End-stage Heart Failure Patients Research Articles

Higher myocardial mitochondrial ketone body oxidation capacity in human heart failure

Abstract Introduction/Purpose Recent studies suggest that the ketone bodies (KB) beta-hydroxybutyrate (HBA) and acetoacetate (ACA) are relevant substrates for myocardial energy metabolism in heart failure (HF). However, the amount of KB-dependent mitochondrial respiration in HF has not yet been quantified. High-resolution respirometry (HRR) is the gold-standard method for quantifying substrate-dependent mitochondrial oxidative capacity. Therefore, we aimed to evaluate the association between myocardial KB-dependent oxidative capacity and human HF using HRR. Methods The primary endpoint of this single-center prospective cohort study was KB-dependent and overall mitochondrial oxidative capacity in permeabilized myocardium. We used two different protocols for our measurements. In the first HRR protocol, conventional respirometry substrates including fatty acids, complex I- and complex II substrates were used to quantify the maximum coupled oxidative phosphorylation capacity (OXPHOS). Leak respiration was quantified using oligomycin to calculate the respiratory control ratio (RCR, state 3/state 4o), and leak control ratio (LCR, state 4o/state u). In the second protocol which was recently established by our working group, HBA and ACA were used as respirometry substrates to quantify KB-dependent respiration down to the enzyme level. The relative contribution of the KBs was obtained by comparing HBA- and ACA-derived respiration to OXPHOS. We applied both protocols to myocardial samples from individuals with advanced HF (HF group, catheter-acquired endomyocardial biopsies from non-ischemic HF patients or samples of explanted hearts collected during orthotopic heart transplantation surgery in end-stage heart failure patients) as well as previously heart transplanted individuals without current heart failure (Control group). Results Controls and HF had similar demographic characteristics, with comparable age distribution (mean±SD, 56.3±10.3 vs. 54.2±10.7 years, p=0.36), sex (68.75% vs. 66.67% male, p=0.87), or body mass index (25.0±5.8 vs. 29.0±10.6 kg/m2, p=0.08) and differed significantly in cardiac index (3.06±0.67 vs. 1.93±0.44) and ejection fraction (55.8±10.2 vs. 26.6±9.1) (both p<0.0001). The HF group exhibited lower OXPHOS and respiration for all substrate combinations tested (Fig. 1A). In contrast, KB-dependent respiration did not differ between HF and controls (Fig. 1B). The relative HBA-dependent respiration (Fig. 1C) and the relative and absolute ACA-dependent respiration (Fig. 1C and D) were higher in the HF group compared to controls. Mitochondrial uncoupling (LCR) (0.47±0.29 vs. 0.44±0.09 [AU], p=0.79) and coupling efficiency (RCR) (2.75±1.38 vs. 2.11±0.39 [AU], p=0.15) were not different between the groups. Conclusion These findings suggest that mitochondria in the failing heart can utilize KBs for OXPHOS to a greater extent and further hint towards KB metabolism as a potential therapeutic target for HF.

Effects of atrial fibrillation ablation on arrhythmia burden and ventricular function in end-stage heart failure: Lessons from CASTLE-HTx.

The CASTLE-HTx trial showed the benefit of atrial fibrillation (AF) ablation compared to medical therapy in decreasing mortality, need for left ventricular assist device implantation or heart transplantation (HTx) in patients with end-stage heart failure (HF). Herein we describe the effects of catheter ablation on AF burden, arrhythmia recurrences, and ventricular function in end-stage HF. The CASTLE-HTx protocol randomized 194 patients in end-stage HF with AF to catheter ablation and medical therapy or medical therapy alone. AF burden, left ventricular ejection fraction (LVEF), and type of AF were assessed at baseline and at each follow-up visit. Overall, 97 patients received ablation; 66 patients (68%) underwent pulmonary vein isolation (PVI) and 31 patients (32%) were treated with PVI and additional ablation. Electroanatomic mapping showed the extent of left atrial low voltage (cardiomyopathy) >10% in 31 (31.9%) patients. At 12 months post-ablation, persistent AF was present in 31/89 patients (34.8%), which was significantly less frequent compared to baseline (p = 0.0001). Median AF burden reduction was 36.3 (interquartile range 13.6-63.3) percentage points at 12 months and LVEF improved from 29.2 ± 6.2% to 39.1 ± 8.3% (p < 0.001) following ablation. AF burden reduction <50% was significantly associated with LVEF improvement ≥5% at 12 months after ablation (p = 0.017). Atrial fibrillation ablation in end-stage HF leads to a substantial decrease in AF burden, a regression from persistent to paroxysmal AF and notably improved LVEF. Favourable ablation outcomes were observed in patients regardless of the presence or absence of signs indicating left atrial cardiomyopathy.

