Background: Despite clear evidence that guideline-directed medical therapy (GDMT) significantly reduces mortality and hospitalizations in patients with heart failure (HF) with reduced and mildly reduced ejection fraction, real-world implementation remains suboptimal. Digital health interventions may promote GDMT titration after hospital discharge. Methods: The ENGAGE-HF trial was a multicenter, two-arm, open-label, randomized controlled trial across three academic centers, funded by the AHA Strategically Focused Research Network (SFRN) for Health Technology and Innovation. Patients recently hospitalized with HF, with or without a primary hospital diagnosis of HF, and LVEF <50% receiving suboptimal GDMT were randomized 1:1 to either the ENGAGE-HF app or usual care for 90 days. The ENGAGE-HF intervention consisted of a patient-facing mobile app and a clinician dashboard overseen by study coordinators. The primary outcome was the Medication Optimization Score (MOS, scale 0-100%) at 90 days. Secondary outcomes were individual GDMT therapies and the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score at 90 days. Results: A total of 134 participants were randomized. At 90 days, the adjusted MOS was significantly higher in the ENGAGE-HF group compared to the control group (83.7% vs. 74.0%, p = 0.010). Results remained consistent across multiple sensitivity analyses. Overall prescribing prevalence increased more in the ENGAGE-HF group for MRAs (+15.9 vs. +2.5 percentage points) and SGLT2 inhibitors (+10.9 vs. +2.5 percentage points). Furthermore, the ENGAGE-HF group demonstrated greater increases in achieving target doses for ARNI (+18.8% vs. +6.3%) and beta-blockers (+8.5% vs. +0.6%). KCCQ-23 CSS at 90 days was 75.2 (SE 2.6) in the intervention group versus 72.2 (SE 2.6) in the control group (between-group p = 0.40). Conclusions: ENGAGE-HF, a digital health intervention that integrates remote monitoring, patient engagement, and clinical decision support, significantly improved GDMT optimization at 90 days compared with usual care among patients with HF. Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT06750549
BACKGROUND: Skeletal muscle dysfunction is a major peripheral determinant of exercise intolerance and physical disability in heart failure with preserved ejection fraction (HFpEF). Metabolic and mitochondrial dysfunction are considered to be key components of skeletal muscle dysfunction, but comprehensive profiling of metabolic pathways has not been conducted. Elucidation of dysregulated metabolic pathways is essential to determine viable targets for the treatment of exercise intolerance in HFpEF. METHODS: Male ZSF1 Obese rats (HFpEF, n=8) and Wistar Kyoto lean normotensive controls (Control, n=8) were studied at 26 weeks of age. The gastrocnemius was analyzed using bulk RNA sequencing, proteomics, metabolomics, and lipidomics. Differential expression across all omics layers was determined using standard statistical modeling with thresholds of absolute fold‑change >1.5 and FDR <0.05, unless otherwise specified. Additional targeted plasma and skeletal muscle metabolomics and lipidomics were performed in HFpEF and control rats, including analyses of the soleus and the extensor digitorum longus, to validate features associated with predominantly oxidative and glycolytic muscle, respectively. RESULTS: Pathway-level analysis for RNA sequencing and proteomics revealed significant downregulation of oxidative phosphorylation (natural enrichment score (NES), −2.1; P <0.005), electron transport chain (NES, −2.0; P <0.005), and tricarboxylic acid cycle cycle (−1.8; P <0.05). The most upregulated pathways were PPAR signaling (NES, 2.2; P <0.0001), tryptophan metabolism (NES, 1.8; P <0.005), and amino acid oxidation (NES, 1.8; P <0.005) pathways. Metabolomics revealed an accumulation of tricarboxylic acid cycle cycle intermediate, isocitrate, and phosphate reduction. Branched-chain amino acids were significantly increased, whereas amino acids related to tryptophan metabolism were reduced and shifted towards increased serotonin accumulation. Phospholipid species were differentially regulated with increased palmitoylated phosphatidylcholines but reduced arachidonoyl-phosphatidylcholine species. Phosphatidylethanolamines species (16:0/16:1–18:0/18:2) were increased. CONCLUSIONS: HFpEF skeletal muscle shows signatures of profound mitochondrial and peroxisomal dysfunction with lipid overload, impaired branched chain amino acid and tryptophan metabolism, and a shift in membrane phospholipid composition, supporting an acquired metabolic myopathy in cardiometabolic HFpEF.
BACKGROUND: Chronic kidney disease is a frequent comorbidity in heart failure with preserved ejection fraction (HFpEF) and has been proposed as a contributor to its development. However, the spectrum of antecedent kidney function before incident HFpEF and its association with subsequent cardiovascular outcomes remains unclear. METHODS: We conducted a multicenter cohort study across 170 US Veterans Affairs hospitals, including patients with incident HFpEF diagnosed between January 1, 2000, and June 30, 2025. HFpEF was ascertained using natural language processing-derived left ventricular ejection fraction ≥50% closest to the incident HF date and a validated HFpEF algorithm incorporating loop diuretic use, elevated natriuretic peptide levels, and an HFpEF–age, body mass index, and atrial fibrillation score >0.5. Antecedent kidney function was classified using 2 estimated glomerular filtration rate (eGFR) measurements obtained ≥90 days apart before incident HFpEF and urine albumin-to-creatinine ratio. We characterized antecedent kidney function, including albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g), and examined its associations with 5-year cardiovascular death and heart failure hospitalization. Competing-risk analysis was performed accounting for noncardiovascular death as a competing event for cardiovascular death. RESULTS: Of 304 712 patients meeting HFpEF ascertainment criteria, 236 910 comprised the final cohort; 51% had antecedent eGFR ≥60 mL/min per 1.73m 2 . Overall, 15% had an eGFR ≥90 mL/min per 1.73m 2 . Patients with eGFR <60 mL/min per 1.73m 2 were older and had more diabetes and hypertension. 51% of the patients with eGFR <60 mL/min per 1.73m 2 had body mass index <30 kg/m 2 , including 20% with body mass index <25 kg/m 2 . Progressively lower antecedent kidney function was associated with graded increases in cardiovascular death and heart failure hospitalization. Among decedents, the proportion of deaths attributed to cardiovascular causes increased from 25% in the preserved eGFR (≥90 mL/min per 1.73m 2 ) without documented albuminuria to 32% with albuminuria and 38% with advanced kidney dysfunction ( P <0.001). CONCLUSIONS: In this nationwide study of patients with incident HFpEF, antecedent kidney dysfunction was common but not uniformly present before HFpEF onset. Furthermore, among patients who developed HFpEF, antecedent kidney dysfunction identified a higher-risk phenotype, with progressively greater cardiovascular mortality and heart failure hospitalization with declining kidney function.
