Han DD, Brooks AC, Baker CD
… +7 more, Dirkx RA, Mickelsen DM, Fisler B, Phadke K, Ashton JM, Delmar M, Small EM
Circ Heart Fail
· 2026 Jun · PMID 42246055
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BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited disease that is characterized by lethal ventricular arrhythmias stemming from myocyte dysfunction. ACM is associated with considerable subepicardial fibrosi...BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited disease that is characterized by lethal ventricular arrhythmias stemming from myocyte dysfunction. ACM is associated with considerable subepicardial fibrosis and inflammation with right ventricle predominance. Most cases of gene-positive ACM are caused by a desmosome protein mutation, with plakophilin-2 () mutations being the most common. We hypothesized that -deficiency in epicardium-derived cells (EPDCs) contributes to fibro-inflammatory signaling and ACM pathogenesis. METHODS: We developed transgenic mice that lack in cardiomyocytes (Pkp2-cKO), in EPDC (Pkp2-eKO), or in both cardiomyocyte and EPDC (Pkp2-ceKO) via the tissue-specific expression of tamoxifen-inducible Cre recombinase. Nonmyocyte populations were isolated 21 days posttamoxifen injection for single-cell RNA-sequencing. Immunohistochemistry, flow cytometry, quantitative reverse transcription polymerase chain reaction, and echocardiography were used to interrogate cardiac physiology and cellular composition. RESULTS: We identified a population of epicardium-derived fibroblasts characterized by the expression of , , , and that accumulated on deletion in both cardiomyocytes and EPDC. deletion in cardiomyocytes induced a moderate fibro-inflammatory EPDC phenotype, while deletion in EPDC did not elicit a pathological phenotype, suggesting cardiomyocyte involvement is necessary for ACM pathogenesis. Proinflammatory fibroblasts acquired the senescence-associated secretory phenotype, correlating with elevated senescence associated-βgal staining in the right ventricle. Gene expression, flow cytometry, and histological data also revealed an exaggerated inflammatory response in Pkp2-ceKO mice, which progresses from right to left ventricular predominance. Importantly, macrophages and B cells accumulate in both Pkp2-cKO and Pkp2-ceKO mice compared with controls. Although B-cell depletion delays the early inflammatory and fibrosis response, it did not alter end-stage cardiac physiology. CONCLUSIONS: deletion in EPDC facilitates the emergence of a fibro-inflammatory phenotype that may contribute to ACM pathogenesis.
BACKGROUND: Acute decompensated heart failure (ADHF) exhibits seasonal variations, yet the short-term effects of ambient temperature, independent of seasonality, remain poorly studied. Moreover, temperature-sensitive exa...BACKGROUND: Acute decompensated heart failure (ADHF) exhibits seasonal variations, yet the short-term effects of ambient temperature, independent of seasonality, remain poorly studied. Moreover, temperature-sensitive exacerbation phenotypes are not well defined, limiting the development of effective preventive strategies. We aimed to investigate the effects of ambient temperature on ADHF admissions and clinical presentation profiles. METHODS: We included 26 874 patients with ADHF who had been registered in the Tokyo Cardiovascular Care Unit Network Database between January 2014 and December 2019. The onset date of ADHF leading to hospitalization, along with clinical characteristics such as age, left ventricular function, cause of ADHF, and hemodynamic profile, was assessed by cardiologists at each participating center. Climate data were obtained from an observatory near the admitting hospital. We used a time-stratified case-crossover design with distributed lag nonlinear models to explore the association between ambient temperature and ADHF admissions over lag days 0 to 5, with stratified analyses by the clinical presentations. RESULTS: Exposure to extremely low temperatures (-4.5 °C [first percentile]) increased the risk of ADHF (1.80, 95% CI, 1.40-2.31) when referenced to the temperature of lowest risk (29.0 °C [99th percentile]). The excess risk of lower temperature appeared immediately on the day of exposure (lag 0). This risk was larger in patients aged ≥70 years and otherwise consistent across subgroups. Notably, the temperature-risk relationship differed by hemodynamic profiles; risk for ADHF with hypertension rose at low temperatures, whereas ADHF with low blood pressure showed the opposite pattern, with risk increasing at high temperatures (odds ratio, 6.25 [95% CI, 1.07-36.6] at the 99th percentile). CONCLUSIONS: Low ambient temperature increased ADHF risk, especially in older adults, while temperature effects differed by hemodynamic phenotype. Incorporating temperature exposure into risk assessment may enable targeted prevention of climate-related decompensation. REGISTRATION:URL: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000015310; Unique identifier: UMIN000013128.
