998). Risk factors for new coronary events in older African-American men and women. American Journal of Cardiology, 82, 902–4.
Ascherio, A. and Hunter, D.J. (1994). Iron and myocardial infarction. Epidemiology, 5, 135–7.
Ascherio, A., Hennekens, C.H., Buring, J.E., Master, C., Stampfer, M.J., and Willett, W.C. (1994). Trans-fatty acids intake and risk of myocardial infarction. Circulation, 89, 94–101.
Ascherio, A., Rimm, E.B., Hernan, M.A., et al. (1999). Relation of consumption of vitamin E, vitamin C, and carotenoids to risk for stroke among men in the United States. Annals of Internal Medicine, 130, 963–70.
Baraona, E. and Lieber, C.S. (1979). Effects of ethanol on lipid metabolism. Journal of Lipid Research, 20, 289–315.
Barefoot, J.C., Dahlstrom, W.G., and Williams, R.B. (1983). Hostility, coronary heart disease incidence and total mortality: a 25-year follow-up study of 255 physicians. Psychosomatic Medicine, 45, 59–63.
Barefoot, J.C., Dodge, K.A., Peterson, B.L., Dahlstrom, W.G., and Williams, R.B. (1989). The Cook-Medley hostility scale: item content and ability to predict survival. Psychosomatic Medicine, 51, 46–57.
Benditt, E.P. and Benditt, J.M. (1973). Evidence for a monoclonal origin of human atherosclerotic plaques. Proceedings of the National Academy of Sciences of the United States of America, 70, 1753–6. National Academy of Sciences, Washington, DC.
Benson, D.W., Jr, Benditt, D.G., Anderson, R.W., et al. (1983). Cardiac arrest in young, ostensibly healthy patients: clinical, hemodynamic, and electrophysiologic findings. American Journal of Cardiology, 51, 65–9.
Blackburn, H. and Jacobs, D. (1984). Sources of the diet–heart controversy: confusion over population versus individual correlations. Circulation, 70, 775–80.
Blackburn, H. and Jacobs, D.R. (1988). Physical activity and the risk of coronary heart disease (editorial). New England Journal of Medicine, 319, 1217–19.
Blackburn, H. and Prineas, R.J. (1983). Diet and hypertension: anthropology, epidemiology, and public health implications. Progress in Biochemical Pharmacology, 19, 31–79.
Blair, S.N., Kohl, H.W., Paffenbarger, R.S., Jr, Clark, D.G., Cooper, K.H., and Gibbons, L.W. (1989) . Physical fitness and all-cause mortality: a prospective study of healthy men and women. Journal of the American Medical Association, 262, 2395–401.
Blair, S.N., Goodyear, N.N., Gibbons, L.W., and Cooper, K.H. (1984). Physical fitness and incidence of hypertension in healthy normotensive men and women. Journal of the American Medical Association, 252, 487–90.
Bland, E.F. and Jones, T.D. (1951). Rheumatic fever and rheumatic heart disease: a twenty year report on 1000 patients followed since childhood. Circulation, 4, 836–43.
Boushey, C.J., Beresford, S.A., Omenn, G.S., and Motulsky, A.G. (1995). A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. Journal of the American Medical Association, 274, 1049–57.
Brown, H.B. and Page, I.H. (1958). Lowering blood lipid levels by changing food patterns. Journal of the American Medical Association, 168, 1989–95.
Buchwald, H., Varco, R.L., Matts, J.P., et al. (1990). Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: five year post-trial follow-up report from POSCH. New England Journal of Medicine, 323, 946–55.
Buchwald, H., Matts, J.P., Fitch, L.L., et al. for the Program on the Surgical Control of the Hyperlipidemias (POSCH) Group (1992). Changes in sequential coronary arteriograms and subsequent coronary events. Journal of the American Medical Association, 268, 1429–33.
Burt, V.L., Whelton, P., Roccella, E.J., et al. (1995). Prevalence of hypertension in the United States adult population: results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension, 25, 305–13.
Canner, P.L., Berge, K.G., Wenger, N.K., et al. (1986). Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. Journal of the American College of Cardiology, 8, 1245–55.
Carleton, R.A., Lasater, T.M., Assaf, A.R., Feldman, H.A., McKinlay, S. and the Pawtucket Heart Health Program Writing Group (1995). The Pawtucket Heart Health Program: community changes in cardiovascular risk factors and projected disease risk. American Journal of Public Health, 85, 777–85.
Carmassi, F., Morale, M., Puccetti, R., et al. (1992). Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus. Thrombosis Research, 67, 643–54.
Case, R.B., Heller, S.S., Case, N.B., et al. (1985). Type A behavior and survival after acute myocardial infarction. New England Journal of Medicine, 312, 737–41.
Catanzaro, F.J., Stetson, C.A., Morris, A.J., et al. (1954). Symposium on rheumatic fever and rheumatic heart disease: the role of the streptococcus in the pathogenesis of rheumatic fever. American Journal of Medicine, 17, 749–56.
Chakko, S. and Gheorghiade, M. (1992). Estimating severity of chronic heart failure: A clinical challenge for the 1990s. American Heart Journal, 124, 260–4.
Clarke, W.R. and Lauer, R.M. (1985). Coronary risk factors from childhood to adult life: the Muscatine Study. Cardiovascular Disease Epidemiology Newsletter, 37, 38.
Clarkson, T.B., Bond, M.G., Bullock, B.C., McLaughlin, K.J., and Sawyer, J.K. (1984). A study of atherosclerosis regression in Macaca mulatta. V. Changes in abdominal aorta and carotid and coronary arteries from animals with atherosclerosis induced for 38 months and then regressed for 24 or 48 months at plasma cholesterol concentrations of 300 or 200 mg/dl. Experimental and Molecular Pathology, 41, 96–118.
Clarkson, P., Celermajer, D.S., Donald, A.E., et al. (1996). Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. Journal of the American College of Cardiology, 28, 573–9.
Cohen, J.B. and Reed, D. (1985). Type A behavior and coronary heart disease among Japanese men in Hawaii. Journal of Behavioral Medicine, 8, 343–52.
Cohn, J.N. (1996). The management of chronic heart failure. New England Journal of Medicine, 335, 490–8.
Cohn, J.N., Archibald, D.G., Ziesche, S., et al. (1986). Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. New England Journal of Medicine, 314, 1547–52.
Colditz, G.A. (1990). A prospective assessment of moderate alcohol intake and major chronic diseases. Annals of Epidemiology, 1, 167–77.
Connolly, H.M., Crary, J.L., McGoon, M.D., et al. (1997). Valvular heart disease associated with fenfluramine-phentermine. New England Journal of Medicine, 337, 581–8.
Cowie, M.R., Mosterd, A., Wood, D.A., et al. (1997). The epidemiology of heart failure. European Heart Journal, 18, 208–25.
