2-Year Outcomes of an Atrial Shunt Device in HFpEF/HFmrEF: Results From REDUCE LAP-HF II.

BACKGROUND: The REDUCE LAP-HF II (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II) trial found that, compared with a sham procedure, the Corvia Atrial Shunt did not improve outcomes in heart failure with preserved or mildly reduced ejection fraction. However, after 12-month follow-up, "responders" (peak-exercise pulmonary vascular resistance <1.74 WU and absence of a cardiac rhythm management device) were identified. OBJECTIVES: This study sought to determine: 1) the overall efficacy and safety of the atrial shunt vs sham control after 2 years of follow-up; and 2) whether the benefits of atrial shunting are sustained in responders during longer-term follow-up or are offset by adverse effects of the shunt. METHODS: The study analyzed 2-year outcomes in the overall REDUCE LAP-HF II trial, as well as in responder and nonresponder subgroups. The primary endpoint was a hierarchical composite of cardiovascular death or nonfatal ischemic/embolic stroke, total heart failure events, and change in health status. RESULTS: In 621 randomized patients, there was no difference between the shunt (n = 309) and sham (n = 312) groups in the primary endpoint (win ratio: 1.01 [95% CI: 0.82-1.24]) or its individual components at 2 years. Shunt patency at 24 months was 98% in shunt-treated patients. Cardiovascular mortality and nonfatal ischemic stroke were not different between the groups; however, major adverse cardiac events were more common in those patients assigned to the shunt compared with sham (6.9% vs 2.7%; P = 0.018). More patients randomized to the shunt had an increase in right ventricular volume of ≥30% compared with the sham control (39% vs 28%, respectively; P < 0.001), but right ventricular dysfunction was uncommon and not different between the treatment groups. In responders (n = 313), the shunt was superior to sham (win ratio: 1.36 [95% CI: 1.02-1.83]; P = 0.037, with 51% fewer HF events [incidence rate ratio: 0.49 [95% CI: 0.25-0.95]; P = 0.034]). In nonresponders (n = 265), atrial shunting was inferior to sham (win ratio: 0.73 [95% CI: 0.54-0.98]). CONCLUSIONS: At 2 years of follow-up in REDUCE LAP-HF II, there was no difference in efficacy between the atrial shunt and sham groups in the overall trial group. The potential clinical benefit identified in the responder group after 1 and 2 years of follow-up is currently being evaluated in the RESPONDER-HF (Re-Evaluation of the Corvia Atrial Shunt Device in a Precision Medicine Trial to Determine Efficacy in Mildly Reduced or Preserved Ejection Fraction Heart Failure) trial. (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II [REDUCE LAP-HF II]; NCT03088033).

A novel controlled metabolic accelerator for the treatment of obesity-related heart failure with preserved ejection fraction: Rationale and design of the Phase 2a HuMAIN trial.

AIMS: Compared with those without obesity, patients with obesity-related heart failure with preserved ejection fraction (HFpEF) have worse symptoms, haemodynamics, and outcomes. Current weight loss strategies (diet, drug, and surgical) work through decreased energy intake rather than increased expenditure and cause significant loss of skeletal muscle mass in addition to adipose tissue. This may have adverse implications for patients with HFpEF, who already have reduced skeletal muscle mass and function and high rates of physical frailty. Mitochondrial uncoupling agents may have unique beneficial effects by producing weight loss via increased catabolism rather than reduced caloric intake, thereby causing loss of adipose tissue while sparing skeletal muscle. HU6 is a controlled metabolic accelerator that is metabolized to the mitochondrial uncoupling agent 2,4-dinotrophenol. HU6 selectively increases carbon oxidation from fat and glucose while also decreasing toxic reactive oxygen species (ROS) production. In addition to sparing skeletal muscle loss, HU6 may have other benefits relevant to obesity-related HFpEF, including reduced specific tissue depots contributing to HFpEF; improved glucose utilization; and reduction in systemic inflammation via both decreased ROS production from mitochondria and decreased cytokine elaboration from excess, dysfunctional adipose. METHODS: We describe the rationale and design of HuMAIN-HFpEF, a Phase 2a randomized, double-blind, placebo-controlled, dose-titration, parallel-group trial in patients with obesity-related HFpEF to evaluate the effects of HU6 on weight loss, body composition, exercise capacity, cardiac structure and function, metabolism, and inflammation, and identify optimal dosage for future Phase 3 trials. CONCLUSIONS: HuMAIN will test a promising novel agent for obesity-related HFpEF.