Desai AS, Zile MR, Ducharme A
… +11 more, Mehra MR, Maisel AS, Sears SF, Costanzo MR, Smart FW, Chien CV, Jonsson O, Hall S, Nie H, Lee FS, Lindenfeld J
Circ Heart Fail
· 2026 Jun · PMID 42206402
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BACKGROUND: While clinical benefits of guideline-directed medical therapy in patients with heart failure (HF) are well established, acute hemodynamic changes after initiation of these agents are not well described. Wirel...BACKGROUND: While clinical benefits of guideline-directed medical therapy in patients with heart failure (HF) are well established, acute hemodynamic changes after initiation of these agents are not well described. Wireless pulmonary artery pressure (PAP) monitoring using implantable sensors is ideally suited to determine changes in pressure following medication titration. METHODS: We compared PAP from 7 days pre-initiation to the 7-day period following 30 days of newly initiated treatment with core HF therapies: angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists, sodium-glucose co-transporter-2 inhibitors, and β-blockers in patients implanted with a PAP sensor (CardioMEMS, Abbott) as part of the GUIDE-HF study (Hemodynamic-Guided Management of HF). Patients with changes in loop diuretics or other core HF therapies during the 30-day interval were excluded from the analysis. RESULTS: Of 2358 patients in the study, 50 patients had new angiotensin receptor-neprilysin inhibitor initiation, 97 patients had new sodium-glucose co-transporter-2 inhibitor initiation, 112 patients had new mineralocorticoid receptor antagonist initiation, and 33 had new β-blocker initiation at least 30 days post-implant, continued to take the medication for at least 30 days, and were included in this analysis. Following angiotensin receptor-neprilysin inhibitor or mineralocorticoid receptor antagonist initiation, diastolic PAP decreased by -1.56 (95% CI, -3.54 to -0.40) and -1.15 (95% CI, -1.82 to -0.47) mm Hg, respectively, in the absence of changes in loop diuretics or other core HF therapies. By contrast, there was no detectable change in PAP following the new initiation of the sodium-glucose co-transporter-2 inhibitor. A trend to higher PAP was observed after β-blocker initiation though differences were not significant. CONCLUSIONS: These results may inform the selection of pharmacological therapy to manage elevated filling pressures during hemodynamic-guided therapy. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03387813.
Liu X, Thomas NH, Berliner D
… +18 more, Schwab J, Rieth A, Strack C, Schallhorn S, Soltani S, Haebel L, Geller W, Zdravkovic M, Hülsmann M, von der Leyen H, Veltmann C, Störk S, Böhm M, Bauersachs J, Koch A, Bavendiek U, Großhennig A, DIGIT-HF Study Group
Dixon DD, Lewsey SC, Contreras J
… +3 more, Shah KS, Deen J, Breathett K
Circ Heart Fail
· 2026 Jun · PMID 42117257
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Institutional and systemic practices and policies contribute to lower-quality care and adverse outcomes among diverse racial and ethnic groups and individuals with limited economic resources. There are ample opportunitie...Institutional and systemic practices and policies contribute to lower-quality care and adverse outcomes among diverse racial and ethnic groups and individuals with limited economic resources. There are ample opportunities to change the trajectory of patients with heart failure (HF) across racial and ethnic groups. Multiple studies and quality improvement initiatives have demonstrated strategies to improve the care of diverse racial and ethnic populations living with HF, yet dissemination remains limited. This state-of-the-art review examines structural racism in the context of HF, outlines evidence-based strategies for HF programs to improve access to advanced HF therapies and reduce disparities in treatment outcomes, and discusses priorities for implementation and dissemination science efforts to address structural causes of disparities in HF care.
