FRAMINGHAM HEART FRAMINGHAM HEART STUDYSTUDY

A history of medical science from CV risk factors to genetics

Presenter Disclosure Presenter Disclosure InformationsInformations

• Name of the speaker:Name of the speaker:

Alexandru Andritoiu

• Potential conflicts of interest to report:Potential conflicts of interest to report:

Speaker for:

Pfizer, Astra-Zeneca, Servier, Abbot, Sanofi-Aventis, KRKA, Ozone, Shering-Plough,

Novartis,Zentiva,Antibiotice Iasi, Terapia-Rambaxy

HistoryHistory

• Cardiovascular disease (CVD) is the leading cause of death and serious illness in the United States.

• In 19481948, the Framingham Heart Study - under the direction of the National Heart National Heart Institute (now known as the National Institute (now known as the National Heart, Lung, and Blood Institute or NHLBIHeart, Lung, and Blood Institute or NHLBI) - embarked on an ambitious project in health research.

BackgroundBackground

• The study, nearly six decades later and now known as the “Framingham Heart Study” (FHS), is the longest running, multigenerational longitudinal study in medical history (Butler, 1999).

• It has helped identify several “risk factors” and their cumulative influence on the manifestation of CVD.

• The term ‘risk factorrisk factor’ was coined by Framingham investigators (Kannel et al 1961)

PARTICIPATING INSTITUTIONS

• Framingham Heart Study

• Boston University School of Medicine

• National Heart, Lung, and Blood Institute

• Boston University College of Arts & Sciences

• Framingham Heart Study Genetics Lab

• Boston University School of Public Health

• National Center for Biotechnology Information

Dr. Thomas Royle (Roy) DawberDr. Thomas Royle (Roy) Dawber

Ann N Y Acad SciAnn N Y Acad Sci 1963, 107 1963, 107::539-556539-556

Dawber TR, Meadors GF, Moore FEJ: Epidemiological approaches to heart disease: the Framingham Study. Am J Public Health 1951, 41:279-286. 

Dawber TR, Kannel WB, Revotskie N, Stokes JI, Kagan A, Gordon T: Some factors associated with the development of coronary heart disease; six years' follow-up experience in the Framingham Study. Am J Public Health 1959, 49:1349-1356. 

The objective of the Framingham The objective of the Framingham Heart StudyHeart Study

to identify the common factors or characteristics that contribute to CVD by following its development over a long period of time in a large group of participants who had not yet developed overt symptoms of CVD or suffered a heart attack or stroke.

MethodsMethods

The researchers recruited 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts

The CohortsThe Cohorts

• Since 1948,1948, the subjects have continued to return to the study every two years for a detailed medical history, physical examination, and laboratory tests, and in 1971, the Study enrolled a second generation - 5,124 of the original participants' adult children and their spouses - to participate in similar examinations.

• In 19941994, the need to establish a new study reflecting a more diverse community of Framingham was recognized, and the first Omni cohort of the Framingham Heart Study was enrolled.

• In April 2002April 2002 the Study entered a new phase, the enrollment of a third generation of participants, the grandchildren of the Original Cohort.

• In 20032003, a second group of Omni participants was enrolled.

The concept of CVD risk factorsThe concept of CVD risk factors

has become an integral part of the modern medical curriculum and has led to the development of effective treatment and preventive strategies in clinical practice.

Identifying major CVD risk factorsIdentifying major CVD risk factors

• high blood pressure, • high blood cholesterol, • smoking, • obesity, • diabetes, • and physical inactivity • valuable information on the effects of related

factors such as blood triglyceride and HDL cholesterol levels, age, gender, and psychosocial issues.

RESEARCH MILESTONES (1)• 1960 Cigarette smoking found to increase the risk of

heart disease• 1961 Cholesterol level, blood pressure, and

electrocardiogram abnormalities found to increase the risk of heart disease

• 1967 Physical activity found to reduce the risk of heart disease and obesity to increase the risk of heart disease

• 1970 High blood pressure found to increase the risk of stroke

• 1970 Atrial fibrillation increases stroke risk 5-fold• 1976 Menopause found to increase the risk of heart

disease• 1978 Psychosocial factors found to affect heart disease

RESEARCH MILESTONES (2)

• 1988 High levels of HDL cholesterol found to reduce risk of death

• 1994 Enlarged left ventricle (one of two lower chambers of the heart) shown to increase the risk of stroke

• 1996 Progression from hypertension to heart failure described

• 1998 Framingham Heart Study researchers identify that atrial fibrillation is associated with an increased risk of all-cause mortality.

