Search Results (268)

Heart transplantation is still the definitive therapy for end-stage heart failure, yet the persistent shortage of suitable donor organs limits its application. Traditionally, static cold storage (SCS) has served as an effective standard preservation method, providing safe and adequate protection for preservation times under four hours. Yet, the need to extend this window and the specific metabolic requirements of donation after circulatory death (DCD) hearts have prompted interest in machine perfusion (MP) technologies. This literature review investigates the influence of temperature in ex situ heart perfusion, comparing normothermic (NMP), hypothermic (HMP), and subnormothermic (SNMP) strategies. Evidence from experimental models and emerging clinical studies suggests that MP can prolong preservation times, mitigate ischemic injury, and enable real-time metabolic and viability assessment of donor hearts prior to transplantation. These strategies represent a central trade-off: NMP enables real-time functional assessment of the beating heart, while HMP and SNMP approaches prioritize profound metabolic suppression to mitigate ischemic injury. Nonetheless, current data are limited by high costs, significant resource requirements, variability in perfusion protocols, and the scarcity of randomized controlled trials, particularly for HMP and SNMP. Standardization of methodologies, direct comparative studies, and the adoption of a risk-stratified preservation ecosystem are needed to clarify optimal temperature strategies. However, recent clinical successes with hypothermic strategies in traditionally normothermia-dependent donor types, such as DCD hearts, signal a potential paradigm shift, challenging established value propositions and prompting a critical re-evaluation of optimal preservation strategies. Full article

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disorder, is usually caused by pathogenic variants in sarcomeric genes and is inherited in an autosomal dominant manner. Around 5% of cases are caused by variants in non-sarcomeric genes, which may involve alternative modes of inheritance. This study presents the first reported case of HCM associated with digenic contribution of heterozygous variants in two non-sarcomeric genes: ALPK3 and TRIM63. The patient was incidentally diagnosed with non-obstructive HCM in childhood and developed extreme myocardial hypertrophy with moderate heart failure at the age of 18. Rapid progressive left ventricular dysfunction promptly resulted in death at the age of 26. Genetic testing with an extended HCM panel identified no sarcomeric variants but revealed two truncating variants in the ALPK3 and TRIM63 genes. Whole-genome sequencing excluded any other causes of the disease. Heterozygous ALPK3 variants are typically associated with late-onset HCM, whereas TRIM63 variants are only considered pathogenic in a recessive state. This case, therefore, suggests a synergistic contribution of both variants to the development of a severe phenotype. The potential mechanisms of interaction between the protein products of ALPK3 and TRIM63 within the M-band of the sarcomere are discussed. Full article

Background: Heart failure (HF) remains a major global health challenge, with orthotopic heart transplantation (OHT) serving as the gold-standard therapy for end-stage disease. Chronic immunosuppression required to prevent graft rejection increases the risk of infections and malignancies. The COVID-19 pandemic underscored the particular vulnerability of transplant recipients to severe SARS-CoV-2 infection. Specific immunosuppressive agents used in OHT patients may differentially affect SARS-CoV-2 infection. In particular, mTOR inhibitors may modulate viral replication and immune responses, potentially influencing disease severity. Objectives: This study evaluated the impact of immunosuppressive regimens—particularly mTOR inhibitors—on COVID-19 outcomes in heart transplant recipients, comparing mTOR-based therapy (with or without calcineurin inhibitors, CNIs) to non-mTOR-based regimens. Methods: This single-center retrospective observational study included 556 orthotopic heart transplant recipients (76.3% male; median age, 58 years) followed from March 2020 to March 2024. To compare patients receiving mTOR inhibitors with similar non-mTOR recipients, 3:1 propensity score matching was performed based on age, sex, and body mass index. Among the study population, 88 patients (15.8%) received mTOR inhibitors (everolimus or sirolimus), of whom 66 were concomitantly treated with calcineurin inhibitors and 22 without. Data were obtained from the National Health Fund database and clinical follow-ups. Results: Overall mortality was 13.5%, and COVID-19-related mortality 3.2%. COVID-19 incidence was 33% in the mTOR group versus 36.7% in the non-mTOR group (p = 0.52). Hospitalization rates were 3.4% and 6.4% (p = 0.29), respectively. All-cause mortality was higher among mTOR users (21.6% vs. 11.7%, p = 0.02), especially in the mTOR+CNI subgroup. Notably, no COVID-19-related deaths occurred in the mTOR CNI-free group. Conclusions: mTOR-based immunosuppression was non-inferior to standard therapy for COVID-19 outcomes. The absence of COVID-19-related deaths in patients on mTOR CNI-free regimens suggests potential protective effects that merit further investigation. Full article