End-stage heart failure patients in ICU: the importance of advance planning and effective communication.

During the disease trajectory, patients with advanced heart failure are often hospitalised with a high probability of admission to the intensive care setting. Using a case study, this article explores the care given to a patient with decompensated heart failure in an intensive care unit (ICU). It will discuss the significance of holistic assessment and effective symptom management, in particular the research related to breathlessness management. The importance of effective communication within the ICU multidisciplinary team, including with the patient/family will be explored, as the ICU environment can often lead to communication breakdown, patients being unable to voice their wishes and over-medicalisation. The effectiveness of early involvement of the palliative care team in ICU will be examined, including the use of tools such advance care planning and a treatment escalation plan and whether use of these can enable a better patient and family experience at the end of life. The role of palliative care champions will be discussed.

Potential of plasma biomarkers for heart failure prediction, management, and prognosis: A multiomics perspective.

Heart failure (HF) remains a major global health challenge, and more effective and comprehensive plasma biomarkers are needed to effectively treat HF patients. Multiomics studies have shown that DNA fragments, noncoding RNAs, proteins, and metabolites may be potential plasma biomarkers for HF. However, comprehensive reviews that focus on research on plasma biomarkers for HF from an omics perspective are lacking. This review summarizes the applications of various omics approaches in the exploration of biomarkers related to the risk assessment, diagnosis, subtype classification, medical management, and prognosis prediction of HF. Moreover, as heart transplantation and left ventricular assistant device (LVAD) implantation are terminal therapies for end-stage HF patients, this review also discusses the role of cell-free DNA as a biomarker for cardiac transplant rejection and omics studies of plasma biomarkers in patients who respond to LVAD therapy. Our findings suggest that future omics research on HF biomarkers should employ integrated multiomics methods and expand the sample size to increase the robustness of the results and that the identified biomarkers should be further validated in large cohorts.

Safety and efficacy of oxycodone for refractory dyspnea in end-stage heart failure patients with chronic kidney disease: a case series of eight patients

BackgroundMorphine is effective in palliative care for patients with end-stage heart failure; however, its use is avoided in patients with impaired renal function because it tends to induce adverse effects. Although oxycodone has been reported to be a useful alternative, the evidence is insufficient. Therefore, we investigated the safety and efficacy of oxycodone in eight patients with end-stage heart failure complicated by chronic kidney disease. MethodsThis single-center retrospective study reviewed patients with end-stage heart failure who were referred to the heart failure multidisciplinary team at our institution and administered oxycodone for refractory dyspnea during hospitalization between January 2011 and December 2018. We examined the details of oxycodone usage, vital signs, and the Modified Borg Scale (MBS), which quantifies the symptoms of dyspnea and adverse events.ResultsOxycodone was administered for refractory dyspnea in eight patients with end-stage heart failure [mean age: 81 years, men: 4, New York Heart Association functional class IV: 8, median left ventricular ejection fraction: < 40% (n = 6) and ≥ 50% (n = 2)]. Renal function was reduced in all patients; the estimated glomerular filtration rate (eGFR) in seven patients was < 30 mL/min/1.73 m2. The median initial intravenous dose of oxycodone was 7.05 mg/day (range: 5–10 mg/day), and the average duration of administration was 15.8 days. Significant decreases in MBS (before: median 9, range 7–10 vs. after: median 2.5, range 1–8; p < 0.01) were observed at a median of 2.0 days (range: 2 h to 7 days) after beginning oxycodone administration. Systolic blood pressure, heart rate, and respiratory rate were not significantly altered after treatment. Adverse events, including constipation, nausea, and tremors, were observed in three patients. However, no lethal adverse events related to oxycodone treatment occurred during treatment.ConclusionsThis study revealed the clinical practice of oxycodone treatment and suggested that it is an alternative therapy as a viable palliative for refractory dyspnea in patients with end-stage heart failure who should avoid the use of morphine.

