Circulation: Heart Failure

BackgroundHeart failure (HF) is an increasingly common comorbidity among people living with HIV (PLHIV), complicating care and heightening vulnerability of this population to social adversity (SA). However, the impact of different SA domains on outcomes in this population remains poorly understood. MethodsWe analyzed data on PLHIV with HF from the NYC Health + Hospitals HIV-Heart Failure cohort. Baseline multidimensional SA was assessed by licensed clinical social workers using standardized evaluations and grouped into five domains: (1) economic hardship, (2) healthcare access barriers, (3) neighborhood/built environment instability, (4) social support challenge, and (5) Psycho-behavioral instability. We used multivariable adjusted Cox models to estimate hazard ratios (HRs) of all-cause, cardiovascular, and infection-related mortality; and logistic regression to estimate odds ratios (ORs) of 6-month rehospitalization risk. ResultsAmong participants 1044 (62.9% males, mean age: 61.6 years), 601 (58%) reported at least 1social adversities: economic hardship (n=130), limited healthcare access (n=155), unstable housing (n=129), social support challenge (n=179), or psycho-behavioral instability (n=438). Over a mean follow up of 3.8 years, exposure to any SA was associated with higher all-cause mortality (HR 4.32; 95% confidence interval [CI] 3.03-6.14), CV mortality (HR 4.05; 95% CI 2.17-6.83), and infection-related mortality (HR 2.37; 95% CI 1.23-4.56). Social support challenge (HR 2.19; 95% CI 1.35-3.55) and psycho-behavioral instability (HR 1.96; 95% CI 1.24-3.11) were associated with higher CV mortality; economic hardship (HR 2.40; 95% CI 1.22-4.70) and social support challenge (HR 3.09; 95% CI 1.75-5.48) were associated with higher infection-related mortality. Compared with patients without SA, those with an environment instability, psycho-behavioral instability, or social support challenges had a 73% (aOR 1.73; 95% CI, 1.15-2.06), 75% (aOR 1.75; 95% CI, 1.31-2.35), and 44% (aOR 1.44; 95% CI, 1.00-2.06) higher risk of rehospitalization within 6 months, respectively. ConclusionSA was significantly associated with mortality and rehospitalization among PLHIV with HF, with domain-specific pathways influencing specific outcomes. A multidimensional assessment of social vulnerability may be useful to risk-stratify HF mortality risk in PLHIV.

PurposeDespite strong evidence, real-world adoption of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) remains suboptimal. The Get With The Guidelines-Heart Failure (GWTG-HF) program was designed to close gaps in care. We evaluated whether hospital participation in GWTG-HF is associated with greater GDMT intensity and improved outcomes. MethodsWe conducted a retrospective analysis (2013-2021) of Medicare beneficiaries with Part A and Part D hospitalized with HFrEF. Using a multiple baseline time series design, we compared changes in GDMT prescribing and outcomes at hospitals before and after GWTG-HF enrollment with hospitals that never participated. The primary outcome was a 90-day post-discharge prescription-fill GDMT score summarizing use and dose of beta blockers, renin-angiotensin system inhibitors (RASI; ACE inhibitor/ARB/ARNI), and mineralocorticoid receptor antagonists (MRA). Secondary outcomes included class-specific medication fills, achievement of [&ge;]50% target doses, and 30-day, 90-day, and 1-year all-cause and HF readmission and mortality. We adjusted for baseline hospital performance, patient characteristics, and temporal trends. ResultsAmong 1,274,863 Medicare beneficiaries hospitalized for HFrEF, 53.5% were treated at hospitals that never participated in GWTG-HF and 9.6% at hospitals that joined GWTG-HF before hospitalization. Unadjusted median GDMT scores increased from 3.0 in both groups to 4.0 in non-participating hospitals and 4.5 in GWTG-HF hospitals at 90 days (p<0.001). Hospital enrollment was associated with a higher 90-day GDMT score (+0.15 points; 95% CI 0.12-0.18; p<0.001), and greater use of beta blockers, RASI, and MRA, but not ARNI. HF readmission did not differ significantly; however, GWTG-HF participation was associated with lower all-cause mortality at 30 days (OR 0.95; 95% CI:0.92-0.98), 90 days (OR: 0.97; 95% CI: 0.95-0.99), and 1 year (0.97; 95% CI: 0.95-.0.99; all p<0.05). ConclusionHospital participation in GWTG-HF was associated with higher GDMT intensity and lower mortality, supporting structured quality programs to improve HFrEF care.