Cardiogenic shock (CS) remains a significant clinical challenge with persistently high mortality rates. Defined by impaired cardiac output resulting in end-organ hypoperfusion, CS commonly arises from acute myocardial infarction (AMI-CS) or acute exacerbations of heart failure (HF-CS). The severity of CS is classified by the Society for Cardiovascular Angiography and Interventions (SCAI) into stages A (at risk) through E (extremis), which informs treatment strategies, including pharmacotherapy and mechanical circulatory support (MCS). Recent advancements in percutaneous mechanical circulatory support devices, including intra-aortic balloon pumps (IABPs), Impella devices, TandemHeart, Protek-Duo, and veno-arterial extracorporeal membrane oxygenation (VA-ECMO), have transformed management paradigms by offering targeted hemodynamic support. While DanGer-SHOCK, a pivotal randomized trial, demonstrated improved outcomes with early Impella use in anterior STEMI-associated CS, the trial’s focus population and center expertise suggest that its findings should be interpreted in the context of broader AMI-CS and HF-CS presentations. Device selection is guided by shock severity, anatomical considerations, comorbidities, and institutional capabilities. This review synthesizes current evidence, evaluates the clinical utility and efficacy of existing and emerging percutaneous MCS technologies, and highlights ongoing clinical trials and future directions in optimizing CS management. Emphasis is placed on individualized patient selection, evidence-based deployment of MCS devices, and multidisciplinary team collaboration, which collectively represent a critical transition towards improving clinical outcomes in CS. Full article

Hypertrophic cardiomyopathy (HCM) progressing to end-stage heart failure and heart transplantation (HT) is a rare clinical scenario with an insufficiently explored genetic background. In this single-center retrospective cohort study, we aimed to characterize the genetic spectrum, variants of HCM adverse remodeling, and aspects of molecular pathogenesis of this subgroup. The study included 14 patients (9 females), among whom 10 developed a dilated/hypokinetic phenotype and 4 a restrictive phenotype. In 13 patients (93%), at least one pathogenic or likely pathogenic genetic variant was identified. Dilated remodeling/hypokinesis was associated with loss-of-function variants in LAMP2 (3) in females, ALPK3homo (1), MYH7 (1), MYBPC3 (1), a heterozygous missense variant in TRIM63 (1), FLNCtv (1), TTNtv (2). For the latter two, electrophoretic analysis of titin isoform composition and protein content in myocardial fragments from explanted hearts confirmed the functional significance of TTN gene variants. The restrictive phenotype in the adult group was associated with carriage of multiple pathogenic sarcomere gene variants: MYL3homo (1), MYBPC3+TPM1 (1), an MYH7 converter domain variant (1), and, in one child, with a TNNT2 variant. This findings support HCM progressing to HT is characterized by a higher frequency of variants in non-sarcomeric genes and Danon disease compared to the general HCM cohort. Full article

