Circulation: Heart Failure

BackgroundMultimorbidity is common among patients with heart failure (HF) and contributes to poor prognosis; however, the influence of age group and sex differences on the prevalence and outcomes of multimorbidity remains unclear. MethodsThis multicenter retrospective study included 3,004 hospitalized patients with HF. Multimorbidity was defined as the presence of two or more comorbidities and was quantified for stratification of comorbidity burden using the age-adjusted Charlson Comorbidity Index (CCI). Patients were dichotomized into high-and low-CCI groups based on the median CCI and were evaluated for prognosis using a composite endpoint of all-cause death or HF readmission. ResultsMultimorbidity increased with age but declined slightly in individuals aged > 85 years. And sex differences were observed, with males demonstrating a steeper increase in multimorbidity prevalence than females. Event-free survival rates were lower in the high-CCI group (hazard ratio [HR], 1.786; 95% confidence interval [CI], 1.483-2.151), consistent across sexes (males: HR, 1.927; 95% CI, 1.520-2.443; females: HR, 1.581; 95% CI, 1.171-2.135). Among individuals aged [≥]75 years with a high CCI, males had a stronger association with events than females (HR, 1.334; 95% CI, 1.031-1.727). ConclusionsIn individuals with HF, sex differences were evident in the prevalence of multimorbidity by age group and were associated with prognosis in older populations with a high comorbidity burden. Recognizing these differences is essential for tailoring HF management strategies to improve outcomes in individuals with multimorbid HF. Clinical trial registrationURL: https://www.umin.ac.jp/ctr; unique identifier: UMIN000054854 Clinical perspective What Is New?O_LIThis multicenter study demonstrated that age-dependent sex differences exist in both the prevalence and prognostic impact of multimorbidity among Japanese individuals with heart failure. C_LIO_LIA three-way interaction analysis (age x sex x comorbidity burden) utilizing restricted cubic splines revealed that, among individuals with a high comorbidity burden, sex-related prognostic differences became increasingly pronounced with age, with older males exhibiting a higher risk than females. C_LI What Are the Clinical Implications?O_LIIncorporating age-and sex-specific risk assessments based on comorbidity burden may enhance individualized management strategies and improve clinical outcomes in individuals with heart failure, particularly in older adults with multiple comorbidities. C_LI

AimTo evaluate whether initiation of cardiac rehabilitation (CR) within 6 weeks improves long-term outcomes of patients with acute heart failure (HF). MethodsPatients with acute HF who participated in an HF disease management program from January 2019 to July 2022 were prospectively enrolled. Eligible patients were divided into two groups: early CR (and continued home-based CR during the follow-up period) and non-CR. The primary outcome was all-cause mortality. Secondary outcomes were rehospitalisation for recurrent HF and changes in 12-item Kansas City Cardiomyopathy Questionnaire scores from baseline to 6 months and 1 year. A post-hoc analysis stratified by lysyl oxidase-like 2 (LOXL2) levels assessed CR benefits for patients with cardiac fibrosis. ResultsOf 162 patients, 34 received early CR. The non-CR group was older (median age: 58.5 vs. 53.0 years, p=0.022) and had higher N-terminal pro-B-type natriuretic peptide levels (4552.5 vs. 1275.0 pg/mL, p=0.002). Propensity score matching yielded 33 patients per group. Over 2.85 years, the early CR group had lower all-cause mortality (0 vs. 87.16 events per 1000 patient-years, rate difference: -0.087 [95% confidence interval {CI}: -0.143 to -0.031], p=0.002). Patients with LOXL2 >200 pg/mL benefited the most (0 vs. 172.3 events per 1000 patient-years, rate difference: -0.172 [95% CI: -0.299 to -0.046], p=0.008). ConclusionEarly post-discharge exercise-based CR was associated with reduced all-cause mortality in patients with acute HF. Patients with more severe cardiac fibrosis, indicated by higher LOXL2 levels, derived greater benefits from the CR program. Large-scale trials are needed to validate these findings. Trial registrationThe study protocol was registered at ClinicalTrials.gov (identifier: NCT03782337). Lay summaryO_LIEarly exercise after discharge for patients with acute heart failure is feasible, and early cardiac rehabilitation with nearly 3 years of follow-up is associated with a reduction in all-cause mortality without significant risks. C_LIO_LIFurthermore, for patients with severe cardiac fibrosis, cardiac rehabilitation can result in an even greater reduction in all-cause mortality. C_LI Based on our findings, cardiac rehabilitation and exercise recommendations should be initiated early after discharge in patients with acute heart failure, particularly those with cardiac fibrosis.

