The Framingham Heart Study: past, present and future (2024)

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The Framingham Heart Study (FHS) is widely recognized for its lasting contributions to cardiovascular epidemiology. In this article we review the study’s history, past accomplishments, current research agenda and future research directions.

Where we came from

With the rapidly rising prevalence of cardiovascular disease (CVD) in the early 20th century, public health and political leaders of the USA agreed that national investment in research must be undertaken towards CVD prevention. The National Heart Institute, which later became the National Heart, Lung and Blood Institute, was formed in 1948. Since CVD encompasses conditions with prolonged subclinical course, a prospectively-followed healthy cohort was deemed to be the perfect sample in which to study development of CVD. Thus, in 1948, the U.S. Public Health Service embarked upon the first large-scale cardiovascular epidemiology study in the country—the FHS. 1 Investigators sampled 2 of every three adults aged 30–59 years in the town of Framingham, Massachusetts, yielding a sample of 5209 men and women enrolled. Data collected included detailed medical and family history and physical examination, as well as X-ray, electrocardiogram and blood tests including cholesterol and glucose, to detect abnormalities thought to play a role in development of CVD.

The initial observations from FHS provided many of the central tenets of cardiovascular epidemiology that have held true over time. Published in 1957 and 1959, the first publications from 4- and 6-year follow-up reported such findings as greater incidence of coronary artery disease (CAD) associated with older age and male sex. 2^,3 The FHS was the first to describe a graded relationship of CVD with obesity, systolic blood pressure, cholesterol and cigarette smoking. Furthermore, the authors noted that these conditions may amplify synergistically, as cholesterol levels were greater in smokers as compared with non-smokers. 3 The initial findings from the FHS revolutionized primary prevention of CVD. In a seminal 1961 manuscript, Dr William Kannel, who subsequently led the FHS, described the key ‘factors of risk’ associated with atherosclerotic CVD, including age, sex, hypertension, elevated cholesterol, diabetes and electrocardiographic left ventricular hypertrophy. 4 This singular work popularized the ubiquitous term ‘risk factors’ used today and defined key variables determining CVD risk in adults. FHS investigators also introduced the notion of multivariable risk, combining several risk factors into a risk score to estimate the absolute risk of developing CAD, stroke and CVD. The Framingham Risk Score 5 has stood the test of time and remains a benchmark for evaluation of patients in a multitude of clinical settings. FHS also identified major risk factors for stroke, including the key role of atrial fibrillation. As the study evolved, measurements of high-density lipoprotein [HDL] cholesterol concentrations underscored the cardioprotective role of this lipid trait. The epidemiology of different forms of CVD, including peripheral arterial disease and heart failure, were also characterized by several landmark FHS reports. Overall, FHS identified the role of lifestyle in mediating CVD risk and origin of several risk factors.

Where we are

In the decades since the FHS was conceived as a single cohort studying now-accepted ‘traditional’ cardiovascular risk factors, it has evolved exponentially in breadth of both participants and measured phenotypes. In addition to the Original Cohort members, the FHS now includes the Offspring Cohort, comprising 5124 of the Original Cohort members’ descendants and their spouses, and the Third Generation Cohort which includes 4000 of the children of the Offspring Cohort. 6^,7 Thus, FHS represents a multigenerational cohort study with availability of multiple longitudinal observations (see below). Furthermore, to address concerns of predominant enrolment of individuals of Western European ancestry, the OMNI study was created in 1995 to include examinations on 506 ethnically and racially diverse community members, thereby capturing the changing demographic profile of the town over time. A second minority cohort was enrolled at the time of recruitment of the Third Generation Cohort. Each of these cohorts has been serially followed with in-person examinations every 3–4 years since enrolment, with virtually no loss to follow-up. 8^,9 At each examination, history and physical examination, including anthropometric, blood pressure, symptoms, risk factors and medication, data have been collected. A large biorepository of blood samples has been established with nearly 1.6 million biosamples (stored at -80°C). Measures include complete blood count, routine blood chemistry and lipid panels as well as urine biomarkers. The availability of serial longitudinal data facilitated ‘lifecourse epidemiology’ studies and statistical methods such as multilevel modelling. Repeated samples over time have allowed for studies describing temporal trends in risk factors and have facilitated investigations relating risk factor trajectories and cumulative exposure to the incidence of CVD. The concept of lifetime risk of developing CAD, stroke and CVD was established using FHS data. Additionally, state of the art non-invasive imaging tests including echocardiography, 10 cardiovascular magnetic resonance, 11 cardiovascular computed tomography, 12 applanation tonometry, 13 flow-mediated dilation 14 and carotid ultrasound 15 have characterized cardiovascular function and atherosclerotic burden in these cohorts over time.

Detailed and extensive longitudinal data characterized by the FHS have been collected in all cohorts and have expanded in recent decades to include not only CVD phenotypes, but those of multiple organ systems. Functional and imaging studies have pioneered understanding of the brain, lungs, kidneys, liver, fat tissue, bones and metabolic systems in health and disease. In addition, harnessing the power of the large community-based sample and sophisticated statistical modelling, data from the FHS have been used to analyse patterns in social networks and related behavioural changes impacting on obesity, 16 as well as air pollutants and brain health in the region. 17 With the expansive breadth of research, perhaps ‘the Framingham Heart Study’ may more appropriately be shortened to simply ‘the Framingham Study’.

