William P. Castelli

Prognostic Implications of Echocardiographically Determined Left Ventricular Mass in the Framingham Heart Study

A pattern of left ventricular hypertrophy evident on the electrocardiogram is a harbinger of morbidity and mortality from cardiovascular disease. Echocardiography permits the noninvasive determination of left ventricular mass and the examination of its role as a precursor of morbidity and mortality. We examined the relation of left ventricular mass to the incidence of cardiovascular disease, mortality from cardiovascular disease, and mortality from all causes in 3220 subjects enrolled in the Framingham Heart Study who were 40 years of age or older and free of clinically apparent cardiovascular disease, in whom left ventricular mass was determined echocardiographically. During a four-year follow-up period, there were 208 incident cardiovascular events, 37 deaths from cardiovascular disease, and 124 deaths from all causes. Left ventricular mass, determined echocardiographically, was associated with all outcome events. This relation persisted after we adjusted for age, diastolic blood pressure, pulse pressure, treatment for hypertension, cigarette smoking, diabetes, obesity, the ratio of total cholesterol to high-density lipoprotein cholesterol, and electrocardiographic evidence of left ventricular hypertrophy. In men, the risk factor-adjusted relative risk of cardiovascular disease was 1.49 for each increment of 50 g per meter in left ventricular mass corrected for the subjects height (95 percent confidence interval, 1.20 to 1.85); in women, it was 1.57 (95 percent confidence interval, 1.20 to 2.04). Left ventricular mass (corrected for height) was also associated with the incidence of death from cardiovascular disease (relative risk, 1.73 [95 percent confidence interval, 1.19 to 2.52] in men and 2.12 [95 percent confidence interval, 1.28 to 3.49] in women). Left ventricular mass (corrected for height) was associated with death from all causes (relative risk, 1.49 [95 percent confidence interval, 1.14 to 1.94] in men and 2.01 [95 percent confidence interval, 1.44 to 2.81] in women). We conclude that the estimation of left ventricular mass by echocardiography offers prognostic information beyond that provided by the evaluation of traditional cardiovascular risk factors. An increase in left ventricular mass predicts a higher incidence of clinical events, including death, attributable to cardiovascular disease.

High density lipoprotein as a protective factor against coronary heart disease: The Framingham study

Lipid and lipoprotein values, including fasting triglycerides and high density lipoproteins (HDL), low density lipoproteins (LDL) and total cholesterol levels, were obtained on 2,815 men and women aged 49 to 82 years chiefly between 1969 and 1971 at Framingham. In the approximately four years following the characterization of lipids, coronary heart disease developed in 79 of the 1,025 men and 63 of the 1,445 women free of coronary heart diseases. At these older ages the major potent lipid risk factor was HDL cholesterol, which had an inverse association with the incidence of coronary heart disease (p less than 0.001) in either men or women. This lipid was associated with each major manifestation of coronary heart disease. These associations were equally significant even when other lipids and other standard risk factors for coronary heart disease were taken into consideration. A weaker association with the incidence of coronary heart disease (p less than 0.05) was observed for LDL cholesterol. Triglycerides were associated with the incidence of coronary heart disease only in women and then only when the level of other lipids was not taken into account. At these ages total cholesterol was not associated with the risk of coronary heart disease.

Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study.

The relationship between the degree of obesity and the incidence of cardiovascular disease (CVD) was reexamined in the 5209 men and women of the original Framingham cohort. Recent observations of disease occurrence over 26 years indicate that obesity, measured by Metropolitan Relative Weight, was a significant independent predictor of CVD, particularly among women. Multiple logistic regression analyses showed that Metropolitan Relative Weight, or percentage of desirable weight, on initial examination predicted 26-year incidence of coronary disease (both angina and coronary disease other than angina), coronary death and congestive heart failure in men independent of age, cholesterol, systolic blood pressure, cigarettes, left ventricular hypertrophy and glucose intolerance. Relative weight in women was also positively and independently associated with coronary disease, stroke, congestive failure, and coronary and CVD death. These data further show that weight gain after the young adult years conveyed an increased risk of CVD in both sexes that could not be attributed either to the initial weight or the levels of the risk factors that may have resulted from weight gain. Intervention in obesity, in addition to the well established risk factors, appears to be an advisable goal in the primary prevention of CVD.

High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.

The British Regional Heart Study (BRHS) reported in 1986 that much of the inverse relation of high-density lipoprotein cholesterol (HDLC) and incidence of coronary heart disease was eliminated by covariance adjustment. Using the proportional hazards model and adjusting for age, blood pressure, smoking, body mass index, and low-density lipoprotein cholesterol, we analyzed this relation separately in the Framingham Heart Study (FHS), Lipid Research Clinics Prevalence Mortality Follow-up Study (LRCF) and Coronary Primary Prevention Trial (CPPT), and Multiple Risk Factor Intervention Trial (MRFIT). In CPPT and MRFIT (both randomized trials in middle-age high-risk men), only the control groups were analyzed. A 1-mg/dl (0.026 mM) increment in HDLC was associated with a significant coronary heart disease risk decrement of 2% in men (FHS, CPPT, and MRFIT) and 3% in women (FHS). In LRCF, where only fatal outcomes were documented, a 1-mg/dl increment in HDLC was associated with significant 3.7% (men) and 4.7% (women) decrements in cardiovascular disease mortality rates. The 95% confidence intervals for these decrements in coronary heart and cardiovascular disease risk in the four studies overlapped considerably, and all contained the range 1.9-2.9%. HDLC levels were essentially unrelated to non-cardiovascular disease mortality. When differences in analytic methodology were eliminated, a consistent inverse relation of HDLC levels and coronary heart disease event rates was apparent in BRHS as well as in the four American studies.

