The adult mammalian heart has a limited regenerative capacity. Following injury, cardiomyocytes undergo a hypertrophic response accompanied by polyploidization, which has been described as a barrier to proliferation and regeneration of the heart1,2. However, the unique molecular programs of polyploidy, or genome multiplied cardiomyocytes, and their influence on the disease-related myocardial remodelling process remains unclear. Here, we integrate single-nuclei and high-resolution spatial multi-omics across human, rat, and mouse hearts to define novel cardiac cell states and their tissue niches in ischemic and non-ischemic heart disease. Computational analysis across scales allowed us to generate detailed networks of the cardiac tissue remodelling process as well as tissue and sub-cellular environments uniquely enriched in polyploid cardiomyocytes or their diploid origins. We identify a conserved, dichotomous transcriptional program distinguishing diploid from polyploid cardiomyocytes. Polyploid cardiomyocytes demonstrated rewired metabolic and chromatin-remodeling transcriptional programs and recapitulate the gene signature of immature human fetal cardiomyocytes. Importantly, they showed selective enrichment for established heart-failure therapy targets including the mineralocorticoid receptor, β1-adrenergic receptor, and glucagon-like peptide-1 receptor. We further identified TNIK, a Wnt-pathway regulator expressed in polyploid cardiomyocytes across species, as a potential therapeutic target and demonstrate that pharmacological TNIK inhibition improves cardiac function after myocardial infarction in rats. Together, this species-spanning, disease-resolved study redefines cardiomyocyte heterogeneity in heart disease and suggests a therapeutic path to heart failure treatment by targeting polyploid cardiomyocytes. ### Competing Interest Statement CK received honoria from within the last 2 years from BAYER and received research funding from Insilico for this study to perform rat snRNA-sequencing experiments. RK acknowledges the following outside of the submitted work, he is founder and board member of Sequantrix GmbH, received honoraria from Bayer, Chugai, Pfizer, Roche, Genentech, Eli Lilly, and GSK, AMGEN, Sobi, Hybridize Therapeutic, Valerio Therapeutics, Exigent Therapeutics for advisory board meetings and received research funding from Travere Therapeutics, Galapagos, Chugai, Novo Nordisk, and Ask Bio. F.R., H.Z., M.Z., and A.Z. are employees of Insilico Medicine, which develops generative artificial intelligence and related technologies for drug discovery, drug development, and aging research. Insilico Medicine has ongoing therapeutic programs, including rentosertib (INS018_055) in fibrotic and other disease areas. The remaining authors declare no competing interests. Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64, 459969915, 545524314, 445703531 European Research Group on Environment and Health in the Transport Sector, 101040726 Else Kröner-Fresenius-Stiftung, https://ror.org/03zcxha54, 2022.EKCS.08 Bundesministerium für Forschung, Technologie und Raumfahrt, https://ror.org/04pz7b180, 031L0307A Deutsche Herzstiftung, https://ror.org/02hq6wv21, Cardio-KI

Background Endomyocardial biopsy has been the cornerstone of monitoring rejection after heart transplantation for decades. Although recommendations advise routine biopsies during the first 3-12 months, this timeframe is broad, and intercenter variability persists in its application. Here, we report the yield and complication rate of routine endomyocardial biopsies during the past 36 years of post-transplantation care to monitor acute cellular rejection. Methods In this retrospective, single-center study, we collected all routine biopsy data after transplantation between 1986 and 2022. The total number of biopsies, type of rejection, complications, and survival were analyzed in the total population as well as per different endomyocardial biopsy protocol over time period (Period 1: 1986-1994; Period 2: 1994-2009; Period 3: 2009-2022). Results In 474 patients (71.1% male, age at transplant 47.7 ± 12.6 years), 8185 routine biopsy procedures were performed: 29.9 ± 11.1 per patient for Period 1 (n = 83), 16.9 ± 3.8 for Period 2 (n = 220) and 11.6 ± 2.4 for Period 3 (n = 171). Complication rate was low (1.7%; n = 139/8185) and 19.8% (n = 94/474) patients experienced clinically-relevant rejection (≥2R) which mainly occurred <6 months post-transplantation (89.4%; n = 84/94). The incidence of rejection decreased over time, leading to an improved rejection-free survival (p < 0.001) with a subsequent increase in Number-Needed-to-Diagnose. Importantly, severe acute cellular rejection did not occur in Period 3 in the first year post-transplantation. Conclusion Acute cellular rejection, including clinically-relevant rejection, has declined significantly over time and is rare beyond 6 months post-transplantation. A low-frequency approach seems feasible and safe, which is relevant for the transition towards less-invasive protocols to detect rejection, especially early post-transplantation.