Genetic Testing Practices and Pathological Assessments in End Stage Heart Failure Patients Undergoing Heart Transplantation and Left Ventricular Assist Device

BackgroundGenetic cardiomyopathies (CM) are increasingly recognized as causes of end-stage heart failure (ESHF). Identification of a genetic etiology in ESHF has important prognostic and family implications. However, genetic testing practices are understudied in ESHF patients. MethodsThis single-center, retrospective study included consecutive ESHF patients who underwent heart transplantation (HT) or left ventricular assist device (LVAD) from 2018 to 2023. Data, including genetic testing and pathology reports, were collected from the electronic medical record. Analyses of demographic and clinical characteristics were stratified by genetic testing completion and presence of clinically actionable variant. Logistic regression was performed to evaluate for associations between histology findings and genetic variants. ResultsA total of 529 adult patients (mean age 57 years) were included in the study and were predominantly male (79%, 422/529) and non-white (61%, 322/529). Genetic testing was performed in 54% (196/360) of patients with either non-ischemic or mixed CM. A clinically actionable result was identified in 36% (70/196) of patients, of which, only 43% (30/70) had a genetic counselor referral. The most common genetic variants were TTN (32%, 24/75), MYBPC3 (13%, 10/75), and TTR (11%, 8/75). Clinically actionable variants were identified in patients with known heart failure precipitators, such as alcohol use. In multivariable analysis, presence of interstitial fibrosis, specifically diffuse, on pathology was significantly associated with a clinically actionable variant (aOR 2.29, 95% CI [1.08-4.86], p = 0.03). ConclusionESHF patients with non-ischemic or mixed CM undergoing advanced therapies had a low uptake of genetic services, including testing and counselors, despite a high burden of genetic disease. Pathology findings, such as interstitial fibrosis, may provide insight into genetic etiology. The underutilization of services suggests a need for implementation strategies to improve uptake.

Fibrin clot permeability (Ks) in patients on left ventricular assist device

Patients on left ventricular assist devices (LVAD) are prone to excessive hemostasis disturbances due to permanent contact of artificial pump surfaces with blood components. We aimed to investigate if fibrin clot permeability is altered in patients on long-term continuous-flow LVAD therapy and if the clot permeability is associated with clinical characteristics and adverse events. We investigated 85 end-stage heart failure patients (90.6% men, age 48.6–63.8 years) scheduled for continuous flow long-term LVAD support according to current clinical indications. The patients were assessed periodically: prior to LVAD implantation (T1), 3–6 months (T2) after LVAD implantation, 6–12 months after (T3) and then every 6 months. We tested the first three blood samples (T1-T3) and the last available blood sample (T4), but no longer than 5 years after LVAD implantation. We assessed hemostasis parameters (Activated Partial Thromboplastin Time (APTT) Prothrombin Time, Activated Partial Thromboplastin Time, Fibrinogen, d-dimer, Antithrombin, Thrombin Time, Factor VIII, and von Willebrand Factor, aspirin-induced platelet inhibition, adenosine-diphosphate test) changes during the study period. Fibrin Clot Permeability was evaluated using a pressure system and Permeability Coefficient (Ks) was calculated. We observed a decrease in fibrin clot permeability (Ks) between T1, T2, T3 and T4 time periods; P < 0.01 for each comparison. Fibrin clot permeability was negatively correlated with fibrinogen concentration: r = − 0.51, P < 0.001, factor VIII activity r = − 0.42, P < 0.001. There was no association of Ks with age, Left Ventricular Ejection Fraction (LVEF) and medications P > 0.001, however cumulative measurements in patients on aspirin showed shortening of Ks in this group P = 0.0123. Major adverse cardiac and cerebrovascular events (MACCE) occurred in 36.5% patients, bleeding events in 25.9%, Net Adverse Clinical Events (NACE) in 62.4%; 31.7% patients died, and 17.6% underwent transplantation. The transplantation was considered as the endpoint. Discrepancies in Ks were observed between patients with MACCE, bleeding, and NACE, and patients without adverse events. Ks showed a constant trend towards normalization (P < 0.01) only in patients without adverse events. Patients with advanced heart failure have disturbed clot structure. A trend towards normalization of the Ks values is associated with fewer thromboembolic and bleeding complications in this group of patients.

Non-alcoholic fatty liver disease and heart failure: A comprehensive bioinformatics and Mendelian randomization analysis.

