Mechanical circulatory support (MCS) is increasingly deployed in cardiogenic shock (CS) and advanced heart failure (HF) with the therapeutic aim of preserving end-organ perfusion while facilitating myocardial recovery and/or reverse remodeling. Recent randomized and observational studies have clarified patient selection and weaning strategies across temporary (tMCS) and durable (dMCS) platforms, yet center-to-center variability persists. This review synthesizes contemporary evidence while integrating prevailing opinion on defining recovery, prognostication, optimal timing and intensity of support, and practical algorithms for separation from MCS. Successful separation from MCS requires alignment of myocardial function, end-organ recovery, and hemodynamic reserve. We propose a practical, stepwise algorithm integrating clinical stability markers, vasoactive dosing (VIS), invasive hemodynamics (cardiac index, cardiac power output, filling pressures), and arterial pulsatility indices to structure de-escalation. A recovery-focused approach to MCS balances myocardial rest with early GDMT, vigilant complication surveillance, and hemodynamic-guided weaning. Prospective studies should validate standardized weaning protocols and incorporate omics-based phenotyping to personalize recovery pathways.

Background Myocardial fibrosis is prevalent in cardiomyopathies that result in heart failure with reduced ejection fraction. Heart failure with reduced ejection fraction treated with a left ventricular assist device (LVAD) yields hemodynamic unloading and may provide partial cardiomyocyte recovery, but contemporary studies reveal no consistent reductions in fibrosis. This study tested the hypothesis that, despite normalization of hemodynamic overload by LVAD, fibrosis and fibroblast activation persist resulting in sustained increases in myocardial stiffness. Methods and Results Tissues from subjects with heart failure with reduced ejection fraction undergoing LVAD implantation (pre‐LVAD), from transplanted hearts with LVAD (post‐LVAD) or without cardiac pathology (control) were collected. Quantification of myocardial stiffness and collagen content revealed significant increases in pre‐LVAD versus control that remained elevated in post‐LVAD. Myocardial fibroblast populations increased in pre‐ and post‐LVAD hearts versus control. Control, pre‐LVAD, and post‐LVAD fibroblasts were isolated and plated on substrates with mechanical stiffnesses reflective of normal (≈2 kPa) or fibrotic (≈8 kPa) myocardium. Quantification of collagen I and α‐smooth muscle actin production demonstrated that control fibroblasts were responsive to substrate stiffness, whereas pre‐ and post‐LVAD fibroblasts were unresponsive and exhibited no significant differences on either substrate. Bulk‐RNA sequence analysis revealed changes in gene expression in pre‐LVAD versus control fibroblasts including mechano‐sensitive pathways that appear to be uncoupled, resulting in increased expression of genes implicated in proliferation, whereas mechano‐sensing genes were decreased. Conclusions These data support that sustained cardiac hemodynamic overload leads to a phenotypic conversion in fibroblasts in which the capacity to detect changes in mechanical input is muted, thus contributing to retention of collagen content and stiffness in both pre‐ and post‐LVAD hearts.

Cardiovascular effects of obesity may be driven, in part, by the distribution of fat. More recently, epicardial adipose tissue (EAT) has gained recognition as an adverse visceral fat impacting cardiac dysfunction in heart failure with preserved ejection fraction (HFpEF). EAT can be identified and measured using several non-invasive imaging techniques, including transthoracic echocardiography, computed tomography, and cardiac magnetic resonance. The presence of EAT is associated with increased risk of HFpEF and worse clinical outcomes among patients with established HFpEF, independent of total adiposity. EAT may serve a pivotal role in the pathogenesis of HFpEF by worsening volume distribution, enhancing pericardial restraint and ventricular interaction, worsening right ventricular dysfunction, and diminishing exercise tolerance. No large trials have tested the effects of reducing fat in specific areas of the body on cardiovascular outcomes, but some studies that followed people in communities and trials over time have suggested that drug and non-drug treatments that lower EAT could improve the risk factors for heart problems in patients with HFpEF. Further understanding the role that pathogenic fat depots play in HFpEF incidence and progression may provide future therapeutic targets in treating the obese-HFpEF phenotype.

