Kitzman, Dalane W.

Background: Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure (HF) cases and remains diagnostically challenging due to nonspecific symptoms and a lack of accessible noninvasive screening tools, leading to widespread underdiagnosis and delayed treatment. The electrocardiogram (ECG) is a low-cost, widely available tool that reflects myocardial electrical remodeling. We previously developed and externally validated an ECG-based artificial intelligence (ECG-AI) model capable of classifying ECGs into four categories: reduced ejection fraction (rEF), mid-range ejection fraction (mEF), HFpEF, and controls. In this study, we evaluate the ability of this ECG-AI model to predict future HFpEF diagnosis using real-world data from a large integrated health system. Methods: We applied the validated ECG-AI model to an independent cohort of 7713 patients from Wake Forest Baptist Health (WFBH), using one ECG per patient recorded before the clinical diagnosis of HFpEF. Model discrimination was evaluated across multiple prediction windows from six months up to ten years before diagnosis using the area under the receiver operating characteristic curve (AUC), with comparisons performed using DeLong’s test. Performance was also compared head-to-head with the H2FPEF score, a validated clinical score for HFpEF, in the subset of patients with complete data for score calculation. ECG-AI outputs were stratified into quartiles and evaluated using Kaplan–Meier survival analysis and multivariable Cox proportional hazards regression adjusted for demographics and major comorbidities. Results: Of the 7713 patients, 283 (3.7%) were subsequently diagnosed with HFpEF. The ECG-AI model achieved an AUC of 0.79 (95% CI, 0.72–0.86) using ECGs recorded within six months before diagnosis. Discrimination remained stable across prediction windows extending up to ten years before diagnosis (AUC range, 0.78–0.80; all DeLong p > 0.01 vs. the six-month window). Compared with the H2FPEF score, ECG-AI demonstrated superior discrimination, improving the AUC by 0.06–0.07 across the evaluated prediction windows. Patients in the highest ECG-AI risk quartile had an unadjusted hazard ratio (HR) of 11.18 (95% CI, 7.27–17.21; C-index, 0.75) and an adjusted HR of 6.60 (95% CI, 4.24–10.28; C-index, 0.82). Adding clinical covariates to ECG-AI improved the C-index by 0.07 and 0.09 for the five- and ten-year prediction windows, respectively. Conclusions: An independently validated ECG-AI model predicted incident HFpEF up to ten years before clinical diagnosis and outperformed the H2FPEF score using ECG alone, indicating that ECG-derived signatures precede clinical recognition of the syndrome. ECG-AI shows promise as a prognostic, risk-stratification tool to prioritize further evaluation; prospective validation and single-lead assessment are needed before screening or wearable deployment.

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti–volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting. Graphical Abstract

Abstract Background The prevalence of heart failure with preserved ejection fraction (HFpEF) increases with age, and older adults with HFpEF have worse physical function, quality of life, and clinical outcomes. Semaglutide demonstrated efficacy in the treatment of obesity-related HFpEF in the STEP-HFpEF trials. Some have speculated that older patients may have less to gain from incretin therapies (and perhaps more to lose) than younger patients. Aims In this pre-specified pooled subanalysis of the STEP-HFpEF trials, we evaluated the efficacy of semaglutide across the age spectrum. Methods The STEP-HFpEF and STEP-HFpEF DM trials enrolled participants with obesity-related HFpEF and randomized them to semaglutide 2.4 mg once weekly (n = 573) or placebo (n = 572) for 52 weeks. Dual primary outcomes (change in Kansas City Cardiomyopathy Questionnaire clinical summary score [KCCQ-CSS] and change in body weight) and secondary outcome measures (6-minute walk distance [6MWD], C-reactive protein, hierarchical composite endpoint containing all-cause death, heart failure events, changes in KCCQ-CSS and 6MWD) were compared across specific age groups; <55 years, 55–64 years, 65–74 years and ≥75 years. Results Among 1145 randomized participants, 8.8% (N = 101) were <55, 23.3% (N = 267) were aged between 55–64, 42.4% (N = 485) were between 65–74, and 25.5% (N = 292) were 75 years or over. The efficacy of semaglutide on the dual primary endpoints was consistent across the age spectrum, KCCQ-CSS (p-interaction = 0.80), and body weight (p-interaction = 0.41). Similar benefits were observed for the key secondary endpoints, with no treatment effect heterogeneity across age groups. Moreover, the safety of semaglutide was consistent across age groups. Conclusion In patients with HFpEF enrolled across the STEP-HFpEF and STEP-HFpEF DM trials, treatment with semaglutide improved disease-specific symptoms, physical function and reduced body weight across the age spectrum. The safety profile of semaglutide was consistent in older and younger patients.

