1. Framingham Heart Study
Dr. Samad Ghaffari
Professor of Cardiologist
Cardiovascular Research Center 
Tabriz University of Medical sciences

2. Origins of the Framingham Heart Study
By the 1940s, cardiovascular disease was the main cause of death for Americans, accounting for half of deaths.
Prevention and treatment were so poorly understood that most Americans accepted early death from heart disease as unavoidable.
Franklin D Roosevelt, the wartime President of the USA from 1933 to 1945, was in no way exempt from the epidemic, with heart failure due to undiagnosed and later untreated HTN

3. Origins of the Framingham Heart Study
In 1932, Roosevelt’s office chose an ENT specialist, Admiral Ross McIntyre, as his personal physician because headaches and sinus problems were predicted to be his main health concern.
Between 1935 and 1941, the President’s blood pressure gradually rose from 140/ 100 mm Hg to 188/ 105 mm Hg.
Despite his rising blood pressure, his personal physician insisted that the President was healthy, and that his blood pressure was “no more than normal for a man of his age”.

4. Origins of the Framingham Heart Study
Lord Charles Moran, Churchill’s personal physician, wrote in his diary “the President appears a very sick man. He has all the symptoms of hardening of the arteries” and “I give him only a few months to live.
As predicted, Roosevelt died a few weeks later on April 12, 1945, at the age of 63, from cerebral haemorrhage, with a blood pressure of 300/ 190 mm Hg.

6. Origins of the Framingham Heart Study
On June 16, 1948, President Harry Truman, signed into law the National Heart Act, in which the US Congress declared:
Nation’s health is seriously threatened by diseases of the heart and circulation, including high blood pressure…
The law allocated a US $500,000 seed grant for a 20 year epidemiological study of heart disease, and also established the National Heart Institute, which today is known as NHLBI.

7. Location of the study: Framingham, MA. Was selected because:
Enthusiastic response of physicians in the area
Framingham geographical proximity to the many cardiologists at Harvard Medical School
had already participated in the Framingham Tuberculosis Demonstration
Study two decades earlier.
a factory town producing rugs, paper products, and General Motors automobiles, with middle-class residents of predominantly European
origin, and was therefore thought to be representative of the USA in the
1940s

8. Location of the study
In 1947, a young officer and physician, Gilcin Meadors, to compile a proposal for the future epidemiological study
The study initially focused on ischaemic heart disease, However, Meadors set the tone for the next 65 years with a proposal:
“to study the expression of coronary artery disease in a ‘normal’ or unselected population and to determine the factors predisposing to the development of the disease through clinical and laboratory exam and long term follow-up.”
The initial budget request was $94350 to cover office supplies, and even included funds to buy ashtrays for the study staff members who smoked.

9. Location of the study:
Meadors as the first director to recruit 6000 of the 10,000 adults.
At the first step he and one of his nurses visited parent–teacher associations, churches, and civic groups and brought in local volunteers to act as telemarketers, who called nearly all the town’s phone numbers.
On Sept 29, 1948, the Framingham Heart Study examined its own staff members “for the purpose of testing schedules, procedures, equipment
On Oct 11, 1948, the study officially examined its first Framingham participant, exactly 12 months after Meadors’ arrival in Massachusetts.

10. In 1948, FHS investigators sent invitation letters based on a random sampling of two of every three families with members aged 30–59 years, living in the town of Framingham, Massachusetts.
Of 6507 contacts, 4494 (69%) men and women agreed to participate and an additional group of volunteers (n = 715) also joined, for a total of 5209 (n = 2336 men and 2873 women) constituting the Original Cohort.

11. 1948 and 1952

12. Design:
A careful, detailed physical examination performed independently by at least 2 physicians that included height and weight, waist circumference, examination of the heart and other organs, x-ray, 12- lead electrocardiogram, urinalysis, and a blood sample for measurement of hemoglobin, cholesterol, phospholipid, uric acid, glucose, and other tests.
((now additionally include study of cardiovascular imaging, serum and urine biomarkers, genetics/genomics, proteomics and metabolomics)
All within a 4-h window typically.