Heart failure (HF) and non-alcoholic fatty liver disease (NAFLD) are significant global health issues with a complex interrelationship. This study investigates their shared biomarkers and causal relationships using bioinformatics and Mendelian randomization (MR) approaches. We analysed NAFLD and HF datasets from the Gene Expression Omnibus (GEO). The GSE126848 dataset included 57 liver biopsy samples [14 healthy individuals, 12 obese subjects, 15 NAFL patients and 16 non-alcoholic steatohepatitis (NASH) patients]. The GSE24807 dataset comprised 12 NASH samples and 5 healthy controls. The GSE57338 dataset included 313 cardiac muscle samples [177 HF patients (95 ischaemic heart disease patients and 82 idiopathic dilated cardiomyopathy patients) and 136 healthy controls]. The GSE84796 dataset consisted of 10 end-stage HF patients and 7 healthy hearts procured from organ donors. We identified differentially expressed genes (DEGs) and constructed a protein-protein interaction (PPI) network. Functional pathways were elucidated through enrichment analyses using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and GeneMANIA annotation. Single nucleotide polymorphism (SNP) data for HF and NAFLD were sourced from genome-wide association studies (GWAS). The HF dataset included 486160 samples (14262 experimental and 471898 control), and the NAFLD dataset comprised 377988 samples (4761 experimental and 373227 control). MR analysis investigates the causal interrelations. Our analysis revealed 4032 DEGs from GSE126848 and 286 DEGs from GSE57338. The top 10 hub genes (CD163, VSIG4, CXCL10, FCER1G, FPR1, C1QB, CCR1, C1orf162, MRC1 and CD38) were significantly enriched in immune response, calcium ion concentration regulation and positive regulation of monocyte chemotaxis. CIBERSORT analysis indicated associations between these hub genes and natural killer (NK) cells and macrophages. Transcription factor (TF) target prediction for CD38, CXCL10 and CCR1 highlighted related TFs. A two-sample MR analysis confirmed a bidirectional causal relationship between NAFLD and HF. The main method [inverse variance weighted (IVW)] demonstrated a significant positive causal relationship between NAFLD and HF [P=0.037; odds ratio (OR)=1.024; 95% confidence interval (CI): 1.001 to 1.048]. Similarly, HF was associated with an increase in the risk of NAFLD (P<0.001; OR=1.117; 95% CI: 1.053 to 1.185). Our findings reveal novel molecular signatures common to NAFLD and HF and confirm their bidirectional causality, highlighting the potential for targeted therapeutic interventions and prompting further investigation into their intricate relationship.

Evaluation of thrombosis and bleeding events in the children with left ventricular assist device (L-VAD)

This study aimed to evaluate thrombosis and bleeding events in the children implanted with two types of ventricular assist devices (VAD). A total of 26 paediatric end-stage heart failure patients with the mean age of 11.32 ± 4.17 years, 15 were boys, implanted with a VAD, either the Berlin Heart EXCOR (BHE group; n = 9) or the HeartWare (HW group, n = 17), were included in this retrospective study. Follow up data on bleeding events, thrombosis events, bridge-to-transplantation rates and survival outcome were recorded. Overall, 16(33.3%) bleeding events and 32(66.7%) thrombosis events occurred, while 14(53.8%) patients had at least one thrombotic event and 8(30.8%) patients had at least one bleeding event. BHE and HW groups were similar in terms of number of patients with at least one thrombotic (33.3% vs. 64.7%, p = .218) or bleeding (22.2% vs.35.3%, p = .399) event. Mortality occurred in 9(34.6%) patients and 13(50.0%) patients achieved bridge-to-transplantation, similarly in BHE and HW groups (mortality: 44.4% vs. 29.4%, p = .667 and transplantation: 77.8% vs. 35.3%, p = .097). In conclusion, our findings revealed that VAD application in children with heart failure enables successful heart transplantation achievement with an acceptable risk of bleeding/thromboembolic events in most of cases. More advanced VAD technologies and more successful management for haematologic complications are necessary to improve the transplantation rates in children.

Undetected Neuromuscular Disease in Patients after Heart Transplantation.

(1) Heart transplantation (HTX) improves the overall survival and functional status of end-stage heart failure patients with cardiomyopathies (CMPs). The majority of CMPs have genetic causes, and the overlap between CMPs and inherited myopathies is well documented. However, the long-term outcome in skeletal muscle function and possibility of an undiagnosed underlying genetic cause of both a cardiac and skeletal pathology remain unknown. (2) Thirty-nine patients were assessed using open and standardized interviews on muscle function, a quality-of-life (EuroQol EQ-5D-3L) questionnaire, and a physical examination (Medical Research Council Muscle scale). Whole-exome sequencing was completed in three stages for those with skeletal muscle weakness. (3) Seven patients (17.9%) reported new-onset muscle weakness and motor limitations. Objective muscle weakness in the upper and lower extremities was seen in four patients. In three of them, exome sequencing revealed pathogenic/likely pathogenic variants in the genes encoding nexilin, myosin heavy chain, titin, and SPG7. (4) Our findings support a positive long-term outcome of skeletal muscle function in HTX patients. However, 10% of patients showed clinical signs of myopathy due to a possible genetic cause. The integration of genetic testing and standardized neurological assessment of motor function during the peri-HTX period should be considered.