AIMS:Elevated hemodynamic load in heart failure (HF) activates fibroblasts and increases collagen deposition, but normalization of load (as occurs with current nonpulsatile left ventricular assist device (LVAD) support) does not reverse fibroblast activation or fibrosis, attributable to a persistently altered fibroblast phenotype. We hypothesized that the combination of reduced load and cyclic stretch in vitro (equivalent to pulsatile LVAD therapy in vivo) would attenuate fibroblast activation. METHODS AND RESULTS:Myocardium from subjects with HF (n = 15) with reduced ejection fraction (HFrEF) and from unused donor hearts (control, n = 5) was used to assess collagen content and for human cardiac fibroblasts (HCF) isolation. HCFs were cultured on substrates with stiffness representing normal (1 kPa) or HFrEF (10 kPa) myocardium and were exposed to 48 hours of cyclic stretch or left unstretched. Alterations in protein production and transcriptional expression in control and HFrEF fibroblasts were assessed. Collagen content was significantly greater in HFrEF tissue than control (6.7% vs 2.1%, p < 0.01). In contrast to control, HFrEF HCFs showed no difference in collagen 1α(I), TIMP1, and αSMA production on 1 vs 10 kPa substrates without cyclic stretch; however, HFrEF HCFs with cyclic stretch produced less collagen1α(I), TIMP1, and αSMA on 1 kPa but not 10 kPa substrates (all p < 0.01). Bulk ribonucleic acid sequencing analysis identified dysregulated pathways in force sensing/signaling in HFrEF HCFs, that, on 1 kPa with stretch, were altered towards that of controls. CONCLUSION:These novel results in primary HCFs demonstrate that normalized substrate stiffness combined with cyclic stretch attenuated HCF activation and identified associated mechanistic pathways for reversing fibroblast phenotype in patients with HF.

The age-related decline in diastolic function can result in heart failure with a preserved ejection fraction (HFpEF) and atrial fibrillation (AF), which are comorbid conditions that are increasingly prevalent and have a high socioeconomic burden. In humans, diastolic dysfunction results from structural and functional changes that increasingly impede diastolic filling after midlife. Comorbidities and pathomechanisms that lead to additional increases in cardiac filling pressures accelerate the age-related deterioration in diastolic function. It is, therefore, that targeting the accelerators of diastolic dysfunction holds the most promise in reducing the risk for HFpEF and AF.

OBJECTIVES/GOALS: Myocardial interstitial fibrosis leads to high hemodynamic load resulting in heart failure (HFrEF). Previous studies show that treatment with a left ventricular assist device (LVAD) does not reduce fibrosis. We hypothesize that human cardiac fibroblasts are highly activated in HFrEF and remain unresponsive to hemodynamic unloading by LVAD. METHODS/STUDY POPULATION: Forty human subjects with HFrEF undergoing LVAD implantation were enrolled to provide a portion of myocardium routinely removed during LVAD placement. In addition, 7 biopsies previously collected from transplanted hearts with extended LVAD treatment were also evaluated (LVEX). RESULTS/ANTICIPATED RESULTS: Quantification of PSR-stained sections reveals a significant increase in collagen content in the HFrEF tissue (CVF = 2.8) compared to control tissues (CVF = 0.9) that remained elevated in LVEX hearts (CVF = 3.1). HCFs from LV biopsies were isolated and grown to confluence. HCFs from HFrEF patients and control HCFs were plated on substrates with stiffnesses reflective of normal myocardium (2kPa) or HFrEF myocardium (8kPa). Cells were collected at 4- and 7-day time points and levels of collagen I and alpha-smooth muscle actin were quantified by western blot analysis. Control HCFs were responsive to changes in substrate stiffness producing more Col I and a-SMA on 8kPa versus 2kPa, HCFs from HFrEF patients were unresponsive to changes in stiffness exhibiting no significant difference in protein production on 2 vs. 8kPa. DISCUSSION/SIGNIFICANCE: Our data suggests that HCFs isolated from the failing myocardium do not respond to changes in mechanical load and might contribute to persistent increases in fibrosis. These findings bring us one step closer to elucidating mechanisms behind fibrosis in HFrEF which could lead to targeted therapies to improve patient outcomes from LVAD support.