We performed a systematic review and meta-analysis of randomized controlled trials evaluating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus placebo in adults with heart failure (HF), searching PubMed, Cochrane CENTRAL, and ClinicalTrials.gov through February 2026. The primary outcome was the composite of cardiovascular death and first HF hospitalization. Random-effects meta-analysis used restricted maximum likelihood estimation with Hartung-Knapp-Sidik-Jonkman adjustment. We included 14 studies (6 dedicated HF trials and 8 cardiovascular outcomes trial HF subgroup analyses) encompassing 18,558 patients, of whom 2,499 were randomized in dedicated HF trials. The primary composite did not reach statistical significance (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.73-1.01; P=0.067; I2=47%). GLP-1 RAs significantly reduced all-cause mortality (HR 0.87, 95% CI 0.81-0.93; P<0.001; I2=0%), major adverse cardiovascular events (HR 0.83, 95% CI 0.73-0.95; P=0.019), and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (+7.4 points, 95% CI 6.3-8.5) and 6-minute walk distance (+17.6 m, 95% CI 13.4-21.7). Excluding the FIGHT trial (acute HFrEF) yielded a significant primary composite (HR 0.83, P=0.011). The mortality signal was driven primarily by CVOT subgroups; the largest dedicated HFpEF trial (SUMMIT) showed numerically higher mortality (HR 1.25). The strongest evidence supports GLP-1 RAs in HFpEF with obesity. HighlightsO_LIPrimary composite of CV death + HHF was not significant (HR 0.86, P=0.067) C_LIO_LIGLP-1 RAs reduced all-cause mortality (HR 0.87) with no heterogeneity C_LIO_LIKCCQ-CSS improved by 7.4 points and 6MWD by 17.6 m in HFpEF trials C_LIO_LIMortality benefit driven by CVOT subgroups, not dedicated HF trials C_LIO_LIStrongest evidence supports GLP-1 RAs in HFpEF with obesity C_LI

BackgroundRight heart failure (RHF) leads to an elevation in central venous pressure and causes hepatic congestion. Apolipoprotein M (ApoM), a hepatocyte-derived lipocalin bound to high-density lipoprotein, transports sphingosine-1-phosphate (S1P), which maintains vascular integrity and modulates inflammation. Although low ApoM predicts adverse outcomes in heart failure (HF), its role in RHF is unclear. We sought to investigate the impact of RHF on circulating ApoM, its prognostic value in RHF mortality, and its functional role in the cardio-hepatic axis. MethodsPatients undergoing right heart catheterization were classified as normal, HF, or RHF. Serum ApoM and S1P were measured by ELISA. Survival was analyzed using Kaplan-Meier and Cox proportional hazards models. Meanwhile, ApoM Tg or WT mice were subjected to pulmonary artery banding (PAB) to induce right ventricular (RV) dysfunction or partial inferior vena cava ligation (pIVCL) to cause hepatic congestion. Cardiac and hepatic pathology were assessed by tissue imaging and molecular analyses. ResultsApoM levels were lowest in RHF patients and inversely correlated with inflammatory markers. Each 0.01 M increase in ApoM was associated with a 6% lower risk of mortality. PAB induced RV dysfunction and reduced serum ApoM in wild-type mice, while ApoM Tg mice showed less severe RV remodeling and improved hepatic congestion. In contrast, ApoM Tg mice subjected to pIVCL showed no significant improvement in liver pathology. ConclusionIn patients with RHF and mice with RV dysfunction, circulating ApoM was reduced. Lower ApoM was independently associated with worse outcomes. Restoring ApoM expression primarily protects the heart and subsequently alleviates liver congestion, underscoring its distinct protective role in the heart-liver axis. Further investigation of the ApoM axis in RHF is warranted. DisclosuresResearch reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number TL1TR002344. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/25342523v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@1ad080forg.highwire.dtl.DTLVardef@ec2522org.highwire.dtl.DTLVardef@17a04aforg.highwire.dtl.DTLVardef@1c99db7_HPS_FORMAT_FIGEXP M_FIG C_FIG

1ObjectiveTo assess the effects of SGLT2 inhibitors on cardiovascular outcomes in HFpEF/HFmrEF. DesignSystematic review, random-effects meta-analysis using Hartung-Knapp, and trial sequential analysis (TSA). Data sourcesMEDLINE, Embase, and CENTRAL; searches updated through August 13, 2025. Eligibility criteriaParallel-group randomized trials enrolling adults with LVEF 40% (HFmrEF 40-49%; HFpEF 50%). Main outcome measuresTime-to-event composite of cardiovascular death or first heart failure hospitalization (primary); Kansas City Cardiomyopathy Questionnaire (KCCQ-TSS), components, and safety (secondary). ResultsTwo dedicated HFpEF trials (n=12,251) reported the primary outcome. The pooled hazard ratio was 0.80 (95% CI 0.73-0.87; I2=0%; 2 0; 95% prediction interval 0.67-0.96). TSA crossed efficacy boundaries and exceeded the diversity-adjusted required information size, indicating conclusive evidence for the composite. Effects were consistent in patients with and without diabetes and across EF 40-49% vs 50% (no significant interactions). KCCQ improved (+2.3 points, 95% CI 1.0-3.6; responders 5 pts: 42% vs 38%). Safety showed more genital mycotic infections, with no increase in serious adverse events or acute kidney injury. ConclusionsSGLT2 inhibitors robustly reduce cardiovascular death/heart failure hospitalization and improve health status in HFpEF/HFmrEF, supporting their role as foundational therapy, irrespective of diabetes status; effects on mortality alone remain imprecise. RegistrationPROSPERO CRD420251167908. Data and code: https://doi.org/10.5281/zenodo.18409428 PROSPEROCRD420251167908 Data availabilityhttps://doi.org/10.5281/zenodo.18409428