BackgroundAcute decompensation is associated with increased mortality in heart failure (HF) patients, though the underlying etiology remains unclear. Extracellular vesicles (EVs) and their cargo may mark specific cardiovascular physiologic states. We hypothesized that EV transcriptomic cargo, including long non-coding RNAs (lncRNAs) and mRNAs, is dynamic from the decompensated to recompensated HF state, reflecting molecular pathways relevant to adverse remodeling. MethodsWe examined differential RNA expression from circulating plasma extracellular RNA in acute HF patients at hospital admission and discharge alongside healthy controls. We leveraged different exRNA carrier isolation methods, publicly available tissue banks, and single nuclear deconvolution of human cardiac tissue to identify cell and compartment specificity of the topmost significantly differentially expressed targets. EV-derived transcript fragments were prioritized by fold change (-1.5 to + 1.5) and significance (<5% false discovery rate), and their expression in EVs was subsequently validated in 182 additional patients (24 control; 86 HFpEF; 72 HFrEF) by qRT-PCR. We finally examined the regulation of EV-derived lncRNA transcripts in human cardiac cellular stress models. ResultsWe identified 138 lncRNAs and 147 mRNAs (present mostly as fragments in EVs) differentially expressed between HF and control. Differentially expressed transcripts between HFrEF vs. control were primarily cardiomyocyte derived, while those between HFpEF vs. control originated from multiple organs and different (non-cardiomyocyte) cell types within the myocardium. We validated 5 lncRNAs and 6 mRNAs to differentiate between HF and control. Of those, 4 lncRNAs (AC092656.1, lnc-CALML5-7, LINC00989, RMRP) were altered by decongestion, with their levels independent of weight changes during hospitalization. Further, these 4 lncRNAs dynamically responded to stress in cardiomyocytes and pericytes in vitro, with a directionality mirroring the acute congested state. ConclusionCirculating EV transcriptome is significantly altered during acute HF, with distinct cell and organ specificity in HFpEF vs. HFrEF consistent with a multi-organ vs. cardiac origin, respectively. Plasma EV-derived lncRNA fragments were more dynamically regulated with acute HF therapy independent of weight change (relative to mRNAs). This dynamicity was further demonstrated with cellular stress in vitro. Prioritizing transcriptional changes in plasma circulating EVs with HF therapy may be a fruitful approach to HF subtype-specific mechanistic discovery. CLINICAL PERSPECTIVEO_ST_ABSWhat is new?C_ST_ABSWe performed extracellular transcriptomic analysis on the plasma of patients with acute decompensated heart failure (HFrEF and HFpEF) before and after decongestive efforts. Long non-coding RNAs (lncRNAs) within extracellular vesicles (EVs) changed dynamically upon decongestion in concordance with changes within human iPSC-derived cardiomyocytes under stress. In acute decompensated HFrEF, EV RNAs are mainly derived from cardiomyocytes, whereas in HFpEF, EV RNAs appear to have broader, non-cardiomyocyte origins. What are the clinical implications?Given their concordance between human expression profiles and dynamic in vitro responses, lncRNAs within EVs during acute HF may provide insight into potential therapeutic targets and mechanistically relevant pathways. These findings provide a "liquid biopsy" support for the burgeoning concept of HFpEF as a systemic disorder extending beyond the heart, as opposed to a more cardiac-focused physiology in HFrEF.

BackgroundTwo general phenotypes of heart failure (HF) are recognized: HF with reduced ejection fraction (HFrEF) and with preserved EF (HFpEF). To develop HF disease phenotype-specific approaches to define and guide treatment, distinguishing biomarkers are needed. The goal of this study was to utilize quantitative metabolomics on a large, diverse population to replicate and extend existing knowledge of the plasma metabolic signatures in human HF. MethodsQuantitative, targeted LC/MS plasma metabolomics was conducted on 787 samples collected by the Penn Medicine BioBank from subjects with HFrEF (n=219), HFpEF (n=357), and matched non-failing Controls (n=211). A total of 90 metabolites were analyzed, comprising 28 amino acids, 8 organic acids, and 54 acylcarnitines. 733 of these samples were also processed via an OLINK protein panel for proteomic profiling. ResultsConsistent with previous studies, unsaturated forms of medium/long chain acylcarnitines were elevated in the HFrEF group to a greater extent than the HFpEF group compared to Controls. A number of amino acid derivatives, including 1- and 3-methylhistidine, homocitrulline, and symmetric (SDMA) and asymmetric (ADMA) dimethylarginine were elevated in HF, with ADMA elevated uniquely in HFpEF. Plasma branched-chain amino acids (BCAA) were not different across the groups; however, short-chain acylcarnitine species indicative of BCAA catabolism were significantly elevated in both HF groups. The ketone body 3-hydroxybutyrate (3-HBA) and its metabolite C4-OH carnitine were uniquely elevated in the HFrEF group. Linear regression models demonstrated a significant correlation between plasma 3-HBA and NT-proBNP in both forms of HF, stronger in HFrEF. ConclusionsThese results identify plasma signatures that are shared as well as potentially distinguish between HFrEF and HFpEF. Metabolite markers for ketogenic metabolic re-programming in extra-cardiac tissues were identified as unique signatures in the HFrEF group, possibly related to the lipolytic action of increased levels of BNP. Future studies will be necessary to further validate these metabolites as HF biosignatures that may guide phenotype-specific therapeutics and provide insight into the systemic metabolic responses to HFpEF and HFrEF. Clinical Perspective What Is New?O_LI"Real world" targeted metabolomic profiling on wide range of metabolites in a diverse population of patients with HFrEF and HFpEF. C_LIO_LILevels of 3-hydroxybutyrate and its metabolite C4OH-carnitine were uniquely increased in the HFrEF group and correlated with levels of plasma NT-proBNP in both the heart failure groups, indicating the possibility of a heart-adipose-liver axis. C_LIO_LIAsymmetric dimethylarginine, a known inhibitor of nitric oxide synthase, was uniquely upregulated in HFpEF suggesting that there may also be an underlying component of vascular dysregulation contributing to HFpEF pathophysiology. C_LI What Are the Clinical Implications?O_LIThe plasma metabolomic changes seen in the heart failure cohorts support the existing theory of metabolic reprogramming, providing further rationale for the pursuit of therapeutic targets for the treatment of heart failure. C_LIO_LIQuantitative metabolomic profiling shows promise for guiding therapeutic decisions in HFrEF and HFpEF. C_LIO_LIModulation of natriuretic peptides may enhance the delivery of ketone and fatty acids to the "fuel starved" failing heart. C_LI