Circulating beta-hydroxybutyrate levels in advanced heart failure with reduced ejection fraction: Determinants and prognostic impact.

AIMS: Patients with heart failure (HF) display metabolic alterations, including heightened ketogenesis, resulting in increased beta-hydroxybutyrate (ß-OHB) formation. We aimed to investigate the determinants and prognostic impact of circulating ß-OHB levels in patients with advanced HF and reduced ejection fraction (HFrEF). METHODS AND RESULTS: A total of 867 patients with advanced HFrEF (age 57 ± 11 years, 83% male, 45% diabetic, 60% New York Heart Association class III), underwent clinical and echocardiographic examination, circulating metabolite assessment, and right heart catheterization (n = 383). The median ß-OHB level was 64 (interquartile range [IQR] 33-161) µmol/L (normal 0-74 µmol/L). ß-OHB levels correlated with increased markers of lipolysis (free fatty acids [FFA]), higher natriuretic peptides, worse pulmonary haemodynamics, and lower humoral regulators of ketogenesis (insulin/glucagon ratio). During a median follow-up of 1126 (IQR 410-1781) days, there were 512 composite events, including 324 deaths, 81 left ventricular assist device implantations and 107 urgent cardiac transplantations. In univariable Cox regression, increased ß-OHB levels (T3 vs. T1: hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.13-1.72, p = 0.002) and elevated FFA levels (T3 vs. T1: HR 1.39, 95% CI 1.09-1.79, p = 0.008) were both predictors of a worse prognosis. In multivariable Cox analysis evaluating the simultaneous associations of FFA and ß-OHB levels with outcomes, only FFA levels remained significantly associated with adverse outcomes. CONCLUSIONS: In patients with advanced HFrEF, increased plasma ß-OHB correlate with FFA levels, worse right ventricular function, greater neurohormonal activation and other markers of HF severity. The association between plasma ß-OHB and adverse outcomes is eliminated after accounting for FFA levels, suggesting that increased ß-OHB is a consequence reflecting heightened lipolytic state, rather than a cause of worsening HF.

Pulmonary hypertension across the spectrum of left heart and lung disease.

AIMS: Patients with pulmonary hypertension (PH) are grouped based upon clinical and haemodynamic characteristics. Groups 2 (G2, left heart disease [LHD]) and 3 (G3, lung disease or hypoxaemia) are most common. Many patients display overlapping characteristics of heart and lung disease (G2-3), but this group is not well-characterized. METHODS AND RESULTS: Patients with PH enrolled in the prospective, NHLBI-sponsored PVDOMICS network underwent intensive clinical, biomarker, imaging, gas exchange and exercise phenotyping. Patients with pure G2, pure G3, or overlapping G2-3 PH were compared across multiple phenotypic domains. Of all patients with predominant G2 (n = 136), 66 (49%) were deemed to have secondary lung disease/hypoxaemia contributors (G2/3), and of all patients categorized as predominant G3 (n = 172), 41 (24%) were judged to have a component of secondary LHD (G3/2), such that 107 had G2-3 (combined G2/3 and G3/2). As compared with G3, patients with G2 and G2-3 were more obese and had greater prevalence of hypertension, atrial fibrillation, and coronary disease. Patients with G2 and G2-3 were more anaemic, with poorer kidney function, more cardiac dysfunction, and higher N-terminal pro-B-type natriuretic peptide than G3. Lung diffusion was more impaired in G3 and G2-3, but commonly abnormal even in G2. Exercise capacity was severely and similarly impaired across all groups, with no differences in 6-min walk distance or peak oxygen consumption, and pulmonary vasoreactivity to nitric oxide did not differ. In a multivariable Cox regression model, patients with G2 had lower risk of death or transplant compared with G3 (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30-0.86), and patients with G2-3 also displayed lower risk compared with G3 (HR 0.57, 95% CI 0.38-0.86). CONCLUSIONS: Overlap is common in patients with a pulmonary or cardiac basis for PH. While lung structure/function is clearly more impaired in G3 and G2-3 than G2, pulmonary abnormalities are common in G2, even when clinically judged as isolated LHD. Further study is required to identify optimal systematic evaluations to guide therapeutic innovation for PH associated with combined heart and lung disease. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02980887.