Precapillary pulmonary hypertension related to obstructive sleep apnea or emphysema? Postcapillary pulmonary hypertension due to left heart disease in the setting of typical comorbidities? Combined pre- and postcapillary pulmonary hypertension with a smattering of various etiologies? Exercise-induced left atrial hypertension in heart failure with preserved ejection fraction (HFpEF)? In the patient referred for dyspnea with multiple comorbidities, a left ventricular ejection fraction (LVEF) ≥ 50% and evidence of elevated estimated pulmonary pressures, clarifying the diagnosis is critically important for treatment decisions—appropriateness of pulmonary vasodilators or guideline-directed medical therapy for HFpEF—and also for understanding prognoses, addressing comorbidities and considering clinical trial enrollment. Systemic Arterial Oxygen Levels Differentiate Pre- and Post-capillary Predominant Hemodynamic Abnormalities During Exercise in Undifferentiated Dyspnea on ExertionJournal of Cardiac FailurePreviewThere is growing recognition of the value of hemodynamic measurements performed during exercise to rule-in the diagnosis of heart failure with preserved ejection fraction (HFpEF). Assessment for elevated exercise pulmonary capillary wedge pressure (PCWP) is now incorporated into HFpEF diagnostic algorithms and as an endpoint in HFpEF interventional clinical trials.1-6 However, to date, the incorporation of exercise-based assessments to diagnose and characterize HFpEF has focused almost singularly on exercise PCWP measurement. Full-Text PDF Open Access

Background: Myocardial interstitial fibrosis is a common pathology in cardiomyopathies leading to ventricular dilation and increased hemodynamic load that result in heart failure with reduced ejection fraction (HFrEF). Previous research has shown that HFrEF patients treated with a left ventricular assist device (LVAD) undergo hemodynamic unloading resulting in at least partial cardiomyocyte recovery. However, evidence supports that these patients do not experience a regression of fibrosis and demonstrate, in some cases, a worsening of fibrosis after LVAD treatment. Purpose: We hypothesize that human cardiac fibroblasts (HCFs) are constitutively activated in HFrEF myocardium but remain unresponsive to hemodynamic unloading with LVAD placement. Methods and Results: Forty human subjects with HFrEF undergoing LVAD implantation were enrolled to provide a portion of myocardium routinely removed during LVAD placement. In addition, 7 biopsies previously collected from transplanted hearts with extended LVAD treatment were also evaluated (LVEX). Quantification of PSR stained sections revealed a significant increase in collagen content in the HFrEF tissue (Collagen volume fraction % (CVF) = 2.8±0.2) in comparison to control tissues (CVF = 0.9±0.2) that remained elevated in LVEX hearts (CVF = 3.1±0.3). HCFs derived from biopsies received at LVAD placement were isolated and grown to confluence. HCFs from HFrEF patients and control HCFs from healthy donors were then plated on substrates with mechanical stiffnesses reflective of either normal myocardium (2kPa) or failing myocardium (8kPa). Cells were collected at 4- and 7-day timepoints and levels of collagen I (Col I) and alpha-smooth muscle actin (α-SMA) were quantified through western blot analysis with β-actin as a loading control. Whereas control HCFs were responsive to changes in substrate stiffness producing more Col I and α-SMA on 8kPa versus 2kPa, HCFs from HFrEF patients were unresponsive to changes in stiffness exhibiting no significant difference in production on 2 vs. 8kPa. Conclusion: These data suggest that HCFs isolated from the failing myocardium do not respond to changes in mechanical load and hence, might contribute to persistent increases in fibrosis in failing and unloaded hearts.

Importance:Patients with heart failure with preserved ejection fraction (HFpEF) with a pacemaker may benefit from a higher, more physiologic backup heart rate than the nominal 60 beats per minute (bpm) setting.Objective:To assess the effects of a moderately accelerated personalized backup heart rate compared with 60 bpm (usual care) in patients with preexisting pacemaker systems that limit pacemaker-mediated dyssynchrony.Design, Setting, and Participants:This blinded randomized clinical trial enrolled patients with stage B and C HFpEF from the University of Vermont Medical Center pacemaker clinic between June 2019 and November 2020. Analysis was modified intention to treat.Interventions:Participants were randomly assigned to personalized accelerated pacing or usual care and were followed up for 1 year. The personalized accelerated pacing heart rate was calculated using a resting heart rate algorithm based on height and modified by ejection fraction.Main Outcomes and Measures:The primary outcome was the serial change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) score. Secondary end points were changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, pacemaker-detected physical activity, atrial fibrillation from baseline, and adverse clinical events.Results:Overall, 107 participants were randomly assigned to the personalized accelerated pacing (n = 50) or usual care (n = 57) groups. The median (IQR) age was 75 (69-81) years, and 48 (48%) were female. Over 1-year follow-up, the median (IQR) pacemaker-detected heart rate was 75 (75-80) bpm in the personalized accelerated pacing arm and 65 (63-68) bpm in usual care. MLHFQ scores improved in the personalized accelerated pacing group (median [IQR] baseline MLHFQ score, 26 [8-45]; at 1 month, 15 [2-25]; at 1 year, 9 [4-21]; P < .001) and worsened with usual care (median [IQR] baseline MLHFQ score, 19 [6-42]; at 1 month, 23 [5-39]; at 1 year, 27 [7-52]; P = .03). In addition, personalized accelerated pacing led to improved changes in NT-proBNP levels (mean [SD] decrease of 109 [498] pg/dL vs increase of 128 [537] pg/dL with usual care; P = .02), activity levels (mean [SD], +47 [67] minutes per day vs -22 [35] minutes per day with usual care; P < .001), and device-detected atrial fibrillation (27% relative risk reduction compared with usual care; P = .04) over 1-year of follow-up. Adverse clinical events occurred in 4 patients in the personalized accelerated pacing group and 11 patients in usual care.Conclusions and Relevance:In this study, among patients with HFpEF and pacemakers, treatment with a moderately accelerated, personalized pacing rate was safe and improved quality of life, NT-proBNP levels, physical activity, and atrial fibrillation compared with the usual 60 bpm setting.Trial Registration:ClinicalTrials.gov Identifier: NCT04721314.