Criqui, M.H. (1987). The roles of alcohol in the epidemiology of cardiovascular diseases. Acta Medica Scandinavica, 717 (Supplement), 73–85.
Dajani, A.S. (1991). Current status of nonsupportive complications of group A streptococci. Pediatric Infectious Disease Journal, 105, S25–7.
Dajani, A., Taubert, K., Ferrieri, P., Peter, G., and Shulman, S. (1995). Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: a statement for health professionals. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, The American Heart Association. Pediatrics, 96, 758–64.
Dattilo, A.M. and Kris-Etherton, P.M. (1992). Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. American Journal of Clinical Nutrition, 56, 320–8.
Davis, R.C., Hobbs, F.D.R., McLeod, S., et al. (1997). Heart failure prevalence in patients in ‘high-risk’ groups. European Heart Journal, 18, 597.
Dawber, T.R., Moore, F.E., and Mann, G.V. (1957). Measuring the risk of coronary heart disease in adult population groups: II. Coronary heart disease in the Framingham Study. American Journal of Public Health, 47, 4–24.
DCCT (Diabetes Control and Complications Trial) Research Group (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New England Journal of Medicine, 329, 977–86.
Denny, F.W., Wannamaker, L.W., Brink, W.R., Rammelkamp, C.H., and Custer, E.A. (1950). Prevention of rheumatic fever: treatment of the preceding streptococcic infection. Journal of the American Medical Association, 143, 151–3.
Derby, C.A., Lapane, K.L., Feldman, H.A., and Carleton, R.A. (2000). Sex-specific trends in validated coronary heart disease rates in Southeastern New England, 1980–1991. American Journal of Epidemiology, 151, 417–29.
Dimsdale, J.E., Gilbert, J., Hutter, A.M., et al. (1981). Predicting cardiac morbidity based on risk factors and coronary angiographic findings. American Journal of Cardiology, 47, 73–6.
Downs, J.R., Clearfield, M., Weis, S., et al. (1998). Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. Journal of the American Medical Association, 279, 1615–22.
Dyer, A.R. and Elliott, P. (1989). The INTERSALT Study: relations of body mass index to blood pressure. Journal of Human Hypertension, 3, 299–308.
Eckel, R.H. and Krauss, R.M. (1998). American Heart Association call to action: obesity as a major risk factor for coronary heart disease. Circulation, 97, 2099–100.
Eriksson, H., Svardsudd, K., Larsson, B., et al. (1989). Risk factors for heart failure in the general population: the study of men born in 1913. European Heart Journal, 10, 647–56.
Farquhar, J.W., Maccoby, N., Wood, P.D., et al. (1977). Community education for cardiovascular health. Lancet, 1, 1192–5.
Farquhar, J.W., Fortmann, S.P., Flora, J.A., et al. (1990). Effects of community-wide education on cardiovascular disease risk factors: the Stanford Five-City Project. Journal of the American Medical Association, 264, 359–65.
Ferencz, C. (1986). Offspring of fathers with cardiovascular malformations. American Heart Journal, 111, 1212–13.
Ferrence, R.G., Truscott, S., and Whitehead, P.C. (1986). Drinking and the prevention of coronary heart disease: findings, issues and public health policy. Journal of Studies on Alcohol, 47, 394–408.
Feskanich, D., Rimm, E.B., Giovannucci, E.L., et al. (1993). Reproducibility and validity of food intake measurements from a semiquantitative food frequency questionnaire. Journal of the American Dietetic Association, 93, 790–6.
Fiore, M.C., Bailey, W.C., Cohen, S.J., et al. (1996). Smoking cessation. Clinical practice guideline No. 18. United States Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research. AHCPR Publication No. 96–0692.
Flegal, K.M. (1996). Trends in body weight and overweight in the US population. Nutrition Reviews, 54, S97–S100
Fowles, R.E. (1985). Progress of research in cardiomyopathy and myocarditis in the USA. International Symposium on Cardiomyopathy and Myocarditis. Heart Vessels, 1, 5–7.
Freedman, D.S. (1995). Relation of body fat distribution to ischemic heart disease. The National Health and Nutrition Examination Survey I (NHANES I) Epidemiologic Follow-up Study. American Journal of Epidemiology, 142, 53–63.
Freis, E.D. (1976). Salt, volume and the prevention of hypertension. Circulation, 53, 589–95.
Frick, M.H., Elo, O., Haapa, K., et al. (1987). Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. New England Journal of Medicine, 317, 1237–45.
Friedman, W.F. (1997). Congenital heart disease in infancy and childhood. In Heart disease: a textbook of cardiovascular medicine (ed. E. Braunwald), (5th edn), pp. 877–962. Saunders, Philadelphia.
Friedman, M. and Rosenman, R.H. (1959). Association of specific overt behavior pattern with blood and cardiovascular findings: blood cholesterol level, blood clotting time, incidence of arcus senilis, and clinical coronary artery disease. Journal of the American Medical Association, 169, 1286–96.
Friedman, M., Thorensen, C.E., Gill, J.J., et al. (1984). Alteration of type A behavior and reduction in cardiac recurrences in post-myocardial infarction patients. American Heart Journal, 108, 237–48.
Fuster, V., Badimon, L., Badimon, J., and Chesebro, J. (1992a). Mechanisms of disease: the pathogenesis of coronary artery disease and the acute coronary syndromes. New England Journal of Medicine, 326, 310–18.
Fuster, V., Badimon, L., Badimon, J.J., and Chesebro, J.H. (1992b). The pathogenesis of coronary artery disease and the acute coronary syndromes. New England Journal of Medicine, 326, 242–50.
Fyfe, D.A. and Kline, C.H. (1990). Fetal echocardiographic diagnosis of congenital heart disease. Pediatric Clinics of North America, 37, 45–67.
Garland, C., Barrett-Connor, E., Suarez, L., Criqui, M.H., and Wingard, D.L. (1985). Effects of passive smoking on ischemic heart disease mortality of non-smokers. American Journal of Epidemiology, 121, 645–50.
GCP Research Group (1988). GCP German Cardiovascular Prevention study. Design, methods, results. Program Report. Scientific Institute of the German Medical Association (WIAD), Bonn, Germany.
Gillum, R.F. (1986). Idiopathic cardiomyopathy in the United States, 1970–1982. American Heart Journal, 111, 752–5.
Ginsberg, H.N., Kris-Etherton, P., Dennis, B., et al. (1998). Effects of reducing dietary saturated fatty acids on plasma lipids and lipoproteins in healthy subjects: the DELTA Study, protocol 1. Arteriosclerosis, Thrombosis and Vascular Biology, 18, 441–9.
Gleiberman, L. (1973). Blood pressure and dietary salt in human populations. Ecology of Food Nutrition, 2, 143–56.
Gordon T. (1988). The diet–heart idea. American Journal of Epidemiology, 127, 220–5.
