Keynote Address: The Future of Cardiovascular Epidemiology: Current Trends?

This is the Research Retreat\u27s Keynote presentation by Vasan S. Ramachandran, MD, who is Principal Investigator and Co-Director, Echocardiography/Vascular Laboratory, Framingham Heart Study. Dr. Ramachandran is also Chief, Section of Preventive Medicine and Epidemiology and Professor of Medicine, Boston University School of Medicine. Dr. Ramachandran discusses the future of cardiovascular epidemiology, including the roles of: cHealth (community), sHealth (social), mHealth (mobile), eHealth (electronic), and gHealth (genomic)

Scientific Contributions of Population-Based Studies to Cardiovascular Epidemiology in the GWAS Era

Longitudinal, well phenotyped, population-based cohort studies offer unique research opportunities in the context of genome-wide association studies (GWAS), including GWAS for new-onset (incident) cardiovascular disease (CVD) events, the assessment of gene x lifestyle interactions, and evaluating the incremental predictive utility of genetic information in apparently healthy individuals. Furthermore, comprehensively phenotyped community-dwelling samples have contributed to GWAS of numerous traits that reflect normal organ function (e.g., cardiac structure and systolic and diastolic function) and for many traits along the CVD continuum (e.g., risk factors, circulating biomarkers, and subclinical disease traits). These GWAS have heretofore identified many genetic loci implicated in normal organ function and different stages of the CVD continuum. Finally, population-based cohort studies have made important contributions to Mendelian Randomization analyses, a statistical approach that uses genetic information to assess observed associations between cardiovascular traits and clinical CVD outcomes for potential causality

Erythrocyte n-6 Fatty Acids and Risk for Cardiovascular Outcomes and Total Mortality in the Framingham Heart Study

Background: The prognostic value of erythrocyte levels of n-6 fatty acids (FAs) for total mortality and cardiovascular disease (CVD) outcomes remains an open question. Methods: We examined cardiovascular (CV) outcomes and death in 2500 individuals in the Framingham Heart Study Offspring cohort without prevalent CVD (mean age 66 years, 57% women) as a function of baseline levels of different length n-6 FAs (18 carbon, 20 carbon, and 22 carbon) in the erythrocyte membranes. Clinical outcomes were monitored for up to 9.5 years (median follow up, 7.26 years). Cox proportional hazards models were adjusted for a variety of demographic characteristics, clinical status, and red blood cell (RBC) n-6 and long chain n-3 FA content. Results: There were 245 CV events, 119 coronary heart disease (CHD) events, 105 ischemic strokes, 58 CVD deaths, and 350 deaths from all causes. Few associations between either mortality or CVD outcomes were observed for n-6 FAs, with those that were observed becoming non-significant after adjusting for n-3 FA levels. Conclusions: Higher circulating levels of marine n-3 FA levels are associated with reduced risk for incident CVD and ischemic stroke and for death from CHD and all-causes; however, in the same sample little evidence exists for association with n-6 FAs. Further work is needed to identify a full profile of FAs associated with cardiovascular risk and mortality

Genome-Wide Association to Body Mass Index and Waist Circumference: The Framingham Heart Study 100K Project

BACKGROUND: Obesity is related to multiple cardiovascular disease (CVD) risk factors as well as CVD and has a strong familial component. We tested for association between SNPs on the Affymetrix 100K SNP GeneChip and measures of adiposity in the Framingham Heart Study. METHODS: A total of 1341 Framingham Heart Study participants in 310 families genotyped with the Affymetrix 100K SNP GeneChip had adiposity traits measured over 30 years of follow up. Body mass index (BMI), waist circumference (WC), weight change, height, and radiographic measures of adiposity (subcutaneous adipose tissue, visceral adipose tissue, waist circumference, sagittal height) were measured at multiple examination cycles. Multivariable-adjusted residuals, adjusting for age, age-squared, sex, smoking, and menopausal status, were evaluated in association with the genotype data using additive Generalized Estimating Equations (GEE) and Family Based Association Test (FBAT) models. We prioritized mean BMI over offspring examinations (1–7) and cohort examinations (10, 16, 18, 20, 22, 24, 26) and mean WC over offspring examinations (4–7) for presentation. We evaluated associations with 70,987 SNPs on autosomes with minor allele frequencies of at least 0.10, Hardy-Weinberg equilibrium p ≥ 0.001, and call rates of at least 80%. RESULTS: The top SNPs to be associated with mean BMI and mean WC by GEE were rs110683 (p-value 1.22*10-7) and rs4471028 (p-values 1.96*10-7). Please see for the complete set of results. We were able to validate SNPs in known genes that have been related to BMI or other adiposity traits, including the ESR1 Xba1 SNP, PPARG, and ADIPOQ. CONCLUSION: Adiposity traits are associated with SNPs on the Affymetrix 100K SNP GeneChip. Replication of these initial findings is necessary. These data will serve as a resource for replication as more genes become identified with BMI and WC.National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195); Atwood (R01 DK066241); National Institutes of Health National Center for Research Resources Shared Instrumentation grant (1S10RR163736-01A1

Joint modeling with time-dependent treatment and heteroskedasticity: Bayesian analysis with application to the Framingham Heart Study

Medical studies for chronic disease are often interested in the relation between longitudinal risk factor profiles and individuals' later life disease outcomes. These profiles may typically be subject to intermediate structural changes due to treatment or environmental influences. Analysis of such studies may be handled by the joint model framework. However, current joint modeling does not consider structural changes in the residual variability of the risk profile nor consider the influence of subject-specific residual variability on the time-to-event outcome. In the present paper, we extend the joint model framework to address these two heterogeneous intra-individual variabilities. A Bayesian approach is used to estimate the unknown parameters and simulation studies are conducted to investigate the performance of the method. The proposed joint model is applied to the Framingham Heart Study to investigate the influence of anti-hypertensive medication on the systolic blood pressure variability together with its effect on the risk of developing cardiovascular disease. We show that anti-hypertensive medication is associated with elevated systolic blood pressure variability and increased variability elevates risk of developing cardiovascular disease.Comment: 34 pages, 4 figure