• 1998 Development of simple coronary disease prediction algorithm involving risk factor categories to allow physicians to predict multivariate coronary heart disease risk in patients without overt CHD factor categories to allow physicians to predict multivariate coronary heart disease risk in patients without overt CHD

RESEARCH MILESTONES (3)• 1999 Lifetime risk at age 40 years of developing coronary heart

disease is one in two for men and one in three for women• 2001 High-normal blood pressure is associated with an increased

risk of cardiovascular disease, emphasizing the need to determine whether lowering high-normal blood pressure can reduce the risk of cardiovascular disease.

• 2002 Lifetime risk of developing high blood pressure in middle-aged adults is 9 in 10.

• 2002 Obesity is a risk factor for heart failure.• 2004 Serum aldosterone levels predict future risk of hypertension in

non-hypertensive individuals.• 2005 Lifetime risk of becoming overweight exceeds 70 percent, that

for obesity approximates 1 in 2.• 2006 The National Heart, Lung and Blood Institute (NHLBI) of the

National Institutes of Health announces a new genome-wide association study at the Framingham Heart Study in collaboration with Boston University School of Medicine to be known as the SHARe project (SNP Health Association Resource).

RESEARCH MILESTONES (4)

• 2007 Based on evaluation of a densely interconnected social network of 12,067 people assessed as part of the Framingham Heart Study, network phenomena appear to be relevant to the biologic and behavioral trait of obesity, and obesity appears to spread through social ties.

• 2008 Based on analysis of a social network of 12,067 people participating in the Framingham Heart Study (FHS), researchers discover that social networks exert key influences on decision to quit smoking.

• 2008 Discovery by Framingham Heart Study and publication of four risk factors that raise probability of developing precursor of heart failure; new 30-year risk estimates developed for serious cardiac events.

RESEARCH MILESTONES (5)

• 2009 Framingham Heart Study cited by the American Heart Association among the top 10 cardiovascular research achievements of 2009, "Genome-wide Association Study of Blood Pressure and Hypertension: Genome-wide association study identifies eight loci associated with blood pressure".

• 2009 A new genetic variant associated with increased susceptibility for atrial fibrillation, a prominent risk factor for stroke and heart failure, is reported in two studies based on data from the Framingham Heart Study.

• 2009 Framingham Heart Study researchers find parental dementia may lead to poor memory in middle-aged adults.

• 2009 Framingham Heart Study researchers find high leptin levels may protect against Alzheimer's disease and dementia

RESEARCH MILESTONES (6)

• 2010 Sleep apnea tied to increased risk of stroke

• 2010 Framingham Heart Study researchers identify additional genes that may play a role in Alzheimer's disease

• 2010 Framingham Heart Study finds fat around the abdomen associated with smaller, older brains in middle-aged adults

• 2010 Framingham Heart Study finds genes link puberty timing and body fat in women

RESEARCH MILESTONES (7)

• 2010 Having first-degree relative with atrial fibrillation associated with increased risk for this disorder

• 2009-2010 Framingham Heart Study researchers contribute to discovering hundreds of new genes underlying major heart disease risk factors—body mass index, blood cholesterol, cigarette smoking, blood pressure and glucose/diabetes

• 2010 First definitive evidence that occurrence of stroke by age 65 years in a parent increased risk of stroke in offspring by 3-fold

RISK SCORE PROFILE

• Atrial Fibrillation (AF) (10-year risk)

• Cardiovascular Disease (30-year risk)

• Congestive Heart Failure

• Coronary Heart Disease (10-year risk)

• Coronary Heart Disease (2-year risk)

• Diabetes Risk Score

• General Cardiovascular Disease

• Hard Coronary Heart Disease and calculator (10-year risk)

• Hypertension Risk Score

• Intermittent Claudication

• Recurring Coronary Heart Disease

• Stroke

• Stroke after Atrial Fibrillation

• Stroke or Death after Atrial Fibrillation

The Framingham Heart Study, The Framingham Heart Study, on its way to becoming the gold on its way to becoming the gold

standard for Cardiovascular standard for Cardiovascular Genetic Epidemiology?Genetic Epidemiology?