Gordon, T., Castelli, W.P., Hjortland, M.C., Kannel, W.B., and Dawber, T.R. (1977). High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. American Journal of Medicine, 62, 707–14.
Gordon, T., Ernst, N., Fisher, M., and Rifkind, B.M. (1981). Alcohol and high-density lipoprotein cholesterol. Circulation, 64, (Supplement III), 63–7.
Graves, E.J. and Gillum, B.S. (1996). 1994 Summary: National hospital discharge survey: advance data. National Center for Health Statistics, 278, 1–12.
Grundy, S.M. (1999). Primary prevention of coronary heart disease: integrating risk assessment with intervention (review). Circulation, 100, 988–98.
Hagar, J.M. and Rahimtoola, S.H. (1991). Chagas’ heart disease in the United States. New England Journal of Medicine, 325, 763–8.
Hagar, J.M. and Rahimtoola, S.H. (1995). Chagas’ heart disease. Current Problems in Cardiology, 20, 825–924.
Harris, T.B., Ballard-Barbasch, R., Madans, J., Makuc, D.M., and Feldman, J.J. (1993). Overweight, weight loss, and risk of coronary heart disease in older women. The NHANES I Epidemiologic Follow-up Study. American Journal of Epidemiology, 137, 1318–27.
Harris, T.B., Launer, L.J., Madans, J., and Feldman, J.J. (1997). Cohort study of effect of being overweight and change in weight on risk of coronary heart disease in old age. British Medical Journal, 314, 1791–4.
Haynes, S.G., Feinleib, M., and Kannel, W.B. (1980). The relationship of psychosocial factors to coronary heart disease in the Framingham Study. III. Eight-year incidence of coronary heart disease. American Journal of Epidemiology, 111, 37–58.
Hearn, M.D., Murray, D.M., and Luepker, R.V. (1988). Hostility, coronary heart disease, and total mortality. A 33-year follow-up study of university students. Journal of Behavioral Medicine, 12, 105–21.
Heart Outcomes Prevention Evaluation Study Investigators (2000). Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. New England Journal of Medicine, 342, 145–53.
Hecker, M.H.L., Chesney, M.A., Black, G.W., and Frautsch, N. (1988). Coronary prone behaviors in the Western Collaborative Group Study. Psychosomatic Medicine, 50, 153–64.
Hegsted, D.M., McGandy, R.B., Myers, M.L., and Stare, F.J. (1965). Quantitative effects of dietary fat on serum cholesterol in man. American Journal of Clinical Nutrition, 17, 281–95.
Helsing, K.J., Sandler, D.P., Comstock, G.W., and Chee, E. (1988). Heart disease mortality in nonsmokers living with smokers. American Journal of Epidemiology, 127, 915–22.
Hennekens, C.H., Buring, J.E., Manson, J.E., et al. (1996). Lack of effect on long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. New England Journal of Medicine, 334, 1145–9.
Hermanson, B., Omenn, G.S., Kronmal, R.A., et al. (1988). Beneficial six-year outcome of smoking cessation in older men and women with coronary artery disease: results from the CASS registry. New England Journal of Medicine, 319, 1365–9.
Higgins, M. and Luepker, R.V. (ed.) (1989). Trends and determinants of coronary heart disease mortality: international comparisons. International Journal of Epidemiology, 18 (Supplement 1), S1–S232.
Hirayama, T. (1984). Lung cancer in Japan: Effects of nutrition and passive smoking. In Lung cancer: causes and prevention (ed. M. Mizell and P. Correa), pp. 175–95. Verlag Chemie International, New York.
Hlatky, M.A., Fleg, J.L., Hinton, P.C., et al. (1986). Physician practice in the management of congestive heart failure. Journal of the American College of Cardiology, 8, 966–70.
Ho, K.K., Pinsky, J.L., Kannel, W.B., and Levy, D. (1993a). The epidemiology of heart failure: the Framingham Study. Journal of the American College of Cardiology, 22, 6A–13A.
Ho, K.K., Anderson, K.M., Kannel, W.B., Grossman, W., and Levy, D. (1993b). Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation, 88, 107–15.
Hole, D.J., Gillis, C.R., Chopra, C., and Hawthorne, V.M. (1989). Passive smoking and cardiorespiratory health in a general population in the west of Scotland. British Medical Journal, 299, 423–7.
Huang, Z., Willett, W.C., Manson, J.E., et al. (1998). Body weight, weight change, and risk for hypertension in women. Annals of Internal Medicine, 128, 81–8.
Hughes, L.O. (1990). Insulin, Indian origin and ischemic heart disease (editorial). International Journal of Cardiology, 26, 1–4.
Hypertension Prevention Trial Research Group (1990). The Hypertension Prevention Trial: three-year effects of dietary changes on blood pressure. Archives of Internal Medicine, 150, 153–62.
INTERSALT Cooperative Research Group (1988). INTERSALT: an international study of electrolyte excretion and blood pressure: results for 24 h urinary sodium and potassium excretion. British Medical Journal, 297, 319–28.
Jacobs, D.R., Anderson, J., and Blackburn, H. (1979). Diet and serum cholesterol: do zero correlations negate the relationships? American Journal of Epidemiology, 10, 77–88.
Jenkins, D.J.A., Wolever, T.M.S., Rao, A.V., et al. (1993). Effect on blood lipids of very high intakes of fiber in diets low in saturated fat and cholesterol. New England Journal of Medicine, 329, 21–6.
Johnson, C.L., Rifkind, B.M., Sempos, C.T., et al. (1993a). Declining serum total cholesterol levels among US adults. Journal of the American Medical Association, 269, 3002–23.
Johnson, G., Carson, P., Francis, G.S., and Cohn, J.N. (1993b). Influence of prerandomization (baseline) variables on mortality and on the reduction of mortality by enalapril: Veterans Affairs Cooperative Study on Vasodilator Therapy of Heart Failure (V-HeFT II). Circulation, 87, VI32–VI39.
Joseph, J.G., Prior, I.A.M., Salmond, C.E., and Stanley, D. (1983). Elevation of systolic and diastolic blood pressure associated with migration: the Tokelau Island Migrant Study. Journal of Chronic Disorders, 36, 507–16.
Kagan, A., Harris, B.R., Winkelstein, W., et al. (1974). Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: demographic, physical, dietary and biochemical characteristics. Journal of Chronic Disorders, 27, 345–64.
Kannel, W.B. (1987). Epidemiology and prevention of cardiac failure: Framingham Study insights. European Heart Journal, 8, 23–6.
Kannel, W.B. and McGee, D.L. (1979). Diabetes and cardiovascular disease. The Framingham Study. Journal of the American Medical Association, 241, 2035–8.