The identification of patients with advanced heart failure (HF) remains challenging, often leading to delayed referrals and suboptimal use of advanced therapies such as long-term mechanical circulatory support (MCS) or heart transplantation (HT). This delay contributes to worse outcomes and missed opportunities for timely intervention. Many eligible patients are not recognized early enough in their clinical trajectory, either due to the complexity of the condition, overlapping HF phenotypes, or limited awareness of referral criteria among non-specialist clinicians. In this context, the aim of this scientific statement from the Heart Failure Association (HFA) of the ESC is to systematically identify and address the multifaceted barriers that hinder early recognition and referral for advanced HF care. These barriers span across different stakeholders-patients, caregivers, referring physicians, HF specialists, the academic community, and health authorities. The document proposes practical, stakeholder-specific solutions to improve awareness, standardize referral criteria, integrate digital decision-support tools, and structure care networks. Ultimately, the goal is to enable earlier access to specialized evaluation, ensure equitable use of HT and MCS when appropriate, and improve both survival and quality of life for patients living with advanced HF.

Anthracycline cardiotoxicity is a severe chemotherapeutic side effect that can lead to heart failure in cancer patients and survivors. Chronomodulated chemotherapy is a promising preventive strategy that encompasses the adjustment of anthracycline administration time to the circadian rhythms (24-hour rhythms) of the body. Circadian rhythms play a major role in cardiovascular physiology and disease and may lead to a time-dependent variation in cardiac sensitivity to anthracyclines. In this review, all available evidence on the topic of chronomodulated anthracyclines for cardiotoxicity reduction and/or oncological efficacy enhancement is summarized. In total, 3 in vitro studies, 12 animal studies, and 9 clinical studies were included. Potential mechanistic explanations involved 24-hour variation in oxidative stress regulation, DNA damage repair, and systemic or intracellular pharmacokinetics. We identified a hypothesized optimal time frame from 3 to 11 AM for anthracycline administration in humans, based on extrapolation of findings in animal studies.

Cardiovascular disease remains a persistent global health burden, underscoring the necessity for effective therapeutic strategies. Despite significant advances, the ability to mechanistically study human disease and predict clinical outcomes remains limited, especially in complex diseases such as heart failure. This limitation is evident through the continuous high attrition rates in drug development pipelines. To address these challenges and contribute to improved preclinical studies, there is a need for platforms that more accurately recapitulate the human heart. This need increased the interest in living myocardial slices (LMS) - thin sections of the heart of approximately 100-400 μm. LMS retain the native multicellular architecture of the heart and enable extended ex vivo culture. However, as their utilization grows, so does variability in preparation methodologies and readouts. This review provides an overview of differences in sample selection, interspecies variations, intra-cardiac differences, and potential confounding factors. Additionally, we examine culture methods, addressing electrical and mechanical stimulation differences, and medium compositions. Our review concludes by highlighting the current limitations of LMS research and offers guidelines for standardization and future applications. The ultimate aim of this review is to serve as a resource for researchers working with LMS and for those entering this field. By presenting the landscape of methodological considerations, we aim to facilitate informed decision-making in study design and execution. We advocate for accurate reporting of methodologies to promote reproducibility and comparability across studies, advancing LMS research and strengthening its role as a valuable addition to the current drug development toolbox and basic cardiovascular research.