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.

BackgroundEjection fraction (EF) is a key component of heart failure (HF) classification, including the increasingly codified HF with mildly reduced EF (HFmrEF) category. However, the biologic basis of HFmrEF as an entity distinct from HF with preserved EF (HFpEF) and reduced EF (HFrEF) has not been well characterized. MethodsThe EXSCEL trial randomized participants with type 2 diabetes (T2DM) to once-weekly exenatide (EQW) vs. placebo. For this study, profiling of [~]5000 proteins using the SomaLogic SomaScan platform was performed in baseline and 12-month serum samples from N=1199 participants with prevalent HF at baseline. Principal component analysis (PCA) and ANOVA (FDR p<0.1) were used to determine differences in proteins between three EF groups, as previously curated in EXSCEL (EF>55% [HFpEF], EF 40-55% [HFmrEF], EF<40% [HFrEF]). Cox proportional hazards was used to assess association between baseline levels of significant proteins, and changes in protein level between baseline and 12-month, with time-to-HF hospitalization. Mixed models were used to assess whether significant proteins changed differentially with exenatide vs. placebo therapy. ResultsOf N=1199 EXSCEL participants with prevalent HF, 284 (24%), 704 (59%) and 211 (18%) had HFpEF, HFmrEF and HFrEF, respectively. Eight PCA protein factors and 221 individual proteins within these factors differed significantly across the three EF groups. Levels of the majority of proteins (83%) demonstrated concordance between HFmrEF and HFpEF, but higher levels in HFrEF, predominated by the domain of extracellular matrix regulation, e.g. COL28A1 and tenascin C [TNC]; p<0.0001. Concordance between HFmrEF and HFrEF was observed in a minority of proteins (1%) including MMP-9 (p<0.0001). Biologic pathways of epithelial mesenchymal transition, ECM receptor interaction, complement and coagulation cascades, and cytokine receptor interaction demonstrated enrichment among proteins with the dominant pattern, i.e. HFmrEF-HFpEF concordance. Baseline levels of 208 (94%) of the 221 proteins were associated with time-to-incident HF hospitalization including domains of extracellular matrix (COL28A1, TNC), angiogenesis (ANG2, VEGFa, VEGFd), myocyte stretch (NT-proBNP), and renal function (cystatin-C). Change in levels of 10 of the 221 proteins from baseline to 12 months (including increase in TNC) predicted incident HF hospitalization (p<0.05). Levels of 30 of the 221 significant proteins (including TNC, NT-proBNP, ANG2) were reduced differentially by EQW compared with placebo (interaction p<0.0001). ConclusionsIn this HF substudy of a large clinical trial of people with T2DM, we found that serum levels of most proteins across multiple biologic domains were similar between HFmrEF and HFpEF. HFmrEF may be more biologically similar to HFpEF than HFrEF, and specific related biomarkers may offer unique data on prognosis and pharmacotherapy modification with variability by EF.