Cardiac function, haemodynamics, and valve competence with exercise in patients with heart failure with preserved ejection fraction and mild to moderate secondary mitral regurgitation.

AIMS: This study aimed to evaluate the clinical significance of secondary mitral regurgitation (MR) in patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We conducted a prospective study enrolling consecutively evaluated patients with HFpEF undergoing invasive haemodynamic exercise testing with simultaneous echocardiography. Compared to HFpEF without MR (n = 145, 79.7%), those with mild or moderate MR (n = 37, 20.3%) were older, more likely to be women, had more left ventricular (LV) systolic dysfunction, and more likely to have left atrial (LA) myopathy reflected by greater burden of atrial fibrillation, more LA dilatation, and poorer LA function. Pulmonary artery (PA) wedge pressure was higher at rest in HFpEF with MR (17 ± 5 mmHg vs. 20 ± 5 mmHg, p = 0.005), but there was no difference with exercise. At rest, only 2 (1.1%) patients had moderate MR, and none developed severe MR. Pulmonary vascular resistance was higher, and right ventricular (RV)-PA coupling was more impaired in patients with HFpEF and MR at rest and exercise. LV and LA myocardial dysfunction remained more severe in patients with MR during stress compared to those without MR, characterized by greater LA dilatation during all stages of exertion, lower LA emptying fraction and compliance, steeper and rightward-shifted LA pressure-volume relationships, and reduced LV longitudinal contractile function. CONCLUSIONS: Patients with HFpEF and mild or moderate MR have more severe LV systolic dysfunction, LA myopathy, RV-PA uncoupling, and more severe pulmonary vascular disease. Mitral valve incompetence in this setting is a phenotypic marker of more advanced disease but is not a causal factor in development of HFpEF.

Screening for Unrecognized HFpEF in Atrial Fibrillation and for Unrecognized Atrial Fibrillation in HFpEF.

Because of the bidirectional relationship between atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF), individuals with either condition require consideration of screening for the other. In this review, we summarize current evidence and rationale for screening for occult HFpEF in adults with clinical AF; and occult AF in patients with clinically recognized HFpEF. Assessment of pretest probability for occult HFpEF in symptomatic AF patients may help guide additional testing such as exercise right heart catheterization to diagnose HFpEF and guide HFpEF-specific therapies. In patients with HFpEF, AF screening will identify cases of occult AF where anticoagulation may decrease stroke risk, and correlation of previously unknown AF episodes with paroxysmal symptoms may prompt consideration for rhythm control. Therefore, screening may help clinicians understand the etiology of the often-overlapping symptoms, and it may help guide treatments to slow progression of both conditions and their complications.

Imaging and Mechanisms of Heart Failure with Preserved Ejection Fraction: A State of the Art Review.

Understanding of the pathophysiology of heart failure with preserved ejection fraction (HFpEF) has advanced rapidly over the past two decades. Currently, HFpEF is recognized as a heterogeneous syndrome, and there is a growing movement towards developing personalized treatments based on phenotype-guided strategies. Left ventricular dysfunction is a fundamental pathophysiological abnormality in HFpEF; however, recent evidence also highlights significant roles for the atria, right ventricle, pericardium, and extracardiac contributors. Imaging plays a central role in characterizing these complex and highly integrated domains of pathophysiology. This review focuses on established evidence, recent insights, and the challenges that need to be addressed concerning the pathophysiology of HFpEF, with a focus on imaging-based evaluations and opportunities for further research.