Background: Living myocardial slices (LMS) are an emerging translational ex vivo model for studying myocardial function, disease mechanisms, and therapeutics. However, the extent to which ex vivo findings correlate with clinical characteristics is unknown. This study aimed to evaluate whether LMS retain patient-specific functional and pathological characteristics, reflecting diverse etiologies, pharmacological regimens, and clinical interventions. Methods: 300-µm-thick LMS were prepared from myocardial biopsies of end-stage heart failure patients (N = 12, n = 138). Functional assessment of freshly prepared LMS included refractory period, stimulation threshold, force-frequency relationship, post pause potentiation, contractile force, alongside simultaneous optical recordings of calcium transients and action potentials. Variability and grouping analyses were conducted to identify features linked to patient-specific parameters, such as etiology and therapeutic history, including prior left ventricular assist device (LVAD) implantation and amiodarone usage. Results: LMS exhibited lower intrapatient variability (LMS from the same patient) compared to interpatient variability (LMS from different patients), confirming their ability to retain patient-specific functional properties. LMS from LVAD-treated patients exhibited reduced intrapatient variability and reduced diastolic tension, correlated with lower N-terminal pro-B-type natriuretic peptide levels. Stratification by etiology revealed distinct functional characteristics, including enhanced contractile force in titin-mutant LMS and a positive force-frequency relationship in ischemic cardiomyopathy-derived LMS. LMS derived from amiodarone-treated patients demonstrated prolonged action potential duration, reduced excitability at higher pacing frequencies, and enhanced post pause potentiation, reflecting the drug’s established pharmacological effects. Conclusions: LMS effectively capture distinct functional parameters associated with patient-specific features. These findings establish LMS as a valuable translational platform for personalized cardiac research, therapeutic testing, and precision medicine.

A rift has opened and is widening between basic research (bench) and clinical research and patients (bed) who need their new treatments, diagnostics and preventive strategies. This problem involving the 'translation' of basic scientific findings into clinical applications and potential treatments or biomarkers for a condition like heart failure is widely recognized both in academia and industry. Despite the attempts that have been made by both sides to improve this situation, the high attrition rates of drug development and the problem with reproducibility and translatability of preclinical findings to human applications still persist. As a result, the return on investment of basic research has been limited in terms of clinical impact. In this scientific statement we describe and discuss various issues with relevance to this theme and try to dissect how to move our field towards the development of more effective heart failure drugs. We zoom in on facilitating the process of heart failure drug development, the unnecessary gaps ('valley of death') between the critical steps in heart failure drug development, validation and de-validation of new concepts as early as possible ('rigorous translation'). We describe forums on how to stimulate cross-talk and interaction between clinician-scientists, basic heart failure researchers, biotech and industry, and how to enable them to speak the same language, and lessons learned from successes outside the heart failure field.

Cardiotoxicity poses a significant challenge in drug development and may lead to withdrawal of approved drugs. To address this issue, there is a critical need for improved models to predict cardiac adverse effects. In line with the FDA's guidelines for animal-free preclinical testing, this study aimed to develop a novel model using human myocardial tissue slices for cardiotoxicity. Human ventricular myocardial tissue slices of 300 μm thick were derived from patient tissues (N = 5) and cultured under physiological mechanical and electrical conditions. Slices were exposed to doxorubicin (n = 11) over a 10-day culture period, and their responses were compared to DMSO-vehicle controls (n = 13). We measured contractile force directly and used fluorescent dyes to record Ca2+ transients and action potentials. Additionally, to assess potential cardioprotection, a subset of slices was pretreated with dexrazoxane (n = 13) 1 day prior to doxorubicin exposure. Doxorubicin-exposed slices exhibited reduced mechanical force, increased threshold potential, and impaired ability to follow pacing at higher frequencies. Furthermore, increased beat-to-beat variability of contraction and calcium transient amplitude, along with an induction of arrhythmias, was observed, particularly in slices from susceptible patients. Encouragingly, pretreatment with dexrazoxane demonstrated a protective effect against doxorubicin-induced cardiac toxicity. In summary, human myocardial tissue slices faithfully recapitulate doxorubicin-induced cardiotoxicity. Importantly, our findings demonstrated for the first time the in vitro cardioprotective potential of dexrazoxane. These findings support the use of ex vivo myocardial tissue slices for evaluating cardiotoxicity. Moreover, our work contributes to the growing body of evidence supporting the reliability and value of human myocardial tissue slices as a powerful tool for evaluating the efficacy and safety of novel therapeutic treatments and delivery approaches.