Erythrocyte Long-Chain Omega-3 Fatty Acid Levels are Inversely Associated with Mortality and with Incident Cardiovascular Disease: The Framingham Heart Study

Background: The extent to which omega-3 fatty acid status is related to risk for death from any cause and for incident cardiovascular disease (CVD) remains controversial. Objective: To examine these associations in the Framingham Heart Study. Design: Prospective and observational. Setting: Framingham Heart Study Offspring cohort. Measurements: The exposure marker was red blood cell levels of eicosapentaenoic and docosahexaenoic acids (the Omega-3 Index) measured at baseline. Outcomes included mortality (total, CVD, cancer, and other) and total CVD events in participants free of CVD at baseline. Follow-up was for a median of 7.3 years. Cox proportional hazards models were adjusted for 18 variables (demographic, clinical status, therapeutic, and CVD risk factors). Results: Among the 2500 participants (mean age 66 years, 54% women), there were 350 deaths (58 from CVD, 146 from cancer, 128 from other known causes, and 18 from unknown causes). There were 245 CVD events. In multivariable-adjusted analyses, a higher Omega-3 Index was associated with significantly lower risks (P-values for trends across quintiles) for total mortality (P = .02), for non-CVD and non-cancer mortality (P = .009), and for total CVD events (P = .008). Those in the highest (\u3e6.8%) compared to those in the lowest Omega-3 Index quintiles (\u3c4.2%) had a 34% lower risk for death from any cause and 39% lower risk for incident CVD. These associations were generally stronger for docosahexaenoic acid than for eicosapentaenoic acid. When total cholesterol was compared with the Omega-3 Index in the same models, the latter was significantly related with these outcomes, but the former was not. Limitations: Relatively short follow-up time and one-time exposure assessment. Conclusions: A higher Omega-3 Index was associated with reduced risk of both CVD and all-cause mortality

Association of metabolic dysregulation with volumetric brain magnetic resonance imaging and cognitive markers of subclinical brain aging in middle-aged adults: the Framingham Offspring Study.

ObjectiveDiabetic and prediabtic states, including insulin resistance, fasting hyperglycemia, and hyperinsulinemia, are associated with metabolic dysregulation. These components have been individually linked to increased risks of cognitive decline and Alzheimer's disease. We aimed to comprehensively relate all of the components of metabolic dysregulation to cognitive function and brain magnetic resonance imaging (MRI) in middle-aged adults.Research design and methodsFramingham Offspring participants who underwent volumetric MRI and detailed cognitive testing and were free of clinical stroke and dementia during examination 7 (1998-2001) constituted our study sample (n = 2,439; 1,311 women; age 61 ± 9 years). We related diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin, and glycohemoglobin levels to cross-sectional MRI measures of total cerebral brain volume (TCBV) and hippocampal volume and to verbal and visuospatial memory and executive function. We serially adjusted for age, sex, and education alone (model A), additionally for other vascular risk factors (model B), and finally, with the inclusion of apolipoprotein E-ε4, plasma homocysteine, C-reactive protein, and interleukin-6 (model C).ResultsWe observed an inverse association between all indices of metabolic dysfunction and TCBV in all models (P < 0.030). The observed difference in TCBV between participants with and without diabetes was equivalent to approximately 6 years of chronologic aging. Diabetes and elevated glycohemoglobin, HOMA-IR, and fasting insulin were related to poorer executive function scores (P < 0.038), whereas only HOMA-IR and fasting insulin were inversely related to visuospatial memory (P < 0.007).ConclusionsMetabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort

Risk of 90 - day readmission in patients after firearm injury hospitalization: a nationally representative retrospective cohort study

Background: National conversation has justifiably been concerned with firearm-related deaths and much less attention has been paid to the consequences of surviving a firearm injury. We assessed the risk of hospital readmission, length of stay (LOS) during hospitalization, and costs within 90-days after surviving an index firearm injury and compared these data with pedestrians and occupants involved in motor vehicle crash (MVC). Methods: Nationwide Readmission Database, a nationally representative readmission database from 2013 and 2014 was used to create a retrospective cohort study. The primary outcome was time-to-first all-cause readmission within 90-days after discharge from the index hospitalization. Secondary outcomes were LOS and hospitalization costs at index events and at 90-days. Results: There were 3,334 (10.5%), 3,818 (10.6%) and 24,672 (9.4%) firearm injury, pedestrian, and occupant MVC readmissions within 90-days. The risk of 90-day readmission among firearm was 20% (HR=1.20, 95%CI=1.09-1.32) and 34% (HR=1.34, 95%CI=1.26-1.44) greater than patients admitted after pedestrian and occupant MVC. The primary causes of firearm readmission were surgical complications, intestinal disorders and open wounds. The mean total costs were lower among patients after firearm injury versus occupant MVC hospitalizations ($9,357 versus$11,032, p=0.028) but mean total LOS was greater (4.48 versus 4.38 days, p=0.003). Medicaid-insured patients had longer LOS at a total lower cost during index hospitalization after firearm injury as compared to MVC occupant injury. Increased LOS and lower costs of 90-day readmissions among firearm patients versus occupant MVC were irrespective of insurance. Conclusions: The patients surviving a firearm injury have a substantial risk of subsequent hospitalizations, higher than pedestrian or occupant MVC injuries. Medicaid is disproportionately burdened by the costs of treatment of firearm injury