IntroductionCirculating biomarkers play an important role in patients with heart failure (HF) for risk stratification and mechanistic insights. We aimed to examine if a diverse set of biomarkers in the REHAB-HF trial would predict improvement in physical function following a 12-week tailored physical therapy rehabilitation intervention compared to attention control. MethodsThe study population consisted of participants [&ge;]60 years of age who were hospitalized with acute HF and randomized to a subsequent multidomain outpatient physical rehabilitation intervention vs. attention control with outcomes of 12-week functional change including the Short Physical Performance Battery (SPPB) and six-minute walk distance (6MWD). Blood was collected prior to randomization and at 12-weeks for cardiac, renal, and inflammatory biomarkers. Linear trends across progressively higher biomarker values versus improvement in functional outcomes based on treatment assignment were evaluated. Classification and regression trees (CART) were created to estimate optimal biomarker levels associated with differential improvement in the two functional outcomes. ResultsA total of 242 of 349 participants (69%) had baseline biomarkers measured. In an adjusted regression model, higher baseline cardiac troponin (cTn) I and T were associated with greater gains in SPPB and 6MWD respectively with the rehabilitation intervention (P=0.04 and 0.03 for interaction) versus attention control. In the CART analysis of the physical rehabilitation and attention control participants, those with baseline C-reactive protein (CRP) [&ge;]9.9 mg/L and hs-cTnT [&ge;]36 ng/L receiving the rehabilitation intervention had a 129 m (95% CI 78-180m) greater 12-week 6MWD increase vs attention control. In contrast, for participants with CRP<9.9 mg/L there was no significant incremental 6MWD difference (30m, 95% CI -0.5m, 60.2m). For SPPB, a CRP [&ge;]9.9 mg/L and creatinine [&ge;]1.4 mg/dL optimally identified a differential improvement with the rehabilitation intervention versus attention control. The biomarkers (except for creatinine) decreased by 12 weeks post hospitalization but with no differences based on treatment assignment. ConclusionHigher baseline levels of biomarkers of inflammation, cardiac injury, and renal dysfunction identified older adults after a HF hospitalization with the greatest differential improvement in physical function with a rehabilitation intervention. Biomarkers may help clinicians predict the benefits of this treatment. (Funded by the National Institutes of Health and others; REHAB-HF ClinicalTrials.gov number, NCT02196038).

BackgroundReal-world evidence shows alarmingly suboptimal utilization of GDMT in HFrEF. One of the barriers of GDMT implementation appears to be concerns about the potential development of drug-related adverse events (AEs), particularly in high-risk patients. This study aimed to evaluate whether advanced HFrEF patients can be up-titrated safely and whether advanced HFrEF predisposes to the occurrence of putatively drug-related AEs. MethodsA total of 373 HFrEF patients from our prospective HF registry were analyzed for HF drug utilization and target dosages (TDs) at baseline, 2 months, and 12 months. Successful up-titration and AEs were evaluated for different stages of HF reflected by NT-proBNP (<1000pg/ml, 1000-2000pg/ml, >2000pg/ml). ResultsA stepwise increase in HF medications could be observed for all drug classes during follow-up. At 12 months 73%, 75%, 62%, 86% and 45% of patients received [&ge;]90% of TDs of beta-blockers (BB), renin-angiotensin system inhibitors (RASi), mineralocorticoid receptor antagonists (MRA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and triple-therapy, respectively. Predictors of successful up-titration in logistic regression were baseline HF-drug TDs, eGFR, and potassium, but not NT-proBNP or age. The development of AEs was rare, with hyperkalemia as the most common event (34% at 12 months). AEs were comparable in all stages of HF. However, development of hyperkalemia was more frequent in patients with higher NT-proBNP and also accounted for most cases for incomplete up-titration. ConclusionsThis study suggests that with dedicated protocols and frequent visits GDMT can be successfully implemented across all stages of HFrEF, including patients with highest NT-proBNP levels who probably profit the most. CLINICAL PERSPECTIVEO_ST_ABSWhat is new?C_ST_ABSO_LIGDMT up-titration is feasible even in advanced HFrEF patients, with this study demonstrating that [&ge;]50% target doses for all HF medications can be achieved in about 90% of patients within 12 months through high-intensity care and frequent follow-up visits. C_LIO_LIAdverse events during up-titration are rare, even in high-risk patients, and the most notable AE, hyperkalemia, can be effectively managed in most cases without discontinuing therapy. C_LI What are the clinical implications?O_LIThis study demonstrates that GDMT up-titration is achievable even in advanced HFrEF, challenging the notion that medication intolerance should be part of the definition of advanced HF. C_LIO_LIPracticing physicians should pursue GDMT up-titration for all HFrEF patients, as AEs are manageable, and its potential benefit to stabilize disease progression and improve outcomes far outweigh the risks. C_LIO_LIThe lack of consensus on when to halt up-titration or define true intolerance, combined with limited evidence on GDMT efficacy or futility in advanced HF, underscores the need for further research to optimize treatment in this high-risk group. C_LI