IntroHeart failure is one of the major causes of death in the United States, characterized by high readmission rates annually. Our study sought to analyze de-identified patient data from the Atrium Health Floyd Medical Center to identify differences in readmission rates for patients based on sex and marital status and propose novel solutions to our findings. MethodsIn this retrospective cohort analysis, 1,122 HF patient discharges (obtained by reviewing heart failure specific diagnosis-related group and principal diagnosis codes) between February 1, 2023 - March 30, 2024 were analyzed to describe demographic trends of readmission and total length of stay. Such analyses included a chi-square test of independence and Kruskal Wallis Test alongside the appropriate post-hoc analyses. Univariable logistic regression analyses were used to understand the odds of readmission amongst the different groups of marital status and sex as well as between different rural/urban statuses. Regressions were visualized with forest plots. ResultsThe heart failure readmission rate was 13.25% (147/1,109). Prior to post-hoc analyses, there was a significant difference in the observed count and expected count of married female readmission (9 vs. 19.161, p=0.020), and two proportion tests revealed a significantly higher readmission rate for single females compared to married females [14.36% (56/390) vs. 6.21% (9/145); p=0.010]. Prior to correction, married females had a statistically longer total length of stay compared to single females (p=0.038). Lastly, univariable logistic regressions revealed that married males, single females, and single males all had significantly higher odds of being readmitted compared to married females (married male: OR=2.248, p=0.045; single female: OR=2.532, p=0.013; single male: OR=2.606, p=0.010). No significant relationship between marital status and sex with length of stay or between geographic classification (metropolitan, micropolitan, rural, small town) with readmission was found. ConclusionsMarried females had the lowest readmission risk, while all others experienced significantly higher odds of readmission, pointing to the potentially protective role of partner-based social support post-discharge. Length of stay was not significantly related to marital or sex groups after correction suggesting that inpatient care delivery may be less sensitive to sociodemographic factors than post-discharge recovery. These findings underscore the need for better transitional care strategies for patients who lack strong support networks at home and stronger research backing to further characterize heart failure readmissions.

Whether the cumulative evidence for remote patient monitoring (RPM) in heart failure (HF) has reached a definitive threshold -- and whether benefits extend to geographically underserved populations -- remains uncertain. We conducted a systematic review, meta-analysis, and trial sequential analysis (TSA) of 65 RCTs (59 poolable; [~]23,000 participants) across four databases through February 2026, encompassing structured telephone support (15 trials), non-invasive telemonitoring (33), and invasive hemodynamic monitoring (11). Random-effects meta-analysis used REML with Hartung-Knapp-Sidik-Jonkman adjustment. RPM significantly reduced all-cause mortality (RR 0.890, 95% CI 0.819-0.966; P=0.007; I2=2.3%; k=41; NNT 84/year; prediction interval 0.820-0.965). TSA confirmed that accrued evidence exceeded the required information size, establishing firm evidence that additional RPM-versus-control trials are unlikely to overturn the mortality benefit. HF hospitalization was reduced (RR 0.782, 95% CI 0.711-0.859; P<0.001; k=39; NNT 17/year), though the prediction interval crossed 1.0 (0.589-1.038), indicating that in some settings the effect may be attenuated. No interaction by RPM type was observed (Pinteraction=0.15-0.24). GRADE certainty was moderate for mortality and low for HF hospitalization. A pre-specified geographic access analysis revealed that only 2 of 59 trials reported rural/urban subgroups -- a critical evidence gap that precludes conclusions about whether RPM differentially benefits underserved populations. HighlightsO_LITrial sequential analysis confirms firm evidence for RPM mortality benefit C_LIO_LIAll-cause mortality reduced 11% (NNT 84/yr, prediction interval excludes null) C_LIO_LIHF hospitalization reduced 22% (NNT 17/yr), though prediction interval crosses 1.0 C_LIO_LINo differential benefit by RPM type (STS vs TM vs invasive; Pinteraction=0.24-0.34) C_LIO_LIOnly 2 of 59 trials reported rural/urban subgroups -- a critical geographic evidence gap C_LI

BackgroundHeart failure with preserved ejection fraction (HFpEF) is increasingly common. While widely used prognostic scores often rely on limited variables and linear assumptions, they are likely to miss complex risk patterns. We aimed to develop and internally validate prediction models for 1-year all-cause mortality after first hospitalization for decompensated HFpEF and to compare them with standard survival models. MethodsWe performed a retrospective cohort study (2010-2020) using electronic medical records from a large academic health system. Adults with HFpEF (EF[&ge;]50%) admitted for a first time heart failure exacerbation were included. Variables spanned demographics, comorbidities, laboratory tests, echocardiography, discharge medications, and outcomes. Data were split into training (80%) and test (20%) sets with stratification by outcome. Missing values were handled with multiple imputation by chained equations. Two tree-based classifiers (Extreme Gradient Boosting and Light Gradient Boosting) were tuned with cross-validation and evaluated by area under the receiver operating characteristic curve (AUROC) and calibration. Time-to-event models included Cox proportional hazards, random survival forest (RSF), and gradient boosting survival (GBS) with concordance index and calibration assessment. Global and local (patient-level) explainability was extracted from each model, with cross-model predictor ranking and comparison. ResultsWe analyzed 7,840 index admissions; mean age was 78 years with 55.6% women. One-year mortality was 31.5%. Test-set AUROC was 0.751 for Extreme Gradient Boosting and 0.749 for Light Gradient Boosting with acceptable calibration. GBS achieved the highest concordance index (0.718), followed by RSF (0.711) and Cox (0.704). Lower serum albumin, older age, higher N-terminal pro B-type natriuretic peptide, renal dysfunction, and lower hemoglobin were the most consistent risk signals. ConclusionsDiverse modeling families produced similar discrimination and coherent predictors. A transparent risk tool using routinely available admission data appears feasible, allowing for patient-level risk assessment for precision health.