Efficacy of Semaglutide by Sex in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Trials.

BACKGROUND: More women than men have heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: The purpose of this study was to assess baseline characteristics and treatment effect of semaglutide by sex across the STEP-HFpEF (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity) program. METHODS: In a prespecified secondary analysis of pooled data from STEP-HFpEF and STEP-HFpEF DM (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes), patients with heart failure (HF), left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to once-weekly semaglutide 2.4 mg or matched placebo for 52 weeks. Dual primary endpoints (KCCQ-CSS change and percentage change in body weight) and confirmatory secondary endpoints (6-minute walking distance [6MWD] change; hierarchical composite endpoint comprising all-cause death, HF events, changes in KCCQ-CSS, and 6MWD; and C-reactive protein) were compared between sexes. RESULTS: Of 1,145 patients, 570 (49.7%) were women. Women had higher body mass index, left ventricular ejection fraction, C-reactive protein, and worse HF symptoms, and were less likely to have atrial fibrillation or coronary artery disease vs men. Semaglutide improved KCCQ-CSS regardless of sex (mean difference in women +7.6 points [95% CI: 4.5-10.7 points]; men +7.5 points [95% CI: 4.3-10.6 points]; P interaction = 0.94) but reduced body weight more in women (mean difference in women -9.6% [95% CI: -10.9% to -8.4%]; men -7.2% [95% CI: -8.4% to -6.0%]; P interaction = 0.006). Semaglutide improved 6MWD (P interaction = 0.21) and the hierarchical composite endpoint (P interaction = 0.66) in both sexes. Fewer serious adverse events were reported with semaglutide vs placebo. CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide 2.4 mg reduced body weight to a greater extent in women, and produced similar improvements in HF-related symptoms, physical limitations, and exercise function, regardless of sex. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; and Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM]; NCT04916470).

Semaglutide and NYHA Functional Class in Obesity-Related Heart Failure With Preserved Ejection Fraction: The STEP-HFpEF Program.

BACKGROUND: In the Semaglutide Treatment Effect in People with obesity and HFpEF (STEP-HFpEF) program, semaglutide improved heart failure (HF)-related symptoms, physical limitations, and exercise function, and reduced bodyweight in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Whether semaglutide improves functional status, as assessed by NYHA functional class, is unknown. OBJECTIVES: The goal of this study was to examine the effects of semaglutide on change in NYHA functional class over time. We also investigated the effects of semaglutide on HF-related symptoms, physical limitations, and bodyweight and other trial endpoints across baseline NYHA functional class categories. METHODS: This was a prespecified analysis of pooled data from 2 international, double-blind, randomized trials (STEP-HFpEF and STEP-HFpEF type 2 diabetes [STEP-HFpEF DM], comprising the STEP-HFpEF program), which collectively randomized 1,145 participants with obesity-related HFpEF to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. The outcome of interest for this analysis was the change in NYHA functional class (baseline to 52 weeks). We also investigated the effects of semaglutide on the dual primary, confirmatory secondary, and selected exploratory endpoints according to baseline NYHA functional class. RESULTS: More semaglutide-treated than placebo-treated patients had an improvement in NYHA functional class (32.6% vs 21.5%, respectively; OR: 2.20 [95% CI: 1.62-2.99; P < 0.001]) and fewer semaglutide-treated patients experienced deterioration in NYHA functional class (2.09% vs 5.24%, respectively; OR: 0.36 [95% CI: 0.19-0.70; P = 0.003]) at 52 weeks. Semaglutide (vs placebo) improved the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CCS) across NYHA functional class categories; this was especially pronounced in those in NYHA functional classes III/IV (10.5 points [95% CI: 6.6-14.4 points]) vs NYHA functional class II (6.0 points [95% CI: 3.4-8.6 points]) (P interaction = 0.06). By contrast, the degree of reduction in bodyweight was similar with semaglutide vs placebo regardless of baseline NYHA functional class category (NYHA functional class II, -8.4% [95% CI: -9.4% to -7.3%]; NYHA functional classes III/IV, -8.3% [95% CI: -9.9% to -6.8%]; P interaction = 0.96). Semaglutide consistently improved 6-minute walking distance (6MWD), the hierarchical composite endpoint (death, HF events, differences in KCCQ-CSS, and 6MWD changes), and reduced C-reactive protein and N-terminal prohormone of brain natriuretic peptide across NYHA functional class categories (all P interactions = NS). CONCLUSIONS: In patients with obesity-related HFpEF, fewer semaglutide-treated than placebo-treated patients had a deterioration, and more had an improvement, in NYHA functional class at 52 weeks. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced bodyweight and biomarkers of inflammation and congestion in all NYHA functional class categories. Semaglutide-mediated improvements in health status were especially large in patients with NYHA functional classes III/IV. (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure and Obesity; NCT04788511) (Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes; NCT04916470).

