The Framingham Study: ITS 50-year legacy and future promise.

The Framingham Study was initiated in 1948 to investigate an epidemic of coronary disease in the USA, using a prospective epidemiological approach. Insights were provided into the prevalence, incidence, full clinical spectrum and predisposing factors. The major "risk factors" (a term coined by the Framingham Study) for coronary disease, stroke, peripheral artery disease and heart failure were identified and clinical misconceptions dispelled about isolated systolic hypertension, left ventricular hypertrophy, dyslipidemia, atrial fibrillation and glucose intolerance. Average values for blood lipids, blood pressure, body weight, glucose and fibrinogen were shown to be dangerously suboptimal and to have a continuous graded relationship to cardiovascular disease without critical values. Dyslipidemia, glucose intolerance and elevated fibrinogen were shown to have smaller hazard ratios in the elderly, but this was offset by a higher absolute risk. Diabetes was shown to operate more strongly in women, eliminating their advantage over men. Serum total cholesterol was shown to derive its atherogenic potential from its LDL component and also to reflect cholesterol being removed in the HDL fraction. The total/HDL-cholesterol ratio was demonstrated to be the most efficient lipid profile for predicting coronary disease. LDL was shown to be correlated with hemostatic factors, suggesting that there would be additional benefits to lowering LDL. High triglyceride associated with reduced HDL, indicating insulin resistance and small dense LDL, was shown to be associated with excess coronary disease. All the risk factors tended to cluster, and this was shown to be promoted by insulin resistance induced by weight gain. Multivariate risk profiles were produced to facilitate risk stratification of candidates for coronary disease, stroke, peripheral artery disease and heart failure. The Framingham Study is now engaged in quantifying the independent contributions of homocysteine Lp(a), insulin resistance, small dense LDL, C reactive protein, clotting factors and genetic determinants of cardiovascular disease. We are now able to estimate the lifetime risk of all the atherosclerotic cardiovascular disease outcomes.