A Multivariable Mendelian Randomization Study of Systolic and Diastolic Blood Pressure, Lipid Profile, and Heart Failure Subtypes

Heart failure (HF) is a significant health burden, with two major clinical subtypes: HF with reduced (HFrEF) and preserved ejection fraction (HFpEF). Blood pressure and lipid profile are established risk factors of HF. We performed univariable and multivariable Mendelian randomization (MR) analyses to assess potential causal effects of blood pressures and lipids on HF subtypes. Genetic instruments for blood pressures and lipids were derived from genome-wide association studies (GWASs) among the European participants of the UK Biobank. GWAS summaries of HFrEF and HFpEF were obtained from the meta-analysis of the European participants from the Million Veteran Program and the Vanderbilt University DNA Databank. Systolic blood pressure exhibited a supportive MR association primarily with HFpEF (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.04-1.23), while diastolic blood pressure had an independent MR association with HFrEF (OR, 1.43; 95% CI, 1.13-1.77). MR associations also supported the observation that higher levels of low-density lipoprotein cholesterol increase the risk for both subtypes (HFrEF OR, 1.10 and 95% CI, 1.05-1.17; HFpEF OR, 1.05 and 95% CI, 1.02-1.09). These findings underscore differences in HF subtype-specific risk profiles and mechanisms, which may lead to different interventional strategies for different HF subtypes.