Semaglutide and NT-proBNP in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program.

BACKGROUND: The glucagon-like peptide-1 receptor agonist, semaglutide, improved health status and reduced body weight in patients with obesity-related heart failure (HF) with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with Obesity and HFpEF) program. Whether benefits were due to mechanical unloading or effects on HF pathobiology is uncertain. OBJECTIVES: This study sought to determine if semaglutide 2.4 mg reduced N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with obesity-related HFpEF and compare treatment responses by baseline NT-proBNP. METHODS: This was a prespecified secondary analysis of pooled data from 2 double-blind, placebo-controlled, randomized trials (STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes]) testing effects of semaglutide in patients with obesity-related HFpEF. The main outcomes were change in NT-proBNP at 52 weeks and change in the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and body weight by baseline NT-proBNP. RESULTS: In total, 1,145 patients were randomized. Semaglutide compared with placebo reduced NT-proBNP at 52 weeks (estimated treatment ratio: 0.82; 95% CI: 0.74-0.91; P = 0.0002). Improvements in health status were more pronounced in those with higher vs lower baseline NT-proBNP (estimated difference: tertile 1: 4.5 points, 95% CI: 0.8-8.2; tertile 2: 6.2 points, 95% CI: 2.4-10.0; tertile 3: 11.9 points, 95% CI: 8.1-15.7; P interaction = 0.02; baseline NT-proBNP as a continuous variable: P interaction = 0.004). Reductions in body weight were consistent across baseline NT-proBNP levels (P interaction = 0.21). CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide reduced NT-proBNP. Participants with higher baseline NT-proBNP had a similar degree of weight loss but experienced larger reductions in HF-related symptoms and physical limitations with semaglutide than those with lower NT-proBNP.

Semaglutide and Diuretic Use in Obesity-Related Heart Failure with Preserved Ejection Fraction: A Pooled Analysis of the STEP-HFpEF and STEP-HFpEF-DM trials.

BACKGROUND AND AIMS: In the STEP-HFpEF trial program, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. METHODS: In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n=1145), which randomized participants with HFpEF and body mass index ≥30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. RESULTS: At baseline, across no diuretic (n=220), non-loop diuretic only (n=223), and loop diuretic (<40 [n=219], 40 [n=309], and >40 [n=174] mg/day furosemide-equivalents) groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from -8.8% [95% CI -10.3, -6.3] to -6.9% [95% CI -9.1, -4.7] from no diuretics to the highest loop diuretic dose category; interaction P=0.39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P=0.042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6-min walk distance) across diuretic subgroups (interaction P=0.24-0.92). Safety also favored semaglutide versus placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P<0.0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P<0.001 for both) from baseline to 52 weeks. CONCLUSIONS: In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide versus placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. CLINICALTRIALS.GOV REGISTRATION: NCT04788511 and NCT04916470.

