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HFpEF Clinical Phenogroups in TOPCAT
Study Questions:
Do clinical phenogroups differ in comprehensive biomarker profiles, cardiac and arterial structure/function, and responses to spironolactone therapy?
Methods:
The study cohort was comprised of 1,765 participants from TOPCAT (Americas in Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). The primary endpoint of TOPCAT was a composite of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest. On this cohort of the study, authors performed latent-class analysis to identify HFpEF phenogroups based on standard clinical features, and they assessed differences in: 1) multiple biomarkers measured from frozen plasma, 2) cardiac and arterial structure/function measured with echocardiography and arterial tonometry, 3) prognosis, and 4) response to spironolactone.
Results:
In the overall study population at baseline, the mean age was 69 years (standard deviation [SD], 10 years), with 52% women and 9% black participants. Chronic kidney disease was present in 43% of participants, the overall mean estimated glomerular filtration rate was 65 ml/min/1.73 m2 (SD, 19), 32% had diabetes mellitus, 55% were obese, 35% had a history of atrial fibrillation, and 10% were smokers. The study authors identified three HFpEF phenogroups (bootstrap likelihood ratio [LR] test for 2 vs. 3 classes, p value = 0.01; LR test for 3 vs. 4 classes, p value = 0.16; Akaike’s Information Criterion, Bayesian Information Criterion [BIC], and sample-size adjusted BIC also supported a three-class solution). Phenogroup 1 (n = 1,214) exhibited younger age, higher smoking prevalence, preserved functional class, and the least evidence of left ventricular (LV) hypertrophy and arterial stiffness. Phenogroup 2 (n = 1,329) was older, with normotrophic concentric LV remodeling, atrial fibrillation, left atrial enlargement, large artery stiffening, and biomarkers of innate immunity and vascular calcification. Phenogroup 3 (n = 899) demonstrated more functional impairment, obesity, diabetes, chronic kidney disease, concentric LV hypertrophy, high renin, and biomarkers of tumor necrosis factor-alpha-mediated inflammation, liver fibrosis, and tissue remodeling. Compared to phenogroup 1, phenogroup 3 exhibited the highest risk of the primary endpoint of cardiovascular death, heart failure hospitalization, or aborted cardiac arrest (hazard ratio [HR], 3.44; 95% confidence interval [CI], 2.79-4.24); phenogroups 2 and 3 demonstrated similar all-cause mortality (phenotype 2 HR, 2.36; 95% CI, 1.89-2.95; phenotype 3 HR, 2.26; 95% CI, 1.77-2.87). Spironolactone randomized therapy was associated with a more pronounced reduction in the risk of the primary endpoint in phenogroup 3 (HR, 0.75; 95% CI, 0.59-0.95; p for interaction = 0.016).
Conclusions:
The study authors identified important differences in circulating biomarkers, cardiac/arterial characteristics, prognosis, and response to spironolactone across clinical HFpEF phenogroups. They concluded that these findings suggest distinct underlying mechanisms across clinically identifiable phenogroups of HFpEF, which may benefit from different targeted interventions.
Perspective:
This is an important study because it demonstrates the disparate phenotypes of HFpEF. It is very likely that many of the patients in phenotype 2 and possibly 3 have underlying TTR transthyretin amyloid. Future studies of HFpEF patients should keep these disparate phenotypes in mind when designing clinical trials.
Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound, Smoking
Keywords: Atrial Fibrillation, Biomarkers, Heart Arrest, Kidney Diseases, Diabetes Mellitus, Diagnostic Imaging, Echocardiography, Fibrosis, Heart Failure, Hypertrophy, Obesity, Phenotype, Receptors, Tumor Necrosis Factor, Secondary Prevention, Smoking, Spironolactone, Stroke Volume
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