Abstract Background In patients with heart failure with preserved ejection fraction (HFpEF), studies have described different HFpEF phenogroups based on medical comorbidities and variable echocardiographic, invasive hemodynamic, and biomarker data. We hypothesized that myocardial histopathologic findings may define phenogroups with differing clinical features and outcomes in patients with HFpEF. Methods We analyzed consecutive patients with left HF and EF ≥50% who underwent right ventricular septal endomyocardial biopsy (EMB) at our institution between 2001 and 2022 to investigate HF etiology. Patients with infiltrative or hypertrophic cardiomyopathy, sarcoidosis, myocarditis, primary valvular heart disease, constrictive pericarditis, isolated right HF, or insufficient EMB samples were excluded. Clinical, echocardiographic, and invasive hemodynamic data were collected. The severity of hypertrophy and fibrosis on EMB specimens was characterized (semiquantitative grading) by experienced cardiac pathologists based on standard histologic stains. Patients were stratified into four phenogroups based on EMB findings: "mild" (none/mild hypertrophy and fibrosis), "hypertrophy" (moderate/marked hypertrophy, minimal/mild fibrosis), "fibrosis" (moderate/marked fibrosis, none/mild hypertrophy), and "severe" (moderate/marked hypertrophy and fibrosis). Results Among the 121 patients analyzed, the median age was 67 years, 50% were female and cardiovascular conditions were common (Table 1). Fibrosis was graded as minimal in 21% (n=25), mild in 64% (n=77), moderate in 12% (n=15), and marked in 3% (n=4). Hypertrophy was graded as none in 4% (n=5), mild in 41% (n=50), moderate in 40% (n=48), and marked in 15% (n=18). Only one patient had the isolated "fibrosis" phenogroup and was excluded from further analysis, while 54 had the "mild", 48 had the "hypertrophy", and 18 had the "severe" phenogroup (Table 1). The "hypertrophy" phenogroup exhibited significantly higher rates of hypertension, diabetes, RV dilation, and higher pulmonary artery pressures. Over a median follow-up of 7.9 years (3.1–13.8), mortality rate varied according to the histopathologic phenogroups (Figure 1, p=0.034) with "severe" having the worst and "mild" having the best outcomes. Survival analyses based on fibrosis grades alone, hypertrophy grades alone, or echocardiographic hypertrophy did not reveal significant differences (all p = NS). Differences in survival remained significant adjusting for age (HR 3.39, 95% CI 1.20-9.58). Conclusions The integrated severity of histopathologic hypertrophic and fibrotic remodeling defined HFpEF phenogroups with variable prognosis. Clinical features did not reliably identify histopathologic phenogroups. These data suggest that advanced myocardial phenotyping (e.g., gene, protein, metabolism) may reveal unique HFpEF myocardial subtypes in need of specific therapies.Figure 1