Autoimmune Disorders in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Inflammation plays a fundamental role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). In most patients, inflammation develops secondary to cardiometabolic comorbidities, but in some, HFpEF develops in the setting of an underlying systemic inflammatory disease such as rheumatoid arthritis or systemic lupus erythematosus. OBJECTIVES: This study aimed to investigate the prevalence, pathophysiology, and outcome of patients with HFpEF and autoimmune or primary inflammatory disorders. METHODS: Of 982 consecutively evaluated patients with HFpEF diagnosed, 79 (8.0%) had autoimmune disorders. HFpEF was defined by invasive cardiopulmonary hemodynamic exercise testing. RESULTS: Female sex, higher heart rate, lower hemoglobin, absence of atrial fibrillation, and absence of coronary artery disease were independently associated with autoimmune disorders. Hemodynamics at rest and exercise did not differ between the groups, but peripheral oxygen extraction was lower in those with autoimmune disorders, reflected by lower arterial-venous oxygen content difference at rest (4.2 ± 0.7 mL/dL vs 4.6 ± 1.0 mL/dL; P < 0.001) and during exercise (9.3 ± 2.2 mL/dL vs 10.4 ± 2.2 mL/dL; P < 0.001), suggesting a greater peripheral deficit, and ventilatory efficiency (VE/VCo2 slope, regression slope relating minute ventilation to carbon dioxide output) was also more impaired (38.0 ± 7.9 vs 36.2 ± 7.3; P = 0.043). Patients with autoimmune disorders had a higher risk of death or heart failure (HF) hospitalization compared with those without in adjusted analyses (HR: 1.95 [95% CI: 1.17-3.27]; P = 0.011) over a median follow-up of 3.0 years, which was primarily attributable to higher risk of HF hospitalization (HR: 2.87 [95% CI: 1.09-7.57]; P = 0.033). CONCLUSIONS: Patients with HFpEF and autoimmune disorders have similar hemodynamic derangements but greater peripheral deficits in oxygen transport and higher risk for adverse outcome compared with those without.

Targeted Metabolomic Profiling of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The PRESERVED-HF Trial.

BACKGROUND: Although sodium glucose co-transporter 2 inhibitors (SGLT2is) improve heart failure (HF)-related symptoms and outcomes in HF with preserved ejection fraction (HFpEF), underlying mechanisms remain unclear. In HF with reduced EF, dapagliflozin altered ketone and fatty acid metabolites vs placebo; however, metabolite signatures of SGLT2is have not been well elucidated in HFpEF. OBJECTIVES: The goal of this study was to assess whether SGLT2i treatment altered systemic metabolic pathways and their relationship to outcomes in HFpEF. METHODS: Targeted profiling of 64 metabolites was performed from 293 participants in PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure), a 12-week, placebo-controlled trial of dapagliflozin. Linear regression assessed changes in metabolite factors defined by principal components analysis (PCA) with dapagliflozin vs placebo. The relationship between changes in metabolite factors with changes in study endpoints was also assessed. RESULTS: The mean age was 70 ± 11 years, 58% were female, and 29% were Black. There were no significant differences in 12 PCA-derived metabolite factors between treatment arms, including metabolites reflecting ketone, fatty acid, or branched-chain amino acid (BCAA) pathways. Combining treatment arms, changes in BCAAs and branched-chain ketoacids were negatively associated with changes in N-terminal pro-B-type natriuretic peptide; changes in medium-/long-chain acylcarnitines were positively associated with changes in N-terminal pro-B-type natriuretic peptide and negatively associated with changes in 6-minute walk test distance; and changes in ketones were negatively associated with changes in weight, without treatment interaction. CONCLUSIONS: Leveraging targeted metabolomics in a placebo-controlled SGLT2i trial of HFpEF, dapagliflozin did not alter systemic metabolic as reflected by circulating metabolites, in contrast with reported effects in HF with reduced ejection fraction. Metabolite biomarkers reflecting BCAA, ketone, and fatty acid metabolism were associated with markers of disease severity, suggesting a role for potential novel treatment targets. (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure [PRESERVED-HF]; NCT03030235).

Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials.

BACKGROUND: In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. METHODS: We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. FINDINGS: Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. INTERPRETATION: In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. FUNDING: Novo Nordisk.

A roadmap for therapeutic discovery in pulmonary hypertension associated with left heart failure. A scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Working Group on Pulmonary Circulation & Right Ventricular Function.