BACKGROUND Although studies consistently show that beta-blockers reduce morbidity and mortality in patients with reduced ejection fraction (EF), data are inconsistent in patients with heart failure with mildly reduced ejection fraction (HFmrEF) and suggest potential negative effects in heart failure with preserved ejection fraction (HFpEF). OBJECTIVES The purpose of this study was to examine the association of beta-blockers with heart failure (HF) hos-pitalization and death in patients with HF and EF >= 40% METHODS Beta-blocker use was assessed at first encounter in outpatients >= 65 years of age with HFmrEF and HFpEF in the U.S. PINNACLE Registry (2013-2017). The associations of beta-blockers with HF hospitalization, death, and the composite of HF hospitalization/death were assessed using propensity-score adjusted multivariable Cox regression models, including interactions of EF x beta-blocker use. RESULTS Among 435,897 patients with HF and EF >= 40% (HFmrEF, n = 75,674; HFpEF = 360,223), 289,377 (66.4%) were using a beta-blocker at first encounter; more commonly in patients with HFmrEF vs HFpEF (77.7% vs 64.0%; P < 0.001). There were significant interactions between EF x beta-blocker use for HF hospitalization, death, and composite of HF hospitalization/death (P < 0.001 for all), with higher risk with beta-blocker use as EF increased. Beta-blockers were associated with decreased risk of HF hospitalization and death in patients with HFmrEF but a lack of survival benefit and a higher risk of HF hospitalization in patients with HFpEF, particularly when EF was >60%. CONCLUSIONS In a large, real-world, propensity score-adjusted cohort of older outpatients with HF and EF >= 40%, beta-blocker use was associated with a higher risk of HF hospitalization as EF increased, with potential benefit in patients with HFmrEF and potential risk in patients with higher EF (particularly >60%). Further studies are needed to understand the appropriateness of beta-blocker use in patients with HFpEF in the absence of compelling indications.(J Am Coll Cardiol HF 2023;11:893-900) (c) 2023 by the American College of Cardiology Foundation.

Background: Heart transplantation is the gold-standard therapy for end-stage heart failure, but rates of donor-heart use remain low due to various factors that are often not evidence based. The impact of donor hemodynamics obtained via right-heart catheterization on recipient survival remains unclear.Methods: The United Network for Organ Sharing registry was used to identify donors and recipients from September 1999-December 2019. Donor hemodynamics data were obtained and analyzed using univariate and multivariable logistical regression, with the primary end-points being 1-and 5-year post-transplant survival.Results: Of the 85,333 donors who consented to heart transplantation during the study period, 6573 (7.7%) underwent right-heart catheterization, of whom 5531 eventually under-went procurement and transplantation. Donors were more likely to undergo right-heart catheterization if they had high-risk criteria. Recipients who had donor hemodynamic assessment had 1-and 5-year survival rates similar to those without donor hemodynamic assessment (87% vs 86%, 1 year). Abnormal hemodynamics were common in donor hearts but did not impact recipient survival rates, even when risk-adjusted in multivariable analysis.Conclusions: Donors with abnormal hemodynamics may represent an opportunity to expand the pool of viable donor hearts. (J Cardiac Fail 2023;29:1288-1295)