BACKGROUND: Although chronic obstructive pulmonary disease (COPD) and heart failure with preserved ejection fraction often coexist with overlapping clinical features, they are usually studied separately. The SPIROMICS HF (Subpopulations and Intermediate Outcome Measures in COPD and Heart Failure Study) is testing hypotheses that new computed tomography emphysema subtypes are associated with specific cardiovascular phenotypes (eg, cor pulmonale , cor pulmonale parvus ), common airway branch variants are associated with right heart dysfunction, and symptomatic tobacco-exposed persons with preserved spirometry have signs of increased left ventricular afterload. METHODS: SPIROMICS is a multicenter observational study of COPD with extensive pulmonary phenotyping of participants with ≥20 pack-years smoking and nonsmoking controls. COPD and COPD severity were defined by standard spirometric criteria and symptomatic tobacco-exposed persons with preserved spirometry by ≥20 pack-years, normal spirometry, and COPD Assessment Test score >10. SPIROMICS HF selected all participants in SPIROMICS visit 5 at major sites. Its comprehensive speckle-tracking echocardiography, which included physiological perturbations of leg raise and low-intensity exercise, was harmonized prospectively with the Multi-Ethnic Study of Atherosclerosis Early Heart Failure and HeartSHARE (Combining Omics, Deep Phenotyping, and Electronic Health Records for Heart Failure Subtypes and Treatment Targets) studies. The cardiopulmonary magnetic resonance imaging protocol with gadolinium administration included myocardial fibrosis sequences, pulmonary angiography, time-resolved 3-dimensional cine magnetic resonance imaging (4-dimensional flow) of venous return, and metronome-paced tachypnea to induce dynamic hyperinflation. Coronary artery calcium was assessed on computed tomography scans. The Kansas City Cardiomyopathy Questionnaire was administered. RESULTS: Of the final sample of 753 participants, 57% had COPD (15% mild, 27% moderate, and 15% severe), 18% had symptomatic tobacco-exposed persons with preserved spirometry, 16% were smoking controls, and 8% were nonsmoking controls. Reproducibility of the main measures from speckle-tracking echocardiography (intraclass correlation coefficient, 0.83–0.99), exercise echocardiography (intraclass correlation coefficient, 0.71–0.99) and magnetic resonance imaging (intraclass correlation coefficient, 0.57–0.99) were good-to-excellent, including in severe COPD. CONCLUSIONS: SPIROMICS HF aims to characterize and understand cardiopulmonary interactions in COPD and COPD-related phenotypes to inform targeted treatments for combined cardiopulmonary failure.

Importance Excess body fat plays a pivotal role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). HU6 is a novel, controlled metabolic accelerator that enhances mitochondrial uncoupling resulting in increased metabolism and fat-specific weight loss. Objective To assess efficacy and safety of HU6 in reducing body weight, improving peak volume of oxygen consumption (VO 2 ) and body composition among patients with obesity-related HFpEF. Design, Setting, and Participants The Exploratory Phase 2A, Double-Blind, Placebo-Controlled Dose Escalation Study of Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of HU6 for Subjects With Obese HFpEF (HuMAIN-HFpEF) trial was a multicenter, dose-escalation randomized clinical trial among patients with chronic stable HFpEF and obesity. Data were analyzed from July to October 2024. Intervention HU6 treatment for 19 weeks, starting at 150 mg per day and potentially up titrated to 450 mg per day based on safety and tolerability vs placebo. Main Outcomes and Measures The primary end point was change in body weight. Results Of 66 participants randomized (mean [SD] age, 64.5 [12] years; 38 female [58%]; mean [SD] weight, 110.9 [22.4] kg), 56 completed the trial. HU6 (vs placebo) significantly decreased weight (between-group difference, −2.86 kg; 95% CI, −4.68 to −1.04 kg; P = .003), total fat mass (between-group difference, −2.96 kg; 95% CI, −4.50 to −1.42 kg; P < .001), and percentage visceral fat (between-group difference,−1.3%; 95% CI, −2.1 to −0.5%; P = .003), with no significant loss of muscle mass. There were no statistically significant changes in peak VO 2 , 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire score, high-sensitivity C-reactive protein level, N-terminal pro–brain natriuretic peptide level, or diastolic function. Serious adverse events were noted in 5 participants (4 in the HU6 group; 1 in the placebo group), including 1 death, all judged unrelated to treatment. Conclusions and Relevance Among patients with obesity-related HFpEF, treatment with HU6 for 19 weeks led to modest but statistically significant weight loss without significant changes in peak VO 2 . Larger trials of longer duration are warranted to determine whether longer-term administration of HU6 can improve exercise function, quality of life, and cardiovascular outcomes in this increasingly common disorder. Trial Registration ClinicalTrials.gov Identifier: NCT05284617

