Does Phenotypic Heterogeneity in Heart Failure With Preserved Ejection Fraction Imply Mechanistic Heterogeneity? The Myth of a Phenotype-Directed Therapeutic Framework and the Mandate for a Falsifiable Hypothesis

Heart failure with preserved ejection fraction (HFpEF) exhibits phenotypic diversity (as is also true for heart failure with a reduced ejection fraction [HFrEF]), but the diversity of clinical presentations or pathophysiological features do not reflect mechanistic heterogeneity. Several lines of evidence undermine the presumption that multiple independent causal pathways contribute to the pathogenesis of HFpEF: (1) characterization of phenotypic heterogeneity by mathematical modeling has not yielded insights into actionable mechanisms or treatment strategies; (2) studies using deep phenotyping in HFpEF have revealed a smooth continuous landscape without phenotypic discreteness; (3) treatments specifically directed to the amelioration of comorbidities or observed pathophysiological derangements (e.g., hypertension, dysglycemia, pulmonary hypertension or coronary microvascular dysfunction) have not favorably influenced the clinical course of HFpEF; (4) the design of randomized clinical trials in HFpEF have specified broad-based eligibility criteria that have not assumed mechanistic heterogeneity; (5) large-scale trials of effective drugs have shown broad-based benefits, without heterogeneity of effect sizes based on phenotypic subgroups; and (6) a unifying hypothesis has been proposed to explain the mechanism of HFpEF in the large majority of patients (analogous to the neurohormonal hypothesis of HFrEF), and it has received institutional recognition and recent prospective validation, as demonstrated by the favorable effects seen with inhibition of activin type II receptor signaling on pulmonary artery wedge pressures and left atrial volumes in HFpEF. Those who believe that phenotypic heterogeneity provides insights into mechanistic heterogeneity must explain how it is possible for causal mechanisms to be identified based on phenotypic features, and additionally, they must demonstrate that phenotype-directed or -informed therapy improves outcomes or leads to new treatments for HFpEF. Advocacy for phenotypic characterization as an approach to guiding treatment decisions in HFpEF should be based on testable and falsifiable hypotheses and grounded on the results of randomized controlled trials.