Aims:Pre-clinical studies point towards an administration time-dependency of anthracycline-induced cancer therapy-related cardiac dysfunction (CTRCD). This retrospective study aimed to investigate the association between time-of-day of AC administration and CTRCD. Methods and results:Patients from two cardio-oncology outpatient clinics, treated with ACs for any malignancy, were included. Percentage of afternoon AC administration was calculated: cumulative dose administered in the afternoon (12 p.m.-11:59 p.m.)/total cumulative dose. Three groups were defined: morning group ≥ 50% of ACs in the morning (12 a.m.-11:59 a.m.), afternoon group ≥ 50% of ACs in the afternoon, and intermediate group = exactly 50% of ACs in the morning and afternoon. Associations between AC timing and occurrence of CTRCD and heart failure (HF) were assessed using survival analyses. Of 270 included patients, 66 developed CTRCD and 17 developed HF. Compared with the morning group, the afternoon group had a higher risk of developing CTRCD: hazard ratio (HR) 2.88 (95% CI: 1.52-5.44). When considering percentage of ACs administered in the afternoon as a continuous variable, the HR for developing CTRCD was 1.14 (95% CI: 1.04-1.24) for each subsequent 10% of afternoon administration. Results were consistent across sensitivity analyses of age, sex, body mass index, malignancy type, cumulative AC dose, and HFA-ICOS risk score. Congruently, the continuous variable of afternoon AC administration was associated with higher risk of HF: HR = 1.19 (95% CI: 1.01-1.41). Conclusion:Afternoon administration of ACs is associated with an increased risk of developing CTRCD and HF, suggesting that morning administration may be preferred. Before widespread implementation, these findings should be confirmed in an RCT.

Primary graft dysfunction (PGD) is the most common cause of early mortality following heart transplantation. Although PGD can affect both ventricles, isolated right ventricular dysfunction (RV-PGD) is observed in nearly half of PGD patients. RV-PGD requires specific medical management to support the preload, afterload, and function of the failing RV; however, the use of mechanical circulatory support of the RV (RV-MCS) might be required when optimal medical therapy is insufficient in preventing forward failure and retrograde venous congestion. While RV-MCS options provide the opportunity to prevent or to recover from circulatory shock states, MCS is associated with a significant risk of complications. As a result of recent developments in short-term mechanical support devices, less invasive, percutaneous options for RV-MCS are available. In this review, we discuss the available devices, their advantages and disadvantages, and reported outcomes in RV-PGD.

Heart failure involves complex pathophysiological processes, best studied in multicellular human cardiac tissues that reflect the native cellular composition and microenvironment. However, maintaining primary cells and tissues in culture for extended periods remains challenging. Developing robust human cardiac models is critical for advancing preclinical research and bridging the gap to clinical applications. This study aims to characterize adaptations occurring in human living myocardial slices (LMS) during ex vivo culture.During culture, LMS demonstrated progressive enhancements in contractile function including stronger force generation, reduced diastolic tension, and faster contraction-relaxation kinetics. However, excitability and force-frequency response decreased over the same period. Cultured LMS showed enhanced calcium handling, including increased ability to follow pacing, higher amplitude, and faster, more stable calcium re-uptake. Structurally, LMS displayed no changes in sarcomeres, cell-cell connections, or mitochondria, despite gene expression changes in cytoskeletal and extracellular matrix-related pathways. Transcriptomic analysis revealed metabolic activation with upregulation of metabolism-related pathways. Interestingly, LMS exhibited increased expression of genes associated with early cardiac development after the culture period.LMS provide a powerful translational model for cardiovascular research, enabling the evaluation of novel therapies and fundamental studies. However, culture-induced adaptations must be carefully considered when interpreting results to ensure physiological and disease relevance.