Kannel, W.B., McGee, D.L., and Castelli, W.P. (1984). Latest perspectives on cigarette smoking and cardiovascular disease: the Framingham Study. Journal of Cardiac Rehabilitation, 4, 267–77.
Kannel, W.B., Neaton, J.D., Wentworth, D., et al. (1986). Overall and coronary heart disease mortality rates in relation to major risk factors in 325,348 men screened for the MRFIT. Multiple Risk Factor Intervention Trial. American Heart Journal, 112, 825–35.
Kannel, W.B., Ho, K., and Thom, T. (1994). Changing epidemiological features of cardiac failure. British Heart Journal, 72, S3–9.
Kaplan, G.A., Salonen, J.T., Cohen, R.D., Brand, R.J., Syme, S.L., and Puska, P. (1988). Social connections and mortality from all causes and from cardiovascular disease. Prospective evidence from Eastern Finland. American Journal of Epidemiology, 128, 370–80.
Kawachi, I., Colditz, G.A., Stampfer, M.J., et al. (1994). Smoking cessation and time course of decreased risks of coronary heart disease in middle-aged women. Archives of Internal Medicine, 154, 169–75.
Kawachi, I., Colditz, G.A., Speizer, F.E., et al. (1997). A prospective study of passive smoking and coronary heart disease. Circulation, 95, 2374–9.
Keren, A. and Popp, R.L. (1992). Assignment of patients into the classification of cardiomyopathies. Circulation, 86, 1622–33.
Kesteloot, H., Vuylsteks, M., and Costenoble, A. (1980). Relationship between blood pressure and sodium and potassium intake in a Belgian male population group. In Epidemiology of arterial blood pressure (ed. K. Kesteloot and J. Joossens), pp. 345–51. Nijhoff, the Hague.
Keys, A. (ed.) (1980). Seven countries: a multivariate analysis of death and coronary heart disease. Harvard University Press, Cambridge, MA.
Keys, A., Anderson, J.T., and Gande, G. (1965). Serum cholesterol response to changes in the diet. Metabolism, 14, 747–87.
Keys, A., Grande, F., and Anderson, J.T. (1974). Bias and misrepresentation revisited—’perspective’ on saturated fat. American Journal of Clinical Nutrition, 27, 188–212.
Knowler, W.C., Bennett, P.H., Hammon, R.F., and Miller, M. (1978). Diabetes incidence and prevalence in Pima Indians: A 19-fold greater incidence than in Rochester, MN. American Journal of Epidemiology, 108, 497–505.
Kramer, K., Kuller, L., and Fisher, R. (1968). The increasing mortality attributed to cirrhosis and fatty liver, in Baltimore (1957–1996). Annals of Internal Medicine, 69, 273–82.
Krauss, R.M., Wonston, M., Fletcher, R.N., and Grundy, S.M. (1998). Obesity: impact of cardiovascular disease. Circulation, 98, 1472–6.
Kritchevsky, S.B., Shimakawa, T., Tell, G.S., et al. (1995). Dietary antioxidants and carotid artery wall thickness: the ARIC Study. Circulation, 92, 2142–50.
Kuller, L.H., Traven, N.D., Rutan, G.H., Perper, J.A., and Ives, D.G. (1989). Marked decline of coronary heart disease mortality in 35–44-year-old white men in Allegheny County, Pennsylvania. Circulation, 80, 261–6.
Kushi, L.H., Lew, R.A., Stare, F.J., et al. (1985). Diet and 20-year mortality from coronary heart disease: the Ireland–Boston Diet–Heart Study. New England Journal of Medicine, 312, 811–18.
Layard, M.W. (1995). Ischemic heart disease and spousal smoking in the National Mortality Followback Survey. Regulatory Toxicology Pharmacology, 21, 180–3.
Lehto, S., Ronnemaa, T., Haffner, S.M., Pyorala, K., Kallio, V., and Laakso, M. (1997). Dyslipidemia and hyperglycemia predict coronary heart disease events in middle-aged patients with NIDDM. Diabetes, 48, 1354–9.
Leon, A.S., Connett, J., Jacobs, D.R. Jr, and Rauramaa, R. (1987). Leisure-time physical activity levels and risk of coronary heart disease and death: the Multiple Risk Factor Intervention Trial. Journal of the American Medical Association, 258, 2388–95.
Leon, G.R., Finn, S.E., Murray, D., and Bailey, J.M. (1988). Inability to predict cardiovascular disease from hostility scores of MMPI items related to type A behavior. Journal of Consulting and Clinical Psychology, 56, 597–600.
Levine, H.D. (1979). Virus myocarditis: a critique of the literature from clinical, electrocardiographic and pathologic standpoints. American Journal of Medical Sciences, 277, 132–43.
Levy, D., Larson, M.G., Vasan, R.S., Kannel, W.B., and Ho, K.K. (1996). The progression from hypertension to congestive heart failure. Journal of the American Medical Association, 275, 1557–62.
Lipid Research Clinics Program (1984). The Lipid Research Clinics Coronary Primary Prevention Trial results: reduction in incidence of coronary heart disease. Journal of the American Medical Association, 251, 351–64.
Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group (1998). Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. New England Journal of Medicine, 339, 1349–57.
Luepker, R.V. (ed.) (1983). Conference on blood lipids in children. Optimal levels for early prevention of coronary artery disease. Preventive Medicine, 12, 725–905.
Luepker, R.V. (1994). Epidemiology of atherosclerotic diseases in population groups. In Primer in preventive cardiology (ed. T.A. Pearson, M.H. Criqui, R.V. Luepker, A. Oberman, and M. Winston), pp. 1–10. American Heart Association, Dallas, TX.
Luepker, R.V. (ed.) (1999). Proceedings from primordial prevention of cardiovascular disease risk factors: an international symposium honoring the career and research of Henry Blackburn, MD. Preventive Medicine, 29.
Luepker, R.V., Murray, D.M., Jacobs, D.R. Jr, et al. (1994). Community education for cardiovascular disease prevention: risk factor changes in the Minnesota Heart Health Program. American Journal of Public Health, 84, 1383–93.
Luepker, R.V., Jacobs, D.R., Prineas, R.J., and Sinaiko, A.R. (1999). Secular trends of blood pressure and body size in a multi-ethnic adolescent population: 1986 to 1996. Journal of Pediatrics, 134, 668–74.
McCranie, E.W., Watkins, L.O., Brandsma, J.M., and Sisson, B.D. (1986). Hostility, coronary heart disease (CHD) incidence, and total mortality: lack of an association in a 25-year follow-up study of 478 physicians. Journal of Behavioral Medicine, 9, 119–25.
McGill, H.C., McMahan, C.A., Malcom, G.T., et al. for the PDAY Research Group (1997). Effects of serum lipoproteins and smoking on atherosclerosis in young men and women. Arteriosclerosis and Thrombosis Vascular Biology, 17, 95–106.
