Abstract 12326: Obesity Increases Heart Failure Incidence and Mortality:Observational and Mendelian Randomisation Studies Totalling Over 1 Million Individuals

Introduction: Whether high body mass index (BMI) causally influences development and prognosis of heart failure has implications for clinical practice. Hypothesis: We tested the hypotheses that high BMI causally influences heart failure incidence and mortality. Methods: Using observational and Mendelian randomization causal, genetic analyses, we studied 106,121 individuals from the Copenhagen General Population Study, 18,407 from the Copenhagen City Heart Study, and 977,323 from publicly available databases. Results: In observational analyses in the Copenhagen studies with 10 years of median follow-up, multivariable adjusted hazard ratios per 1 kg/m 2 increment of BMI were 1.06 (95% confidence interval: 1.05-1.07; p<0.001; n=124,528; events=6,589) for heart failure incidence, 1.04 (1.03-1.06; p<0.001; n=124,528; events=1,237) for heart failure mortality, and 1.01 (1.00-1.01; p<0.001; n=124,528; events=24,144) for all-cause mortality. In genetic analyses in the Copenhagen studies, the age and sex adjusted causal risk ratios per 1 kg/m 2 increment of BMI were 1.19 (1.05-1.36; p=0.008; n=118,200; events=6,541) for heart failure incidence, 1.27 (0.82-1.98; p=0.28; n=118,200; events=889) for heart failure mortality, and 1.11 (1.02-1.22; p=0.022; n=118,200; events=16,814) for all-cause mortality. Finally, combining genetic data from the Copenhagen studies, the Genetic Investigation of ANthropometric Traits (GIANT), the Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES), and the UK Biobank, the unadjusted causal risk ratios per 1 kg/m 2 increment of BMI were 1.39 (1.27-1.52; p<0.001; n=1,095,523; events=53,850) for heart failure incidence, 1.18 (1.00-1.38; p=0.05; n=576,853; events=2,373) for heart failure mortality, and 1.02 (1.00-1.04; p=0.03; n=576,853; events=44,734) for all-cause mortality. Conclusions: High body mass index causally increases the risk of both heart failure incidence and mortality. Obesity should be recognised as a causal factor for development of heart failure, heart failure mortality, and all-cause mortality in treatment guidelines.