AbstracO_ST_ABSBackgroundC_ST_ABSSodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in heart failure (HF), yet comparative effectiveness between individual agents in heart failure with mildly reduced ejection fraction (HFmrEF) remains limited. MethodsWe conducted a retrospective cohort study using the TriNetX Global Collaborative Network electronic health record database. Adults ([&ge;]18 years) with HF and left ventricular ejection fraction (LVEF) 41-49% initiating empagliflozin or dapagliflozin between September 2021 and December 2025 were included. Propensity score matching (1:1) balanced demographics, comorbidities, medications, and laboratory values, yielding 1,466 patients per group. Outcomes were assessed over 1 year after treatment initiation and included all-cause mortality, hospitalization, HF exacerbation, and urinary tract infection (UTI). Risk analyses and Kaplan-Meier survival analyses with hazard ratios (HRs) were performed. ResultsIn the matched cohort, empagliflozin was associated with lower all-cause mortality (HR 0.75, 95% CI 0.59-0.96), substantially fewer hospitalizations (HR 0.61, 95% CI 0.55-0.67), and HF exacerbations (HR 0.64, 95% CI 0.57-0.73) compared to dapagliflozin. Rates of UTI were similar between groups (HR 0.81, 95% CI 0.65-1.01). ConclusionsIn this large real-world HFmrEF population, empagliflozin was associated with lower mortality, hospitalization, and HF exacerbation compared with dapagliflozin, with no significant difference in UTI risk. These findings suggest potential heterogeneity in clinical effectiveness among SGLT2 inhibitors in HFmrEF and warrant confirmation in prospective comparative studies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=146 HEIGHT=200 SRC="FIGDIR/small/26343819v1_ufig1.gif" ALT="Figure 1000"> View larger version (46K): org.highwire.dtl.DTLVardef@1a0ce4corg.highwire.dtl.DTLVardef@481df6org.highwire.dtl.DTLVardef@a71830org.highwire.dtl.DTLVardef@25114a_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundHeart failure (HF) is an increasingly common complication among patients with type 2 diabetes (T2D), yet its early detection remains challenging, especially in those with concomitant chronic kidney disease (CKD). NT-proBNP is a key biomarker for diagnosing and prognosticating HF, but its reference thresholds are influenced by renal function, age, and ethnicity. Current guideline cutoffs, largely derived from Western populations, may not apply to Asian patients. MethodsThis retrospective cohort study included 10,587 adults with T2D who underwent NT-proBNP testing between 2006 and 2021 at the National Taiwan University Hospital. Patients with prior HF were excluded. Generalized additive models identified NT-proBNP thresholds associated with HF hospitalization, and Kaplan-Meier analysis validated outcome separation. Subgroup analyses were stratified by age, sex, body mass index (BMI), and estimated glomerular filtration rate (eGFR). ResultsDuring a mean follow-up of 3.5 years, 1,892 (17.9%) patients were hospitalized for HF. NT-proBNP levels of 179 pg/mL (outpatient) and 728 pg/mL (emergency) marked inflection points for rising event risk (log-rank p < 0.0001). Age-specific analyses showed progressive increases in optimal thresholds: from 85 (<50 years old), 150 (50-74 years old) and 290 pg/mL ([&ge;]75 years old) in outpatients, and from 310, 600 and 1,165 pg/mL, respectively, in emergency settings. In the BMI-stratified analysis, NT-proBNP thresholds demonstrated an inverse relation with BMI. Considering renal function, the optimal cutoffs were 100, 310, and 935 pg/mL for eGFR > 60, 30-60, and < 30 mL/min/1.73 m{superscript 2}, respectively; in the emergency cohort, the corresponding thresholds were 290, 835, and 3,905 pg/mL. ConclusionsThis large Asian cohort defines setting- and renal function-specific NT-proBNP thresholds for predicting HF hospitalization in patients with T2D. The lower optimal cutoffs compared with Western guidelines highlight the need for ethnicity-adjusted diagnostic criteria to improve early identification and risk stratification of HF in clinical practice. What is new?O_LIIn a large real-world Asian cohort of patients with type 2 diabetes, we identified setting-specific NT-proBNP thresholds (179 pg/mL outpatient; 728 pg/mL emergency) associated with heart failure hospitalization risk. C_LIO_LIAge-, BMI-, and kidney function-stratified cutoffs revealed substantial heterogeneity in optimal NT-proBNP thresholds. C_LIO_LICompared with guideline-recommended values, Asian-specific thresholds were consistently lower ([~]30-40%), supporting ethnic differences in natriuretic peptide biology. C_LIO_LIA generalized additive model (GAM) captured nonlinear biomarker-risk relationships, enabling data-driven and clinically interpretable cutoff identification. C_LI What are the clinical implications?O_LIUse of ethnicity- and context-specific NT-proBNP thresholds may improve early detection of heart failure in Asian patients with type 2 diabetes. C_LIO_LIIncorporating kidney function and BMI into NT-proBNP interpretation enhances risk stratification, particularly in patients with CKD. C_LIO_LIReliance on Western guideline cutoffs may underestimate heart failure risk in Asian populations. C_LIO_LIThese findings support a precision medicine approach to biomarker interpretation and highlight the need for population-specific guideline refinement. C_LI