Objective Several prediction models for right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation are available, but obtained in a heterogeneous population with several types of LVADs. Our goal is to externally validate these prediction models in a homogeneous HeartMate 3 (HM3) patient cohort and to develop a novel, HM3 specific, prediction model incorporating both preoperative and intraoperative variables. Design and method In this single-center, retrospective cohort study, adult patients who underwent a primary HM3 implantation between December 2015 and March 2025 were included. The EUROMACS and STOP-RVF risk models were evaluated using the area under the receiver operating characteristic curve (AUC) and Hosmer-Lemeshow calibration analyses. A new THUNDERBALL risk score will be derived using univariate and multivariate logistic regression analysis. Results and conclusions The incidence of RVF in this cohort was 28.2% (69 of 245 patients) using the EUROMACS definition and 21.2% (52 of 245 patients) using the STOP-RVF risk score definition of RVF. The EUROMACS and STOP-RVF risk scores showed limited discriminative performance with an AUC of 0.57 (95%CI 0.47-0.67) and 0.66 (95%CI 0.55-0.77), respectively. Hosmer-Lemeshow goodness-of-fit tests resulted in a p-value of 0.217 for the EUROMACS risk score and a p-value of 0.100 for the STOP-RVF risk score. The THUNDERBALL risk score, including body surface area, Interagency Registry for Mechanically Assisted Circulatory Support class 1, platelet count and right atrial/pulmonary capillary wedge pressure ratio, showed good discriminative performance with an AUC of 0.74 (95%CI 0.66-0.83, p <0.001). Therefore, the THUNDERBALL risk score outperformed the EUROMACS and STOP-RVF risk scores in the prediction of RVF after HM3 implantation. This novel risk score may be useful in the management of future HM3 recipients.

Heart failure (HF) represents a significant global health burden, with approximately 10% of patients progressing to advanced stages characterized by severe symptoms and recurrent hospitalizations despite conventional treatments such as guideline-directed medical therapy, devices, and surgery. This clinical consensus statement from the Heart Failure Association of the European Society of Cardiology discusses the applications of imaging modalities in patients with advanced HF. Transthoracic echocardiography remains the cornerstone for initial diagnosis and monitoring, providing critical insights into cardiac volumes, function, and valvular integrity, as well as congestion status. Transoesophageal echocardiography offers detailed evaluations of valve pathology, essential for surgical or transcatheter planning. Cardiovascular magnetic resonance provides comprehensive assessments of biventricular size and function, tissue characterization, and flow dynamics, proving particularly useful for diagnosing specific HF aetiologies. Computed tomography offers valuable insights into pulmonary artery diameter, right ventricular volume, and valvular anatomy, which are crucial for guiding percutaneous procedures. Nuclear imaging techniques allow assessing viability and diagnosing non-ischaemic HF conditions, guiding revascularization decisions. Advanced imaging techniques have expanded the understanding and management of right ventricular dysfunction. The integration of these advanced imaging modalities enhances diagnostic accuracy, risk stratification, and therapeutic decision-making, ultimately improving the prognosis and quality of life for patients with advanced HF. This clinical consensus statement highlights the critical role of various imaging modalities in managing patients with advanced HF, excluding those needing mechanical circulatory support or heart transplantation, emphasizing the multifaceted approach required for effective management.