In recent years, lactate has transitioned from being considered a mere metabolic end-product to being regarded as a critical signaling molecule that links cellular metabolism with gene regulation. Protein lactylation, a post-translational modification (PTM) mediated by lactate, is central to this functional transformation. In vascular diseases, the lactate–lactylation process demonstrates a marked double-edged sword characteristic, with its regulatory effects highly dependent on cell type, disease stage, and the pathological microenvironment. On one hand, lactylation can exert protective roles by promoting reparative gene expression, driving anti-inflammatory cell polarization, and maintaining myocardial structural integrity; on the other hand, aberrant lactylation can exacerbate inflammatory responses, promote fibrosis, and induce cell death and vascular calcification, thereby driving the development and progression of atherosclerosis, heart failure, and stroke. This review systematically delineates the paradoxical yet unified dual roles of lactylation across various vascular diseases and explores the molecular bases that underlie these functional differences. We propose that deciphering and precisely modulating the ‘double-edged sword’ of lactylation—selectively enhancing its protective functions while suppressing its pathological actions—represents a central challenge and a critical opportunity for translating basic research into clinical applications. Such advances could provide a novel theoretical framework for the development of diagnostic biomarkers and cell-specific precision therapeutic strategies. Full article

Background: Orthotopic heart transplantation (OHT) remains the gold standard for end-stage heart failure, yet individualized risk assessment for postoperative mortality remains challenging. We aimed to develop and interpret random forest-based models for predicting 30-day and 1-year mortality and to examine whether the key predictors differ between the 30-day and 1-year models. Methods: We analyzed 581 patients who underwent OHT between 2012 and 2024. The 30-day and 1-year mortality rates were 9.9% and 17.6%, respectively. Eighty-seven preoperative and forty-eight postoperative variables were considered as input features for model development. Random forest models were trained and validated using five-fold cross-validation, and explainability was assessed using SHapley Additive exPlanations (SHAP). Results: Using preoperative features only, the random forest models achieved AUCs of 0.62 (95% CI, 0.48–0.75) for 30-day and 0.67 (95% CI, 0.56–0.78) for 1-year mortality. SHAP analysis revealed that early mortality predictions were primarily driven by features reflecting acute physiological stress—hepatic dysfunction, inflammation, and hemodynamic instability—whereas long-term predictions were increasingly influenced by renal function, metabolic reserve, and frailty. Incorporating postoperative features improved performance (AUC 0.98 [95% CI, 0.97–0.99] and 0.86 [95% CI, 0.80–0.92], respectively), with model predictions dominated by the severity and persistence of organ dysfunction: short-term risk driven by hepatic injury, hemodynamic compromise, and critical illness, and long-term risk by sustained hepatic and renal impairment, metabolic resilience, and duration of circulatory support. Conclusions: Random forest models integrating preoperative and immediate postoperative data could predict short- and mid-term mortality after OHT. SHAP analysis demonstrated temporal shifts in the most important predictors, supporting the role of dynamic, data-driven risk assessment in transplant care. Full article

Heart transplantation is the gold standard in patients with end stage heart failure, offering vastly improved survival, mortality and quality of life. However, hypertension occurring after cardiac transplantation is a serious issue, with the incidence ranging from 50 to 80% of patients. The pathophysiology of the hypertension encompasses a more varied and unique set of causes than those identified in non-organ transplant patients, particularly related to the use of calcineurin inhibitors (CNIs) especially cyclosporine. An in-depth understanding of hypertension after heart transplantation remains a critical issue that necessitates further clarification, due to its deleterious long-term consequence such as impaired graft survival, cardiac allograft vasculopathy (CAV), and overall survival. This article provides a comprehensive review of the prevalence, risk factors, etiology, complications, and management of hypertension after heart transplantation. Full article

