Clinical phenotype-based HFpEF subgroups respond differently to aldosterone antagonist therapy
Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction - Detailed Phenotypes, Prognosis, and Response to Spironolactone
Introduction and methods
To date, no pharmacological therapies are known to improve patient outcomes in heart failure with preserved ejection fraction (HFpEF). The difficulty to find effective treatment may be explained by a large heterogeneity of patients with HFpEF, in symptomatology but also in variable underlying cardiac structural and functional abnormalities [1-3]. Various studies have proposed that several phenotypes of HFpEF exist, with distinct clinical features and possibly different prognosis; referred to as phenogroups [4,5]. Little is known about whether the different phenogroups show different responses to treatment.
This study aimed to use data and samples from TOPCAT to study plasma protein profiles, outcomes and response to spironolactone therapy between clinical phenogroups. TOPCAT was a large international trial that evaluated the efficacy of spironolactone therapy in 3445 patients over 50 years old with symptomatic HFpEF and LVEF ≥45% . The primary endpoint was a composite of CV death, HF hospitalization or aborted cardiac arrest.
Latent class analysis (LCA) was used to determine clusters of clinical phenotypes, with mutually exclusive and exhaustive subgroups, with maximal within-group similarities and between-group differences. Widely available clinical covariates were used to identify the clusters. The optimal number of clinical phenogroups was determined to be 3. The phenogroups had the following characteristics:
-Phenogroup 1: younger (mean: 61±6), relatively preserved functional class, 24% smoking, preserved renal function (mean eGFR: 76±16 mL/min/1.73m²), low prevalence of diabetes (9%).
-Phenogroup 2: older (mean: 77±5), highest proportion of women (56%), high prevalence of AF (49%) and CKD (mean eGFR: 58±16 mL/min/1.73m²), low prevalence of diabetes and obesity.
-Phenogroup 3: intermediate age (mean: 66±8), very high prevalence of obesity (98%) and diabetes (88%) and prominently impaired functional class. High prevalence of CKD (57%), depression (36%) and higher proportion of black participants (21%).
Striking differences in circulating biomarker levels between phenogroups included:
- Phenogroup 1 showed lowest NT-proBNP levels and much higher levels of extracellular turnover marker MMP-9 and cell-matrix interaction marker syndecan-4 compared with the other groups.
- Phenogroup 2 showed the highest levels of osteoprotegerin (regulator of mineral metabolism and tissue calcification), tissue inhibitor MMP and inflammatory biomarkers related to the innate immune response.
- Phenogroup 3 showed the highest levels of biomarkers of TNF-mediated inflammation, YKL-40 (liver fibrosis), plasma renin, kidney injury, mineral metabolism/calcification, angiogenesis and tissue remodeling.
- In echocardiographic analysis of 935 subjects, the groups also showed distinct characteristics with regard to LV hypertrophy, wall thickness and LV cavities, with phenogroup 1 generally showing normal LV geometry and group 3 showing most signs of hypertrophy.
- Compared with the younger individuals in phenogroup 1 with mild symptoms and normal LV geometry, participants in phenogroup 2 who are older, with stiff arteries and small ventricles, had a higher risk of the primary endpoint (HR: 2.17, 1.76-2.68), as did those in phenogroup 3, older obese with diabetes and LVH (HR: 3.44, 95%CI: 2.79-4.24).
- Even greater differences were seen in the risk of HF hospitalization: phenogroup 2 showed HR: 3.07, (95%CI: 2.28-4.12) and group 3 HR: 5.91 (95%CI: 4.42-7.89), compared to group 1.
- A significant interaction of the phenogroups with spironolactone treatment effect was seen for both the primary composite outcome and HF hospitalization. In phenogroup 3, spironolactone treatment was associated with a significantly lower risk of the primary endpoint (HR: 0.75, 95%CI: 0.59-0.95) and HF hospitalization (HR: 0.69, 95%CI: 0.53-0.90), while it did not seem to benefit the other groups.
In TOPCAT data, three phenogroups of HFpEF patients were identified based on standard clinical features. The phenogroups differed in circulating biomarker profiles, cardiac and vascular phenotypes, outcomes and response to spironolactone therapy. These data suggest distinct underlying pathophysiologic processes in the groups, which seem to have consequences for responsiveness to spironolactone therapy.