BACKGROUND:With notable improvements in long-term survival and hemocompatibility-related events, heart failure (HF) is emerging as a leading cause of death in the contemporary left ventricular assist device (LVAD) population. Although prospective randomized controlled trials have not investigated the use of HF therapies in recipients of LVAD, observational data suggest benefits of neurohormonal blockers, especially in achieving blood pressure (BP) targets associated with improved outcomes. METHODS:The study "multicENter, randomized, open-label, parallel group, pilot study to evaluate the use of sacubitril/valsartan in HeartMate 3 LVAD recipients" (ENVAD-HF) is an investigator-initiated prospective multicenter, randomized, open-label, parallel group, pilot study of recipients of HeartMate 3 (HM3) LVADs to evaluate the safety and tolerability and insights on efficacy of sacubitril/valsartan compared to standard of care (SOC) for managing BP. Medically stable recipients of LVADs after a recent HM3 implantation or in ambulatory follow-up were eligible for participation and randomized 1:1 to receive sacubitril/valsartan or SOC used for treating BP, both titrated aiming for a mean arterial pressure goal 75-90 mm Hg over a 12-month follow-up. The primary endpoint, designed to assess the safety and efficacy of sacubitril/valsartan compared with SOC, is a composite of freedom from all-cause death, deterioration in renal function, hyperkalemia, or symptomatic hypotension. The occurrence of the primary endpoint will be assessed in the first three months and during the overall duration of the trial (12 months). Other endpoints include clinical and patient-reported outcomes, biomarker, and echocardiography assessments during follow-up. RESULTS:ENVAD-HF enrolled 60 patients between February 2021 and March 2024: 17% were female, mean age was 57 ± 12 years, 67% were in ambulatory follow-up, 55% had ischemic etiology, and 25% were receiving an LVAD as destination therapy, with mean baseline mean arterial pressure 87 ± 7 mm Hg and median N-terminal pro B-type natriuretic peptide 2552 (1595-3543) pg/mL. CONCLUSION:ENVAD-HF is the first prospective randomized controlled trial of pharmacologic therapy for the management of BP in stable recipients with HM3 LVADs achieving target enrollment. It will provide data on safety, tolerability, and insights on efficacy of sacubitril/valsartan versus SOC used for treating BP.

BACKGROUND:The role of heart failure-specific therapies in left ventricular assist device (LVAD) recipients is unclear, and observational data suggest improved outcomes with neurohormonal blockers. OBJECTIVES:ENVAD-HF (Multicenter, Randomized, Open-Label, Parallel Group, Study to Evaluate the Use of Sacubitril/Valsartan in HeartMate 3 LVAD Recipients) sought to evaluate the safety and tolerability of the angiotensin-neprilysin inhibitor sacubitril/valsartan vs standard of care (SOC) for managing blood pressure (BP) in HeartMate 3 LVAD recipients. METHODS:ENVAD-HF was a prospective multicenter, randomized, open-label study of sacubitril/valsartan vs SOC for managing BP (mean arterial pressure goal: 75-90 mm Hg) in stable LVAD recipients with 12-month follow-up. The composite primary endpoint was time to death, deterioration in renal function, hyperkalemia, or symptomatic hypotension leading to drug withdrawal. Exploratory endpoints included clinical and biomarker assessments and patient-reported outcomes. RESULTS:In 60 randomized patients (30 in each arm), sacubitril/valsartan compared with SOC demonstrated an HR of 0.42 (95% CI: 0.08-2.18; P = 0.30) for the primary endpoint at 12 months. Two primary endpoints were reached in the sacubitril/valsartan group (1 death and 1 symptomatic hypotension event) compared with 5 in the SOC group (2 deaths, 2 worsening renal function events, and 1 symptomatic hypotension event). Numerical trends in favor of sacubitril/valsartan were noted for other exploratory endpoints, including a reduced number of BP medications (difference: -1.09 [95% CI: -1.52 to -0.66]; P < 0.0001) and a significantly better Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (improvement: +10.6 [95% CI: 2.6-18.7]; P = 0.011). CONCLUSIONS:ENVAD-HF, a prospective randomized controlled trial of angiotensin-neprilysin inhibition in stable HeartMate 3 LVAD recipients, demonstrated the safety and tolerability of this therapy in this unique population. The trial forms the basis for a pivotal trial to investigate the usefulness of HF-specific therapies in the LVAD population. (Sacubitril/Valsartan in Left Ventricular Assist Device Recipients [ENVAD-HF], NCT04103554; A multicENter, randomized, open-label, parallel group, pilot study to evaluate the use of sacubitril/valsartan in HeartMate 3 LVAD recipients, 2019-003888-22).