Background: Heart failure (HF) is highly prevalent among patients on maintenance hemodialysis (HD) and contributes substantially to morbidity and mortality. This study aimed to evaluate the prevalence, clinical characteristics, and prognostic impact of HF in a chronic HD population. Methods: A single-center observational study was conducted on 271 HD patients (January 2022–September 2024). HF was defined and classified according to 2021 ESC criteria using echocardiography and NT-proBNP. Clinical, laboratory, and dialysis parameters were compared between HF and non-HF patients. Predictors of HF were assessed using multivariable logistic regression, and survival analyses were performed using Cox regression and Kaplan–Meier curves. Results: HF was identified in 75% of patients: 45% had a preserved EF, 31% had a mildly reduced EF, and 24% had a reduced EF. HF patients were older, had higher NT-proBNP, lower EF, more atrial fibrillation, CAD, and increased interdialytic weight gain. In the multivariable analysis, a reduced EF (OR = 0.77, p = 0.001), older age (OR = 1.12, p = 0.001), and UF rate (OR = 1.31, p = 0.02) were found to independently predict HF. During the 34-month follow-up, HF was found to be associated with significantly higher all-cause and cardiac mortality and more frequent HF-related hospitalizations (log-rank p < 0.001). In the multivariable Cox regression, two variables were found to independently predict all-cause death, NT-proBNP (per 1000 pg/mL) (HR 1.030, p = 0.029) and a lower EF: (HR 0.97, p = 0.019). For cardiac death, a higher NT-proBNP (HR 1.038, p = 0.033) and a lower EF (HR 0.933, p = 0.001) together with a lower BMI (HR = 0.929, p = 0.028) persisted as independent predictors. Conclusions: HF is extremely common in HD patients and identifies a subgroup with distinct clinical characteristics and poor prognosis. NT-proBNP and left ventricular ejection fraction are key independent predictors of mortality, underscoring the importance of early cardiac evaluation and integrated volume and dialysis management to improve outcomes. Full article

Background: Ventricular assist devices serve as a critical bridge to transplantation for pediatric patients with end-stage heart failure. This study evaluated the outcomes of pediatric patients who received Berlin Heart EXCOR support for end-stage heart failure. Methods: We retrospectively analyzed data from 11 consecutive pediatric patients (63.64% male, median age 60 months) who underwent Berlin Heart implantation from November 2021 to April 2025. The majority (90.90%) had dilated cardiomyopathy, and 72.73% were INTERMACS class I. Results: Of the 11 patients, 54.54% received an LVAD only, 36.36% received a BiVAD, and 9.09% required an LVAD followed by an RVAD. The postoperative mean ICU stay was 140 ± 73 days, and total hospital stay was 192 ± 96 days. Significant post-implant complications included stroke (27.27%), bleeding requiring exploration (27.27%), and pneumonia (36.36%). Ten patients (90.91%) were successfully bridged to heart transplantation, with one pre-transplant mortality (9.09%) due to brain hemorrhage. The median time to transplantation was 88 days (interquartile range, IQR: 78–177). During a median follow-up of 17 months (IQR: 7–32), two patients died post-transplant, resulting in an overall survival rate of 67.50% at 3 years. Conclusions: Despite significant complications and prolonged hospitalization, the Berlin Heart demonstrated effectiveness as a mechanical circulatory support device for pediatric patients, with a high rate of successful bridging to transplantation and acceptable mid-term survival. These findings support its use as a viable bridge to transplantation in pediatric end-stage heart failure. Full article

Background: Individuals with heart failure (HF) are at increased risk of magnesium deficiency. Magnesium supplements are widely available and being used without clear evidence of efficacy in HF. Methods: We emulated a target trial to assess the association between magnesium supplements and adverse outcomes in U.S. veterans with newly diagnosed HF. Eligible patients were outpatients who received ambulatory care in the Veterans Health Administration between 1 January 2000 and 31 December 2020. Veterans with a hospitalization within 30 days prior to the eligible date, previous magnesium supplement or replacement use, or end-stage renal disease were ineligible for the trial. Initial self-reported magnesium supplement use (measured at eligible date) was identified in medical records using natural language processing and then checked repeatedly to confirm continuous use. The outcome was all-cause hospitalization or death. Patients were followed for up to five years from the eligible date and were censored if they changed from the assigned treatment strategy or initiated prescribed magnesium replacement. We applied inverse probability treatment weighting and Cox’s regression to estimate hazard ratios (HRs), with sensitivity analyses in patients surviving ≥ 6 months and those with continuous documentation of magnesium supplement use. Results: We enrolled 9900 magnesium supplement users and 9900 matched non-users. In the weighted cohort (mean age 72.6 years; 12.6% African American; 3.4% women; median follow-up 0.7 years), users had significantly better survival in both primary and sensitivity analyses (HR in primary analysis: 0.81 [0.77–0.86], p < 0.0001; HRs in sensitivity analyses: 0.91 [0.85–0.97], p = 0.0025 and 0.77 [0.72–0.82], p < 0.0001, respectively). Conclusions: magnesium supplement use was associated with a reduced risk of all-cause mortality or hospitalization among veterans with HF. Full article

