Genetic architecture of heart failure with preserved versus reduced ejection fraction

Abstract

Pharmacologic clinical trials for heart failure with preserved ejection fraction have been largely unsuccessful as compared to those for heart failure with reduced ejection fraction. Whether differences in the genetic underpinnings of these major heart failure subtypes may provide insights into the disparate outcomes of clinical trials remains unknown. We utilize a large, uniformly phenotyped, single cohort of heart failure sub-classified into heart failure with reduced and with preserved ejection fractions based on current clinical definitions, to conduct detailed genetic analyses of the two heart failure sub-types. We find different genetic architectures and distinct genetic association profiles between heart failure with reduced and with preserved ejection fraction suggesting differences in underlying pathobiology. The modest genetic discovery for heart failure with preserved ejection fraction (one locus) compared to heart failure with reduced ejection fraction (13 loci) despite comparable sample sizes indicates that clinically defined heart failure with preserved ejection fraction likely represents the amalgamation of several, distinct pathobiological entities. Development of consensus sub-phenotyping of heart failure with preserved ejection fraction is paramount to better dissect the underlying genetic signals and contributors to this highly prevalent condition.

Fig. 1. Study schema.

Schematic diagram detailing datasets and analyses used in the study.

Fig. 2. Algorithm for phenotyping of cohorts for genetic analyses.

Consort diagram describes the methodology utilized to accurately phenotype the case cohorts (unclassified HF, HFrEF, HFpEF, restrictive case definition of HFpEF) and controls included in the study from the Million Veteran Program.

Fig. 3. Genome-wide associations of HFrEF and HFpEF.

Genome-wide significant loci association studies of HFpEF and HFrEF among non-Hispanic White veterans. Sentinel SNPs and the nearest mapped genes are shown. Y-axis shows chromosomal position. Sentinel SNPs and their nearest genes are shown. All tests were two-sided without adjustment for multiple comparisons. *: novel HF locus; #: unique locus in the HFrEF GWAS but not in the HF meta-analysis; dashed vertical line indicates genome-wide significance threshold (P = 5 × 10⁻⁸).

Fig. 4. Genetic associations between HFrEF/HFpEF risk variants and HF risk factors.

The genetic associations were identified from published GWAS of HF risk factors. All tests were two-sided without adjustment for multiple comparisons. *Beta: beta coefficients for continuous risk factors, log (odds ratio) for binary risk factors, percent change in eGFR. CAD coronary artery disease, AFib atrial fibrillation, T2D type 2 diabetes, BMI body mass index, HDL high-density lipoprotein cholesterol, LDL low-density lipoprotein cholesterol, TC total cholesterol, TG triglycerides, SBP systolic blood pressure, DBP diastolic blood pressure, PP pulse pressure, eGFR estimated glomerular filtration rate.

Fig. 5. Mendelian randomization analysis of HF risk factors in relation to HFpEF and HFrEF.

X-axis shows odds ratios (ORs), with error bars showing 95% confidence intervals. CAD coronary artery disease, AFib atrial fibrillation, T2D type 2 diabetes, BMI body mass index, HDL high-density lipoprotein cholesterol, LDL low-density lipoprotein cholesterol, TC total cholesterol, TG triglycerides, SBP systolic blood pressure, DBP diastolic blood pressure, PP pulse pressure, eGFR estimated glomerular filtration rate.

Fig. 6. Limited genetic discovery in HFpEF due to pathophysiological heterogeneity.

All tests were two-sided without adjustment for multiple comparisons.