BackgroundIn 2018, the United Network for Organ Sharing (UNOS) revised the donor heart allocation policy, replacing the single urgency status for left ventricular assist device (LVAD)-related complications with three distinct categories. We evaluated the impact of this policy modification on transplant access and outcomes. MethodsThe UNOS Standard Transplant Analysis and Research File was queried to identify adult patients listed for heart transplantation with a LVAD-related complication in the United States between 2018 and 2023. The cumulative incidence of heart transplantation, mortality on device, and overall mortality following complication were assessed. ResultsDuring the study period, 792 patients experienced an LVAD complication that led to an initial listing or change in urgency status. Device infection was the most frequent complication (n=472, 59.6%), followed by device malfunction (n=80, 10.1%), aortic regurgitation (n=73, 9.2%), ventricular arrhythmias (n=46, 5.8%), thrombosis/hemolysis (n=43, 5.4%), bleeding (n=42, 5.3%), and right heart failure (n=36, 4.5%). At 1 year, transplantation incidence was 71.5% (95% CI, 67.9-74.8%), mortality on device was 3.8% (95% CI, 2.5-5.4%), and overall mortality was 12.3% (95% CI, 9.9-15.1%). Right heart failure was associated with increased 1-year mortality (34.1%, 95% CI, 18.2-50.8%; adjusted HR 2.0, 95% CI, 1.1-3.8). ConclusionsThe revised allocation system provides LVAD patients with complications timely access to transplantation, reflected in high transplant rates and low mortality. Right heart failure remains a distinct subgroup, with one-third of patients not surviving to one year, suggesting this complication may warrant consideration for higher urgency status.

Structured AbstractO_ST_ABSBackgroundC_ST_ABSVericiguat and sacubitril/valsartan both modulate the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling pathway and may improve myocardial function in patients with heart failure. ObjectivesTo compare the effects of vericiguat, sacubitril/valsartan, and their combination on left ventricular function and clinical outcomes in heart failure with nonpreserved ejection fraction patients. MethodsIn this retrospective real-world study, patients were classified into three groups: vericiguat added to guideline-directed medical therapy (vericiguat group), sacubitril/valsartan-based therapy (sacubitril/valsartan group), and combined sacubitril/valsartan plus vericiguat therapy (add-vericiguat group). Changes in left ventricular ejection fraction ({Delta}LVEF), in stroke volume ({Delta}SV), and in log-transformed N-terminal pro-B-type natriuretic peptide ({Delta}Log10 NT-pro BNP) from baseline to 1 year were evaluated. Clinical outcomes were also assessed. ResultsAt 1 year, LVEF significantly improved in both the vericiguat group (p = 0.02) and the sacubitril/valsartan group (p < 0.001). There was no significant difference in {Delta}LVEF between these two groups (p = 0.25). In contrast, the add-vericiguat group demonstrated a significantly greater improvement in {Delta}LVEF compared with the vericiguat group alone (p = 0.01). ConclusionsIn a real-world setting, vericiguat was associated with improvements in left ventricular function comparable to those of sacubitril/valsartan, and combination therapy provided incremental benefits. Vericiguat may serve as an alternative or adjunctive treatment option, particularly in patients unable to tolerate or maintain angiotensin receptor-neprilysin inhibitor therapy.

BackgroundSodium glucose co-transport inhibitors (SGLT2i), although established heart failure (HF) therapy in acquired heart disease, are not well-studied in adult congenital heart disease (ACHD). We aimed to conduct a systematic review and meta-analysis of SGLT2i therapy in moderate or severe complexity ACHD. MethodsFive databases (Pubmed, Medline, Embase, SCOPUS, and Cochrane) were searched for peer-reviewed journal articles describing SGLT2i HF therapy in moderate or severe complexity ACHD. Outcomes included adverse clinical events, biochemical markers of HF (N-terminal pro-brain natriuretic peptide [NT-proBNP] or BNP), and imaging markers of cardiac function (global longitudinal strain [GLS] and fractional area change [FAC]). Forest plots demonstrated mean study effects as individual and pooled estimates. The impact of heterogeneity on the overall variance was evaluated. ResultsThe systematic review included 10 studies (n=174 patients, 60% male). SGLT2i therapy was associated with a statistically significant improvement in GLS (mean difference -1.6 [-2.4,-0.9]) but not FAC (mean difference +1.86 [-6.2,+9.9]); there was no significant post therapy change in NT-proBNP or BNP (mean difference -240 pg/mL [-516,45] and -52 pg/mL [-129,26], respectively). Heterogeneity for the pooled effects for GLS and FAC was low (I2=0%), although moderate to high for NT-proBNP and BNP (I2=47% and I2=90%, respectively). Data were insufficient for evaluation of SGLT2i impact on clinical outcomes. ConclusionsPooled results across studies suggest that SGLT2i therapy can improve GLS among people with ACHD-HF, however the clinical implications of this observation warrant further study. Randomized controlled trials are now needed to evaluate the impact of SGLT2i therapy in ACHD.