McGovern, P.G., Pankow, J.S., Shahar, E., et al. for the Minnesota Heart Survey Investigators (1996). Recent trends in acute coronary heart disease mortality, morbidity, medical care and risk factors. New England Journal of Medicine, 334, 884–90.
Maouad J., Fernandez F., Barrillon, A., et al. (1984). Diffuse or segmental narrowing (spasm) of coronary arteries during smoking demonstrated on angiography. American Journal of Cardiology, 53, 354–5.
Matthews, K.A., Glass, D.C., Rosenman, R.H., et al. (1977). Competitive drive, pattern A, and coronary heart disease: a further analysis of some data from the Western Collaborative Group Study. Journal of Chronic Disorders, 30, 489–98.
Mattson, F.H. and Grundy, S.M. (1985). Comparison of effects of dietary saturated, monounsaturated, and polyunsaturated fatty acids on plasma lipids and lipoproteins in man. Journal of Lipid Research, 26, 194–202.
Meade, T.W., Imeson, J., and Stirling, Y. (1987). Effects of changes in smoking and other characteristics on clotting factors and the risk of ischaemic heart disease. Lancet, 2, 986–8.
Meneely, G.R. and Battarbee, H.D. (1976). High sodium-low potassium environment and hypertension. American Journal of Cardiology, 38, 768–85.
Milner, M.R., Gallino, R.A., Leffingwell, A., et al. (1989). Usefulness of fish oil supplements in preventing clinical evidence of restenosis after percutaneous transluminal coronary angioplasty. American Journal of Cardiology, 64, 294–9.
Mittleman, M.A., Maclure, M., Tofler, G.H., et al. for the Determinants of Myocardial Infarction Onset Study Investigators (1993). Triggering of acute myocardial infarction by heavy physical exertion: protection against triggering of regular exertion. New England Journal of Medicine, 329, 1677–83.
Morris, S.A., Tanowitz, H.B., Wittner, M., and Bilezikian, J.P. (1990). Pathophysiological insights into the cardiomyopathy of Chagas’ disease. Circulation, 82, 1900–9.
Moser, M. and Hebert, P.R. (1996). Prevention of disease progression, left ventricular hypertrophy and congestive heart failure in hypertension treatment trials. Journal of the American College of Cardiology, 27, 1214–18.
Muller, J.E., Ludmer, P.L., Willich, S.N., et al. (1987). Circadian variation in the frequency of sudden cardiac death. Circulation, 75, 131–8.
Muller, J.E., Kaufmann, P.G., Luepker, R.V., Weisfeldt, M.L., Deedwanis, P.C., and Willerson, J.T. (1997). Mechanisms precipitating acute cardiac events: Review and recommendations of an NHLBI workshop. Circulation, 96, 3233–9.
Multiple Risk Factor Intervention Trial Research Group (1996). Mortality after 16 years for participants randomized to the Multiple Risk Factor Intervention Trial. Circulation, 94, 946–51.
Munger, R.G., Folsom, A.R., Kushi, L.H., Kaye, S.A., and Sellers, T.A. (1992). Dietary assessment of older Iowa women with a food frequency questionnaire: nutrient intake, reproducibility, and comparison with 24-hour dietary recall interviews. American Journal of Epidemiology, 136, 192–200.
National Task Force on Prevention and Treatment of Obesity (1994). Towards prevention of obesity: research directions. Obesity Research, 2, 571–84.
Neaton, J.D. and Wentworth, D. for the Multiple Risk Factor Intervention Trial Research Group (1992). Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease: Overall findings and differences by age for 316 099 white men. Archives of Internal Medicine, 152, 56–64.
Neaton, J.D., Grimm, R.H., Jr, Prineas, R.J., et al. (1993). Treatment of mild hypertension study: final results. Journal of the American Medical Association, 270, 713–24.
NHLBI (National Heart, Lung, and Blood Institute) (1978). Proceedings of the Conference on the Decline in Coronary Heart Disease Mortality. US Department of Health and Human Services, National Institutes of Health. US Government Printing Office, Washington, DC.
NHLBI (National Heart, Lung, and Blood Institute) (1979). NHLBI Working Group on Heart Disease Epidemiology Report. NIH Report 79-1667. US Government Printing Office, Washington, DC.
NHLBI (National Heart, Lung, and Blood Institute) (1997). The sixth report of the Joint National Commission on Detection, Evaluation and Treatment of High Blood Pressure. NIH Publication No. 98-4080. National Institutes of Health, Bethesda, MD.
NHLBI (National Heart, Lung, and Blood Institute) (1998). Morbidity and mortality: 1998 chartbook on cardiovascular, lung, and blood diseases. National Institutes of Health, Washington, DC.
NIH (National Institutes of Health) (1993a). Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. National Cholesterol Education Program. US Department of Health and Human Services. NIH Publication No. 93–3095. National Institutes of Health, Washington, DC.
NIH (National Institutes of Health) Consensus Conference (1993b). Triglyceride, high-density lipoprotein, and coronary heart disease. NIH Consensus Development Panel on Triglyceride, High-Density Lipoprotein, and Coronary Heart Disease. Journal of the American Medical Association, 269, 505–10.
NIH (National Institutes of Health) Consensus Conference (1996). Physical activity and cardiovascular health. Journal of the American Medical Association, 276, 241–6.
Noonan, J. (1978). Twins, conjoined twins and cardiac defects. American Journal of Diseased Children, 132, 17–18.
Nora, J.J. (1971). Etiologic factors in congenital heart diseases. Pediatric Clinics of North America, 18, 1059–74.
O’Connor, G.T., Buring, J.E., Yusuf, S., et al. (1989). An overview of randomized trials of rehabilitation with exercise after myocardial infarction. Circulation, 80, 234–44.
Okada, R. and Wakafuji, S. (1985). Myocarditis in autopsy. International Symposium on Cardiomyopathy and Myocarditis. Heart Vessels, 1, 23–9.
Oldridge, N.B., Guyatt, G.H., Fischer, M.E., and Rimm, A.A. (1988). Cardiac rehabilitation after myocardial infarction. Combined experience of randomized clinical trials. Journal of the American Medical Association, 260, 945–50.
Ornish, D., Brown, S.E., Scherwitz, L.W., et al. (1990). Can lifestyle changes reverse coronary heart disease? The lifestyle heart trial. Lancet, 336, 129–33.
Orth-Gomer, K. and Johnson, J.V. (1987). Social network interaction and mortality: a six year follow-up study of a random sample of the Swedish population. Journal of Chronic Disorders, 40, 949–57.
Osganian, S.K., Stampfer, M.J., Spiegelman, D., et al. (1999). Distribution of and factors associated with serum homocysteine levels in children: Child and Adolescent Trial for Cardiovascular Health. Journal of the American Medical Association, 281, 1189–96.