Truly a transformative organization, the FHS has integrated clinical epidemiology with translational research. In addition to ‘macro-phenotypes’ described, the FHS has also been able to study ‘micro-phenotypes’ using novel serological testing, furthering our understanding of human pathophysiology. The FHS has been at the forefront of identification of novel biomarkers predictive of CVD, and has embarked upon extensive genetic and ‘omics’ data. The three-tiered family structure has been particularly advantageous for genotyping, where 40 million single nucleotide polymorphisms ‘SNPs’ have been measured or imputed by the 1000 Genomes project, facilitated by the availability of immortalized lymphoblastoid cell lines in over 9000 participants across the different generations. The FHS participates in numerous national and international genetic consortia, including the Cohorts for Heart and Aging Research in Genomic Epidemiology, which have been responsible for uncovering genetic variations associated with multiple CVD and non-CVD phenotypes. In addition, the human exome has been investigated using the Exome chip, Exome Sequence Project and whole-genome sequencing with high fidelity. 8 FHS ‘omics’ data collected include whole-blood DNA methylation, transcriptomics, microRNA, metabolomics and proteomics. Embodying collaboration and innovation in genetic studies, the FHS has led several pivotal investigations of the role of genetics in multiple aspects of CVD. 8^,18–20 A successful FHS training programme in cardiovascular epidemiology has contributed to the training of a large number of scientists. In summary, FHS currently is a very richly phenotyped and genotyped population health laboratory in which novel hypotheses can be tested. It brings together such a dense array of phenotypes such that it can be likened to a human phenome project.

In addition to the epidemiological foundations laid by FHS, the FHS legacy can be seen in the formation of additional epidemiological cohort studies in the wake of FHS successes. Such cohorts as Atherosclerosis Risk in Communities and the Cardiovascular Health Study in middle-aged and older adults, respectively, and the Multi-Ethnic Study of Atherosclerosis created in recent decades, were designed similarly to the FHS, including longitudinally followed examination cycles and standardized protocols in measures and to define outcomes of interest. These studies, which have included greater racial and ethnic diversity in their participants, likewise have been critical in defining epidemiological associations of subclinical CVD. Thus, the legacy of the FHS is far-reaching and the principles established decades ago have only expanded to greater depths.

Where we are headed

Epidemiological cohort studies including the FHS have led to dramatic advances in our understanding and reduction in the prevalence and incidence of CVD in the USA over the past several decades. Greater amounts of data collected on individuals, including digital data, e-health data (electronic health record and CMS data), m-health data (collected using mobile devices) and the notion of the ‘quantified self’ may result in greater scientific discoveries. Efforts are ongoing to better capture the diversity of the ‘exposome’, including that of the ‘built environment’. Critics remark upon the high cost: incremental knowledge ratio, lack of replication of findings and failure to pursue highest merit studies. 21 Yet one only needs to skim scientific journals and PubMed to discover the continued plethora of epidemiology research answering critical questions, shaping our understanding of disease. In the current and anticipated future era, the field is faced with unique challenges including the push for ‘big data’, fuelled by the ability of advanced technology to characterize phenotypes and genotypes with increasing granularity, coupled with the dichotomy of increasingly limited resources and funding in which to conduct the research.

Clearly, for epidemiology cohort studies to remain successful, adaptation must occur at multiple levels. It would be advantageous for the FHS and other epidemiological cohort studies to expand the studied phenotypes and outcomes of interest, apply novel technologies to population science, develop sophisticated algorithms to integrate different aspects of the data, analyse pooled individual participant data from different cohorts (the notion of a ‘data Commons’), all while optimizing use of scarce resources. At the level of each individual cohort study, centralization must replace fragmentation of data storage within each constituent cohort, and the infrastructure to hold such expanded datasets must be put in place. Such data centralization would facilitate cross-phenotype and interdisciplinary studies. In addition, to truly harness the power of the modern epidemiology, data access and data sharing should be fostered among diverse cohort studies for collaboration and replication. There is an increasing emphasis on cardiovascular epidemiological results being directly applicable to patient outcomes. Thus, results from cohort studies should be integrated with those of clinical trial data, for example by conducting trials in cohort samples. In addition, for the scientific community to advance, forums are essential in which all results, both positive and negative, may be presented and disseminated. Approaching this task ‘from the ground up’, it is important to share these ideals to bring about a cultural shift in our methods of studying the epidemiology of CVD. Paralleling these changes is the evolution of a multidisciplinary training programme in cardiovascular epidemiology that integrates clinical epidemiology with knowledge of statistical genetics and bioinformatics. Thus there is much more work to be done in the field of cardiovascular epidemiology, and if the FHS continues to evolve, scientific discoveries will follow to benefit researchers worldwide and to impact on public health.

The FHS has come a long way from the initial formation of a large cohort which identified elevated blood pressure, cholesterol and biobehavioural factors for conferring risk of CVD, to a multigenerational study of ∼15 000 participants who have contributed to hundreds of cutting-edge imaging, biomarker and ‘omic’ measures (systems biology approach) extending across nearly every human organ system. The rich array of expanded data collection, close longitudinal follow-up of participants and interdisciplinary and cross-cohort partnerships will ensure a wide spectrum of epidemiological discoveries and fruitful collaborations for generations to come.

Acknowledgements

The FHS is indebted to the dedication of its participants and staff for making the decades-long journey and groundbreaking discoveries in cardiovascular disease possible.

References

© The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association

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