What are the major risk factors for cardiovascular disease found by the Framingham study?

Major Findings of the Framingham Heart Study

The Framingham Heart Study identified that age, blood pressure, cholesterol levels, smoking status, and diabetes are the major risk factors for cardiovascular disease, and demonstrated that these factors interact multiplicatively rather than additively to increase cardiovascular risk. 1

Core Risk Factors Identified

The Framingham study, established in 1948, was pioneering in establishing the classical risk factor concept for coronary heart disease through decades of longitudinal observation 2, 3, 4:

• Age and sex emerged as non-modifiable risk markers, with age being the single strongest predictor in the Framingham risk score 1
• Systolic blood pressure (both treated and untreated) was identified as a major modifiable risk factor, with each 20-mm Hg elevation roughly doubling the risk of dying from ischemic heart disease or stroke 1
• Total cholesterol and HDL cholesterol levels were established as independent predictors, with the study demonstrating graded severity of risk based on lipid levels 1, 2
• Smoking behavior was confirmed as a direct cause of cardiovascular disease through pathological correlation studies 2, 3, 5
• Diabetes mellitus was recognized as a major risk factor that approximately doubles cardiovascular risk 2, 3, 5
• Left ventricular hypertrophy detected on electrocardiogram was identified as an independent predictor of coronary heart disease 3, 4

Development of Risk Prediction Algorithms

The Framingham investigators developed multivariate risk functions (Framingham Risk Scores) that combine these risk factors to estimate 10-year or 30-year cardiovascular disease risk 2, 4:

• The algorithm provides quantitative absolute risk over a decade by incorporating interactions for age and sex, and graded severity of risk factors 1
• Risk assessment tools were made readily available, including online calculators that use categorical variables for age, blood pressure, cholesterol, smoking status, and diabetes 1
• The scoring system became the basis for treatment guidelines, including the National Cholesterol Education Program's Adult Treatment Panel III guidelines for managing dyslipidemias 1

Multiplicative Nature of Risk Factors

A critical finding was that cardiovascular risk factors operate independently but interact in a multiplicative rather than additive fashion 1:

• The presence of multiple risk factors exponentially increases atherosclerosis risk more than any single severe risk factor alone 6
• Risk factor interactions were quantified, demonstrating for example that smoking carries much higher risk in persons with elevated cholesterol 5
• This multiplicative effect led to the concept that treatment thresholds and goals should be lowered in patients with multiple risk factors 1

Clinical Impact and Validation

The Framingham findings were subsequently validated through randomized controlled trials demonstrating that treating modifiable risk factors reduces cardiovascular disease occurrence 2, 5:

• Meta-analyses of trials showed that 1% reduction in serum cholesterol produces 2-3% decline in coronary heart disease risk 5
• Blood pressure reduction of 1 mmHg in diastolic pressure produces 2-3% decline in coronary heart disease risk 5
• Smoking cessation results in 50-70% lower risk within 1-5 years compared to current smokers 5

Limitations Recognized

The Framingham algorithm has acknowledged limitations that clinicians should understand 1:

• Limited applicability to certain minority populations due to the predominantly white middle-aged cohort 1
• Absence of more recently appreciated risk factors such as obesity (BMI or waist circumference), family history, high-sensitivity C-reactive protein, physical activity, and alcohol consumption 1
• The original scoring system was developed for coronary endpoints rather than cerebrovascular disease, though a separate stroke risk profile was subsequently developed using Framingham models 1
• Difficulty accounting for variability of risk factor levels across visits and purely historical risk factors 1

Evolution of the Study

The Framingham Heart Study has evolved to include three generations of participants (approximately 15,000 individuals) with deep phenotyping including subclinical disease assessment, physiological profiling, and 'omics' profiling (whole-genome sequencing, proteomics, metabolomics) 4.