BACKGROUNDPeak oxygen uptake (pVO2) is a strong, independent predictor of adverse cardiovascular outcomes, supporting cardiopulmonary exercise testing as a primary end point assessing efficacy of novel drug therapies in obstructive hypertrophic cardiomyopathy (oHCM) clinical trials. However, characterizing changes in pVO2 that patients perceive as beneficial or meaningful (ie, minimal important difference [MID]) has not been determined. METHODSData from patients with symptomatic oHCM enrolled in SEQUOIA-HCM and MAPLE-HCM were pooled. A total of 282 patients were randomized 1:1 to aficamten (5-20 mg daily) or matching placebo in SEQUOIA-HCM, and 175 patients were randomized 1:1 to aficamten (5-20mg daily) or to metoprolol (50-200 mg) in MAPLE-HCM; follow-up in both trials was 24 weeks. Primary outcome was change from baseline to week 24 ({Delta}) in pVO2 using Patient Global Impression of Change with anchor-based analysis to define MID. RESULTSAt week 24, {Delta}pVO2 (mL/kg/min) that corresponded to no change, one-category improvement, and one-category worsening were -0.05 (95% CI, -0.58 to 0.48), +0.35 (95% CI, -0.22 to 0.91), and -0.61 (95% CI, -1.36 to 0.13), respectively. Similarly, minute ventilation to carbon dioxide production ratio (VE/VCO2) slope that corresponded to no change, one-category improvement, and one-category worsening were 0.16 (95% CI, -0.59 to 0.90), -1.15 (95% CI, - 1.89 to -0.42), and 0.88 (95% CI, -0.42 to 2.19), respectively. In a responder analysis using this new threshold for pVO2, 60% of patients receiving aficamten achieved a {Delta}pVO2 [&ge;]0.35 versus 31% of patients on placebo or metoprolol (odds ratio, 3.4 [95% CI, 2.3-4.9], P<0.001). Consistent findings were seen with VE/VCO2 responder analysis. CONCLUSIONSChanges in pVO2 of +0.35 and -0.61 mL/kg/min were associated with a small but perceptible clinical improvement and worsening, respectively, in patients with oHCM. Applying this newly defined threshold resulted in excellent differentiation of treatment effect in a clinical trial. These novel data provide a measure of clarity to patients and clinicians regarding the interpretation of changes in pVO2 following therapeutic interventions, with potential impact on HCM management strategies and future clinical trials. Clinical Trial RegistrationSEQUOIA-HCM (NCT05186818; https://clinicaltrials.gov/study/NCT05186818?term=sequoia-hcm&rank=1); MAPLE-HCM (NCT05767346; https://clinicaltrials.gov/study/NCT05767346?term=maple-hcm&rank=1) Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIUsing pooled data from over 440 patients with symptomatic obstructive hypertrophic cardiomyopathy enrolled in two phase 3 clinical trials, we define, for the first time, the minimally important difference for peak oxygen uptake (pVO2) and ventilatory efficiency (VE/VCO2) using patient-anchored and distribution-based methodologies. C_LIO_LIA change in pVO2 of +0.35 mL/kg/min and a change in VE/VCO2 of -1.15 represent the minimal thresholds associated with patient-perceived clinical improvement. C_LIO_LIResponder analyses using these thresholds demonstrated robust differentiation between aficamten and placebo/metoprolol, with an odds ratio exceeding 3 for achieving a meaningful improvement in pVO2. C_LI What Are the Clinical Implications?O_LIThese newly defined thresholds bridge the gap between statistically significant changes in cardiopulmonary exercise testing measures and clinically meaningful benefit as perceived by patients with obstructive hypertrophic cardiomyopathy. C_LIO_LIClinicians can use these benchmarks to contextualize individual patient responses to medical therapy, informing shared decision-making regarding treatment continuation or modification. C_LIO_LIThese data provide a standardized, patient-centered framework for designing and interpreting primary end points in future hypertrophic cardiomyopathy clinical trials. C_LI

Structured abstractO_ST_ABSBackgroundC_ST_ABSTransthyretin amyloid cardiomyopathy (ATTR-CM) has historically been underdiagnosed but has recently become increasingly recognized due to advances in diagnostic techniques and heightened clinical awareness. Despite this progress, treatment options remain limited, as current approved therapies are costly and not widely accessible. Given the benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in broader heart failure (HF) populations, we aimed to evaluate their efficacy in reducing mortality and hospitalizations in ATTR-CM. ObjectivesTo determine whether SGLT2 inhibitors reduce all-cause mortality, CV mortality, and HF hospitalizations in ATTR-CM, offering a potential adjunctive therapy for this undertreated population. MethodsWe performed a systematic review and meta-analysis of SGLT2 inhibitors against SGLT2 inhibitors-naive patients with ATTR-CM. PubMed, Embase, Scopus and Cochrane databases were searched for trials published up to January 31, 2025. Data were extracted from published reports, and quality assessment was performed per Cochrane recommendations. Risk ratios (RRs) with 95% confidence interval (CI) were pooled across trials. Outcomes included all-cause mortality, CV mortality and HF hospitalization. ResultsOut of 177 database results, four observational studies and 5039 patients were included; 2489 (49.39%) received a SGLT2 inhibitor. All-cause mortality (RR 0.44; 95% CI 0.33-0.59; p<0.00001; I{superscript 2}=54%) and CV mortality (RR 0.30; 95% CI 0.16-0.55; p=0.0001; I{superscript 2}=25%) were significantly lower in patients treated with SGLT2 inhibitors compared with control. HF hospitalization (RR 0.68; 95% CI 0.33-1.41; p=0.30; I{superscript 2}=89%) showed a downward trend, yet this was not statistically significant. ConclusionsIn patients with ATTR-CM, SGLT2 inhibitors significantly reduce both all-cause and cardiovascular mortality compared to standard care, suggesting they may serve as a valuable adjunctive therapy for this undertreated population. Although HF hospitalization showed a nonsignificant downward trend, these findings underscore the need for large randomized trials to confirm and expand on these promising results.

