Heart failure with preserved ejection fraction (HFpEF) has limited therapeutic options. Abnormal calcium handling through impaired sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) activity contributes to diastolic dysfunction. AAV1.SERCA2A, an Adeno-Associated Virus Serotype 1 (AAV1) vector encoding SERCA2a, may improve myocardial relaxation in HFpEF. Modulation of SERCA2a of Intra-myocytic Calcium Trafficking in Heart Failure With Preserved Ejection Fraction (MUSIC-HFpEF) is a Phase 1b, open-label, multicenter trial (NCT06061549) currently enrolling 10 patients with hemodynamically confirmed HFpEF. Patients receive a one-time intracoronary infusion of AAV1.SERCA2A. The primary objective is to assess safety and tolerability; secondary endpoints include effects on resting and exercise hemodynamics, echocardiographic measures of relaxation, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and functional status. MUSIC-HFpEF is the first-in-human trial of SERCA2a gene therapy in HFpEF. Findings will inform the feasibility, safety, and potential clinical benefit of targeted gene therapy in this population. The study is enrolling participants and aims to clarify the safety profile and potential benefits of administering a single dose of AAV1.SERCA2A to individuals with HFpEF.

Patients with advanced valvular disease frequently experience oral diuretic resistance. We describe the use of intranasal bumetanide, a nonoral diuretic, in a 76-year-old woman with severe mitral regurgitation who had recurrent volume overload and oral diuretic resistance. Decongestion following intranasal bumetanide ultimately allowed for advanced evaluation and successful transcatheter mitral valve replacement. This case demonstrates that nonoral diuretic therapy may serve as an effective bridge to advanced structural interventions, allowing for home administration and avoidance of hospitalizations. Nonoral diuretics can be an alternative to preadmission and in-hospital optimization before minimally invasive valvular procedures.

AIMS:Congestion signals heart failure progression and drives decompensation. Reliable management strategies remain poorly developed. We evaluated 12-months of congestion-guided clinical management following implantation of an inferior vena cava (IVC) sensor. METHODS AND RESULTS:Data were combined from two prospective studies (FUTURE-HF and FUTURE-HFII) (N=65, mean age 65.7±9.5 years; 75.4% NYHA III; 90.8% HFrEF). Patients recorded daily IVC parameters. Adjudicated safety outcomes, sensor-derived IVC area measurement versus CT imaging, medication adjustments, and clinical outcomes at 12-months were analysed.No adjudicated device or procedure-related serious adverse events occurred. Excellent correlation was observed between sensor-derived and CT-derived IVC area (n=44; R2=0.97; mean relative error <5%). Patient adherence was 93% and a sustained, significant reduction in IVC area was observed (8.1%, p<0.005), correlated with clinical improvements (p<0.001), despite no significant change in body weight. Improvements were observed in NYHA functional class (Class III: 74.5% improved to 40.0%; p<0.01) and NT-proBNP (median 1697 reduced to 998 ng/L; p<0.001). HF events (HFEs) were lower post-implant (0.31/year, 1.67/year pre-implant; 84.5% relative reduction; rate ratio: 0.18; 95% CI: 0.08-0.29). Medication adjustments (n=415) included diuretic titration (57%) and increased use of guideline directed medical therapy from baseline to 12-months (28%). CONCLUSIONS:Congestion management through ambulatory IVC monitoring demonstrated excellent safety, sustained accuracy, and high levels of patient adherence at 12-months after sensor implantation. This was associated with improved HF congestion status and a lower observed rate of HFEs, supporting investigation of congestion-guided management using IVC monitoring in a pivotal randomized clinical trial.

Systemic inflammation has gained attention in heart failure (HF), particularly HF with preserved ejection fraction (HFpEF); a heterogeneous syndrome representing over half of HF cases and increasingly recognized in individuals with systemic rheumatologic diseases. Although myocardial infarction and HF with reduced EF have traditionally been emphasized in the context of systemic inflammation, recent data suggest that HFpEF is the predominant phenotype, often arising independently of overt coronary artery disease. Despite substantial cardiovascular morbidity and mortality, patients with rheumatologic disease remain underrepresented in HF research, and the mechanisms linking inflammation to HFpEF remain underdescribed in this population. This review examines the intersection of systemic rheumatologic disease and HFpEF, focusing on shared pathophysiology, diagnostic challenges, and therapeutic opportunities. Patients with rheumatologic diseases, including rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, and systemic sclerosis, exhibit a markedly increased risk of HFpEF. Chronic inflammation, microvascular dysfunction, and myocardial fibrosis emerge as key drivers. These conditions complicate diagnosis because of atypical symptoms and overlapping comorbidities. Although existing HFpEF therapies primarily target hemodynamic and metabolic contributors, they seldom address immune‐mediated mechanisms. Anti‐inflammatory strategies have shown cardiovascular benefit in selected populations; yet their role in HFpEF among rheumatologic subgroups remains underexplored. Exclusion of patients with rheumatologic disease or immunosuppressive therapy from HFpEF trials further limits generalizability. In conclusion, HFpEF associated with rheumatologic disease represents a distinct, underrecognized inflammatory phenotype. Collaborative cardiology‐rheumatology research is needed to refine diagnosis, evaluate immunomodulatory strategies, and design inclusive clinical trials to improve outcomes in this growing population.

BACKGROUND:Obesity and systemic inflammation have each been independently associated with an increased risk of heart failure (HF). However, whether inflammatory pathways mediate the association between obesity and the development of heart failure remains unclear. METHODS:We analyzed data from a community-based cohort of 1998 participants to evaluate multiple adiposity indicators in relation to incident HF. hs-CRP (high-sensitivity C-reactive protein) was examined as a mediator using causal mediation analysis to quantify the contribution of systemic inflammation. Kaplan-Meier analyses and multivariable Weibull accelerated failure time models were applied to estimate hazard ratios (HRs) for HF occurrence. RESULTS:Over a median follow-up of 6.9 years, individuals with elevated hs-CRP levels showed significantly lower HF-free survival (log-rank P=0.010). In multivariable accelerated failure time models, indicators of central obesity and hs-CRP-but not BMI-were significantly associated with higher HF risk (eg, waist circumference: HR=1.30 [95% CI: 1.05-1.61], P=0.017; hs-CRP: HR=1.25 [1.05-1.51], P=0.013). Mediation analysis revealed that hs-CRP accounted for 26.5% of the effect of waist circumference and 32.4% of the effect of waist-to-height ratio on HF risk, with statistically significant indirect effects for both. CONCLUSIONS:Our findings build upon recent conceptual advances by demonstrating that central obesity contributes to HF largely through inflammation. By quantifying the proportion of HF risk attributable to systemic inflammation, this study reinforces the rationale for prioritizing both anti-obesity and anti-inflammatory strategies in HF prevention.

BACKGROUND:The accuracy of the methods of cardiac index (CI) calculation and their relationship with clinical outcomes in patients with left ventricular assist devices (LVADs) is unclear. OBJECTIVES:We sought to evaluate direct and indirect methods for CI calculation in patients with LVADs and assess the association of these estimations with clinical outcomes. METHODS:We reviewed all adult patients who underwent right heart catheterization (RHC) at a Duke University Hospital between March 1, 2021 and April 30, 2025 and identified 140 patients (151 instances of RHC) with LVADs and simultaneous resting oxygen consumption (VO2) measurement. VO2 was measured for calculation of direct Fick (dFick) CI and estimated VO2 was used to calculate indirect Fick (iFick). Coefficient of determination and Bland-Altman analysis was used to compare the iFick and dFick methods. Univariate and multivariate logistic regressions were performed to assess the relationship of the CI method and composite outcome of death/heart transplant/heart failure hospitalization. RESULTS:Correlation between dFick CI and iFick CI estimation was poor (R2 = 0.37, 0.36, 0.25, 0.42 for Dehmer, LaFarge, Bergstra, and body mass index-adjusted Dehmer, respectively) without directional bias. Greater than 25% difference between the indirect and direct Fick was common. In a multivariate model, only direct CI was associated with decreased odds of the composite outcome (odds ratio, 0.440; P = .022). CONCLUSIONS:There is poor correlation between indirect methods of CI calculation compared with dFick CI in patients with LVADs. In our cohort, a lower dFick significantly predicted a composite outcome of death, heart failure, and need for heart transplantation.