Cardiomyopathy remains a leading cause of heart failure-related morbidity and mortality, driven by diverse genetic architectures that include monogenic variants, oligogenic interactions, and polygenic risk. Rapid advance...Cardiomyopathy remains a leading cause of heart failure-related morbidity and mortality, driven by diverse genetic architectures that include monogenic variants, oligogenic interactions, and polygenic risk. Rapid advances in genomic medicine and vector engineering have positioned cardiac gene therapy as a transformative therapeutic approach. Adeno-associated virus-mediated gene replacement for hypertrophic, dilated, and arrhythmogenic cardiomyopathies has transitioned into early-phase clinical trials, with emerging data providing promising signals of myocardial transgene expression and improvements in circulating biomarkers such as NT-proBNP (N-terminal pro-B-type natriuretic peptide). Genome-editing platforms-including CRISPR-mediated base editing and prime editing-offer the potential for durable variant correction without introducing double-stranded breaks. Yet, major translational challenges remain, including strategies to bypass liver uptake to ensure high-efficiency transduction of cardiomyocytes, overcoming delivery constraints, including the cargo size of adeno-associated virus vectors, addressing toxicities, and establishing adequate immunosuppressive regimens. Novel strategies such as direct antegrade and retrograde coronary infusion, capsid engineering, split-intein dual-adeno-associated virus systems, miniaturization of CRISPR-related proteins, and nonviral nanoparticles are underway. As first-in-human cardiomyopathy gene therapy trials begin to define safety, dosing, and vector tropism in the failing human heart, the field is entering an inflection point where genomic diagnosis, molecular correction, and phenotype-guided delivery can converge into precision heart failure therapeutics. This review highlights current progress, emerging platforms, and scientific hurdles that must be overcome to realize a new era of potentially curative, mechanism-directed therapy for inherited and acquired cardiomyopathies.
Perramon-Llussà J, Skorupko G, Rao S
… +10 more, Pujadas ER, Jouide El Kaderi S, Stepin I, Mamouei M, Boonstra M, Triantafyllidis A, Asselbergs FW, Salimi-Khorshidi G, Lekadir K, Gkontra P
The rapid evolution of machine learning techniques, combined with the growing availability of large and diverse data sets, is poised to transform heart failure research and clinical care. This review first provides an ov...The rapid evolution of machine learning techniques, combined with the growing availability of large and diverse data sets, is poised to transform heart failure research and clinical care. This review first provides an overview of key machine learning and artificial intelligence concepts used in heart failure research and then examines how diverse data modalities-including electronic health records, patient registries, biobanks, imaging, telemonitoring, and synthetic data-are leveraged to develop machine learning applications for heart failure diagnosis, prognosis, risk stratification, and personalized treatment strategies. While the potential is considerable, we highlight key barriers to clinical translation, such as data heterogeneity, algorithmic bias, lack of interoperability, and privacy concerns. The review also examines the need for explainable and equitable artificial intelligence systems and evaluates emerging solutions, including Federated Learning and synthetic data generation to address fairness and data privacy challenges. Beyond technical innovations, we underscore the importance of human-centered design, stakeholder engagement, and regulatory readiness. We conclude by identifying future priorities and calling for interdisciplinary collaboration to ensure the scalable, ethical, and effective integration of AI in heart failure management.
Gunnthorsdottir I, Gunnarsdottir AI, Andersen K
… +5 more, Svansdottir E, Thrainsdottir IS, Forsyth P, Ingimarsdottir IJ, Almarsdottir AB
Circ Heart Fail
· 2026 May · PMID 42108747
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BACKGROUND: Medication adherence (MA) is essential for achieving the benefits of guideline-directed medical therapy in heart failure, yet it is seldom assessed systematically in routine care. Understanding how patients e...BACKGROUND: Medication adherence (MA) is essential for achieving the benefits of guideline-directed medical therapy in heart failure, yet it is seldom assessed systematically in routine care. Understanding how patients experience and manage long-term medication use in everyday life is critical for designing effective, patient-centered MA support. METHODS: A qualitative study explored the experiences of patients with heart failure of factors influencing MA. Data were derived from 4 focus groups and 12 in-depth interviews with 27 participants (May 2022-November 2023) recruited from the Icelandic Heart Failure Registry and a cardiac rehabilitation program. Data were analyzed using inductive thematic analysis, supported by field notes and multidisciplinary review. RESULTS: Four interdependent themes emerged: (1) practical aspects of medication use, including daily routines, dose timing, MA aids, formulation challenges, and polypharmacy; (2) psychosocial influences, such as stress, mood, cognition, social support, and socioeconomic context; (3) interactions with the health care system and providers, including education, follow-up, access, costs, patient-provider relationships, and home support; and (4) disease- and medication-related factors, including symptoms, physical limitations, diuretic burden, and side effects. MA was most consistent when regimens aligned with daily life and when tolerability, follow-up, psychosocial needs, and costs were addressed proactively. CONCLUSIONS: Patients with heart failure experience MA as a dynamic process of integrating treatment into daily life rather than a matter of motivation alone. Effective MA support requires regimen simplification, explicit diuretic planning, psychosocial and cost screening, and coordinated multidisciplinary follow-up, including pharmacist involvement. These findings provide patient-derived evidence to inform heart failure-specific MA assessment in routine clinical practice.