13. Hospital admissions
were recorded by daily visits of hospitals
Deaths were recorded by
scanning of newspapers, communications from personal physicians,
or coroner reports.

14. Data gathering:
participants who are unable to return for an on-site examination (e.g. elderly, home- or nursing home-bound), staff members travel to the participants
Additionally, in between cycle examinations, interim questionnaires detailing updates of medical and family history are mailed, and information is obtained via regular phone calls, thereby maintaining continuous surveillance of the participants.

15. • Subjects were re-evaluated every two years.
They were not treated; This was not a clinical trial
• Personal characteristics of those who developed CHD or stroke during F/U were compared to those who remained well

16. Early Findings:
The first major findings : reported in 1957, almost a decade after the first participant was examined.
Defining hypertension as blood pressure of 160/95 mm Hg or higher, the investigators noted a nearly four-times increase in incidence of CAD
A few years later, they noted that stroke was also a major consequence of high blood pressure.

17. Studies from this period helped to elucidate cardiovascular risk factors, such as hypertension, hyperlipidaemia, and diabetes mellitus.
Indeed, the term “risk factor” was popularised in the medical lexicon by Dawber and Kannel in their 1961 publication, Factors of Risk in the Development of Coronary Heart Disease

18. Framingham risk scores
The Framingham investigators proposed multivariable logistic models with seven risk factors:
age, total cholesterol, weight, ECG abnormalities, Hb, number of cigarettes smoked, and systolic BP.
Men in the top decile had a 30-times higher incidence of CAD than did men in the bottom decile, and women in the top decile had a 70-times higher incidence than did women in the bottom decile.

19. Framingham and epidemiology of heart failure
HTN as major cause of HF More common in general population than MI

21. Epidemiology of stroke and atrial fibrillation
By the 1960s, stroke was still the third-biggest cause of death for Americans
link between systolic blood pressure and stroke, Framingham investigators showed that the risk of stroke from hypertension was even greater than that conferred by CAD.
One of the most valuable clinical contributions from the Framingham study has been the finding that non-rheumatic atrial fibrillation is a potent risk factor for stroke (with a five-times excess risk of stroke), an observation that led them to call for “controlled trials of anticoagulation or antiarrhythmic
agents in persons with chronic atrial fibrillation.”

22. Budget problem in 1966
Donors included a large number of life insurance corporations that recognised the actuarial benefits of the study.
The list also included some surprising contributors, such as the Tobacco Research Institute and the Oscar Mayer Company, a meat manufacturer.
After White notified impending closure of the study, President Richard Nixon intervened and allowed the study to continue to fulfil its mission.

23. Second Phase:
With the renewal of funding, the study began to recruit the children of the original Framingham participants into a new Offspring cohort.
The purpose of this new cohort was to provide insights into familial clustering of disease.
Because the study also needed to include biologically unrelated individuals, spouses of offspring participants were invited into the study

24. Offspring cohort:
In 1971, the 2656 children of the 1644 husband-wife pairs in the Original Cohort, a group of children of Original Cohort members with coronary disease (n=899) and the spouses of these groups of children (n=1212 and
368, respectively), were enrolled in the Offspring Cohort (total n=5124).

25. Third Generation Cohort
The Third Generation Cohort was then begun in 2002, with the objective of expanding the phenotypic and genotypic spectrum for the study of CVD.
Focus on genetic and environmental risk factors for cardiovascular disease.
For this cohort, adults who were at least 20 years of age with at least one parent in the Offspring Cohort were invited to participate
Of 6553 eligible individuals, 4095 participants were enrolled.
To add to familial data, 103 parents of Third Generation participants who were not previously enrolled in the Offspring Cohort were enrolled as the New Offspring Spouses Cohort.

26. Third generation cohort:
Additional goals for recruitment of a young Third Generation cohort were to study subclinical CVD earlier in adulthood using novel cardiovascular imaging and to evaluate temporal trends in CVD and its risk factors.
The three-generational FHS structure is unique among CVD epidemiology studies and has provided greater statistical power in genome wide association studies.

