Genetic and phenotypic profiling of supranormal ejection fraction reveals decreased survival and underdiagnosed heart failure

Abstract

Aims: Individuals with supranormal left ventricular ejection fraction (snLVEF; LVEF >70%) have increased mortality. However, the genetic and phenotypic profile of snLVEF remains unknown. This study aimed to determine the relationship of both snLVEF genetic risk and phenotype with survival and underdiagnosed heart failure (HF).

Methods and results: A snLVEF genetic risk score (GRS) was applied and cases of snLVEF were identified in 486 754 individuals across two population-based cohorts (BioMe Biobank and UK Biobank). The snLVEF GRS and phenotype were evaluated for association with survival, as well as HF diagnosis, markers, symptoms, and medications. Of 486 754 participants, the median age was 58 years, 20 069 (4.1%) died, and 10 088 (2.1%) had diagnosed HF. Both snLVEF GRS (hazard ratio [HR] 1.1 for top 10% vs. bottom 10% GRS; p = 0.002) and phenotype (HR 1.4; p = 0.003) were associated with increased all-cause mortality. Both snLVEF GRS and phenotype were associated with reduced HF diagnosis (odds ratio [OR] 0.97 and OR 0.63, respectively; both p ≤0.002). However, the snLVEF GRS and phenotype were both associated with elevated brain natriuretic peptide (BNP) levels (146 and 185 pg/ml increase, respectively; p <0.001), including 268 out of 455 (59%) individuals with snLVEF phenotype who had BNP >100 pg/ml. Among 476 666 participants without HF diagnoses, snLVEF GRS and phenotype were associated with increased HF symptoms (e.g. exertional dyspnoea OR 1.4 and OR 1.3; p <0.003) and HF medications (e.g. loop diuretic OR 1.2 and OR 1.03; p <0.02). Associations were consistent in hypertensive individuals without cardiac comorbidities.

Conclusions: Genetic predisposition to and presence of snLVEF are associated with decreased survival and underdiagnosed HF.

Keywords: Biobank; Electronic health record; Genetic risk score; Heart failure; Supranormal ejection fraction; Underdiagnosis.

Figure 1.

Graphical abstract of study of supranormal left ventricular ejection fraction in two biobanks. The study assessed the genetic and phenotypic characteristics of supranormal left ventricular ejection fraction (snLVEF). Sixteen genetic variants were found in a genome-wide association study to be associated with snLVEF and were incorporated into a genetic risk score (GRS). Both snLVEF GRS and phenotype were associated with increased hazard ratio (HR) for mortality, including in heart failure (HF) and hypertension subgroups. Both snLVEF GRS and phenotype were associated with reduced odds ratio (OR) for HF diagnosis, but increased brain natriuretic peptide (BNP) levels and increased OR for HF symptoms and medications. Individuals with a genetic predisposition or phenotype of snLVEF have worse survival and may be underdiagnosed for HF. Further study is needed to define snLVEF in clinical guidelines for HF diagnosis and risk stratification.

Figure 2.

Genome-wide associations with supranormal left ventricular ejection fraction across two biobanks. A Manhattan plot depicts the results for the genome-wide associations of supranormal left ventricular ejection fraction meta-analyzed across the UK Biobank and BioMe Biobank. An inverse-variance weighted fixed effects meta-analysis was conducted to aggregate association results across biobanks. Genome-wide significance threshold (P<5×10⁻⁸) is indicated by a dashed horizontal line. The nearest gene to each genome-wide significant lead single nucleotide polymorphism (SNP) is annotated. A tabulated summary of the 16 lead SNPs is provided (Supplemental Table 3).

Figure 3.

Heart failure underdiagnosis in supranormal left ventricular ejection fraction across two biobanks. Logistic regression was performed to assess the association of supranormal left ventricular ejection fraction (snLVEF) phenotype and genetic risk score (GRS) with: (A) diagnosis of heart failure (HF) using an inverse-variance weighted fixed effects meta-analysis to combine results of snLVEF phenotype (heterogeneity P=0.1) and snLVEF GRS (heterogeneity P=0.6) across the UK Biobank and BioMe Biobank cohorts; (B–C) brain natriuretic peptide (BNP) levels on a base-10 logarithmic scale, with the median shown as points and first and third quartiles shown as horizontal lines in each violin plot in the BioMe Biobank; and (D) physician-documented symptoms of HF in the BioMe Biobank. Logistic regression analyses were adjusted for age, sex, body mass index, and 10 principal components of ancestry. Principal components were based on observed genotypic differences across subpopulations of race or ethnicity within each biobank cohort. Association results of the snLVEF GRS are reported as adjusted odds ratio (OR) of HF diagnosis per standard deviation increase in snLVEF GRS. OR = adjusted odds ratio; 95% CI = 95% adjusted confidence interval; rLVEF = reduced LVEF (≤40%), mrLVEF = midrange LVEF (between 40–50%), nmLVEF = normal LVEF (between 55–65%), snLVEF = supranormal LVEF (>70%); GRS = snLVEF genetic risk score; ns = P≥0.05, * = P<0.05, ** = P<0.01, *** = P<0.001.