Cashell E Jaquish - BMC Medical Genetics 2007; 8:63 

The participants in the Framingham Study The participants in the Framingham Study are readily divided into three groupsare readily divided into three groups

• Gen 1 (5209 p):Gen 1 (5209 p): those recruited in 1948 as part of the Original Cohort

• Gen 2Gen 2 (5124 p):(5124 p): those recruited in 1971 as part of the Offspring Cohort

• Gen 3 (4095 p):Gen 3 (4095 p): those recruited in 2002 as part of the third Generation Cohort.

• The Family Structure FileFamily Structure File contains information for biologically related Framingham participants.

• A total of 1538 families1538 families are present 

• Framingham SHAR(SNP Health Association Resource) includes data on more than 9300 participants spanning three generations, including more than 900 families, who had their DNA tested for 550 000 genetic variations (single nucleotide polymorphisms [SNPs]).

• "As one of the most comprehensive studies ever undertaken, the Framingham Heart Study will play a vital role in laying the foundation for this vast data set to help researchers link genes and disease.“

• Analyzing individual-level data with computer programs, researchers will be able to search for new connections between genetic variations and phenotypes such as high cholesterol.

Dr Elizabeth Nabel - Director of the National Heart, Lung, and Blood Institute 

Dr Christopher O'Donnell, associate director of the Framingham Heart Study and scientific director of Framingham SHARe

• "This important study will take genetic research in the Framingham study to the next level - accelerating discoveries on the causes, prevention, and treatment of major chronic diseases"

• "Using the latest technology, researchers will be able to obtain more information about the connection between unique genetic variations in DNA and cardiovascular disease risk factors as well as the genetic basis for heart attack, stroke, and other chronic diseases."

Nabel EG, 2006

• The genome-wide association studies at Framingham represent unparalleled opportunities as well as challenges.

• The challenges include bioinformatics, logistical, and ethical concerns.

• However, the extensive genotypic and phenotypic characterizations of Framingham participants represent unique steps in the goal of achieving medical care that is predictive, preemptive and personalized

Nabel EG, 2006

• "This is certainly going to be a valuable resource for the cardiovascular genomics community.

• Having a large, exceptionally well-characterized cohort followed for decades with genomewide SNP/variant coverage is far better than waiting for years for prospective studies to accrue.

• It's terrific that the NHLBI made this possible."

Dr Eric Topol (Scripps Translational Science Institute, San Diego, CA

Cardiovascular risk between parents and offspring in relation to quintiles of major risk factors: systolic blood pressure, body mass index, total to high density lipoprotein-cholesterol, diabetes and smoking.

Lloyd-Jones et al. 2004

Association of known polymorphisms in Association of known polymorphisms in candidate genes with cardiovascular risk factorscandidate genes with cardiovascular risk factors

• the association between two polymorphisms in the estrogen receptor-β gene with left ventricular mass and wall thickness in women with hypertension (Peter et al., 2005);

• L162 polymorphisms of the peroxisome proliferator-activated receptor alpha (PPARA) and plasma lipids (Tai et al., 2002);

• ATP-binding cassette transporter -1 (ABCA1; polymorphisms with HDL concentrations (Brousseau et al., 2001)

In 2015…In 2015…

,,In conclusion, GWAS have reported on many SNP associationsIn conclusion, GWAS have reported on many SNP associationswith various traits and diseases. Although these numbers are quitewith various traits and diseases. Although these numbers are quiteimpressive, we still have to carry out a lot of additional research toimpressive, we still have to carry out a lot of additional research tofind the mechanisms underlying diseases and to build a bridge to afind the mechanisms underlying diseases and to build a bridge to aclinical setting,,clinical setting,,

Medical possibilities are unlimited; possibilities are limited only for patients