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Aims: The aim of this study is to use six previously described heart failure with preserved ejection fraction (HFpEF) phenotypes to describe differences in (i) the biological response to spironolactone, (ii) clinical endpoints, and (iii) patient‐reported health status by HFpEF phenotype and treatment arm in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT). Methods and results: We analysed 1767 patients in TOPCAT from the Americas. Using 11 clinical variables, patients were classified according to six HFpEF phenotypes previously identified in the I‐PRESERVE and CHARM‐Preserved studies. Kansas City Cardiomyopathy Questionnaire (KCCQ) measured health status. All phenotypes showed increase in potassium with spironolactone, although only three phenotypes showed significant increase in creatinine, and two phenotypes showed significant decrease in systolic blood pressure. Rate of the TOPCAT primary outcome (cardiovascular death, aborted cardiac arrest, or heart failure hospitalization) differed by HFpEF phenotype (P < 0.001) but not by treatment arm within each HFpEF phenotype. Baseline KCCQ score differed by HFpEF phenotype (P < 0.001), although some phenotypes with poor health status had lower rates of the TOPCAT primary outcome, and some phenotypes with better health status had higher rates of the TOPCAT primary outcome. However, within 3/6 phenotypes, higher baseline KCCQ score was associated with lower risk of the TOPCAT primary outcome. Change in KCCQ scores at 4 and 12 months did not differ among HFpEF phenotypes overall or by treatment arm. Conclusions: Complex, data‐driven HFpEF phenotypes differ according to biological response to spironolactone, baseline health status, and clinical endpoints. These differences may inform the design of targeted clinical trials focusing on improvement in outcomes most relevant for specific HFpEF phenotypes. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the biologic relevance of cross-platform concordant changes in gene expression in intact human failing/hypertrophied ventricular myocardium undergoing reverse remodeling. Background: Information is lacking on genes and networks involved in remodeled human LVs, and in the associated investigative best practices. Methods: We measured mRNA expression in ventricular septal endomyocardial biopsies from 47 idiopathic dilated cardiomyopathy patients, at baseline and after 3–12 months of β-blocker treatment to effect left ventricular (LV) reverse remodeling as measured by ejection fraction (LVEF). Cross-platform gene expression change concordance was investigated in reverse remodeling Responders (R) and Nonresponders (NR) using 3 platforms (RT-qPCR, microarray, and RNA-Seq) and two cohorts (All 47 subjects (A-S) and a 12 patient “Super-Responder” (S-R) subset of A-S). Results: For 50 prespecified candidate genes, in A-S mRNA expression 2 platform concordance (CcpT), but not single platform change, was directly related to reverse remodeling, indicating CcpT has biologic significance. Candidate genes yielded a CcpT (PCR/microarray) of 62% for Responder vs. Nonresponder (R/NR) change from baseline analysis in A-S, and ranged from 38% to 100% in S-R for PCR/microarray/RNA-Seq 2 platform comparisons. Global gene CcpT measured by microarray/RNA-Seq was less than for candidate genes, in S-R R/NR 17.5% vs. 38% (P = 0.036). For S-R global gene expression changes, both cross-cohort concordance (CccT) and CcpT yielded markedly greater values for an R/NR vs. an R-only analysis (by 22 fold for CccT and 7 fold for CcpT). Pathway analysis of concordant global changes for R/NR in S-R revealed signals for downregulation of multiple phosphoinositide canonical pathways, plus expected evidence of a β1-adrenergic receptor gene network including enhanced Ca2+ signaling. Conclusions: Two-platform concordant change in candidate gene expression is associated with LV biologic effects, and global expression concordant changes are best identified in an R/NR design that can yield novel information. [ABSTRACT FROM AUTHOR]

The article discusses a research which aims to further test the hypothesis that reverse-remodeling in nonischemic dilated cardiomyopathy is associated with changes in myocardial gene expression. It shows that changes in gene expression is associated with ventricular reverse-remodeling in response to β-adrenergic receptor (AR) antagonists. It reveals that AR genes would exhibit changes comprising a therapeutic molecular phenotype associated with ventricular reverse-remodeling.