Paffenbarger, R.S., Jr, Hyde, R.T., Wing, A.L., and Steinmetz, C.H. (1984). A natural history of athleticism and cardiovascular health. Journal of the American Medical Association, 252, 491–5.
PAHO (Pan American Health Organization) (1970). Fourth Meeting of the Working Group on Prevention of Rheumatic Fever, Quito, Ecuador.
Paisey, R.B., Harvey, P., Rice, S., et al. (1998). An intensive weight loss programme in established type 2 diabetes and controls: effects on weight and atherosclerosis risk factors at 1 year. Diabetic Medicine, 15, 73–9.
Perry, C.L., Kelder, S.H., Murray, D.M., et al. (1992). Community-wide smoking prevention: long-term outcomes of the Minnesota Heart Health Program and the Class of 1989 Study. American Journal of Public Health, 82, 1210–16.
Poole-Wilson, P.A. (1989). Chronic heart failure: cause, pathophysiology, prognosis, clinical manifestations, investigations. In Disease of the heart (ed. D.G. Julian, A.J. Camm, K.F. Fox, R.J.C. Hall, and P.A. Poole-Wilson), pp. 24–36. Baillière-Tindall, London.
Pooling Project Research Group (1978). Relationship of blood pressure, serum cholesterol, smoking habit, relative weight, and ECG abnormalities to incidence of major coronary events: final report of the pooling project. Journal of Chronic Diseases, 31, 201–6.
Powell, K.E., Thompson, P.D., Caspersen, C.J., and Kendrick, J.S. (1987). Physical activity and the incidence of coronary heart disease. Annual Review of Public Health, 8, 253–87.
Psaty, B.M., Smith, N.L., Siscovick, D.S., et al. (1997). Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. Journal of the American Medical Association, 277, 739–45.
Puska, P., Tuomilehto, J., Nissinen, A., Vartiainen, E. (ed.) (1995). The North Karelia Project: 20 year results and experiences. Helsinki University Printing House.
Pyorala, K., Laakso, M., and Uusitupa, M. (1987). Diabetes and atherosclerosis: an epidemiologic view. Diabetes/Metabolism Review, 3, 463–524.
Ragland, D.R. and Brand, R.J. (1988a). Coronary heart disease mortality in the Western Collaborative Group Study. Follow-up experience of 22 years. American Journal of Epidemiology, 127, 462–75.
Ragland, D.R. and Brand, R.J. (1988b). Type A behavior and mortality from coronary heart disease. New England Journal of Medicine, 318, 65–9.
Ranofsky, A. (1974). Inpatient utilization of short-stay hospitals by diagnosis: United States, 1971. Publication no. HRA-75-1767. National Center for Health Statistics, Department of Health Education and Welfare, Washington, DC.
Regan, T.J. (1990). Alcohol and the cardiovascular system. Journal of the American Medical Association, 264, 377–81.
Regan, T.J., Haider, B., Ahmed, S.S., et al. (1977). Whisky and the heart. Cardiovascular Medicine, 2, 165.
Remes, J., Reunanen, A., Aromaa, A., and Pyorala, K. (1992). Incidence of heart failure in Eastern Finland: a population-based surveillance study. European Heart Journal, 13, 588–93.
Richardson, P., McKenna, W., Bristow, M., et al. (1996). Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation, 93, 841–2.
Ridker, P.M., Manson, J.E., Buring, J.E., Muller, J.E., and Hennekens, C.H. (1990). Circadian variation of acute myocardial infarction and the effect of low-dose aspirin in a randomized trial of physicians. Circulation, 82, 897–902.
Rimm, E.B., Stampfer, M.J., Ascherio, A., Giovannucci, E., Colditz, G.A., and Willett, W.C. (1993). Vitamin E consumption and the risk of coronary heart disease in men. New England Journal of Medicine, 328, 1450–6.
Ripsin, C.M., Keenan, J.M., Jacobs, D.R., et al. (1992). Oat products and lipid-lowering: a meta-analysis. Journal of the American Medical Association, 267, 3317–25.
Rodeheffer, R.J., Jacobsen, S.J., Gersh, B.J., et al. (1993). The incidence and prevalence of congestive heart failure in Rochester, Minnesota. Mayo Clinic Proceedings, 68, 1143–50.
Rosenberg, L., Miller, D.R., Kaufman, D.W., et al. (1983). Myocardial infarction in women under 50 years of age. Journal of the American Medical Association, 250, 2801–6.
Rosenberg, L., Kaufman, D.W., Helmrich, S.P., et al. (1985). The risk of myocardial infarction after quitting smoking in men under 55 years of age. New England Journal of Medicine, 313, 1511–14.
Rosenman, R.H., Brand, R.J., Jenkins, C.D., et al. (1975). Coronary heart disease in the Western Collaborative Group Study: final follow-up experience of 8.5 years. Journal of the American Medical Association, 233, 872–7.
Ross, R. and Fuster, V. (1996). The pathogenesis of atherosclerosis. In Atherosclerosis and coronary artery disease (ed. V. Fuster, R. Ross, and E.J. Topol), pp. 441–62. Lippincott–Raven, Philadelphia, PA.
Ross, R. and Glomset, J.A. (1973). Atherosclerosis and the arterial smooth muscle cell: proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science, 180, 1332–9.
Rubin, E. (1979). Alcoholic myopathy in heart and skeletal muscle. New England Journal of Medicine, 301, 28–33.
Rubin, S.M., Sidney, S., Black, D.M., Browner, W.S., Hulley, S.B., and Cummings, S.R. (1990). High blood cholesterol in elderly men and the excess risk for coronary heart disease. Annals of Internal Medicine, 113, 916–20.
Rubins, H.B., Robins, S.J., Collins, D., et al. (1999). Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. New England Journal of Medicine, 341, 410–18.
Sacks, F.M., Pfeffer, M.A., Moye, L.A., et al. (1996). The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators. New England Journal of Medicine, 335, 1001–9.
Samanck, M. (1994). Boy : girl ratio in children born with different forms of cardiac malformation: a population-based study. Pediatric Cardiology, 15, 53–7.
Scandinavian Simvastatin Survival Study (1994). Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet, 344, 1383–9.
Schaefer, E.J., Lamon-Fava, S., Jenner, J.L., et al. (1994). Lipoprotein(a) levels and risk of coronary heart disease in men. The Lipid Research Clinics Coronary Primary Prevention Trial. Journal of the American Medical Association, 271, 999–1003.
Schnall, P.L., Pieper, C., Schwartz, J.E., et al. (1990). The relationship between ‘job strain’ workplace diastolic blood pressure, and left ventricular mass index. Results of a case-control study. Journal of the American Medical Association, 263, 1929–35.
Schocken, D.D., Arrieta, M.I., Leaverton, P.E., and Ross, E.A. (1992). Prevalence and mortality rate of congestive heart failure in the United States. Journal of the American College of Cardiology, 20, 301–6.