IntroductionHFpEF is one of the leading causes of death whose burden is estimated to expand in the coming decades. This paper examines the relationship between circulating levels of galectin-3, an emerging risk factor for cardiovascular disease, and the clinical diagnosis of HFpEF. MethodsThe authors reviewed peer-reviewed literature and 18 studies met inclusion criteria. Study characteristics, study outcome definitions, assay characteristics, main findings, and measures of association were tabulated and summarized. ResultsFive (1-5) studies found significant associations between galectin-3 and HFpEF diagnosis compared to healthy controls, and one (6) did not. Five studies (7-11) found significant associations between galectin-3 concentration in circulation and severity of diastolic dysfunction. Three studies (12-14) found a statistically significant association between circulating galectin-3 and all-cause mortality or rehospitalization. Two studies (15,16) found levels of circulating galectin-3 to be a statistically significant predictor of later HFpEF onset. Finally, two studies examined whether galectin-3 was associated with incident HFpEF, one (17) found a significant association and the other (18) did not. ConclusionGiven the paucity of effective therapeutics for HFpEF, galectin-3 shows promise as a possible HFpEF-linked biomarker that may, with further study, inform and predict treatment course to reduce morbidity and mortality.

BackgroundLeft ventricular reverse remodeling (LVRR) is a surrogate marker of treatment response in heart failure with reduced ejection fraction (HFrEF), usually observed within 24 months. Some patients experience LVRR beyond this period, but its prognostic significance remains unclear. MethodsWe retrospectively analyzed symptomatic HFrEF patients with left ventricular ejection fraction (LVEF) [&le;]40%. All patients underwent echocardiography at baseline and at two follow-up points: 6-24 months (Follow-up 1) and 24-78 months (Follow-up 2). LVRR was defined as an LVEF increase [&ge;]10% to >40% and classified as Early (at Follow-up 1) or Late (at Follow-up 2). The Simple-GDMT Score was used to assess guideline-directed medical therapy (GDMT). The primary outcome was a composite of all-cause death or HF hospitalization, evaluated from Follow-up 2 onward. ResultsOf 213 patients, 84 (39.4%) achieved Early LVRR, 25 (11.7%) Late LVRR, and 104 (48.8%) showed no LVRR. The primary endpoint was lower in both Early and Late LVRR groups compared with the No-LVRR group (vs Early; p < 0.001, vs Late; p = 0.015). The Simple-GDMT Score increased over time in all groups, but trajectories differed, with a gradual up-titration only in the Late LVRR group. In Cox models, Late LVRR was independently associated with a lower risk of the composite outcome compared with the No-LVRR group. ConclusionsBoth early- and late-onset LVRR were associated with improved prognosis compared with no LVRR. Even delayed remodeling carried prognostic value, underscoring the importance of long-term follow-up in HFrEF management. (245/250 words) Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LIThis study demonstrates that late-onset LVRR, occurring beyond 24 months, is associated with favorable prognosis in HFrEF, extending its prognostic relevance across a broader timeframe and multiple etiologies. C_LIO_LIIn patients with late LVRR, reverse remodeling was seen alongside gradual GDMT intensification, suggesting that delayed titration may have contributed. C_LI What are the Clinical Implications?O_LIEarly initiation and optimization of GDMT is ideal, yet even patients with initially inadequate or delayed therapy should still undergo intensification, as this can promote reverse remodeling and improve outcomes. C_LIO_LISuch patients should not be excluded from aggressive management; timely escalation of therapy remains essential to achieving survival benefit. C_LI

BackgroundRecently, patients with supra-normal left ventricular ejection fraction (snLVEF) are reported to have high risk of adverse outcomes, especially in women. We sought to evaluate sex-related differences in the association between LVEF and long-term outcomes in heart failure (HF) patients. MethodsThe multicenter WET-HF Registry enrolled all patients hospitalized for acute decompensated HF (ADHF). We analyzed 3,943 patients (age 77 years; 59.8% male) registered from 2006 to 2017. According to LVEF the patients were divided into the 3 groups: HF with reduced EF (HFrEF), mildly reduced EF (HFmrEF) and preserved EF (HFpEF). The primary endpoint was defined as the composite of cardiac death and ADHF rehospitalization after discharge. ResultsImplementation of guideline-directed medical therapy (GDMT) such as renin-angiotensin-system inhibitor (RASi), {beta}-blocker and their combination at discharge was significantly lower in women than men in HFmrEF. Lower prescription of RASi + {beta}-blocker combination in female HFmrEF was noted even after adjustment for covariates (p=0.007). There were no such sex-related differences in HFrEF. Female sex was associated with higher incidence of the primary endpoint and ADHF rehospitalization after adjustment for covariates exclusively in HFmrEF. Restricted cubic spline analysis demonstrated a U-shaped relationship between LVEF and the hazard ratio of the primary endpoint in women, but such relationship was not observed in men (p for interaction=0.037). ConclusionsIn women, not only lower LVEF but also snLVEF were associated with worse long-term outcomes. Additionally, sex-related differences in the GDMT implementation for HFmrEF highlight the need for sex-specific guidelines to optimize HF management.