Pulmonary hypertension (PH) associated with left heart failure (LHF) (PH-LHF) is one of the most common causes of PH. It directly contributes to symptoms and reduced functional capacity and negatively affects right heart function, ultimately leading to a poor prognosis. There are no specific treatments for PH-LHF, despite the high number of drugs tested so far. This scientific document addresses the main knowledge gaps in PH-LHF with emphasis on pathophysiology and clinical trials. Key identified issues include better understanding of the role of pulmonary venous versus arteriolar remodelling, multidimensional phenotyping to recognize patient subgroups positioned to respond to different therapies, and conduct of rigorous pre-clinical studies combining small and large animal models. Advancements in these areas are expected to better inform the design of clinical trials and extend treatment options beyond those effective in pulmonary arterial hypertension. Enrichment strategies, endpoint assessments, and thorough haemodynamic studies, both at rest and during exercise, are proposed to play primary roles to optimize early-stage development of candidate therapies for PH-LHF.

Atrial Shunt Device Effects on Cardiac Structure and Function in Heart Failure With Preserved Ejection Fraction: The REDUCE LAP-HF II Randomized Clinical Trial.

Importance: Although the results of A Study to Evaluate the Corvia Medical Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF II) trial were neutral overall, atrial shunt therapy demonstrated potential efficacy in responders (no latent pulmonary vascular disease and no cardiac rhythm management device). Post hoc analyses were conducted to evaluate the effect of shunt vs sham stratified by responder status. Objective: To evaluate the effect of atrial shunt vs sham control on cardiac structure/function in the overall study and stratified by responder status. Design, Setting, and Participants: This was a sham-controlled randomized clinical trial of an atrial shunt device in heart failure with preserved ejection fraction (HFpEF)/HF with mildly reduced EF (HFmrEF). Trial participants with evaluable echocardiography scans were recruited from 89 international medical centers. Data were analyzed from April 2023 to January 2024. Interventions: Atrial shunt device or sham control. Main Outcome Measures: Changes in echocardiographic measures from baseline to 1, 6, 12, and 24 months after index procedure. Results: The modified intention-to-treat analysis of the REDUCE LAP-HF II trial included 621 randomized patients (median [IQR] age, 72.0 [66.0-77.0] years; 382 female [61.5%]; shunt arm, 309 [49.8%]; sham control arm, 312 [50.2%]). Through 24 months, 212 of 217 patients (98%) in the shunt arm with evaluable echocardiograms had patent shunts. In the overall trial population, the shunt reduced left ventricular (LV) end-diastolic volume (mean difference, -5.65 mL; P <.001), left atrial (LA) minimal volume (mean difference, -2.8 mL; P =.01), and improved LV systolic tissue Doppler velocity (mean difference, 0.69 cm/s; P <.001) and LA emptying fraction (mean difference, 1.88 percentage units; P =.02) compared with sham. Shunt treatment also increased right ventricular (RV; mean difference, 9.58 mL; P <.001) and right atrial (RA; mean difference, 9.71 mL; P <.001) volumes but had no effect on RV systolic function, pulmonary artery pressure, or RA pressure compared with sham. In the shunt arm, responders had smaller increases in RV end-diastolic volume (mean difference, 5.71 mL vs 15.18 mL; interaction P =.01), RV end-systolic volume (mean difference, 1.58 mL vs 7.89 mL; interaction P =.002), and RV/LV ratio (mean difference, 0.07 vs 0.20; interaction P <.001) and larger increases in transmitral A wave velocity (mean difference, 5.08 cm/s vs -1.97 cm/s; interaction P =.02) compared with nonresponders randomized to the shunt, suggesting greater ability to accommodate shunted blood through the pulmonary circulation enabling LA unloading. Conclusions and Relevance: In this post hoc analysis of the REDUCE LAP-HF II trial, over 2 years of follow-up, atrial shunting led to reverse remodeling of left-sided chambers and increases in volume of right-sided chambers consistent with the shunt flow but no change in RV systolic function compared with sham. Changes in cardiac structure/function were more favorable in responders compared with nonresponders treated with the shunt, supporting the previously identified responder group hypothesis and mechanism, although further evaluation with longer follow-up is needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03088033.