Introduction: Heart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure cases. Clinical trials have not shown effective therapies. Defining and exploring distinct HFpEF phenotypes may help develop targeted therapies for this condition. We used latent class analysis (LCA) to identify different echocardiographic phenotypes of HFpEF in the Americas cohort of TOPCAT. Hypothesis: Complex HFpEF echocardiographic phenotypes identified using LCA would vary in prognosis and response to spironolactone. Methods: Echo phenotype definitions were derived using maximum likelihood estimation to identify the most common patterns of 7 echocardiographic features. The optimal number of phenotypes was determined using the Bayesian Information Criterion and χ2 error statistics. Hazard ratios between echo phenotype and treatment response were determined using Cox proportional hazards models. The primary outcome was a composite of cardiovascular (CV) mortality or heart failure (HF) hospitalization. Results: Four phenotypes were identified with distinct combinations of diastolic dysfunction, structural heart disease, and elevated left atrial pressures (Table). There were significant differences between echo phenotypes in the primary outcome of CV mortality or HF hospitalization. There were no significant interactions between echo phenotype and spironolactone with respect to the primary outcome. There was a significantly increased risk of CV hospitalization with the use of spironolactone in the phenotype of diastolic dysfunction without significant structural disease (HR 1.9, p = 0.006), whereas the phenotype characterized by severe LVH and RV dysfunction showed a strong trend towards reduced risk of CV hospitalization with spironolactone (HR 0.70, p=0.053). Conclusions: Using LCA, 4 echocardiographic phenotypes were identified and predictive of CV outcomes and response to spironolactone including both harm and benefit in HFpEF. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure (HF) are heterogeneous with multiple complex phenotypes across the ejection fraction (EF) spectrum. Phenotype-specific response to various treatments have not been well-described. Hypothesis: Clinical response to specific interventions will vary according to HF phenotype. Methods: Using latent class analysis, six cluster-based HF phenotypes across the EF spectrum were previously identified using patient data from 2130 patients enrolled in HF-ACTION (LVEF ≤ 35%) and 1767 patients enrolled from the Americas in TOPCAT (LVEF ≥ 45%) based on age, sex, race, CAD, BMI, hyperlipidemia, hypertension, diabetes mellitus, atrial fibrillation, COPD, anemia, and renal function, but not LVEF. Response to aerobic exercise training vs. usual care (HF-ACTION) and spironolactone vs. placebo (TOPCAT) were quantified by phenotype. The primary outcome was a composite of cardiovascular mortality (CVM) or HF hospitalization (HFH). Secondary outcomes included CVM, HFH, and all-cause mortality (ACM). Change in peak VO2 at 3 and 12 months were also analyzed in HF-ACTION. Results: Of the established phenotypes, the phenotype composed of elderly non-ischemic patients as well as the non-white/non-ischemic/hypertensive phenotype experienced improvement in combined CVM and HFH, ACM and exercise capacity (28% vs 38%, HR: 0.66 [0.46-0.94], 8% vs 16% HR: 0.49 [0.27-0.91], change in VO2: 1.06±3.01 vs 0.04±3.14, p<0.05). Elderly patients with non-ischemic HFrEF enrolled in HF-ACTION randomized to therapeutic exercise program demonstrated significantly improved exercise capacity compared to usual care (change in VO2: 1.45±2.82 vs -0.09±2.49 and 1.25±3.18 vs 0.66±3.64 respectively, p<0.05). Elderly non-ischemic patients treated with spironolactone in TOPCAT had a lower risk of the primary outcome CVM and HFH (20% vs 27%, HR: 0.67 [0.48-0.95]), driven mostly by reduced CVM (9% vs 17%, HR: 0.52 [0.32-0.84]). Conclusions: Response to varied treatments such as exercise training and spironolactone varies among complex HF phenotypes in both HFpEF and HFrEF. Additional investigation which further characterizes phenotype-specific treatments may help select specific interventions most likely to benefit specific phenotypes. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is typically classified according to ejection fraction (EF). The underlying pathophysiology is a heterogeneous process that may be better characterized by clinical phenotypes. Methods: Individual patient data from 2130 patients enrolled in HF-ACTION (LVEF ≤ 35%) and 1767 patients enrolled from the Americas in TOPCAT (LVEF ≥ 45%) were harmonized and aggregated. Cluster-based HF phenotypes were identified using latent class analysis based on 13 clinical characteristics (Table) but excluding LVEF. LVEF distribution within phenotypes was then quantified following phenotyping. The primary outcome was a composite of cardiovascular mortality (CVM) or HF hospitalization (HFH). Secondary outcomes included CVM, HFH, and all-cause mortality (ACM). Phenotype characteristics were analyzed in aggregate and outcomes were stratified by LVEF (< 45% = HFrEF vs. ≥ 45% = HFpEF). Results: Six phenotypes were identified with distinct clinical profiles (Table): nonischemic CM in young patients without significant comorbidities (A), diabetic/insulin resistant CM (B), premature ischemic CM (C), older patients with CAD and multiple risk factors (D), older patients with AF and hypertension but little CAD (E), and hypertensive, non-ischemic, non-white subjects (F). Rates of all outcomes varied significantly with phenotype (p<0.001) across the EF spectrum. Within each phenotype, there were no significant differences in outcome among patients with HFrEF vs. HFpEF except for the primary outcome in phenotype D (40 vs. 30%, p=0.006), ACM in phenotype C (11 vs. 18%, p=0.036) and HFH in phenotype D (32 vs. 22%, p=0.004). Conclusions: HF phenotypes identified by cluster-type analysis can span the EF spectrum with variation in predominance of HFpEF and rEF depending on underlying pathophysiologic mechanisms. Variation in outcomes was driven largely by phenotype rather than LVEF. [ABSTRACT FROM AUTHOR]

Introduction: Patients with heart failure with reduced ejection fraction (HFrEF) are phenotypically heterogeneous, and functional status and prognosis associated with complex phenotypes are poorly described. Hypothesis: Complex HFrEF phenotypes identified in the HF-ACTION trial using exercise and phenotypic characteristics will have differential association with all-cause mortality. Methods: We used latent class analysis (LCA) and a variable selection method developed by Fop et. al to identify important clustering variables and define distinct HFrEF phenotypes among 2130 subjects enrolled in the HF-ACTION study. Relevant variables identified included history of CABG or PCI, sex, chronic kidney disease, race, CPX duration, peak VO2, and Ve/VCO2. We evaluated differences between phenotypes using the Mann Whitney U for continuous and chi square for categorical variables (Table 1). We used Cox proportional hazards modeling to evaluate the association between phenotype and mortality. Results: Four HFrEF phenotypes were identified (Table 1). Exercise variables clustered in expected manners, with clusters with high adverse event rates having worse functional measures and decreased exercise capacity as evidenced by lower peak VO2, higher Ve/VCO2 slopes, and decreased walking distance. Phenotype A was characterized by younger patients (mean age 51 years), with balanced race and sex. Phenotype B was characterized by black (56%), NICM (79%) females (49%) with mean age 58. Phenotype C was primarily white (78%) males (85%) with ICM (100%) and mean age of 68. Phenotype D was primarily white (81%) males (90%) with ICM (99.9%) with mean age 60. Phenotype C had highest association with mortality after adjustment for traditional CV risk factors (HR 4.94; 95% CI 3.51-7.02) compared to Phenotype A, followed by Phenotype B (HR 3.28; 95% CI 2.26-4.77) and Phenotype D (HR 1.44; 95% CI 0.89-2.32). Conclusions: Data-driven phenotyping using LCA effectively identifies patient clusters with distinct clinical, functional, and prognostic characteristics among patients with HFrEF enrolled in the HF-ACTION trial. Identification of novel phenotypic profiles may identify future opportunities for targeted intervention among additional patient cohorts. [ABSTRACT FROM AUTHOR]