Background: Acute heart failure (AHF) exhibits marked heterogeneity in diastolic hemodynamics, yet comprehensive echocardiographic assessment of diastolic function (DF) and filling pressure (FP) is often infeasible. We evaluated whether artificial intelligence-enabled electrocardiography (AI-ECG) could provide scalable DF grading and FP estimation in hospitalized AHF patients. Methods: We retrospectively studied adults hospitalized for AHF across Mayo Clinic sites (2013-2023) who received 1 dose of intravenous loop diuretic and had paired 12-lead ECG and TTE. The previously validated AI-ECG DF model was applied without retraining to generate four DF grades and a continuous FP probability. Clinical outcomes were all-cause mortality and heart failure rehospitalization. Associations with clinical severity markers and echocardiographic indices were examined. Kaplan-Meier survival analysis and adjusted multivariable Cox proportional hazards models were performed. Exploratory analyses examine the kinetics of change in FP probability and impact on mortality. Results: Among 11,513 patients (median age 75 years, 39% female), AI-ECG DF grading was feasible in 100%, whereas echocardiographic DF was indeterminate in 44% of clinically eligible patients. In 2,582 patients with determinate echocardiographic DF, AI-ECG FP probability discriminated TTE Grade 2-3 dysfunction with AUC 0.85 (95% CI 0.83 - 0.86). Higher AI-ECG DF grades were associated with higher comorbidity burden, worse NYHA class, elevated NT-proBNP, higher MAGGIC scores, elevated PCWP, and more advanced structural remodeling. After multivariable adjustment, AI-ECG DF remained independently associated with mortality (hazard ratio [HR] 1.25, 95% CI 1.16-1.35 for Grade 2; HR 1.44, 95% CI 1.33-1.56 for Grade 3 versus Normal/Grade 1). Combining AI-ECG DF with MAGGIC scores yielded ordered risk gradients, with highest mortality in patients with both high MAGGIC and Grade 2-3 DF. Among patients with serial ECGs, improvement in FP probability was independently associated with lower mortality (HR 0.85, 95% CI 0.79-0.91), whereas worsening did not show a consistent adverse gradient beyond baseline DF. Conclusions: In a large, geographically diverse AHF cohort, AI-ECG DF grading was universally feasible, correlated with established hemodynamic severity markers, and provided independent prognostic information beyond established risk factors, supporting its role as a pragmatic, scalable diastolic biomarker in AHF.

BackgroundCardiovascular disease (CVD) is the leading cause of pregnancy-related morbidity and mortality in the United States. Several studies have evaluated readmission rates in the general HF population, but in patients with pregnancy-related HF, readmissions have been understudied. This study aims to characterize the 30-day HF readmission patterns in pregnancy-related admissions to identify vulnerable patient populations. MethodsThe National Readmission Database from 2016 to 2021 was used to identify women aged 13-49 with an index hospitalization in which HF was coded as either the primary or secondary diagnosis during a pregnancy-related antepartum, delivery, or postpartum admission, identified by diagnosis-related group (DRG) codes and ICD-10 codes. The primary outcome was 30-day all-cause readmission. We performed descriptive and comparative analyses to describe the differences in patient characteristics and readmission patterns between groups. ResultsThe overall 30-day all-cause readmission rate was 13% when readmissions for delivery were excluded. The readmission rate increased with age, peaking at 15.1% in the 38-49yr age group. Higher readmission rates were also associated with combined (systolic and diastolic) HF (16.1%), systolic HF (14.8%), lower socioeconomic status (15.3%), substance use disorder (17.2%), and alcohol use (18.6%). Patients whose index hospitalization was for delivery had the highest absolute risk of 30-day readmission at 19.3%. Readmissions peaked between days 6 and 8 post discharge, with more than 50% of all readmissions occurring within the first two weeks post-discharge ConclusionsIn our study, the highest risk of readmission occurred after an index hospitalization for delivery, and most readmissions occurred in the first 2 weeks post-discharge. Our findings suggest that a post-discharge follow up within 7 days of admission complicated by HF should be extended to patients with pregnancy-related HF and effective readmission reduction strategies must include a better understanding of heart failure phenotypes, and a proactive approach to addressing social risk factors.