Diabetes mellitus (DM) continues to be a global world health problem. Despite medical advances, both DM and chronic kidney disease (CKD) remain global health issues with high mortality and limited options to prevent end-stage renal failure. Current therapies encompass five classes of drugs: (1) angiotensin-converting-enzyme inhibitors (ACEI) or angiotensin II receptor blockers (AIIRB); (2) sodium-glucose-transporter 2 (SGLT2) inhibitors; (3) glucagon-like peptide-1 receptor agonists (GLP-1 RA); and (4) an antagonist of type 1 endothelin receptor (ET1R) with proven efficacy to reduce albuminuria and proteinuria. (5) The mineralocorticoid receptor antagonist (MRA) finerenone has been tested in RCTs as a kidney protective agent. In our review, we summarize many of the principal trials that have generated evidence in this regard. Many novel agents—many of them proven not only for DM management but also for the treatment of obesity with or without DM or heart failure (HF)—are now in development and may be added to the five classical pillars: other non-steroidal MRA (balcinrenone); aldosterone synthase inhibitors (baxdrostat and vicadrostat); other GLP-1 RA (tirzepatide, survodutide, retatrutide, and cagrilintide); ET1 R antagonists, (zibotentan); and soluble guanylate cyclase activators (avenciguat). These new agents aim to slow disease progression further and reduce cardiovascular risk. Future strategies rely on integrated, patient-centered approaches and personalized therapy to curb renal disease and its related complications. Full article

Cardiac muscle has limited proliferative potential; therefore, loss of cardiomyocytes is irreversible and can cause or exacerbate heart failure. Although both pharmacological and non-pharmacological therapies are available, these interventions act primarily on surviving myocardium to manage symptoms and reduce—rather than reverse—adverse remodeling. The only curative option for end-stage heart failure remains heart transplantation; however, its clinical use is severely constrained by the shortage of donor organs. Consequently, regenerative therapies have gained increasing attention as potential novel treatments. Among these, cardiomyocytes derived from patient-specific pluripotent stem cells (PSCs) represent a particularly promising experimental platform for cardiac regeneration. To evaluate the potential of PSCs for cardiac repair through both in vivo and in vitro approaches, we (1) examined the hallmarks of cardiomyocyte maturation and the regulatory systems that coordinate these processes, (2) reviewed recent advances in maturation protocols and derivation techniques, (3) discussed how the cellular microenvironment enhances maturation and function, and (4) identified current barriers to clinical translation. Importantly, we integrated developmental biology with protocol design to provide a mechanistic foundation for PSC-based regeneration. Specifically, insights from cardiac development—such as signaling pathways governing proliferation, alignment, and excitation-contraction coupling—were explicitly linked to the refinement of PSC differentiation and maturation protocols. This developmental perspective allows us to bridge pathology and stem-cell methodology, explaining how disruptions in native cardiac maturation can inform strategies to produce functionally mature PSC-derived cardiomyocytes. Finally, we assessed the clinical prospects of PSC-derived cardiomyocytes, highlighting both the most recent advances and the persistent translational challenges that must be addressed before widespread therapeutic use. Full article