Masri A, Cappelli F, Davis MK
… +18 more, Fontana M, Garcia-Pavia P, Gillmore JD, Hanna M, Obici L, Solomon SD, Sperry BW, Tahara N, Waddington-Cruz M, Kristen AV, Falk RH, Shah SJ, Nativi-Nicolau J, Viney NJ, Yang Q, Chen J, Tsimikas S, Maurer MS
Circ Heart Fail
· 2026 Jun · PMID 42104840
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BACKGROUND: Transthyretin amyloidosis with cardiomyopathy is a progressive, fatal disease characterized by deposition of extracellular misfolded transthyretin (TTR) in the myocardium. Eplontersen is an N-acetylgalactosam...BACKGROUND: Transthyretin amyloidosis with cardiomyopathy is a progressive, fatal disease characterized by deposition of extracellular misfolded transthyretin (TTR) in the myocardium. Eplontersen is an N-acetylgalactosamine ligand-conjugated antisense oligonucleotide targeting hepatocyte messenger RNA to reduce the production of circulating TTR. METHODS: CARDIO-TTRansform is a Phase 3, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of eplontersen in transthyretin amyloidosis with cardiomyopathy. Key inclusion criteria include histological evidence of amyloid deposits or grade 2 to 3 cardiac uptake on cardiac scintigraphy in the absence of plasma cell dyscrasia, New York Heart Association class I-III, and end-diastolic interventricular septum thickness >12 millimeters. Participants were randomized 1:1 to receive eplontersen 45 mg or placebo, administered subcutaneously every 4 weeks for up to 140 weeks, followed by a 20-week post-treatment evaluation period or open-label extension. Participants received locally available standard of care, including unrestricted use of TTR stabilizers. The primary end point is a composite of cardiovascular mortality and recurrent clinical cardiovascular events through 140 weeks. Secondary end points, in order of testing hierarchy, include changes from baseline in 6-minute walk distance and Kansas City Cardiomyopathy Questionnaire overall summary score, recurrent cardiovascular events, all-cause mortality, the primary end point in the patient subgroup receiving stabilizers at baseline, and cardiovascular mortality. Echocardiography was performed in all participants, with cardiovascular magnetic resonance imaging and technetium scintigraphy in a subset. CONCLUSIONS: CARDIO-TTRansform is fully enrolled, with 1432 randomized participants who were dosed with study drug or placebo. As the largest transthyretin amyloidosis with cardiomyopathy study to date, it will evaluate whether eplontersen improves cardiovascular outcomes in patients receiving locally available standard of care, including TTR stabilizers. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04136171. URL: http://ClinicalTrialsRegister.eu; Unique identifier: EudraCT number 2019-002835-27.
