Clinical phenogroup diversity and multiplicity: Impact on mechanisms of exercise intolerance in heart failure with preserved ejection fraction

Abstract

Aims: We aimed to clarify the extent to which cardiac and peripheral impairments to oxygen delivery and utilization contribute to exercise intolerance and risk for adverse events, and how this relates to diversity and multiplicity in pathophysiologic traits.

Methods and results: Individuals with heart failure with preserved ejection fraction (HFpEF) and non-cardiac dyspnoea (controls) underwent invasive cardiopulmonary exercise testing and clinical follow-up. Haemodynamics and oxygen transport responses were compared. HFpEF patients were then categorized a priori into previously-proposed, non-exclusive descriptive clinical trait phenogroups, including cardiometabolic, pulmonary vascular disease, left atrial myopathy, and vascular stiffening phenogroups based on clinical and haemodynamic profiles to contrast pathophysiology and clinical risk. Overall, patients with HFpEF (n = 643) had impaired cardiac output reserve with exercise (2.3 vs. 2.8 L/min, p = 0.025) and greater reliance on peripheral oxygen extraction augmentation (4.5 vs. 3.8 ml/dl, p < 0.001) compared to dyspnoeic controls (n = 219). Most (94%) patients with HFpEF met criteria for at least one clinical phenogroup, and 67% fulfilled criteria for multiple overlapping phenogroups. There was greater impairment in peripheral limitations in the cardiometabolic group and greater cardiac output limitations and higher pulmonary vascular resistance during exertion in the other phenogroups. Increasing trait multiplicity within a given patient was associated with worse exercise haemodynamics, poorer exercise capacity, lower cardiac output reserve, and greater risk for heart failure hospitalization or death (hazard ratio 1.74, 95% confidence interval 1.08-2.79 for 0-1 vs. ≥2 phenogroup traits present).

Conclusions: Though cardiac output response to exercise is limited in patients with HFpEF compared to those with non-cardiac dyspnoea, the relative contributions of cardiac and peripheral limitations vary with differing numbers and types of clinical phenotypic traits present. Patients fulfilling criteria for greater multiplicity and diversity of HFpEF phenogroup traits have poorer exercise capacity, worsening haemodynamic perturbations, and greater risk for adverse outcome.

Keywords: Exercise capacity; HFpEF; Heart failure; Outcome; Phenotype.

Figure 1.

[A] Proportions and distributions of non-exclusive HFpEF phenogroups. Each colored square represents distinct phenogroups among all patients with HFpEF in the study cohort. Each square’s area is proportional to frequency of its respective phenogroup and the frequency of overlap with other phenogroups. The cardiometabolic phenogroup was the most common (present among 72% of the HFpEF cohort, blue), followed by the stiff vascular (57%, yellow), left atrial myopathy (53%, green) and pulmonary vascular (40%, red) phenogroups. A small proportion (5.7%) of all patients with HFpEF belonged to no phenogroups. [B] Histogram of the phenogroup burden among patients with HFpEF. Most patients with HFpEF (94%) belonged to at least one phenogroup, and 67% of HFpEF patients belonged to 2 or more phenogroups.

Figure 2.

Mean right atrial pressure [A], mean pulmonary artery pressure [B], cardiac output [C], and VO₂ [D] at peak exercise stratified by the number of phenogroups present among HFpEF patients. As the number of phenogroups present increases, filling pressures increase further and cardiac output and VO₂ decrease.

Figure 3.

Kaplan-Meier estimate of composite outcome of death, or death or heart failure hospitalization for HFpEF patients compared with controls [A], and for the composite of death or heart failure hospitalization for patients with HFpEF fulfilling criteria for <2 or ≥2 phenogroups [B]. Log-rank test comparing curves P <0.001.

Figure 4.

Kaplan-Meier estimate of death and composite outcome (death or heart failure hospitalization, for HFpEF patients fulfilling criteria for each individual phenogroup (green), HFpEF patients not fulfilling criteria that phenogroup (orange), and controls (blue); with cardiometabolic phenogroup shown in [A], left atrial (LA) myopathy in [B], pulmonary vascular disease in [C], and stiff vascular phenotype in [D]. Log-rank test comparing curves P <0.001.