Introduction: The prevalence of cardiorenal syndrome (CRS) and its management might be challenging, so an interdisciplinary approach is advocated. The aim of this study was to identify and describe the population which might profit from such an interdisciplinary clinic at the University Hospital of Zürich. Methods: We screened 551 patients who were seen at least once in the nephrology and cardiology outpatient clinics from 2015 to 2022. Patients with kidney (87) or heart (47) transplantation, on dialysis (179), without concomitant chronic kidney disease (CKD) and heart failure (HF) (179), and those who died before the end of follow-up (94), were excluded, resulting in a cohort of 150 patients. Characteristics related to the type and cause of renal and cardiac disease, cardiovascular risk factors, adequacy of therapy, and incidence of hospitalization for HF were recorded. Results: The median age of the population was 71 years, with one-third having diabetes and two-thirds being male. The median BMI was 28 kg/m². The predominant cause of chronic kidney disease (CKD) was cardiorenal syndrome type 2, affecting 44% (66 out of 150 patients). At the start of the follow-up, the distribution of CKD stages was as follows: 52 patients (34.7%) had CKD stage 2, 30 (20%) had CKD stage 3a, 21 (14%) had CKD stage 3b, 11 (7.3%) had CKD stage 4, and 1 (0.6%) had CKD stage 5. Notably, 81 patients (54%) had moderate or severe albuminuria. Ischemic cardiomyopathy was the leading cause of heart failure, affecting 36.4% (47 patients). Among the heart failure classifications, 73 patients (48.7%) had HFrEF, 32 (21.3%) had HFmrEF, and 45 (30%) had HFpEF. A total of 54 patients (36%) were treated with SGLT2 inhibitors, while 116 (77.3%) received RAAS inhibitors, including 32 patients (21.3%) on an ARNI. Those using both RAAS inhibitors and SGLT2 inhibitors were younger (average age 66 vs. 73 years, p = 0.005) and had a higher prevalence of diabetes (44% vs. 30%) and HFrEF compared to HFpEF (70% vs. 7%, p = 0.002). The hospitalization rate was notably high at 2.2 admissions per patient per year, with an incidence of acute kidney injury (AKI) at 0.23 events per patient per year. Conclusions: We identified a high-risk patient population with cardiorenal disease that might particularly benefit from evidence-based and patient-centered interdisciplinary care. Full article

Background: Despite advancements in pharmacological therapy, lung transplantation (LuTX) remains the only life-prolonging treatment in end-stage idiopathic pulmonary fibrosis (IPF). However, real-world referral patterns in Central and Eastern European (CEE) countries remain poorly characterized. We aimed to comprehensively review factors influencing referral and identify systemic barriers to LuTX access. Methods: Baseline characteristics of IPF patients potentially eligible for LuTX, enrolled in the European MultiPartner IPF Registry between 2012 and 2022 (n = 1256), were retrospectively analyzed. LuTX (n = 94) and potentially eligible but not transplanted (n = 1162) subgroups were compared. National experts also completed a questionnaire assessing transplant referral and listing practices across different healthcare systems. Results: Only 7.5% of potentially eligible subjects were transplanted, revealing substantial geographic disparities, with Israel having the highest rates (43.1%), followed by Austria (9.5%), Hungary (7.8%), and the Czech Republic (4.6%). LuTX patients were younger (60.2 ± 7.4 vs. 62.6 ± 6.2 years, p < 0.001), had worse lung function (FVC 60 ± 15 vs. 74 ± 21% predicted; p < 0.001, TLCO 41 ± 15 vs. 49 ± 19% predicted; p < 0.001), and were more likely to receive antifibrotic and oxygen therapies. The most frequent reasons for exclusion from referral/listing were age > 70 years and concomitant heart/renal failure. Conclusions: This first comprehensive CEE analysis demonstrates low IPF transplant rates with high inter-country variability. Patients presenting early with functionally advanced disease are more likely transplanted, while advanced age remains the primary exclusion factor, highlighting critical access gaps potentially contributing to regional outcome differences. Full article