BACKGROUND AND PURPOSE:The increasing number of cancer survivors has caused growing concern over chemotherapy-induced cardiotoxicity. This study aimed to investigate a novel human model of cardiotoxicity and explore cardioprotection. EXPERIMENTAL APPROACH:Living myocardial slices (LMS) were obtained from explanted end-stage heart failure hearts, then exposed to doxorubicin (Dox) to investigate cardiotoxic effects and to dexrazoxane (Dex) to explore cardioprotection. We assessed contractile function and glucose consumption, followed by evaluation of calcium transients, structural integrity and transcriptomic changes. Additionally, electrocardiogram (ECG) alterations were analysed in patients treated with anthracyclines to corroborate the cardiotoxicity findings from LMS. KEY RESULTS:We observed distinct functional responses to Dox, with LMS derived from some patients exhibiting high susceptibility to Dox-induced cardiotoxicity. LMS from susceptible patients displayed reduced contractile function and excitability, myofibre dyssynchrony, structural damage and decreased metabolic activity. Dex pretreatment partially mitigated these effects, preserving contractile function and preventing structural damage. Consistent with ex vivo findings, patients treated with anthracyclines exhibited acute and chronic alterations in T-, P- and R-wave morphology of the ECG, confirming variable susceptibility at the clinical level. CONCLUSIONS AND IMPLICATIONS:We highlight the value of human LMS in studying Dox-induced cardiotoxicity and the cardioprotective potential of Dex, even when sourced from end-stage heart failure patients. Susceptible patients harboured cardiomyopathy-associated genetic mutations, suggesting that genetic screening including cardiomyopathy-associated genes, prior to anthracycline treatment, could enable improved patient risk stratification. We demonstrate the potential utility of ECG changes for early detection of subclinical cardiotoxicity.

Arrhythmogenic cardiomyopathy (ACM) is frequently attributed to desmosomal mutations, such as those in the desmoplakin (DSP) gene. Patients with DSP- cardiomyopathy are predisposed to myocardial degeneration and arrhythmias. Despite advancements, the underlying molecular mechanisms remain incompletely understood, thus limiting therapeutic options. Here, we employed spatial transcriptomics on an explanted heart from a patient with a pathogenic DSP variant. Our transcriptional analysis revealed endothelial PAS domain-containing protein 1 (EPAS1) as a potential regulator of mitochondrial homeostasis in stressed cardiomyocytes. Elevated EPAS1 levels were associated with mitochondrial dysfunction and hypoxic stress in both human-relevant in vitro ACM models and additional explanted hearts with genetic cardiomyopathy. Collectively, cardiomyocytes bearing pathogenic DSP variants exhibit mitochondrial dysfunction, increased apoptosis, and impaired contractility, which are linked to the increased EPAS1 levels. These findings implicate EPAS1 as a key regulator of myocardial degeneration in DSP-cardiomyopathy, which expand to other forms of ACM.

This clinical consensus statement outlines the vital role of multimodality imaging in managing patients with advanced heart failure (HF), particularly those receiving mechanical circulatory support (MCS) and heart transplantation (HT). For both temporary and durable MCS, multimodality imaging, primarily echocardiography, is crucial for selecting candidates, ensuring proper device placement, and monitoring in the post-implantation period. Preoperatively, it helps to identify HF phenotypes, assess ventricular functions, detect intracardiac thrombi, and evaluate valvular conditions. Key measurements include ventricular size, ejection fraction, and cardiac output. Intraoperative imaging ensures optimal device placement and complication detection. Post-implantation echocardiography gives an impression of the interplay between heart and MCS, detects early complications, and evaluates ventricular unloading and right ventricular function. Serial imaging evaluations are essential for the management of the patient and the device and for diagnosing and treatment of complications. In temporary MCS, imaging is vital in the weaning process. Imaging is crucial across various post-transplant phases, from early postoperative monitoring to long-term follow-up. Echocardiography is the first-line technique. Cardiovascular magnetic resonance provides detailed evaluation of cardiac structure and function, offering insights into fibrosis, oedema, and myocardial perfusion. Coronary computed tomography angiography and positron emission tomography are possible alternatives for assessing coronary allograft vasculopathy. Overall, multimodality imaging is pivotal for comprehensive management of patients potentially eligible to or undergoing MCS or HT, enhancing diagnostic accuracy and guiding therapeutic decisions.