BackgroundMedication non-adherence is a critical problem among patients with heart failure (HF). Current evidence has shown its association with increased morbidity, mortality and healthcare costs. Prescription discrepancy is a significant risk factor that can increase non-adherence and subsequently increases the risk of HF-related hospitalization and mortality. Current literature has not provided a clear understanding of the non-adherence problem or contributing factors among Saudi HF patients. Measuring the prevalence of non-adherence and its associated factors can direct clinicians to implement effective interventions to optimize pharmacotherapy benefits, and thus, improving outcomes. AimTo assess the Saudi Arabian population of HF patients for degree of adherence to their medications, the amount of medication discrepancies, and its association with re-hospitalization rate. MethodA prospective observational study conducted at a tertiary care hospital on eligible HF patients attending the ambulatory clinic from July 2023 through April 2024. All patients were followed for six months. Primary outcomes were percentage of patients adherent to their medications and number and type of prescription discrepancies. Secondary outcomes were degree of health literacy, prevalence of non-adherence risk factors, and HF-related re-hospitalization rate. Adherence was measured utilizing the Eight-item Morisky Medication Adherence Scale (MMAS-8). Three-item Brief Health Literacy Screen (BHLS) was used to measure health literacy. ResultA total of 202 patients were included in the study. Average age was 60 years, and 69% were males. For the primary outcomes, 43.5% of patients demonstrated high adherence, while 39.6% and 16.8% fell into medium and low adherence categories, respectively. Prescription discrepancies were identified in 51.5% of the patients. Causes of discrepancies ranged from patient generated, healthcare system generated, or multifactorial, generated by both, the patient and the system. Degree of health literacy was adequate in 23.8% of the patients, marginal and inadequate in 51.5% and 24.8%, respectively. Of potential non-adherence risk factors, polypharmacy, age [&ge;]65 years, and marginal and inadequate health literacy, were the most common. HF-related re-hospitalization occurred in 18 patients, all of which were either non-adherent or had prescription discrepancies. ConclusionAmong HF patients, medication non-adherence is a significant problem that is associated with increased morbidity and mortality. In our study, around half of the patients either experienced difficulties with adherence, prescription discrepancies, or both. Measuring the local prevalence of factors affecting non-adherence can be of use to identify strategies that suit our population the best, in order to mitigate their negative effect.

BackgroundMyocardial 18fluorodeoxyglucose (18FDG)-avidity is frequently seen in patients with genetic cardiomyopathy (CMP), as well as a growing "idiopathic 18FDG-avidity" group of genotype-negative patients who do not clearly have cardiac sarcoidosis (CS). ObjectivesTo determine the prognostic implications of 18FDG-avidity in patients with and without genetic CMP, and the effects of immunosuppression in the latter. MethodsThis multicenter, retrospective study included all patients who were referred for both 18FDG-PET and CMP genetic testing. Patients with acute myocarditis, biopsy-proven sarcoidosis or extracardiac 18FDG-avidity were excluded. We investigated heart failure (HF) composite (left ventricular assist device, heart transplant, HF hospitalization, death) and arrhythmia composite (sustained ventricular arrhythmias (VT/VF), atrio-ventricular block, death) outcomes using survival analysis including Cox proportional hazards modeling and inverse probability of treatment weighting (IPWT). ResultsAmong 372 patients, 142 (38%) were 18FDG-avid. Prevalence of genetic CMP among 18FDG-avid patients (12%) was similar to that of 18FDG-negative patients (19%, p=0.07). 18FDG-avidity was associated with increased risk of HF composite (HR 1.69 (1.04-2.75), p=0.034) and arrhythmia composite (HR 1.63 (1.1-2.4), p=0.014) outcomes compared to 18FDG-negative patients. However, these associations were present only in genotype-negative patients, and not in genetic CMP. After IPWT, immunosuppression of 18FDG-avid patients (n=49) was not associated with a reduction in HF (HR 3.31 (1.25, 8.77), p=0.016) or arrhythmia composite outcomes (HR 1.61 (0.79, 3.25), p=0.19) compared with those who were not immunosuppressed (n=93). ConclusionsMyocardial-only 18FDG-avidity is only associated with adverse HF and arrhythmia outcomes in genotype-negative patients who do not clearly have CS. IST does not seem to modify the disease course, suggesting that not all myocardial 18FDG uptake reflects clinically significant inflammation.

Heart failure with preserved ejection fraction (HFpEF) is an increasingly common cause of morbidity and mortality in older adults that is driven by cardiac and non-cardiac mechanisms. Physical rehabilitation improves frailty and functional capacity in HFpEF, though underlying mechanisms remain less clear. We quantified >5,000 circulating proteins across two randomized clinical trials of rehabilitation in HFpEF (REHAB-HF, SECRET-II), identifying proteins associated with prognostic measures of physical function (short physical performance battery, 6-minute walk distance) and protein changes after rehabilitation. Using an artificial intelligence (AI)-enabled multiplex network analysis (MENTOR-IA), we identified biologically plausible networks central to this "physical function proteome," including endothelial remodeling, mitochondrial metabolism, calcium handling, and immune modulation. Expression of prioritized proteins at the transcriptional level localized to heart, skeletal muscle, and brain tissue, with several cognate transcripts implicated in frailty via tissue-specific transcriptome-wide genetic association studies. In addition, using novel human genetic approaches, we implicated select proteins as mediating tissue-specific genetic effects on frailty. These findings motivated us to construct multi-protein signatures of physical function, which correlated with functional changes observed with rehabilitation in REHAB-HF and SECRET-II and that were associated with heart failure and multi-dimensional clinical outcomes in >26,000 individuals. These findings collectively delineate a multi-system molecular program underlying physical function impairment and rehabilitation response in HFpEF, offering insights into potential precision risk estimators and therapeutic targets for surveillance and promotion of physiologic resilience.