Shabeter, R. (1983). Cardiomyopathy: How far have we come in 25 years? How far yet to go? Journal of the American College of Cardiology, 1, 252–63.
Shaw, L.W. (1981). Effects of a prescribed supervised exercise program on mortality and cardiovascular morbidity in patients after myocardial infarction. The National Exercise and Heart Disease Project. American Journal of Cardiology, 48, 39–46.
Shekelle, R.B., Gale, M., Ostfeld, A.M., and Paul, O. (1983). Hostility, risk of coronary heart disease, and mortality. Psychosomatic Medicine, 45, 109–14.
Shekelle, R.B., Hulley, S.B., Neaton, J.D., et al. (1985a). The MRFIT behavior pattern study. I. Type A behavior and incidence of coronary heart disease. American Journal of Epidemiology, 122, 559–70.
Shekelle, R.B., Gale, M., and Norusis, M. (1985b). Type A score (Jenkins Activity Survey) and risk of recurrent coronary heart disease in the Aspirin Myocardial Infarction Study. American Journal of Cardiology, 56, 221–5.
Shepherd, J., Cobbe, S.M., Ford, I., et al. for the West of Scotland Coronary Prevention Study Group (1995). Prevention of coronary heart disease with pravastatin in me with hypercholesterolemia. New England Journal of Medicine, 333, 1301–7.
Sheps, S.G. (chair) (1997). Sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Archives of Internal Medicine, 157, 2413–46.
Siegel, A.C., Johnson, E.E., and Stollerman, G.H. (1961). Controlled studies of streptococcal pharyngitis in a pediatric population: 1. factors related to the attack rate of rheumatic fever. New England Journal of Medicine, 265, 559–66.
Singer, D.R., Markandu, N.D., Cappuccio, F.P., Miller, M.A., Sagnella, G.A., and MacGregor, G.A. (1995). Reduction of salt intake during converting enzyme inhibitor treatment compared with addition of a thiazide. Hypertension, 25, 1042–4.
Siscovick, D.S., Weiss, N.S., Fletcher, R.H., and Lasky, T. (1984). The incidence of primary cardiac arrest during vigorous exercise. New England Journal of Medicine, 311, 874–7.
Sjostrom, L.V. (1992). Mortality of severely obese subjects. American Journal of Clinical Nutrition, 55, 516S–23S.
Solomon, C.G. and Manson, J.E. (1997). Obesity and mortality: a review of the epidemiologic data. American Journal of Clinical Nutrition, 66, 1044S–50S.
SOLVD Investigators (1991). Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. New England Journal of Medicine, 325, 293–302.
SOLVD Investigators (1992). Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricle ejection fractions. New England Journal of Medicine, 327, 685–91.
Sowers, J.R., Sowers, P.S., and Peuler, J.D. (1994). Role of insulin resistance and hyperinsulinemia in development of hypertension and atherosclerosis. Journal of Laboratory and Clinical Medicine, 123, 647–52.
Stamler, R., Stamler, J., Lindberg, H.A., et al. (1979). Asymptomatic hyperglycemia and coronary heart disease in middle-aged men in two employed populations in Chicago. Journal of Chronic Disorders, 32, 805–15.
Stamler, J., Wentworth, D., and Neaton, J.D. (1986). Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356 222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). Journal of the American Medical Association, 256, 2823–8.
Stamler, R., Stamler, J., Grimm, R., et al. (1987). Nutritional therapy for high blood pressure. Final report of a four-year randomized controlled trial—The Hypertension Control Program. Journal of the American Medical Association, 257, 1484–91.
Stamler, J., Vaccaro, O., Neaton, J.D., and Wentworth, D. (1993). Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care, 16, 434–44.
Stampfer, M.J. and Rimm, E.B. (1995). Epidemiologic evidence for vitamin E in prevention of cardiovascular disease. American Journal of Clinical Nutrition, 62, 1365S–9S.
Stampfer, M.J., Hennekens, C.H., Manson, J.E., Colditz, G.A., Rosner, B., and Willett, W.C. (1993). Vitamin E consumption and the risk of coronary disease in women. New England Journal of Medicine, 328, 1444–9,
Stary, H.C., Chandler, A.B., Glagov, S., et al. (1994). A definition of initial, fatty streak and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation, 89, 2462–78.
Stary, H.C., Chandler, A.B., Dinsmore, R.E., et al. (1995). A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arteriosclerosis, Thrombosis and Vascular Biology, 15, 1512–31.
Steenland, K., Thun, M., Lally, C., et al. (1996). Environmental tobacco smoke and coronary heart disease in the American Cancer Society CPS-II cohort. Circulation, 94, 622–8.
Stone, E.J., Pearson, T.A., Fortmann, S.P., and McKinlay, J.B. (1997). Community-based prevention trials: challenges and directions for public health practice, policy, and research. Annals of Epidemiology, S7, S113–S120.
Suarez, L. and Barrett-Connor, E. (1984). Interaction between cigarette smoking and diabetes mellitus in the prediction of death attributed to cardiovascular disease. American Journal of Epidemiology, 120, 670–5.
Sussman, S., Lichtman, K., Ritt, A., et al. (1999). Effects of thirty four adolescent tobacco use and prevention trials on regular users of tobacco products. Substance Use and Misuse, 34, 1469–1503.
Svendsen, K.H., Kuller, L.H., Martin, M.J., and Ockene, J.K. (1987). Effects of passive smoking in the Multiple Risk Intervention Trial. American Journal of Epidemiology, 126, 783–95.
Swedberg, K., Held, P., Kjekshus, J., Rasmussen, K., Ryden, L., and Wedel, H. (1992). Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandanian Enalapril Survival Study II (Consensus II). New England Journal of Medicine, 327, 678–84.
Trials of Hypertension Prevention Collaborative Research Group (1992). The effects of nonpharmacologic interventions on blood pressure of persons with high normal levels: results of the Trials of Hypertension Prevention, Phase I. Journal of the American Medical Association, 267, 1213–20.
Trials of Hypertension Prevention Collaborative Research Group (1997). Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure: the Trials of Hypertension Prevention, phase II. Archives of Internal Medicine, 157, 657–67.
Tunstall-Pedoe, H., Brown, C.A., Woodward, M., and Travendale, R. (1995). Passive smoking by self report and serum cotinine and the prevalence of respiratory and coronary heart disease in the Scottish Heart Health Study. Journal of Epidemiology and Community Health, 49, 139–43.
Tunstall-Pedoe, H., Morrison, C., Woodward, M., Fitzpatrick, B., and Watt, G. (1996). Sex differences in myocardial infarction and coronary deaths in the Scottish MONICA population of Glasgow 1985 to 1991: presentation, diagnosis, treatment, and 28-day case fatality of 3991 events in men and 1551 events in women. Circulation, 93, 1981–92.