Abstract Aims Sodium–glucose co-transporter-2 (SGLT2) inhibitors improve health status and outcomes in the setting of heart failure (HF) across the range of ejection fraction (EF). Baseline kidney disease is common in HF, complicates HF management and is strongly linked to worse health status. This study aimed to assess whether the treatment effects of dapagliflozin on health status vary based on estimated glomerular filtration rate (eGFR). Methods and Results We conducted a pooled participant-level analysis of two double-blind, randomized trials, DEFINE-HF (n = 236) and PRESERVED-HF (n = 324), which evaluated dapagliflozin versus placebo. Both multicentre studies enrolled adults with HF, New York Heart Association Class II or higher, elevated natriuretic peptides, and an EF < 40% in DEFINE-HF or >45% in PRESERVED-HF. The primary exposure was eGFR. The main outcome was the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 12 weeks. Across both trials, there were 583 (99.3%) participants with a baseline eGFR. The median (25th, 75th) eGFR was 59 (46, 77) mL/min/1.73 m2. Dapagliflozin improved KCCQ-CSS at 12 weeks [placebo-adjusted difference, +5.0 points, 95% confidence interval (CI) 2.6–7.5; P < 0.001], and this was consistent in participants with an eGFR ≥ 60 (+6.0 points, 95% CI 2.4–9.7; P = 0.001) and eGFR < 60 (+4.1 points, 95% CI 0.5–7.7; P = 0.025) (P interaction = 0.46). The benefits of dapagliflozin on KCCQ-CSS remained robust across eGFR when modelled as a continuous variable (P interaction = 0.48). Conclusions Dapagliflozin led to early and clinically meaningful improvements in health status in HF patients, regardless of EF or baseline eGFR.

Introduction: Patients with heart failure with preserved ejection fraction (HFpEF) have a high burden of comorbidities. To recognize the complex interplay of obesity, diabetes, and chronic kidney disease (CKD) in patients with cardiovascular disease, the cardiovascular-kidney-metabolic (CKM) syndrome was recently defined, but data on the burden of CKM in HFpEF is limited. Aim: We sought to describe the prevalence of CKM components in HFpEF leveraging data from control participants in clinical trials and NHANES. Methods: We analyzed data presented in publications from four randomized clinical trials that enrolled participants with HFpEF (all of which are available via NHLBI BioLINCC and will be included in the extant HeartShare dataset): TOPCAT, RELAX, NEAT-HFpEF, and INDIE. We abstracted baseline demographic and clinical variables from study publications to define CKM components (e.g., body mass index [BMI], diabetes status, hypertension, CKD status). We compared prevalence of CKM in these trials with a representative sample of US adults with self-reported history of heart failure (HF) from NHANES 2011-2018. Results: We included 1937 patients with HFpEF from four trials with enrollment between 2006-2016 and 715 adults representing 5.6 million adults aged ≥40 years with a self-report of HF between 2011-2018 from NHANES ( Table ). Mean age was similar among enrolled trial participants with HFpEF and those with HF in NHANES (~68-69 years). Mean BMI was in the obesity range and was similar among trial participants with HFpEF and HF in NHANES (31-35 kg/m 2 ). A significant proportion of individuals had hypertension in HFpEF trials (>80%) and in the NHANES sample with HF (89%). The proportion of stage ≥ 3 CKD in HFpEF trials (≥ 37%) was similar to the NHANES sample with HF (37%). Results are shown in Table . Conclusions: Patients with HFpEF enrolled in clinical trials and those with HF in general population are significantly enriched with CKM components that may contribute to morbidity and mortality. Similar prevalence estimates were observed despite variability in trial inclusion criteria and heterogeneity in defining HFpEF and highlight CKM as a central target for HFpEF management.