Hamilton DE, Shriver JL, Patel SM
… +36 more, Park JG, Michos ZE, Mathis MR, Adie SK, Alviar CL, Barnett CF, Berg DD, Bennett CE, Bohula EA, Carnicelli AP, Daniels LB, Dodson MW, Gage A, Gidwani U, Goldfarb M, Katz JN, Ketcham SW, Kwon Y, Leibner ES, Loriaux DB, Luk A, Marano P, Miller PE, Mukundan SV, Papolos AI, Pisani BA, Proudfoot AG, Roswell RO, Shah KS, Solomon MA, Tomey MI, van Diepen S, Zakaria S, Morrow DA, Thompson AD, CCCTN Investigators
Circ Heart Fail
· 2026 May · PMID 42093634
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BACKGROUND: The paucity of data to guide selection of specific vasoactive agents in patients with cardiogenic shock (CS) may lead to variability in practice patterns. The level of variability and specific factors that ar...BACKGROUND: The paucity of data to guide selection of specific vasoactive agents in patients with cardiogenic shock (CS) may lead to variability in practice patterns. The level of variability and specific factors that are associated with the use of vasoactive medications and inodilators have not been previously described. METHODS: The CCCTN (Critical Care Cardiology Trials Network) is an international, multicenter network of cardiac intensive care units (CICUs) coordinated by the TIMI Study Group. This analysis included CICU admissions for CS from 2019 to 2023. Variation in the use of inodilator treatment (dobutamine/milrinone) was assessed with multivariable mixed-effects logistic modeling. RESULTS: A total of 3282 admissions from 37 CICUs comprised the analysis cohort. The use of vasoactive medications, including inodilator treatment, varied substantially across institutions. Patient-level variables associated with greater use of inodilators included history of heart failure (odds ratio, 1.98 [95% CI, 1.61-2.44]), biventricular failure (1.59 [95% CI, 1.27-2.00]), Society of Cardiovascular Angiography and Interventions stage D (1.34 [95% CI, 1.07-1.68]), valvular disease (1.34 [95% CI, 1.03-1.74]), and male sex (1.23 [95% CI, 1.02-1.49]). Variables associated with less inodilator use included cardiac arrest (0.33 [95% CI, 0.27-0.42]), right ventricular failure (0.50 [95% CI, 0.33-0.73]), Society of Cardiovascular Angiography and Interventions stage E (0.57 [95% CI, 0.41-0.81]), acute myocardial infarction-CS (0.71 [95% CI, 0.56-0.90]), peripheral arterial disease (0.73 [95% CI, 0.54-0.99]), older age (0.77 [95% CI, 0.72-0.83], per 10-year increase), and estimated glomerular filtration rate (0.96 [95% CI, 0.93-0.99], per 10 mL/min per 1.73 m increase). No individual measurable institution-level factors (eg, transplant center) were associated with variability in inodilator use. In mixed-effects logistic modeling, 45.7% of variation in inodilator use was attributed to patient-level factors and 22.7% to the random effect of individual CICU centers. Similarly, 35.3% of variation in the use of dobutamine versus milrinone was attributed to patient-level factors and 32.6% to the random effect of individual CICU centers. CONCLUSIONS: There is significant variation in vasoactive treatment and inodilator use in CS. Variation in inodilator use was associated with patient-level factors and with substantial individual CICU practice variation. Such variability underscores the need for additional high-quality evidence to guide vasoactive treatment strategies in CS.
BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) affects millions worldwide and is characterized by chronic cardiac dysfunction, impaired perfusion, altered skeletal muscle energetics, and, thus, exercise...BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) affects millions worldwide and is characterized by chronic cardiac dysfunction, impaired perfusion, altered skeletal muscle energetics, and, thus, exercise intolerance. Efficient therapeutic strategies reducing the burden of the impaired muscle metabolism in HFrEF are currently lacking. Hence, in the present study, we sought to determine whether myosin dynamics and its important role in ATP consumption can constitute a potent biochemical target to optimize skeletal muscle energy usage in HFrEF. METHODS: We used skeletal muscle tissue from 11 human patients with HFrEF and 10 controls with comparable age, sex, and body mass index. We isolated individual myofibres and incubated them ex vivo with varying concentrations of a myosin inhibitor, mavacamten. We then performed 2'-(or-3')-O-(N-Methylanthraniloyl) adenosine 5'-triphosphate chase experiments, together with LC/MS-based proteomics profiling. RESULTS: We observed a distinct regulation of acetyl-lysine sites and higher myosin energy consumption in resting muscle fibers from patients with HFrEF than in controls. When exposed to mavacamten, we found a dose-dependent reduction in myosin ATP consumption in myofibres of patients with HFrEF, reversing the pathological over-consumption. CONCLUSIONS: Skeletal muscle myosin becomes inefficient in HFrEF. Pharmacological inhibition of myosin ATPase activity offers an inventive strategy to lower muscle energy demand and potentially address metabolic disturbances in HFrEF.