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HFpEF Clinical Phenogroups in TOPCAT Trial
Study Questions:
How 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 participants from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) trial. The study authors performed latent-class analysis to identify heart failure with preserved ejection fraction (HFpEF) phenogroups based on standard clinical features, and assessed differences in multiple biomarkers measured from frozen plasma; cardiac and arterial structure/function measured with echocardiography and arterial tonometry; prognosis; and response to spironolactone. The metrics utilized by the authors to determine the optimal number of phenogroups included the parametric bootstrap likelihood ratio test, Akaike’s Information Criterion, Bayesian Information Criterion (BIC), and sample-size-adjusted BIC.
Results:
The authors identified three HFpEF phenogroups.
- Phenogroup 1 (n = 1,214) exhibited younger age, higher prevalence of smoking, 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.
The study authors found that when compared with phenogroup 1, phenogroup 3 exhibited the highest risk of the primary endpoint of cardiovascular death, HF 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). Results were similar after excluding participants from Eastern Europe.
Conclusions:
The authors concluded that they have identified important differences in circulating biomarkers, cardiac/arterial characteristics, prognosis, and response to spironolactone across clinical HFpEF phenogroups. In the authors’ opinion, these findings suggest distinct underlying mechanisms across clinically identifiable phenogroups of HFpEF that may benefit from different targeted interventions.
Perspective:
This is an important study because it adds value to an earlier single-center study on phenomapping of 397 HFpEF patients discussed earlier (see Journal Scan). As the authors point out, identifying phenogroups of HFpEF should help to better design clinical trials targeting such patients.
Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, 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, Diabetes Mellitus, Diuretics, Echocardiography, Heart Arrest, Heart Failure, Hospitalization, Hypertrophy, Left Ventricular, Inflammation, Liver Cirrhosis, Manometry, Obesity, Phenotype, Renal Insufficiency, Chronic, Secondary Prevention, Smoking, Spironolactone, Stroke Volume, Tumor Necrosis Factor-alpha, Vascular Calcification, Vascular Stiffness
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