The Natural History of Congestive Heart Failure: The Framingham Study

Abstract The natural history of congestive heart failure was studied over a 16-year period in 5192 persons initially free of the disease. Over this period, overt evidence of congestive heart failure developed in 142 persons. In almost every five-year age group, from 30 to 62 years, the incidence rate was greater for men than for women. Although the usual etiologic precursors were found, the dominant one was clearly hypertension, which preceded failure in 75 per cent of the cases. Coronary heart disease was noted at an earlier examination in 39 per cent, but in 29 per cent of the cases it was accompanied by hypertension. Precursive rheumatic heart disease, noted in 21 per cent of cases of congestive heart failure, was accompanied by hypertension in 11 per cent. Despite modern management, congestive heart failure proved to be extremely lethal. The probability of dying within five years from onset of congestive heart failure was 62 per cent for men and 42 per cent for women.

Serum Cholesterol, Lipoproteins, and the Risk of Coronary Heart Disease: The Framingham Study

Abstract Risk of coronary heart disease over 14 years was examined prospectively in 2,282 men and 2,845 women according to their antecedent cholesterol and lipoprotein status. An increased risk pro...

Role of diabetes in congestive heart failure: The Framingham study

Abstract The incidence of congestive heart failure was determined in relation to prior diabetic status in 5,209 men and women aged 30 to 62 years followed up for 18 years in the Framingham study. Men aged 45 to 74 years had more than twice the frequency of congestive failure as their nondiabetic cohorts, and diabetic women had a fivefold increased risk. This excessive risk appears to be caused by factors other than accelerated atherogenesis and coronary heart disease. Even when patients with prior coronary or rheumatic heart disease were excluded, the diabetic subjects had a four- to fivefold increased risk of congestive heart failure. In women (but not men) with prior coronary disease, diabetes also imposed a threefold increased risk of congestive failure. Furthermore, the increased risk of heart failure in the diabetic patients persisted after taking into account age, blood pressure, weight and cholesterol values as well as coronary heart disease. Women with diabetes appeared to be especially vulnerable and, irrespective of coronary disease status, had twice the frequency of congestive heart failure as men. The excessive risk of heart failure among diabetic subjects was confined to those treated with insulin. The data suggest that diabetes is another discrete cause of congestive heart failure and that some form of cardiomyopathy is associated with diabetes, as a result of either small vessel disease or metabolic disorders.

HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study.

The relation between coronary heart disease (CHD) prevalence and fasting lipid levels was assessed by a case-control study in five populations with a total of 6859 men and women of black, Japanese and white ancestry drawn from subjects aged 40 years and older from populations in Albany, Framingham, Evans County, Honolulu and San Francisco. In each major study group mean levels of high density lipoprotein (HDL) cholesterol were lower in persons with CHD than in those without the disease. The average difference was small - typically 3–4 mg/dl - but statistically significant. It was found in most agerace-sex specific groups. The inverse HDL cholesterol-CHD association was not appreciably diminished when adjusted for levels of low density lipoprotein (LDL) cholesterol and triglyceride. LDL, total cholesterol and triglycerides were directly related to CHD prevalence; surprisingly, these findings were less uniformly present in the various study groups than the inverse HDL cholesterol-CHD association.

Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham study.

Prospective data at Framingham and elsewhere have shown conclusively that risk of coronary heart disease in persons younger than age 50 is strikingly related to the serum total cholesterol level. Within so-called normal limits risk has been found to mount over a five-fold range. The impact has been found to be augmented by other risk factors. The contribution of the serum total cholesterol to risk has also been found to be determined by its partition in the various lipoprotein fractions. A relatively large amount of cholesterol in the low-density lipoprotein fraction is atherogenic, whereas that in the high-density fraction appears protective. The independent contribution of very-low density lipoprotein and its triglyceride or cholesterol content has, on the other hand, not been established. The previous position that virtually all of the lipid information pertaining to coronary heart disease resided in the serum total cholesterol must be accordingly modified.

Echocardiographic criteria for left ventricular hypertrophy: The Framingham heart study

Of 6,148 original cohort and offspring subjects of the Framingham Heart Study who underwent routine evaluation, a healthy group of 347 men (aged 42 +/- 12 years) and 517 women (aged 43 +/- 12 years) was identified to develop echocardiographic criteria for left ventricular (LV) hypertrophy. Healthy subjects were defined as normotensive, receiving no cardiac or antihypertensive medications, nonobese and free of cardiopulmonary disease. Echocardiographic criteria (in accordance with the American Society of Echocardiography convention) for LV hypertrophy, based on mean plus 2 standard deviations for LV mass, LV mass corrected for body surface area and LV mass corrected for height in this healthy sample are, respectively: 294 g, 150 g/m2 and 163 g/m in men and 198 g, 120 g/m2 and 121 g/m in women. Criteria based on LV mass/height result in higher prevalence rates of LV hypertrophy than LV mass/body surface area while still correcting for body size. The prevalence of LV hypertrophy in the entire study population (using LV mass/height criteria) is 16% in men and 19% in women. Until outcome guided criteria for LV hypertrophy are developed, application of sex-specific criteria based on a healthy population distribution of LV mass offer the best approach to echocardiographic diagnosis of LV hypertrophy.