Tunstall-Pedoe, H., Kuulasmaa, K., Mahonen, M., Tolonen, H., Ruokokoski, E., and Amouyel, P. (1999). Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations: monitoring trends and determinants in cardiovascular disease. Lancet, 353, 1547–57.
UGDP (University Group Diabetes Program) (1975). A study of the effects of hypoglycemic agents on vascular complications in patients with adult onset diabetes. V. Evaluation of phenoformin therapy. Diabetes, 24, 65–184.
UKPDS (United Kingdom Prospective Diabetes Study) Group (1995). UKPDS 13: relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. British Medical Journal, 310, 83–8.
USDHHS (United States Department of Health and Human Services) (1983). The health consequences of smoking: cardiovascular disease: a report of the Surgeon General. DHHS Publication No. PHS-84-50204. USDHHS, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health, Washington, DC.
USDHHS (United States Department of Health and Human Services) (1990). The health benefits of smoking cessation: a report of the Surgeon General. DHHS Publication No. CDC-90-8416. USDHHS, Centers for Disease Control, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Washington, DC.
USDHHS (United States Department of Health and Human Services) (1996). Data fact sheet. Congestive Heart failure in the United States: a new epidemic. USDHHS, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, Washington, DC.
USDHHS (United States Department of Health and Human Services) (1997). Changes in cigarette-related disease risks and their implication for prevention and control. NIH Publication No. 97-4213. Monograph 8. USDHHS, Public Health Services, National Institutes of Health, National Cancer Institute, Washington, DC.
USDHHS (United States Department of Health and Human Services) (1998a). Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report. USDHHS, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, Washington, DC.
USDHHS (United States Department of Health and Human Services) (1998b). Targeting tobacco use: the nation’s leading cause of death: at-a-glance. Centers for Disease Control and Prevention, Washington, DC.
Van de Lisdonk, E.H., Van den Bosch, W.J.H.M., Huygen, F.J.A., and Lagro-Jansen, A.L.M. (1990). Diseases in general practice (in Dutch). Bunge, Utrecht, the Netherlands.
Virchow, R. (1856). Phlogose and thrombose in gefassystem. In Gesammelte Abdhandlungen zur Wissenschaftlichen Medicin (ed. R. Virchow), p. 458. Meidinger Sohn, Berlin.
Wallace, R.B. and Anderson, R.A. (1987). Blood lipids, lipid-related measures, and the risk of atherosclerotic cardiovascular disease. Epidemiologic Reviews, 9, 95–119.
Wannamaker, L.W. (1973). The chain that links the heart to the throat. Circulation, 48, 9–18.
Wassertheil-Smoller, S., Oberman, A., Blaufox, M.D., Davis, B., and Langford, H. (1992). The Trial of Antihypertensive Interventions and Management (TAIM) Study. Final results with regard to blood pressure, cardiovascular risk, and quality of life. American Journal of Hypertension, 5, 37–44.
Watts, G.F., Lewis, B., Brunt, J.N., et al. (1992). Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas’ Atherosclerosis Regression Study (STARS). Lancet, 339, 563–9.
Webber, L.S., Cresanta, J.L., Croft, J.B., Srinivasan, S.R., Berenson, G.S. (1986). Transitions of cardiovascular risk from adolescence to young adulthood—the Bogalusa Heart Study: II. Alterations in anthropometric blood pressure and serum lipoprotein variables. Journal of Chronic Diseases, 39, 91–103.
West, K.M. (1978). Epidemiology of diabetes and its vascular lesions, pp. 375–402. Elsevier, New York.
WHO (World Health Organization) (1982). Prevention of coronary heart disease. Technical Report Series, No. 678. Report of the WHO Expert Committee. WHO, Geneva.
WHO (World Health Organization) (1984a). Cardiomyopathies.Technical Report Series No. 697. Report of a WHO Expert Committee. WHO, Geneva.
WHO (World Health Organization) (1984b). Intensified program: action to prevent rheumatic fever/rheumatic heart disease. WHO, Geneva.
WHO (World Health Organization) (1988). Rheumatic fever and rheumatic heart disease. Technical Report Series No. 764. WHO, Geneva.
WHO (World Health Organization) (1995). World health statistics annual. WHO, Geneva.
WHO (World Health Organization) (1996). World health statistics annual. WHO, Geneva.
Wigle, E.D. (1988). Hypertrophic cardiomyopathy 1988. Modern Concepts in Cardiovascular Disease, 57, 1–6.
Wilhelmsen, L., Sanne, H., Elmfeldt, D., Grimby, G., Tibblin, G., and Wedel H. (1975). A controlled trial of physical training after myocardial infarction. Effects on risk factors, nonfatal reinfarction, and death. Preventive Medicine, 4, 491–8.
Williams, R.R., Hasstedt, S.J., Wilson, D.E., et al. (1986). Evidence that men with familial hypercholesterolemia can avoid early coronary death: an analysis of 77 gene carriers in four Utah pedigrees. Journal of the American Medical Association, 255, 219–24.
Willich, S.N., Maclure, M., Mittleman, M., Arntz, H.R., and Muller, J.E. (1993). Sudden cardiac death. Support for a role of triggering in causation. Circulation, 87, 1442–50.
Winocour, P.D. (1992). Platelet abnormalities in diabetes mellitus. Diabetes, 41, 26–31.
Wissler, R.W. and Vesselinovitch, D. (1976). Studies of regression of advanced atherosclerosis in experimental animals and man. Annals of the New York Academy of Sciences, 275, 363–78.
Wood, D., De Backer, G., Faergeman, O., Graham, I., Mancia, G., and Pyörälä, K. (1998a). Prevention of coronary heart disease in clinical practice. European Heart Journal, 19, 1434–1503.
Wood, D., DeBacker, G., Faergeman, O., Graham, I., Mancia, G., and Pyörälä, K. (1998b). Prevention of coronary heart disease in clinical practice. Summary of recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Journal of Hypertension, 16, 1407–14.
Yusuf, S., Thom, T., and Abbott, R.D. (1989). Changes in hypertension treatment and in congestive heart failure mortality in the United States. Hypertension, 13, 174–9.
Zierler, S. (1985). Maternal drugs and congenital heart disease. Obstetrics and Gynecology, 65, 155–65.
Zimmerman, M. and McGeachie, J. (1987). The effect of nicotine on aortic endothelium: a quantitative ultrastructural study. Atherosclerosis, 63, 33–41.

2 comments on “9.1 Cardiovascular diseases

  1. Great post , Thank you for writing so well on such a difficult but important subject. It was really helpful to solve my confusion,

    General and Cosmetic Dentistry

  2. Great post,
    Keep on writing such stuffs.
    I will be keeping track of your next one.

    Medical Transcription Company

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: