Circulation: Heart Failure

Background: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) are indicated for weight reduction and offer cardiometabolic health benefits, yet there is little real-world evidence regarding their association with healthcare resource utilization (HCRU) and costs for Medicare Advantage (MA) beneficiaries with heart failure and obesity. Methods: We used a prevalent new-user study design and the Humana Healthcare Research database to identify MA beneficiaries with heart failure (HF) and obesity receiving standard HF therapy or HF therapy + newly initiating GLP-1 RA between January 1, 2022, and December 31, 2023. We observed adjusted, one-year mean difference in all-cause and heart failure-related HCRU. Results: In our cohort of 4,677 matched pairs (mean age 72 years, male: 41%), one-year, adjusted risk ratio (RR) for HF therapy + GLP-1 RA vs HF therapy was 0.89 (95% CI: 0.84 ? 0.93) for all-cause inpatient utilization, 0.88 (95% CI: 0.82 ? 0.94) for avoidable hospitalizations, and 0.99 (95% CI: 0.95 ? 1.03) for emergency department visits. For individuals receiving HF therapy + GLP-1 RA vs HF therapy, the mean difference was 30.6% (95% CI: 26.7% ?34.7%) for all-cause total costs, 105.9% (95% CI: 99.1% ?112.9%) for pharmacy costs, and ?4.7% (95% CI: ?8.7% to ?0.6%) for medical costs. HF-related HCRU measures were lower among beneficiaries augmenting HF therapy with GLP 1 RA vs individuals receiving HF therapy alone. Conclusions: Among MA beneficiaries with heart failure and obesity, the addition of GLP-1 RA to standard heart failure therapy reduced the likelihood of inpatient admissions or avoidable hospitalizations compared with HF therapy alone.

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome, and patients with a small left ventricular (LV) volume phenotype exhibit greater preload dependency. Whether the association between persistent outpatient oral loop diuretic use and clinical outcomes differs by LV volume phenotype remains unclear. Methods: We conducted a retrospective single-center cohort study of consecutive patients with heart failure and an LV ejection fraction [≥]50% who underwent transthoracic echocardiography between 2009 and 2024. Patients were stratified by LV volume phenotype using sex-specific LV end-diastolic volume index cutoffs. Associations between outpatient oral loop diuretic use and HF hospitalization, worsening renal function, and all-cause death were evaluated using multivariable time-varying Cox proportional hazards models, including interaction testing by LV phenotype. Results: Among 12,748 eligible patients, 1,437 had a small LV phenotype and 11,311 had a normal LV phenotype. Patients with a small LV phenotype initiated outpatient oral loop diuretics earlier and more frequently than those with a normal LV phenotype, while maintenance doses were comparable between groups. Outpatient oral loop diuretic use was associated with HF hospitalization in both phenotypes, with a significantly stronger association in the small LV group (hazard ratio [HR], 2.52; 95% confidence interval [CI], 1.68-3.78) than in the normal LV group (HR, 2.10; 95% CI, 1.77-2.49; P for interaction = 0.001). No significant interaction by LV phenotype was observed for worsening renal function or all-cause death. Fine-Gray competing-risk analyses showed a consistent interaction pattern. Conclusions: Persistent outpatient oral loop diuretic use was more strongly associated with HF hospitalization in patients with a small LV phenotype than in those with a normal LV phenotype. LV volume phenotype may help identify patients who warrant closer monitoring and more individualized diuretic management.

Background: Pulmonary vascular disease identifies an important phenotype of heart failure with preserved ejection fraction (HFpEF), but the relationship between systemic leukocyte activation and invasively measured pulmonary vascular hemodynamics is incompletely understood. We investigated whether the neutrophil-to-lymphocyte ratio (NLR) is associated with combined post- and precapillary pulmonary hypertension (CpcPH), pulmonary vascular burden, and subsequent cardiovascular events in HFpEF. Methods: We retrospectively studied 169 adults with HFpEF and invasively confirmed postcapillary pulmonary hypertension undergoing clinically indicated right heart catheterization. CpcPH was defined as pulmonary vascular resistance (PVR) >2 Wood units. Associations between NLR and CpcPH were evaluated using multivariable logistic regression. Fine-Gray competing-risk models assessed the composite of cardiovascular death or first heart failure hospitalization. Results: Overall, 80 patients had isolated postcapillary pulmonary hypertension and 89 had CpcPH. PVR increased across ascending NLR tertiles (1.8 [1.4-2.5], 2.2 [1.6-3.1], and 2.6 [1.7-3.8] Wood units; P for trend=0.002), whereas pulmonary artery wedge pressure showed no significant trend. Compared with the lowest NLR tertile, the highest tertile was associated with greater odds of CpcPH after adjustment for clinical covariates and filling pressure (adjusted odds ratio, 2.47 [95% CI, 1.01-6.01]; P=0.047). Higher NLR tertiles were also associated with a graded increase in cardiovascular events (Gray's P<0.001). The highest NLR tertile remained associated with outcome after adjustment for clinical and hemodynamic variables (adjusted subdistribution hazard ratio [sHR], 2.37 [95% CI, 1.12-5.03]; P=0.024). Conclusions: Among patients with HFpEF and postcapillary pulmonary hypertension, higher NLR was associated with greater pulmonary vascular hemodynamic burden, CpcPH, and subsequent cardiovascular risk. NLR may provide a readily available marker of a high-risk HFpEF phenotype warranting prospective validation.

Background: Comprehensive guideline-directed medical therapy (GDMT) remains underused in older patients with HFrEF, but whether the potential for treatment-associated myocardial recovery is preserved with advancing age remains uncertain. Objectives: To characterize age-related GDMT gaps and determine whether GDMT intensity is associated with left ventricular (LV) reverse remodeling across age and subsequent outcomes. Methods: We studied 1,795 patients with HFrEF receiving angiotensin receptor-neprilysin inhibitor (ARNI)-based therapy in the multicenter STRATS-HF-ARNI registry. GDMT intensity was defined by the number of foundational therapies used during the first year after ARNI initiation. Serial LV remodeling and subsequent death or HF hospitalization were evaluated using multivariable models and a 1-year landmark analysis. Results: Triple/quadruple GDMT was achieved in 59.1%, 50.8%, 53.4%, and 43.0% of patients aged <60, 60-69, 70-79, and [&ge;]80 years, respectively (P<0.001). Older age and renal dysfunction independently predicted less comprehensive GDMT. Each additional GDMT pillar was associated with greater improvements in LVEF (+1.23 percentage points; P=0.012) and LV global longitudinal strain (+0.32 percentage points; P=0.049) and greater reductions in LV volumes. Substantial remodeling remained evident at advanced age. Greater LV reverse remodeling predicted lower subsequent risk, and exploratory bootstrap analyses supported significant indirect associations between greater GDMT intensity and lower risk through all four LV remodeling measures. Conclusions: Older patients received less comprehensive GDMT despite preserved potential for LV reverse remodeling. Greater GDMT intensity was associated with greater myocardial recovery, which may represent a pathway to better prognosis. These findings support intensive GDMT implementation in older patients when clinically tolerated.

Background: Adults with congenital heart disease (ACHD) represent a rapidly expanding population with evolving mortality patterns. Despite improved survival, excess mortality persists. Objective: To evaluate the incidence, causes, and predictors of mortality in a contemporary ACHD cohort. Methods: We performed a retrospective cohort study of adults (?18 years) first evaluated at Mayo Clinic from 2002?2023. Baseline clinical, imaging, and electrocardiographic data were analyzed. Vital status was determined using institutional records and the Accurint national mortality database. Kaplan-Meier analysis and Cox proportional hazard models were used to evaluate mortality and identify independent predictors of mortality Results: A total of 7,678 ACHD patients were included, with median age of 36.8 years and median follow-up of 11.4 years. During 78,768 patient-years of follow-up, 1,116 patients died (median age at death 57.2 years), corresponding to an annual mortality rate of 1.4%. The cumulative rate of all-cause mortality at 5, 10, 15, and 20 years was 6.9%, 12.0%, 19.0%, and 26.2%, respectively. When stratified by CHD complexity, the annual death rate in patients with severe CHD (2.4%/year) was twice that of patients with moderate or mild CHD (both 1.2%/year). Older age and ACHD subtypes, specifically, cyanotic heart disease (HR 3.9, 95% CI 2.9?5.3) and Fontan physiology (HR 3.2, 95% CI 2.3?4.4), were strongly associated with increased mortality. Additional independent predictors included male sex, ventricular dysfunction, advanced NYHA class, prior heart failure hospitalization, hypertension, smoking, coronary artery disease, renal dysfunction, and abnormal hemoglobin levels. Cardiovascular causes accounted for 57.7% of deaths with known etiology, predominantly heart failure (48.9%) and sudden cardiac death (21.9%), while non-cardiovascular causes were driven mainly by infection and malignancy. Conclusions: In this large contemporary ACHD cohort, mortality was driven by ventricular dysfunction, heart failure, and systemic end-organ involvement in addition to the underlying congenital anatomy. Both cardiovascular and non-cardiovascular causes contributed significantly to mortality. These findings underscore the need for comprehensive multidisciplinary ACHD care focused on early recognition of cardiac functional decline, management of acquired comorbidities, and end-organ dysfunction.

Background: Patients with heart failure (HF) experience high mortality, yet survival estimates remain challenging. Available prognostic tools commonly predict survival beyond 1-year, limiting goals of care discussions and enrollment on palliative care programs. The objective of this project was to develop a novel prognostic score to better predict 6-month mortality. Methods: Patients with HF admitted to the St. Boniface Hospital (Winnipeg, Canada) between January 1, 2019 and January 1, 2024 were identified. Patient characteristics, imaging parameters, laboratory values, and functional assessments (Palliative Performance Scale; PPSv2) were collected. Patients were randomly divided into development (80%) and validation (20%) cohorts. Penalized LASSO regression was used to select variables most predictive of 6-month mortality in the development cohort. Retained variables were incorporated into a multivariable logistic regression model to derive the CARDIO-PAL score, the performance of which was assessed in the holdout validation cohort. Results: Characteristics were similar between the development (n = 2036) and validation (n = 508) cohorts, with 6-month mortality rates of 29% and 31%, respectively. 8 candidate variables were retained: age (adjusted odds ratio [aOR] 1.01), PPSv2 (aOR 2.08), systolic blood pressure (aOR 1.14), discontinued use of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (aOR 2.58), beta-blocker (aOR 1.59), and mineralocorticoid receptor antagonist (aOR 2.67), right ventricular systolic pressure (aOR 2.06), and urea (aOR 2.13). The CARDIO-PAL score demonstrated good discrimination, with an area under the curve of 0.80 (95% confidence interval 0.75 - 0.84) and good calibration (slope 0.84, intercept -0.04). 6-month mortality across low, intermediate, and high-risk groups was 2%, 15%, and 54%, respectively. Conclusion: The CARDIO-PAL score is a novel tool to predict 6-month mortality in HF inpatients. A collaborative approach integrating CARDIO-PAL with other prognostic scores and serial clinical assessments has the potential to promote patient-centered care and improve referral to palliative care programs.

Background Hospitalizations and mortality due to heart failure (HF) are rising in rural areas. However, inpatient outcomes for young adults with HF are not well understood. We aimed to compare in-hospital mortality, advanced procedure utilization, length of stay, and total charges among rural and urban HF patients ages 18-45. Methods We analyzed hospitalizations from the National Inpatient Sample (2016-2022), categorizing discharges as rural (National Center for Health Statistics [NCHS] 5-6), small and medium metropolitan (NCHS 3-4), and urban (NCHS 1-2). Generalized estimating equations were used to model outcomes and adjust for demographics, comorbidities, and hospital characteristics. Outcomes are reported as adjusted rate (aIRRs) or risk ratios (aRRs) with 95% confidence intervals. Results Among 79,258 HF hospitalizations among young adults, 45,075 and 10,722 were for patients from urban and rural areas, respectively. Rural patients had higher rates of in-hospital mortality (1.6% vs. 1.2%; aIRR = 1.28, 95% CI = 1.05, 1.56, p = 0.043), advanced cardiac procedure utilization (15.0% vs. 14.8%; aIRR = 1.19, 95% CI = 1.11, 1.28, p < 0.001), and longer hospital stays (aIRR = 1.10, 95% CI = 1.05, 1.14, p = 0.003). Small and medium metropolitan residents had similar outcomes to urban residents. In interaction analyses, the association between rural-urban residence and mortality differed by race (pint = 0.003) and payer type (pint < 0.001). Conclusions Young adults in rural areas may be prone to poor outcomes following hospitalization for HF. Strategies to identify rural adults at risk for HF and provide affordable and timely care may improve disparities.

Background: Tirzepatide and semaglutide improve functional status and heart failure (HF) events in patients with obesity and HF with preserved ejection fraction. Tirzepatide has been associated with greater control of cardiometabolic risk factors in patients with obesity compared to semaglutide. Whether tirzepatide is associated with lower risk of new-onset HF than semaglutide in patients with obesity is underexplored. Methods: A retrospective cohort study was conducted using data pooled from the TriNetX platform. Patients with obesity who initiated therapy with tirzepatide or semaglutide during the period Jun 4, 2021 to Aug 13, 2026 were identified and 1:1 propensity-score matched to produce two study cohorts. The one-year incidence of new-onset HF was calculated and compared between the two cohorts. Secondary outcomes included new-onset systolic HF, new-onset diastolic heart failure, new-onset atrial fibrillation or flutter, all-cause mortality, and hospital encounters. Cox proportional hazards models were fitted to calculate hazard ratios (HR) along with 95% confidence intervals (CI). Results: Two well-matched cohorts (N=424,269 in each) were formed. The incidence of new-onset HF was lower in the tirzepatide group (1.0% vs. 1.3%; absolute risk difference -0.3%, 95% CI -0.35 to -0.26; HR 0.9, 95% CI 0.86[boxh]0.93). The tirzepatide group were also at lower risk of all-cause mortality (HR, 95% CI: 0.8, 0.77[boxh]0.91) and new-onset systolic HF (0.8, 0.79[boxh]0.92). All other secondary outcomes occurred at similar rates in both study groups. Conclusion: Among patients with obesity, tirzepatide therapy was associated with lower risk of new-onset HF compared to semaglutide although the effect sizes were modest.

Background: Sleep-disordered breathing (SDB) is an established adverse prognostic factor in heart failure (HF). Sleep apnea-specific hypoxic burden (SASHB), which reflects the duration and depth of respiratory event-related oxygen desaturation, has shown stronger prognostic value than the apnea-hypopnea index (AHI) in general populations and patients with coronary artery disease. However, its clinical utility in patients hospitalized due to acute HF remains unclear. Objectives: This study evaluated the prognostic value of SASHB in patients hospitalized for acute HF and compared its performance with AHI for risk stratification and identification of patients who may benefit from positive airway pressure (PAP) therapy. Methods: This post hoc analysis included 230 patients from a prospective single-center observational cohort of adults hospitalized for acute HF. The primary analysis included 178 patients who did not receive PAP treatment. Associations of SASHB and AHI with the composite endpoint of cardiovascular death or rehospitalization for worsening HF were evaluated using Cox proportional hazards models. Model improvement after adding SASHB or AHI to a model including established clinical risk factors was assessed using changes in the C index and Brier score, reflecting changes in model discrimination and prediction error, respectively. In the full cohort, the interaction between PAP treatment and SDB metrics was evaluated using the g-formula. Results: During a median follow-up of 3.7 years, 58 of 178 patients (32.6%) reached the composite endpoint. Both SASHB and AHI were independently associated with the composite outcome after multivariable adjustment. However, only SASHB consistently predicted outcomes across analyses and improved model performance beyond established prognostic factors (bootstrap {Delta} C index, 0.020 [95% CI: 0.008 - 0.031]; bootstrap {Delta} Brier score, - 0.007 [95% CI: - 0.014 to - 0.001]), whereas AHI did not. In the analysis including PAP-treated patients, both SASHB and AHI showed interaction with PAP treatment. Conclusions: In patients hospitalized for acute HF, SASHB showed a consistent independent association with adverse clinical outcomes and provided additional prognostic information beyond AHI. SASHB may improve risk stratification and may help identify patients who are more likely to benefit from PAP therapy.

BACKGROUND: Because of the high mortality rate associated with fulminant myocarditis (FM), there is limited evidence regarding the prognostic efficacy of endomyocardial biopsy (EMB). In this study, we aimed to evaluate the influence of EMB in the early phase after admission on treatment and prognosis in FM using a large-scale nationwide registry in Japan. METHODS: Patients with FM who required catecholamine or mechanical circulatory support between 2012 and 2017 from 235 hospitals across Japan were included. The primary outcome of death or heart transplantation within 90 days according to performance of early EMB were determined using Kaplan-Meier and Cox regression analyses. Factors associated with performance of early EMB, and subsequent medical treatment were analyzed. RESULTS: The median age of 736 patients with clinical FM was 56 years, and 407 patients (55%) received EMB. Most EMB (89%) were performed during the early phase (within 5 days of admission) and 63% were performed on the first day of admission. The prognosis of FM patients who underwent EMB was more favorable than that of those who did not based on the landmark analysis (log-rank test, P=0.04). Factor analysis demonstrated that FM patients who underwent EMB had a lower left ventricular ejection fraction, higher incidence of cardiogenic shock on admission, and higher rate of early mechanical circulatory support, as well as early initiation of corticosteroids and guideline-directed medical therapy (GDMT) for heart failure. Absence of any GDMT was associated with a less favorable prognosis on multivariate analysis (hazard ratio, 4.34 [95% CI, 3.14?6.01]; P<0.0001). CONCLUSIONS: Although performing EMB in the early phase after admission depends on disease severity in FM patients, it is associated with early initiation of advanced medical treatment and may contribute to improving the prognosis.

Background: DNA methylation (DNAm) signatures capture cumulative lifestyle exposures and biological aging. This prospective study evaluated whether DNAm-based scores and epigenetic aging clocks are associated with clinical outcomes and mortality in a multinational cohort of patients with heart failure (HF). Methods: We studied 2,594 patients with HF from 40 countries in the Global Congestive Heart Failure (G-CHF) registry with whole-blood DNAm data. Fifteen published DNAm-based scores and epigenetic aging clocks reflecting lifestyle, environmental and physiological exposures, inflammation, frailty, mortality risk, and biological aging were derived. Associations with HF hospitalization, cardiovascular death, and all-cause death were assessed using multivariable Cox regression adjusted for age, sex, ancestry, the MAGGIC risk score, and NT-proBNP. Incremental prognostic value was compared to MAGGIC score and NT-proBNP. Extreme DNAm profiles were defined as scores or clocks exceeding {+/-}1.5 standard deviations (s.d.) from the population mean. Results: Mean age was 62.7{+/-}14.0 years, 66.2% were male, and mean left ventricular ejection fraction was 40.1{+/-}14.1%. During a median follow-up of 3.0 years, 338 patients were hospitalized for HF, 349 died from cardiovascular causes, and 565 died from any cause. Higher epigenetic age and DNAm scores for CRP, frailty, and mortality were associated with increased risk, whereas higher diet-related DNAm scores were inversely associated. For all-cause death, adjusted hazard ratios per 1-s.d. were 1.36 (95% CI, 1.24-1.50) for GrimAge, 1.27 (95% CI, 1.17-1.38) for the DNAm score for CRP, 1.44 (95% CI, 1.28-1.63) for the DNAm score for frailty, and 1.48 (95% CI, 1.32-1.65) for the DNAm score for mortality, compared with 0.81 (95% CI, 0.75-0.88) and 0.86 (95% CI, 0.79-0.94) for the DNAm scores for Alternative Healthy Eating Index and Mediterranean Diet Score. These patterns were directionally consistent for cardiovascular death and weaker for HF hospitalization and were more pronounced among patients with lower clinical risk (MAGGIC<17, Pinteraction<0.05), particularly for all-cause death. Patients with 4-5 extreme-high DNAm scores or clocks had more than twice the risk of death (HR, 2.27; 95% CI, 1.65-3.13). Conclusions: DNAm-based scores and epigenetic aging clocks reflect multiple dimensions of biological vulnerability in HF and are associated with clinical outcomes and mortality beyond clinical risk factors.

Background: Established heart-failure (HF) risk scores were developed largely in Western cohorts, assume linear predictor effects, and stop at prognosis without indicating action. We developed and externally validated machine-learning (ML) models for 30-day and 1-year mortality in a multi-ethnic Asian HF population, benchmarked against three established scores, and tested whether they localised correctable guideline-directed medical therapy (GDMT) gaps. Methods: We analysed 9,050 adults hospitalised with HF across eight Singapore hospitals (November 2016?March 2023). Gradient-boosted trees (XGBoost, primary) and elastic-net logistic regression were developed on three hospitals (n=4,034) and validated on five independent hospitals (n=5,016), without patient or site overlap. Comparators (MAGGIC, Singapore HF Score, OPTIMIZE-HF-Asia) were logistically recalibrated on development data. Results: On external validation XGBoost achieved AUROCs of 0.862 (95% CI 0.833?0.890) for 30-day and 0.749 (0.734?0.764) for 1-year mortality, versus 0.711?0.754 and 0.682?0.699 for the three recalibrated scores; logistic regression performed near-identically (0.864, 0.757) and was better calibrated at 1 year. Superiority held under temporal validation, multiple imputation and optimism correction, although the 30-day advantage was no longer distinguishable from MAGGIC once medications were removed. Among predicted-high-risk patients with reduced ejection fraction, mean GDMT exposure was 0.92 of four pillars versus 1.87 across all HFrEF patients, and 36.3% received none of the four versus 2.0% of low-risk patients. Ten variables reproduced full-model 30-day discrimination (AUROC 0.865). Conclusions: In external validation, interpretable models substantially outperformed established HF risk scores for short- and long-term mortality and simultaneously localised correctable therapeutic gaps, supporting a prediction-to-action tool deployable with ten bedside variables.

Background: Blood volume (BV) in patients with chronic heart failure (HF) is characterized by heterogeneity in volume profiles; one profile being "normal BV". While overall intravascular volume may be considered normal clinically, the relative contributions of red blood cell (RBC) mass and plasma volume (PV) may not be. Objective: Assess how normal is a "normal BV" based on quantitative measures of RBC mass and PV. Methods: Retrospective analysis was undertaken in 395 patients with Class II-III HF. BV was quantitated using indicator-dilution methodology. Cohort was stratified by normal and hypervolemic BV. Results: Of the cohort, 31% (123/395) demonstrated normal total BV and 62% (244/395) hypervolemic BV. Of patients with "normal BV", 36% (44/123) demonstrated normal RBC mass and 60% normal PV (74/123). Importantly, 60% (74/123) demonstrated a deficit in RBC mass (true anemia), while a low hemoglobin (<12 g/dL) was present in just 29% (36/123). An excess in RBC mass (erythrocytosis) in 4% (5/123). Notably, true normal BV (i.e., normal RBC mass and normal PV) was observed in only 30% (37/123) of patients with an overall "normal" intravascular volume. Conclusions: Findings reveal that "normal BV" can be misleading by concealing substantial variability in RBC mass (including unrecognized anemia and erythrocytosis) as well as different degrees of PV expansion and contraction. An actual normal BV was identified in a minority of "normal BV" patients. This underscores the importance of looking beyond overall "normal BV" to the contributing elements of RBC mass and PV with significant implications for patient management and outcomes.

Heart failure (HF) is a leading cause of morbidity and mortality. We conducted multi-ancestry genome-wide association studies of 345,687 HF cases (4,468,166 individuals), and 47,192 and 46,934 cases of HF with preserved (HFpEF) and reduced ejection fraction (HFrEF), respectively, integrating plasma proteomics and multi-tissue transcriptomics to identify druggable targets. Across HF, HFrEF, and HFpEF, we identified 383 loci (166 novel) and 568 genes (375 novel). Eleven novel genes are targets of approved or investigational cardiovascular therapies, supporting indication expansion of aldosterone synthase inhibitors (CYP11B2) and type-II activin receptor antagonists (ACVR2A) to HF. Six cardiomyopathy genes were novel for HF and associated with cardiac structure and function. We identified nearly 100 genes involved in food intake and energy expenditure; metabolism of fatty acids, glucose, and branched-chain amino acids; and mitochondrial proteome, sustaining myocardial energy production. Our findings highlight the primordial role of metabolic pathways and adipokines as therapeutic targets for HF management.

Background: Glucagon-like peptide-1 receptor agonists (GLP1-RA) improve cardiovascular outcomes in patients with type 2 diabetes (T2D) and obesity, and more recently they have been shown to be beneficial in patients with obesity and heart failure with preserved ejection fraction. Their role in patients with heart failure and reduced ejection fraction (HFrEF) and T2D remains underexplored. Methods: A retrospective cohort study was conducted using data pooled from the TriNetX platform. Patients with T2D and HFrEF who were initiated on GLP1-RA therapy during the period May-13-2026 to Jun-6-2026 were identified. One:one propensity-score matching with controls was performed. Time-to-event analysis was conducted to compare the one-year incidences of all-cause mortality and a primary composite outcome of acute myocardial infarction, ischemic stroke and acute heart failure, between the two matched-cohorts. Secondary outcomes included individual components of the primary composite outcome and any inhospital encounter. Results: Two well-matched cohorts with 38,879 patients in each were formed. Patients treated with GLP1-RAs had a lower incidence of all-cause mortality (4.2% vs. 12%; absolute risk difference [ARD] -7.8, 95% CI -8.17 to -7.41; HR 0.4, 95% CI 0.34[boxh]0.38) and the primary composite outcome (32.5% vs. 48.3%; ARD -15.8, 95% CI -16.47 to -15.11; HR 0.6, 95% CI 0.57[boxh]0.60) compared to the control group. The GLP1-RA group were also at lower risk of all secondary outcomes compared to the control group. Conclusion: In a real-world study, GLP1-RA therapy was associated with lower risk of all-cause mortality and cardiovascular outcomes in patients with T2D and HFrEF.

Background: HFpEF accounts for roughly half of heart failure admissions and lacks disease-modifying therapy. Autotaxin (ENPP2) generates lysophosphatidic acid (LPA), a profibrotic and pro-inflammatory bioactive lipid. Whether circulating lysophospholipid metabolism is altered in HFpEF, and whether autotaxin inhibition modifies an established experimental HFpEF phenotype, is untested. Methods: Plasma from patients with HFpEF (n=210) and non-heart-failure comparators (n=27) underwent untargeted and LPA-targeted mass spectrometry and a nine-analyte multiplex immunoassay. Male C57BL/6J mice received a high-fat diet plus L-NAME (0.85 g/L) or chow for 5 weeks; after phenotype confirmation, they received oral PF-8380 (30 mg/kg/day) or vehicle for 10 weeks. Endpoints were echocardiography, functional assessment, gravimetric studies, tail-cuff pressure, trichrome fibrosis, and flow cytometry of heart and spleen. Results: All nine analytes, including the autotaxin protein ENPP2, were higher in HFpEF than comparators. HFpEF plasma showed higher LPE O16:1, LPE O18:2, PS 38:4 and PC 36:4;O, and lower SM 39:2; O3 and PS 36:0. LPA 20:0 was 3.5-fold higher in both sexes, whereas LPA 18:2 was lower in women. Diet plus LNAME raised blood pressure, LV mass, and isovolumic relaxation time with preserved ejection fraction. PF-8380 reduced echocardiographic indices of diastolic dysfunction, fibrosis area, cardiomyocyte area, and cardiac CD11b+, CD64+, CD86+, and Ly6G+ frequencies, without altering fat or lean mass. Conclusion: In male mice with established two-hit HFpEF, autotaxin inhibition improved diastolic indices and reduced fibrosis, hypertrophy, and cardiac myeloid accumulation. Human data show altered lysophospholipid composition. Collectively, these findings nominate the autotaxin/LPA axis as a tractable therapeutic target and support further evaluation of autotaxin inhibition as a candidate disease-modifying strategy for HFpEF management.

Background: Cardiac myosin inhibitors (CMIs) directly target sarcomeric hypercontractility and have demonstrated clinical efficacy in obstructive hypertrophic cardiomyopathy (HCM). In symptomatic nonobstructive HCM (nHCM), the phase 3 randomized controlled trials (RCT) differed in whether their primary efficacy endpoints reached statistical significance, although the direction and magnitude of treatment effects were broadly comparable. We therefore conducted a systematic review and meta-analysis to synthesize the randomized evidence on the efficacy and safety of CMIs in symptomatic nHCM. Methods: We systematically searched for randomized placebo-controlled trials evaluating CMIs in adults with symptomatic nHCM according to PRISMA guidance and a prospectively registered protocol (PROSPERO CRD420261466576). Primary efficacy outcomes were changes from baseline in peak oxygen uptake (pVO2) and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), assessed at each trial's primary endpoint. Secondary outcomes included improvement by at least 1 New York Heart Association (NYHA) functional class and change in N-terminal pro-B-type natriuretic peptide (NT-proBNP). The safety outcome was LVEF <50%. Random-effects models were used to pool mean differences (MDs), risk ratios (RRs), and ratios of geometric mean changes. Results: Three RCTs comprising 1,156 participants were included: MAVERICK-HCM, ODYSSEY-HCM, and ACACIA-HCM. Compared with placebo, CMIs were associated with improvements in pVO2 (MD, 0.55 mL/kg/min; 95% CI, 0.22-0.87; I2=0%; P=0.001) and KCCQ-CSS (MD, 2.71 points; 95% CI, 0.87-4.55; I2=0%; P=0.004). Improvement by at least 1 NYHA functional class was more frequent with CMIs (RR, 1.29; 95% CI, 1.03-1.62; I2=24.3%; P=0.024). Across the two phase 3 trials, CMIs reduced NT-proBNP (ratio of geometric mean changes, 0.42; 95% CI, 0.39-0.46; I2=0%; P<0.001), while LVEF <50% occurred more frequently with CMIs (RR, 12.77; 95% CI, 5.98-27.27; I2=0%; P<0.001). Conclusions: In this meta-analysis of randomized trials in symptomatic nHCM, CMIs' pooled estimates favoured CMIs over placebo for improvements in exercise capacity, health status, and NYHA functional class, together with a marked reduction in NT-proBNP. These potential benefits were accompanied by an increased risk of LVEF reduction below 50%.

Background Several disease-modifying agents for transthyretin amyloid cardiomyopathy (ATTR-CM) have been investigated, but differences in trial design and background stabilizer use complicate interpretation of their efficacy. This meta-analysis assessed their efficacy overall and by background stabilizer use. Methods PubMed, Embase, and the Cochrane Library were searched through September 2026 for phase III randomized, placebo-controlled trials of disease-modifying therapy in ATTR-CM. Primary endpoints were all-cause mortality, 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP), pooled with a random-effects model. Treatment effects were compared between the monotherapy and baseline stabilizer strata using a mixed-effects model. Results Five trials (ATTR-ACT, APOLLO-B, ATTRibute-CM, HELIOS-B, CARDIO-TTRansform; N=3497) were included. Disease-modifying therapy reduced all-cause mortality (risk ratio, 0.76; 95% confidence interval [CI], 0.66-0.87; I2=0%) and improved 6MWD (pooled standardized mean difference [SMD], 0.43; 95% CI, 0.20-0.67), KCCQ-OS score (SMD, 0.37; 95% CI, 0.19-0.55), and NT-proBNP (SMD, -0.53; 95% CI, -0.89 to -0.18). The mortality benefit was similar whether therapy was given alone or added to a background stabilizer (pooled risk ratio, 0.77 vs. 0.71; P for interaction = 0.59), but treatment effects on 6MWD (pooled SMD, 0.49 vs. 0.14), KCCQ-OS score (0.44 vs. 0.07), and NT-proBNP (-0.65 vs. -0.13) were smaller among patients receiving a background stabilizer (P for interaction = 0.012, <0.001, and 0.029, respectively). Conclusion Disease-modifying treatments reduced all-cause mortality and favored functional capacity, health status, and NT-proBNP outcomes in patients with ATTR-CM. Exploratory subgroup analyses showed smaller treatment effects on 6MWD, KCCQ-OS score, and NT-proBNP among patients receiving a background stabilizer, with no statistically significant difference in the mortality effect according to baseline stabilizer use.

Rural patients with heart failure (HF) have poor access to care, worse outcomes, and may benefit from at-home monitoring. We evaluated whether foot temperature measured using a thermographic floor mat was associated with invasively measured cardiac output and whether longitudinal temperature changes preceded HF events. We conducted a two-part prospective, observational single-center study using the SmartMat (Podimetrics, Somerville, MA), which acquires plantar thermograms and ambient temperature. In the acute study, patients undergoing clinically indicated right heart catheterization completed 4 scans on the same day. In the chronic study, patients with a HF hospitalization in the past year and New York Heart Association Class II-III symptoms were instructed to use the device and a scale daily for 6 months. A HF event was defined as receiving at least one dose of intravenous or subcutaneous diuretic. Thirty patients were enrolled in the acute study. Mean right hallux temperature positively correlated with thermodilution cardiac output (r=0.63, p<0.001). 42 patients were enrolled in the chronic study. Among patients experiencing an HF event, ambient-adjusted hallux temperature declined in the 15 days immediately preceding the event compared with days 15-30 before the event. Plantar thermograms are associated with invasively measured cardiac output and may detect subclinical worsening before HF events. Foot temperature may provide complementary information regarding HF decompensation, supporting further evaluation of plantar thermography for remote HF monitoring.

BACKGROUND: Left ventricular ejection fraction (LVEF) independently predicts mortality in repaired tetralogy of Fallot (ToF), but the causes of LV dysfunction are incompletely understood. The intrinsic aortopathy of ToF increases pulsatile afterload, yet whether this contributes to LV dysfunction is unknown. We sought to determine whether aortic dimensions and flow-derived afterload act as cross-sectional markers of LV dysfunction, dynamic contributors to change in LV function over time, or both. METHODS: Retrospective longitudinal study of 554 patients with repaired ToF (1,448 serial cardiovascular magnetic resonance examinations, 2003-2026). Aortic root dimensions, total arterial compliance (TAC: aortic forward flow volume/pulse pressure), and systemic vascular resistance (SVR) were derived, and a within-between decomposition separated between-patient from within-patient associations with LVEF in mixed-effects models. RESULTS: In the analytic sample (1,053 observations, 521 patients), aortic sinus diameter predicted LVEF at both levels (within:{beta} = -0.23, p<0.001; between: {beta} = -0.20, p=0.003). Associations were reproduced at the sinotubular junction but absent at the ascending aorta, localising the effect to the root. TAC predicted LVEF within patients ({beta}=0.90 per mL/mmHg, p=0.014) but not between patients (p=0.62), indicating that pulsatile afterload is a dynamic contributor to LV function. SVR predicted LVEF at both levels (within: {beta} = -0.23; between: {beta} = -0.25; both p<0.001). Blood pressure components alone, expressed as systolic and diastolic or as mean arterial and pulse pressure, did not predict LVEF and fitted the data less well. Adjustment for right ventricular ejection fraction attenuated the within-patient compliance association by 35%, suggesting a component shared with right ventricular function. CONCLUSIONS: Aortic root dimensions, TAC and SVR are independent longitudinal determinants of LVEF in repaired ToF, establishing an important role for aortic haemodynamics in LV function and identifying the systemic vasculature as a potentially modifiable contributor to LV dysfunction.