BACKGROUND:Glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy is increasingly used, but the physiological effects in patients with heart failure and reduced ejection fraction (HFrEF) remain uncertain. Continuously collected data from implantable cardiac devices may enable evaluation of drug effects in a real-world setting. METHODS:In a nationwide Danish retrospective matched cohort study, GLP-1RA initiators with implantable cardiac devices were matched 1:5 to unexposed device recipients by sex and age. Sensor data were assessed from 30 days before to 30 days after initiation. Primary outcomes were changes in heart rate and thoracic impedance. Analyses were adjusted for baseline sensor value, BMI category, hypertension, and type 2 diabetes. Prespecified subgroup analyses were performed in patients with HFrEF. RESULTS:In 666 patients (111 GLP-1RA initiators, 555 matched controls), semaglutide was used in 95% of initiators. Compared with controls, GLP-1RA initiation was associated with higher night heart rate (adjusted difference 2.12 bpm; 95% CI, 1.38 to 2.87), higher daily heart rate (1.46 bpm; 95% CI, 0.65 to 2.06), and higher thoracic impedance (0.66 Ω; 95% CI, 0.17 to 1.15) (all P<0.01). S1 amplitude decreased (-0.09 mG; 95% CI, -0.14 to -0.04; P<0.01). Heart rate increases followed a stepwise pattern across semaglutide dose levels, with an average increase of 2.5 bpm per dose escalation. Findings were directionally consistent in patients with HFrEF (GLP-1RA n=80), with no evidence of effect modification. CONCLUSION:GLP-1RA initiation was associated with measurable changes in device-derived physiology. Larger studies are needed to evaluate clinical implications, including in HFrEF. TRIAL REGISTRATION:Clinicaltrials.gov (NCT06099158).

Background: Central obesity is a stronger determinant of cardiovascular diseases than body mass index (BMI), yet the biological mechanisms linking adiposity distribution to heart failure (HF) remain unclear. Recent evidence suggests that diabetes-associated HF is driven primarily by visceral adiposity rather than hyperglycemia. Whether systemic inflammation quantitatively mediates the relationship between central obesity and HF has not been well established. Hypothesis: We hypothesized that systemic inflammation, indexed by high-sensitivity C-reactive protein (hs-CRP), mediates the association between central adiposity and incident HF. Methods: We analyzed 1,998 adults from the Jackson Heart Study without HF at baseline. Adiposity indicators included weight, BMI, waist circumference (WC), and waist-to-height ratio (WHtR). hs-CRP was measured as a marker of systemic inflammation. Weibull accelerated failure time models estimated adjusted hazard ratios (HRs) for HF, and causal mediation analysis quantified the proportion of adiposity-related HF risk mediated through hs-CRP. Results: Over a median follow-up of 6.9 years, elevated hs-CRP (≥ 1 mg/L) was associated with lower HF-free survival (log-rank p = 0.010). In adjusted models, WC (HR 1.31, 95% CI 1.06–1.62) and WHtR (HR 1.27, 95% CI 1.02–1.58) were independent predictors of HF, whereas BMI was not. Mediation analysis showed that hs-CRP accounted for 25.4% of the effect of WC and 28.5% of the effect of WHtR on HF risk, both with statistically significant indirect effects. Conclusions: Systemic inflammation mediates approximately one quarter of the relationship between central obesity and incident HF, reinforcing the paradigm that visceral fat–driven inflammation is a key causal pathway linking obesity to HF. These findings underscore the importance of targeting adiposity-related inflammation in HF prevention strategies.

AIM:Heart failure with preserved ejection fraction (HFpEF) presents a therapeutic challenge, characterised by a paucity of validated treatments. Emerging data suggest that targeting adiposity is central to HFpEF pathogenesis. We conducted an updated network meta-analysis to compare the efficacy of emerging and established HFpEF therapies. MATERIALS AND METHODS:We systematically searched PubMed, Embase and Cochrane Library from inception to April 2025 for randomised controlled trials enrolling patients with HFpEF and evaluating pharmacotherapies, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, mineralocorticoid receptor antagonists (MRAs), digoxin, angiotensin receptor-neprilysin inhibitor, sodium-glucose transporter 2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), nitrates and nitrites. The primary outcome was a composite of cardiovascular death and heart failure (HF) hospitalisation. The secondary outcomes included cardiovascular death, all-cause mortality, worsening HF events, change in the 6-min walk test (6MWT) distance, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and N-terminal pro-B-type natriuretic peptide levels. A frequentist random-effects NMA was conducted. RESULTS:Thirty-nine trials with 78 treatment arms and 48 235 patients were enrolled. Compared with placebo, GLP-1 RAs (HR: 0.73, 95% CI 0.61-0.88) and SGLT2is (HR: 0.79, 95% CI 0.70-0.90; P-score: 0.807) significantly reduced the risk of cardiovascular death and HF hospitalisation. GLP-1 RAs showed the highest probability of ranking first (P-score: 0.871). GLP-1 RAs elicited the greatest improvement in functional outcomes, including the 6MWT (mean difference: +17.60 m, 95% CI 8.53-26.67) and KCCQ-CSS (mean difference: +7.38 points, 95% CI 5.51-9.26). No statistically significant differences in cardiovascular death or all-cause mortality were observed among the treatments. CONCLUSIONS:In patients with HFpEF, GLP-1RA, SGLT2i and MRA significantly reduced the risk of cardiovascular death and HF hospitalisation, while GLP-1RA additionally improved the functional and quality-of-life outcomes. GLP-1RA and SGLT2i significantly reduced HF morbidity, and GLP-1RA uniquely improved functional status, positioning adiposity modulation as a central therapeutic target in HFpEF.