BACKGROUNDPrior studies have demonstrated an association of depression with adverse clinical outcomes in patients with HFrEF, but the possible mechanisms responsible for the association are not unserstood. METHODS142 men and women with HFrEF were enrolled through HF clinics and followed over time. At baseline and 6-months, depression was assessed by the Beck Depression Inventory (BDI-II) and disease activity by B-type natriuretic peptide (BNP). Proportional Hazards Regression Models assessed the contribution of depressive symptoms and HFrEF disease biomarkers on death or cardiovascular hospitalization. RESULTSOver a median follow-up period of 4 years, 42 patients (30%) died, and 84 (60%) had cardiovascular hospitalizations. A 10-point higher baseline BDI-II score was associated with a 35% higher hazard of death or cardiovascular hospitalization. Greater baseline BDI-II scores were associated with poorer HF self-care maintenance (R=-0.30, p<0.001) and fewer daily steps (R=-0.19, p=0.04), suggesting that depression may adversely affect important health behaviors. Increases in plasma BNP over 6 months were associated with worse outcomes. Changes in BDI-II score and plasma BNP over 6 months were positively correlated (R=0.25, p=0.004). CONCLUSIONSThis study underscores the importance of elevated depression symptoms and their association with an increased likelihood of adverse clinical outcomes in patients with HFrEF. Health behaviors may play a greater role than direct biobehavioral pathways in the adverse effects of depression on the HF disease trajectory and resultant clinical outcomes.

BackgroundHeart failure remains a leading cause of morbidity and mortality in the United States. Systolic heart failure (SHF; HFrEF) used to be considered as more lethal than diastolic heart failure (DHF; HFpEF). This study evaluates national age-adjusted mortality trends for SHF and DHF from 2016 to 2020, with particular attention to sex- and race-based differences. MethodsWe performed a retrospective analysis of adults [&ge;]20 years hospitalized with SHF or DHF in the Healthcare Cost and Utilization Project National Inpatient Sample from 2016 to 2020. Age-adjusted mortality rates per 100,000 population were calculated using direct standardization to the 2000 U.S. standard population. Trends were stratified by sex and race to identify demographic disparities. ResultsWe identified 7.36 million SHF and 10.06 million DHF hospitalizations between 2016 and 2020. SHF maintained higher absolute mortality throughout the study, almost double that of diastolic heart failure (250.4 to 328.6 per 100,000; +31.2%), but DHF mortality rose more sharply in relative terms (164.1 to 225.8 per 100,000; +37.6%). From 2016-2019, mortality rates were relatively stable, but between 2019 and 2020, SHF mortality increased by 27.8% and DHF mortality by 33.5%. Minority populations experienced the steepest mortality surges, particularly Native American, Hispanic, and Black patients, narrowing their historical mortality gaps between SHF and DHF. Similarly, male DHF mortality increased disproportionately in 2020 (47.7% rise vs. 22.2% for females). ConclusionsDHF does represent the predominant heart failure phenotype in the United States in terms of hospitalization occurrences, and shows a faster growth trajectory in mortality relative to SHF. Importantly, however, SHF remains more lethal in absolute terms and has not come close to being surpassed by DHF despite a sharp rise in DHF mortality during 2020.

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.

AimsIt remains uncertain which patients would benefit the most from transcatheter edge-to-edge repair (TEER). We aim to investigate the relationship between right ventricular function, as assessed by pressure-strain loops (PSL), and post-TEER clinical improvement. Methods and resultsA total of 48 heart failure with reduced ejection fraction (HFrEF) patients (68{+/-}15 yrs) with moderate-to-severe or severe SMR were enrolled for TEER. Impaired health status (Kansas City Cardiomyopathy Questionnaire Overall Summary Score [KCCQ-OS]) and exercise capacity (6-min walk distance [6MWD]) were evaluated at baseline and during 1-year follow up. Before and right after TEER, myocardial work (MW) metrics were non-invasively evaluated, including global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE). RV GLS, RVGWI, RVGCW, RVGWE were significantly increased after MitraClip treatment (-9.7{+/-}3.8%, 452.4{+/-}112.5 mmHg%, 596.3{+/-}127.5 mmHg% and 85.7{+/-}15.6% before vs -12.5{+/-}3.5%, 589.4{+/-}119.6 mmHg%, 778.8{+/-}135.3 mmHg% and 91.2{+/-}22.4% after MitraClip treatment, p = 0.025, 0.030, 0.025 and 0.037, respectively). The Kaplan-Meier estimates for survival, freedom from HF hospitalization at 12 months were 95.8% and 89.1%. On multivariable linear regression analysis, RVGWI and RVGCW immediate change was independently associated with KCCQ-OS ({bigtriangleup}RVGWI: {beta} = 0.40, P < 0.001; {bigtriangleup}RVGCW: {beta} = 0.39, P =0.003), RVGWI, RVGCW and RVGLS immediate change were independently associated with 6MWD improvement ({bigtriangleup}RVGWI: {beta} = 0.31, P = 0.029; {bigtriangleup}RVGCW: {beta} = 0.30, P = 0.039; {bigtriangleup}RVGLS: {beta} = 0.35, P = 0.041). ConclusionRVMW was significantly increased after MitraClip treatment. And RV reserve function is an important predictor of clinical improvement in HFrEF patients with TEER.

