Phenomapping for novel classification of heart failure with preserved ejection fraction

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome in need of improved phenotypic classification. We sought to evaluate whether unbiased clustering analysis using dense phenotypic data (phenomapping) could identify phenotypically distinct HFpEF categories.

Methods and results: We prospectively studied 397 patients with HFpEF and performed detailed clinical, laboratory, ECG, and echocardiographic phenotyping of the study participants. We used several statistical learning algorithms, including unbiased hierarchical cluster analysis of phenotypic data (67 continuous variables) and penalized model-based clustering, to define and characterize mutually exclusive groups making up a novel classification of HFpEF. All phenomapping analyses were performed by investigators blinded to clinical outcomes, and Cox regression was used to demonstrate the clinical validity of phenomapping. The mean age was 65±12 years; 62% were female; 39% were black; and comorbidities were common. Although all patients met published criteria for the diagnosis of HFpEF, phenomapping analysis classified study participants into 3 distinct groups that differed markedly in clinical characteristics, cardiac structure/function, invasive hemodynamics, and outcomes (eg, phenogroup 3 had an increased risk of HF hospitalization [hazard ratio, 4.2; 95% confidence interval, 2.0-9.1] even after adjustment for traditional risk factors [P<0.001]). The HFpEF phenogroup classification, including its ability to stratify risk, was successfully replicated in a prospective validation cohort (n=107).

Conclusions: Phenomapping results in a novel classification of HFpEF. Statistical learning algorithms applied to dense phenotypic data may allow improved classification of heterogeneous clinical syndromes, with the ultimate goal of defining therapeutically homogeneous patient subclasses.

Keywords: cluster analysis; echocardiography; heart failure, diastolic; patient outcome assessment.

Figure 1

Phenotype Heatmap (PhenoMap) of HFpEF. Columns represent individual study participants and rows represent individual phenotypes. Red = increased value of a phenotype; Blue = decreased value of a phenotype.

Figure 2

Bayesian Information Criterion Analysis for the Identification of the Optimal Number of Pheno-Groups.

Figure 3

Outcomes by HFpEF Pheno-Group. Stacked bar graph of outcomes shows the step-wise increase in adverse events from pheno-group #1 to pheno-group #3.

Figure 4

Survival Free of Cardiovascular Hospitalization or Death, Stratified by Pheno-Group. Kaplan-Meier curves for the combined outcome of heart failure hospitalization, cardiovascular hospitalization, or death, stratified by pheno-group. CV = cardiovascular.