Despite major advances in guideline-directed medical therapy (GDMT), many patients with heart failure with reduced ejection fraction (HFrEF) remain symptomatic, with persistent limitations in functional capacity and health status, underscoring the need for adjunctive therapeutic strategies. Direct cardiac microcurrent (C-MIC) therapy is a non-excitatory bioelectrical intervention device to modulate myocardial remodeling rather than rhythm or acute contractility. C-MIC therapy influence myocardial biology, including pathways related to fibrosis, inflammation, and cellular homeostasis by delivering continuous, subthreshold direct current. Preclinical studies across cardiomyocytes, animal models, and cardiac fibroblasts suggest that microcurrent exposure may attenuate profibrotic signaling, regulate extracellular matrix turnover, and improve calcium handling, providing a mechanistic rationale for reverse remodeling. Early clinical experience, including first-in-human studies and a randomized trial in carefully selected patients with non-ischemic HFrEF, demonstrates feasibility and a consistent signal of improvement in left ventricular function, functional capacity, and patient-reported outcomes. However, the current evidence base remains limited by small sample size, open-label designs, and the absence of sham-controlled evaluation. All available clinical data are derived from surgically implanted systems, and the effectiveness of less invasive configurations remains uncertain. Accordingly, C-MIC should be considered an investigational therapy. Future development will require rigorous mechanistic validation, optimization of device programming and delivery parameters, and confirmation of efficacy in adequately powered, sham-controlled trials to define its role in contemporary HF management.

This 2026 focused update of the original iCARDIO Alliance Global Implementation Guidelines on Heart Failure published in 2025 incorporates emerging evidence relevant to acute and chronic HF, including heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and cardiomyopathies. When patients with HFrEF experience substantial improvement in LVEF they are commonly diagnosed as having HF with improved EF (HFimpEF). We define HFimpEF to be present, when in a patient who previously was diagnosed with HFrEF an improvement in the LVEF of at least 10 percentage points to an LVEF ≥50% is observed. The main updates in the therapeutic recommendations of the Global Implementation Guidelines on Heart Failure pertain to evolving data on the soluble guanylate cyclase stimulator vericiguat, cardiac glycosides, GLP-1 receptor agonists, cardiac myosin inhibitors, and preventive vaccination strategies. Revised recommendations were informed by recently published randomized trials, and selected additional post-hoc analyses and meta-analyses demonstrating improvements in symptoms, quality of life, HF hospitalization or mortality among patients receiving contemporary guideline-directed medical therapy (GDMT) regarding the approaches mentioned above. Consistent with the overarching iCARDIO Alliance framework, these recommendations additionally consider the feasibility, monitoring requirements, multidisciplinary expertise, and globally varying levels of healthcare resources. In selected cases, specific implementation guidance is provided for settings in which resources are somewhat limited or severely limited. Accordingly, this document provides a concise, evidence-informed, and globally applicable focused update to HF management strategies, aiming to support clinicians in optimizing HF care and improving patient outcomes across a broad range of healthcare systems worldwide.