BackgroundThe use of beta blockers in patients with heart failure with preserved ejection fraction (HFpEF) is common, with about 75% of patients in recent landmark clinical trials on beta blockers. Though the implementation of this medication class is routine, there is sparse data to support their use. Furthermore, beta blocker effects on exercise capacity, diastolic function, and quality of life in HFpEF patients is unclear. MethodsA retrospective cohort study was completed using patient-level data from two prior randomized trials. Cohorts were generated based on beta blocker use at the time of trial enrollment, demographic information was compared. Primary outcomes assessed were exercise capacity, diastolic function, and quality of life metrics. The results of baseline testing were utilized to avoid potential bias from each trials intervention. ResultsAfter multivariate linear regression, HFpEF patients on beta blockers had no difference in exercise capacity (peak VO2 (mL/kg/min): 12.5 vs 13.5, P=0.933), diastolic function (average E/e: 16 vs 14, P=0.125; left atrial volume index (mL/m2): 47 vs 42, P=0.665; peak tricuspid regurgitation velocity (m/s): 2.85 vs 2.70, P=0.165), or quality of life survey scores (KCCQ: 54 vs 60, P=0.206; MLHFQ 44 vs 48, P=0.762) compared to those not taking beta blockers. ConclusionsIn this secondary analysis of patient-level data, there was no association with beta blocker use and worsened exercise capacity, diastolic function, or quality of life in HFpEF patients. Randomized controlled trials are necessary to definitively determine the clinical and functional impact of beta blockers in HFpEF. RESEARCH PERSPECTIVEO_LIIn this secondary analysis or INDIE-HFpEF and RELAX, there was no significant association with beta blocker use and worsened exercise capacity, diastolic dysfunction, or quality of life in HFpEF patients. C_LIO_LIWith little available evidence to suggest clinical or functional benefits from implementation of beta blockers in HFpEF, randomized controlled trials are warranted to more definitively evaluate the potential effects of this medication class. C_LIO_LIEvaluating unique HFpEF phenotypes with different comorbidity profiles would provide specific insights that could be translated to the clinical management of HFpEF patients. C_LI

BackgroundHypoxic hypercapnic respiratory failure is a major cause of acute hospitalization. Cardiopulmonary insults can lead to respiratory distress and, if untreated, respiratory failure. West Virginia has the highest prevalence of obesity in the nation, accounting for the higher incidence of heart failure with preserved ejection fraction (HFpEF). This diagnosis is elusive in younger patients below age 65 years because echocardiograms are often normal and invasive hemodynamics are not widely measured. H2FPEF score, "obesity age" (BMI + age), and newly described HFpEF-ABA scores may predict obesity-related HFpEF in acute respiratory failure settings. Given the global rise in obesity, early identification of HFpEF is critical to optimizing respiratory failure care. PurposeThis cohort study investigates the burden of obesity-related HFpEF in patients younger than 65 years old presenting with respiratory failure. MethodsThe study included patients [&le;]65 years of age admitted to Charleston Area Medical Center from 1/2023-12/2023 with respiratory failure, BMI > 30 kg/m2, and EF > 50%. Patients with specific cardiomyopathies or identifiable triggers for for respiratory failure were excluded. "Premature HFpEF" was defined as obesity years >100. Demographic data on BMI, echocardiographic and hemodynamic findings were analyzed. Logistic regression was used to assess the relationship between premature HFpEF and respiratory failure, adjusting for confounders. ResultsAmong 44 patients with respiratory failure, 64% exhibited premature obesity-related heart failure with preserved ejection fraction (HFpEF), characterized by a mean age and body mass index (BMI) of 111.5 kg/m2-years. These patients demonstrated elevated left ventricular end-diastolic pressure (LVEDP) exceeding 18 mmHg during cardiac catheterization. H2FPEF score could not be measured due to obesity limiting Doppler echocardiographic studies. The HFpEF -ABA score was > 80% and obesity age was > 95 in 85% of the cohort. ConclusionEarly recognition of obesity-related HFpEF enables healthcare providers to tailor individualized treatment regimens. Preventive strategies focused on obesity reduction can reverse associated comorbidities, improve patient outcomes, and lower healthcare costs in the long run.