HomeCirculation: Heart FailureAhead of PrintWill the SGLT2i Responders Please Stand Up? No AccessEditorialRequest AccessAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessEditorialRequest AccessWill the SGLT2i Responders Please Stand Up? Kane Banner and Daniel N. Silverman Kane BannerKane Banner College of Medicine, Medical University of South Carolina, Charleston. (K.B.) and Daniel N. SilvermanDaniel N. Silverman Correspondence to: Daniel Silverman, MD, Medicine/Cardiology, Section of Advanced Heart Failure & Transplant Cardiology, 30 Courtenay Dr, BM326a, MSC592, Charleston, SC 29425. Email E-mail Address: [email protected] Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston.(D.N.S.) Division of Cardiology, Ralph H. Johnson Department of Veterans Affairs Health Care System, Charleston, SC (D.N.S.). Originally published23 Oct 2023https://doi.org/10.1161/CIRCHEARTFAILURE.123.011124Circulation: Heart Failure. 2023;0:e011124FootnotesThis manuscript was sent to Finn Gustafsson, Senior Guest Editor, for review by expert referees, editorial decision, and final dispositionFor Disclosures, see page xxx.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Daniel Silverman, MD, Medicine/Cardiology, Section of Advanced Heart Failure & Transplant Cardiology, 30 Courtenay Dr, BM326a, MSC592, Charleston, SC 29425. Email silvermd@musc.edu Previous Back to top Next FiguresReferencesRelatedDetails Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.123.011124PMID: 37869883 Originally publishedOctober 23, 2023 Keywordsempagliflozinheart failureEditorialssodium/glucose cotransporter-2 inhibitordapagliflozinPDF download Advertisement SubjectsCardiomyopathyHeart Failure

Elevated left atrial pressure is a common physiologic perturbation in symptomatic heart failure. A number of interatrial septal devices (IASD) are being studied with a goal of reducing left atrial pressure at rest and during exertion to improve symptoms. Our review discusses historical perspectives, physiologic rationale of IASD therapy, and summarizes recent results and ongoing studies. Although preliminary studies showed promising hemodynamic results and improvements in function capacity, the recent sham-controlled, randomized REDUCE LAP-HF II trial failed to meet its primary endpoint. Several exploratory analyses have been performed suggesting benefits could be limited to a more selective phenotype. Despite challenges, IASD as a therapeutic strategy remains promising. Several on-going studies will determine if certain patient phenotypes may benefit from this therapy.

Pacemaker patients with preclinical or overt heart failure with preserved ejection fraction (HFpEF) may benefit from a backup heart rate (HR) that is higher than the standard 60 beats per minute (bpm) setting.

Background: Multiple studies have shown better outcomes for simultaneous heart-kidney transplant (sHKT) than for isolated orthotopic heart transplant (iOHT) in recipients with chronic kidney disease (CKD). However, outcomes in patients supported by durable left ven-tricular assist devices (LVADs) have not been well studied. Methods: Patients with durable LVADs and stage 3 or higher CKD (eGFR < 60 mL/min/1.73 m2) undergoing iOHT or sHKT between 2008 and 2020 were identified from the United Network for Organ Sharing registry. A Kaplan-Meier survival analysis with associated log-rank test was conducted to compare post-transplant survival rates. Multivariable modeling was used to identify risk-adjusted predictors of 1 year post-transplant mortality. Results: We identified 4375 patients; 366 underwent sHKT, and 4009 underwent iOHT. The fre-quency of sHKT increased during the study period. The 1-year post-transplant survival rate was worse in patients after sHKT than in patients after iOHT (80.3% vs 88.3%; P < 0.001) and persisted up to 5 years post-transplant (P = 0.001). sHKT recipients were more likely to require dialysis after transplantation and had longer hospital lengths of stay (P < 0.001). Multivariable analysis showed that sHKT remained an independent risk factor for mortality at 1 year (OR 1.58; P = 0.002). Conclusions: sHKT is becoming more common in patients with durable LVADs. Compared with iOHT, patients with sHKTs have worse short-and long-term survival rates and are more likely to require post-transplant dialysis. (J Cardiac Fail 2022;28:1584-1592)

Pacemaker patients with preclinical or overt heart failure with preserved ejection fraction (HFpEF) may benefit from a backup heart rate (HR) that is higher than the standard 60 beats per minute (bpm) setting.