Patients with heart failure with preserved ejection fraction (HFpEF) account for over half of heart failure (HF) cases globally and the presence of HFpEF is closely linked with systemic hypertension, which contributes to the structural, hemodynamic, and symptomatic burden of the disease. HFpEF is a heterogeneous syndrome in which concentric remodeling/hypertrophy and diastolic dysfunction commonly arise from chronic pressure overload (often hypertension) and/or age-related arterial stiffening, metabolic comorbidity, and other myocardial substrates. This review critically examines the rationale for intensive blood pressure (BP) management in HF, particularly HFpEF, emphasizing its dual role in disease prevention and symptom alleviation. Drawing from landmark trials and mechanistic studies, the review demonstrates how acute and sustained BP reductions can improve hemodynamic profiles, reverse remodeling, and enhance functional capacity. It further explores the pathophysiologic underpinnings of hypertensive HFpEF, including left ventricular remodeling, arterial stiffness, pulmonary hypertension, right ventricular dysfunction, and metabolic-renal comorbidities; all of which amplify symptomatic burden. In addition, this review evaluates pharmacologic agents with antihypertensive and HF benefits, such as mineralocorticoid receptor antagonists (MRAs), angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and sodium–glucose cotransporter 2 inhibitors (SGLT2i). It also presents emerging evidence for renal denervation (RDN) as a novel adjunctive therapy, particularly in patients with resistant hypertension or autonomic imbalance. Preclinical and early clinical findings suggest that RDN may reduce sympathetic overactivity, enhance arterial compliance, and promote reverse cardiac remodeling in HFpEF. Ultimately, this review highlights BP modulation as a modifiable target capable of altering the trajectory of HFpEF, advocating for earlier and more intensive intervention strategies to improve both clinical and patient-reported outcomes.

Background Current diagnostic criteria for postural orthostatic tachycardia syndrome (POTS) require history of orthostatic intolerance and heart rate elevation of ≥30 bpm in adults or ≥40 bpm in adolescents during a 10-minute standing or a tilt table test. Many patients with orthostatic intolerance experience autonomic dysfunction and functional impairment despite not meeting the required heart rate increase. These patients remain undiagnosed, untreated and excluded from research studies. We sought to develop international multidisciplinary consensus guidance statements addressing the recognition, diagnosis, treatment, functional impact, and future directions of POTS and non-POTS dysautonomia using a modified Delphi methodology. Methods A multidisciplinary international expert panel of pediatric and adult specialists in POTS and dysautonomia, including patient advocacy representatives, voted on consensus statements developed through iterative expert discussion, meetings and literature review by an independent core collaborative group consisting of clinicians specializing in POTS and dysautonomia. Statements addressing pathophysiology, diagnosis, treatment, education, advocacy, and research priorities were evaluated. Consensus was predefined as ≥70% agreement. Results 31 consensus statements were evaluated by the international multidisciplinary panel of experts from 7 countries (40 contributors). All statements achieved very strong (> 90%) to unanimous (100%) consensus, with 24 of 31 statements achieving unanimous consensus. Qualitative analysis of comments highlighted need for standardized nomenclature and classification system. Conclusion This international multidisciplinary consensus guidance statement addressed an unmet clinical gap by providing recommendations for recognition, diagnosis and management of POTS and non-POTS dysautonomia. Adoption of these recommendations may improve diagnostic accuracy, patient care, clinical trial inclusion, and future therapeutic development.

BACKGROUND:Cardiorenal dysfunction is a major contributor to morbidity, rehospitalization, and mortality in advanced heart failure (HF) and cardiogenic shock. Traditional decongestive approaches-loop diuretics, combination natriuretics, and ultrafiltration-are frequently inadequate in the setting of diuretic resistance or persistent venous and interstitial congestion, underscoring a substantial therapeutic gap. CONTENT:Novel device-based therapies have emerged to address the hemodynamic mechanisms underlying cardiorenal syndrome (CRS). These technologies can be categorized into five mechanistic families: (1) Pushers, which augment forward aortic flow to improve renal arterial perfusion; (2) Pullers, which selectively reduce renal venous hypertension; (3) Fluid Shifters, which mobilize interstitial fluid through lymphatic or peritoneal pathways; (4) Automated Diuresis Systems, which maintain euvolemia and optimize natriuresis during intensive loop diuresis; and (5) Splanchnic Nerve Ablation/Modulation, which increases venous capacitance and lowers cardiac filling pressures. Early feasibility studies report improvements in hemodynamics, enhanced natriuresis, reductions in filling pressures, and stabilization of renal function, reinforcing the physiologic rationale central to CRS management. GAPS AND FUTURE DIRECTIONS:Despite encouraging early results, substantial uncertainties remain. Criteria for patient selection, standardized trial endpoints, integration with guideline-directed therapy, and long-term renal and cardiovascular outcomes are not yet established. Small sample sizes, short follow-up durations, and a lack of randomized comparative trials limit existing evidence. CONCLUSION:Device-based therapies represent a shift from symptomatic fluid removal toward targeted, mechanism-driven decongestion in advanced HF and CRS. Future phenotype-guided, rigorously designed randomized trials are essential to determine whether these technologies can meaningfully modify renal trajectory, reduce hospitalization burden, and improve survival in this high-risk population.