Introduction: Preload insufficiency can mimic HFpEF or complicate its treatment, and SGLT2 inhibitors may worsen preload insufficiency by reducing stressed blood volume. A drop in pulse pressure (PP) when going from supine to standing (i.e., orthostatic PP) may indicate an inability to vasoconstrict the splanchnic circulation, leading to preload insufficiency. We, therefore, sought to determine baseline characteristics associated with orthostatic PP and whether the effects of dapagliflozin vary by baseline orthostatic PP in patients with HFpEF. Hypothesis: In patients with HFpEF, the magnitude of treatment response to dapagliflozin – in terms of efficacy and safety - may be associated with orthostatic PP at baseline. Methods: We measured orthostatic PP (standing PP – supine PP) at baseline in 321 of the 324 patients with HFpEF randomized in the PRESERVED-HF trial. We categorized patients into tertiles of orthostatic PP and compared baseline characteristics. We examined the interaction between baseline orthostatic PP, treatment, and the following outcomes during 12 weeks of follow-up: (1) Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS); (2) 6-minute walk distance (6MWD); (3) volume depletion events. Results: At baseline, the median orthostatic PP was 0 mmHg (25 th -75 th percentile, -8.0, +5.3 mmHg). Patients with lower orthostatic PP had higher supine SBP and lower standing SBP. There were no differences in age, comorbidities, laboratory studies, KCCQ, and 6MWD among tertiles of orthostatic PP. Dapagliflozin improved KCCQ-CSS and 6MWD across the range of orthostatic PP; participants with the highest (vs lowest) orthostatic PP appeared to have numerically greater improvements with dapagliflozin, but these differences were not statistically significant (Table). Overall, 18 (5.6%) experienced volume depletion events (dapagliflozin 11 [6.8%], placebo 7 [4.3%]). In tertile 1 (lowest orthostatic PP), there were numerically more volume depletion events with dapagliflozin than placebo (8 [14.3%] vs 3 [5.0%] events); whereas the numbers of such events were similar in tertiles 2 and 3 (Table). Conclusions: In patients with HFpEF, dapagliflozin improved KCCQ and 6MWD across the range of orthostatic PP, although those with the highest (vs lowest) orthostatic PP appeared to have numerically greater improvements. Very low orthostatic PP may identify patients who could be at increased risk of volume depletion events with SGLT2 inhibitors.

BACKGROUND: Mechanisms of benefit with SGLT2is (sodium-glucose cotransporter-2 inhibitors) in heart failure (HF) remain incompletely characterized. Dapagliflozin alters ketone and fatty acid metabolism in HF with reduced ejection fraction though similar effects have not been observed in HF with preserved ejection fraction. We explore whether metabolic effects of SGLT2is vary across the left ventricular ejection fraction spectrum and their relationship with cardiometabolic end points in 2 randomized trials of dapagliflozin in HF. METHODS: Metabolomic profiling of 61 metabolites was performed in 527 participants from DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) and PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction HF; 12-week, placebo-controlled trials of dapagliflozin in HF with reduced ejection fraction and HF with preserved ejection fraction, respectively). Linear regression was used to assess changes in principal components analysis–defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points. RESULTS: The mean age was 66±11 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis–derived metabolite factors (which were comprised of ketone and short-/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate >500 μM) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo ( P =0.03). There were no appreciable treatment effects on amino acids, including branched-chain amino acids. Increases in several acylcarnitines were consistent across LVEF ( P interaction >0.10), whereas the ketogenic effect diminished at higher LVEF ( P interaction =0.01 for 3-hydroxybutyrate). Increases in metabolites reflecting mitochondrial dysfunction (particularly long-chain acylcarnitines) and aromatic amino acids and decreases in branched-chain amino acids were associated with worse HF-related outcomes in the overall cohort, with consistency across treatment and LVEF. CONCLUSIONS: SGLT2is demonstrate common (fatty acid) and distinct (ketogenic) metabolic signatures across the LVEF spectrum. Changes in key pathways related to fatty acid and amino acid metabolism are associated with HF-related end points and may serve as therapeutic targets across HF subtypes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique Identifiers: NCT03030235 and NCT02653482.