BackgroundRight ventricular failure (RVF) after left ventricular assist devices (LVAD) is associated with significant morbidity and mortality and identifying patients at risk for severe RVF is an important clinical goal. Current risk prediction models were not developed in contemporary LVAD populations and have limited clinical applicability. ObjectivesTo evaluate whether the Model for End Stage Liver Disease - eXcluding INR (MELD-XI) can predict severe RVF after HeartMate 3 (HM3) implantation. MethodsWe retrospectively analyzed all adult patients who received HM3 LVAD as initial implantation at two academic medical centers. We assessed whether MELD-XI is an independent risk factor for severe RVF in multivariate analysis and compared the predictive accuracy of MELD-XI with previously published risk scores. We also investigated the relationship between MELD-XI and markers of right ventricular function and whether MELD-XI was associated with death or pump exchange at 1-year follow-up. ResultsOur study included a total of 246 patients, of which 74 (30%) experienced severe RVF. After adjusting for relevant covariables, MELD-XI was independently associated with severe RVF (OR 1.18, CI 1.09-1.29, p<0.001) and performed similarly to the EUROMACS and Michigan RVF risk scores. In addition, MELD-XI was not reflective of traditional echocardiographic or hemodynamic measures of right ventricular function. Finally, MELD-XI [&ge;] 14 predicted worse in-hospital mortality. ConclusionsAmong patients undergoing HM3 implantation, MELD-XI is independently associated with an increased risk of RVF and in-hospital mortality.

IntroductionHeart failure (HF) is a life-threatening syndrome with significant morbidity and mortality. While evidence-based drug treatments have effectively reduced morbidity and mortality in HF with reduced ejection fraction (HFrEF), few therapies have been demonstrated to improve outcomes in HF with preserved ejection fraction (HFpEF). The multifaceted clinical presentation is one of the main reasons why the current understanding of HFpEF remains limited. This may be caused by the existence of several HFpEF disease subtypes that each need different treatments. There is therefore an unmet need for a holistic approach that combines comprehensive imaging with metabolomic, transcriptomic and genomic mapping to subtype HFpEF patients. This protocol details the approach employed in the HeartMagic study to address this gap in understanding. MethodsThis prospective multi-center observational cohort study will include 500 consecutive patients with actual or recent hospitalization for treatment of HFpEF at two Swiss university hospitals, along with 50 age-matched HFrEF patients and 50 age-matched healthy controls. Diagnosis of heart failure is based on clinical signs and symptoms and subgrouping HF patients is based on the left-ventricular ejection fraction. In addition to routine clinical workup, participants undergo genomic, transcriptomic, and metabolomic analyses, while the anatomy, composition, and function of the heart are quantified by comprehensive echocardiography and magnetic resonance imaging (MRI). Quantitative MRI is also applied to characterize the kidney. The primary outcome is a composite of one-year cardiovascular mortality or rehospitalization. Machine learning (ML) based multi-modal clustering will be employed to identify distinct HFpEF subtypes in the holistic data. The clinical importance of these subtypes shall be evaluated based on their association with the primary outcome. Statistical analysis will include group comparisons across modalities, survival analysis for the primary outcome, and integrative multi-modal clustering combining clinical, imaging, ECG, genomic, transcriptomic, and metabolomic data to identify and validate HFpEF subtypes. DiscussionThe integration of comprehensive MRI with extensive genomic and metabolomic profiling in this study will result in an unprecedented panoramic view of HFpEF and should enable us to distinguish functional subgroups of HFpEF patients. This approach has the potential to provide unprecedented insights on HFpEF disease and should provide a basis for personalized therapies. Beyond this, identifying HFpEF subtypes with specific molecular and structural characteristics could lead to new targeted pharmacological interventions, with the potential to improve patient outcomes.

BackgroundChronic heart failure (HF) is a complex syndrome with significant morbidity and mortality, where inflammation is increasingly recognized as a critical factor in its progression. This study investigated the association of cytokine and chemokine profiles with mild cognitive impairment (MCI) and long-term mortality in patients with chronic HF. MethodsSerum concentrations of 13 cytokines were measured in 145 patients from the Cognition.Matters-HF study baseline cohort using a bead-based multiplex assay. Detailed clinical and cognitive evaluations were conducted, and survival data were tracked over 10 years. Cox proportional hazards regression and logistic regression models were applied to assess independent associations with mortality and MCI. ResultsNo cytokine was independently associated with MCI. However, high interleukin-8 (IL-8) levels (>5.3 pg/ml) were significantly and independently associated with all-cause mortality (HR 2.30; 95% CI 1.30-4.07; p=0.004). After adjusting for age and sex, IL-8 remained a strong predictor (Adj. HR 2.28; 95% CI 1.29-4.05; p=0.005). Further adjustments for clinical and biochemical variables showed that IL-8 (Adj. HR 3.31; 95% CI 1.61-6.79; p=0.001) was the only cytokine independently associated with mortality. In the final multivariable model, IL-8 (Adj. HR 2.57; 95% CI 1.44-4.57; p=0.001) remained a significant predictor along with age, body mass index, left atrial volume index, and six-minute walk distance. Other cytokines, including IL-6 and tumor necrosis factor-, showed no independent associations with mortality. ConclusionsThese findings suggest IL-8s unique role in HF pathophysiology and its potential as a biomarker and therapeutic target. Further research is needed to validate these results and explore the clinical utility of IL-8 modulation in HF management.