27. New Cohorts Omni 1 & 2
disadvantages of a cohort that was predominantly white and of European descent.
The Omni 1 cohort was recruited in 1994, and included 506 ethnic minority
residents of Framingham.
A decade later, an additional 410 ethnic minority participants were recruited through the Omni 2 cohort.

28. In 2006, the National Institutes of Health supports genome-wide genotyping across all the Framingham cohorts.
led to the identification of hundreds of common genetic variants that affect the risk of cardiovascular disease.

35. Genetic studies:
Additionally, the FHS has led efforts to identify variants in single-nucleotide polymorphisms (SNPs) associated with CVD. The FHS is part of the SNP Health Association Resource (SHARe) and Candidate Gene Association Resource (CARe)90 projects, through which 9300 participants underwent genotyping of:
Imputation to 40 million SNPs was achieved using the 1000 Genomes project.
FHS efforts have enabled the identification of SNPs for traits including blood pressure, lipids, obesity, arterial stiffness and imaging measures of cardiovascular function including ventricular mass and dimensions, endothelial function, valvular calcification and carotid atherosclerosis

36. Furthermore, whole-genome sequencing is underway via the NHLBI TOPMed project, highlighting the importance of regulatory and non-protein coding regions, in addition to the protein coding regions that have been common targets for investigation.

37. Strengths The strength of the FHS lies in the :
Dedicated participants,
its highly trained staff
and its diverse body of scientific investigators over the years.
The commitment of the participants despite the fact that many participants live remotely.
The FHS is also the only longitudinally followed cohort evaluating CVD risk across three generations of participants
extensive serial measurements
standardized definitions to adjudicate CVD outcomes, including coronary heart disease and congestive heart failure, and these definitions have been applied consistently to the studies over the several-decades
a great emphasis on quality control issues including reproducibility

38. Legacy:
Dr. William Kannel’s 1961 publication, “Factors of Risk in the Development of Coronary Heart Disease,” first highlighted the term risk factors, and it described how specific levels of cholesterol, blood pressure, as well as
how electrocardiographic LVH predicted future
CHD incidence.

51. 20 years impact of FHD

53. Eur Heart J. 2009 Apr;30(7):850-6. doi: 10. 1093/eurheartj/ehn573
Eur Heart J Apr;30(7): doi: /eurheartj/ehn573. Epub 2009 Jan 9.
Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart Study.
Mahabadi AA1, Massaro JM, Rosito GA, Levy D, Murabito JM, Wolf PA, O'Donnell CJ, Fox CS, Hoffmann U.
Author information
Abstract
AIMS:
The aim of this study was to assess whether pericardial fat, intrathoracic fat, and visceral abdominal adipose tissue (VAT) are associated with the prevalence of cardiovascular disease (CVD).
METHODS AND RESULTS:
Participants from the Framingham Heart Study Offspring cohort underwent abdominal and chest multidetector computed tomography to quantify volumes of pericardial fat, intrathoracic fat, and VAT. Relations between each fat depot and CVD were assessed using logistic regression. The analysis of participants (mean age 60 years, 53.8% women, 9.7% with prevalent CVD) demonstrated that pericardial fat [odds ratio (OR) 1.32, 95% confidence interval (CI) ; P = 0.002] and VAT (OR 1.35, 95% CI ; P = 0.003), but not intrathoracic fat (OR 1.14, 95% CI ; P = 0.22), were significantly associated with prevalent CVD in age-sex-adjusted models and after adjustment for body mass index and waist circumference. After multivariable adjustment, associations were attenuated (P > 0.14). Only pericardial fat was associated with prevalent myocardial infarction after adjusting for conventional measures of adiposity (OR 1.37, 95% CI ; P = 0.03).
CONCLUSION:
Pericardial fat and VAT, but not intrathoracic fat, are associated with CVD independent of traditional measures of obesity but not after further adjustment for traditional risk factor. Taken together with our prior work, these findings may support the hypothesis that pericardial fat contributes to coronary atherosclerosis