The Impact of Ipsilateral Implantable Cardioverter Defibrillator in Axillary Intra-Aortic Balloon Pump Support as Bridge to Heart Transplantation.

The axillary artery (AX) access for intra-aortic balloon pump (IABP) as a bridge to heart transplant (HT) allows mobility while awaiting a suitable donor. As end-stage heart failure patients often have an implantable cardioverter defibrillator (ICD) on the left side, the left AX approach may be avoided due to the perception of difficult access and proximity of two devices. We aimed to evaluate the outcomes of patients bridged to HT with a left-sided AX IABP with or without ipsilateral ICDs. We retrospectively reviewed HT candidates at our institution supported by left-sided axillary IABP from November 2019 to February 2024, dividing them into two groups based on the presence (Group ICD, n = 48) or absence (Group No-ICD, N = 19) of an ipsilateral left-sided ICD. The exposure time was defined as the time from skin incision to the beginning of anastomoses of a Dacron graft. Technical success was achieved in 100% of the cohort, with median exposure times for AX access similar between groups (ICD, 12 [7.8, 18.2] vs. No ICD, 11 [7, 19] min; p = 0.75). The rate of procedural adverse events, such as significant access site bleeding and ipsilateral limb ischemia, did not significantly differ between both groups. Device malfunction rates were comparable (ICD, 29.2%vs. No ICD, 15.8%; p = 0.35). Posttransplant, in-hospital mortality, severe primary graft dysfunction, and stroke rates were comparable in both groups. The presence of an ipsilateral left-sided ICD does not adversely impact the procedural efficacy, complication rates, or posttransplant outcomes of left-sided AX IABP insertion in HT candidates.

18F-FDG PET/CT for the diagnosis and evaluation of antibiotic response in patients with left ventricular assistive device infection: A case report

The left ventricular assistive device (LVAD) is critical for end-stage heart failure patients. Centrifugal flow LVAD recipients have a 4-year survival rate of nearly 60%, with infection occurring in over 50% of patients within 2 years. Herein, we report a case of LVAD infection in a 60-year-old man. The patient presented with fever after 49 days following LVAD implantation. Culture of both blood and areas around the outflow cannula indicated an infection with Enterobacter cloacae and Staphylococcus aureus. After sequential treatment with meropenem and daptomycin, as well as abdominal incisional debridement, the patient&amp;rsquo;s symptoms of fever disappeared, but the inflammatory markers, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level, remained abnormal. Five 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scans were performed to evaluate the infection. PET/CT revealed infected lesions around the lower segment of the outflow cannula with high FDG uptake. After continuous oral antibiotic treatment for more than 1 year, the infected areas with high FDG uptake around the outflow cannula gradually declined and eventually disappeared, consistent with the noted changes in both ESR and CRP levels in the serum. Multiple continuous 18F-FDG PET/CT scans can distinguish high FDG uptake areas of infection from sterile inflammatory areas, assisting in the accurate diagnosis of infection and evaluation of antibiotic treatment after LVAD implantation.

Unmet need for heart transplantation in Africa.

Heart transplantation is a critical treatment option for end-stage heart failure patients, offering a lifeline for those with severe cardiac conditions. However, in Africa, the unmet need for heart transplantation is a significant issue that poses challenges to the healthcare system and patient outcomes. Africa faces multiple barriers to heart transplantation, including limited infrastructure, a shortage of skilled healthcare professionals, a lack of funding, and inadequate organ donation systems. These challenges result in a considerable gap between the demand for heart transplants and the available resources to meet this need. As a result, many patients in Africa do not have access to life-saving heart transplantation procedures, leading to high mortality rates among those awaiting transplants. Addressing the unmet need for heart transplantation in Africa requires a multifaceted approach. The authors recommend that Africa as a continent build up a heart transplantation workforce involving a multidisciplinary team that consists of transplant surgeons, transplant physicians, nurses, anesthetists, pharmacists, etc. Heart transplant education and training programs should be well-constructed to ensure the delivery of safe and effective transplantation services. International collaborations have proven to be effective and should be encouraged between African institutions and transplant centers worldwide to facilitate knowledge transfer. Foreign and local organizations should promote public awareness about organ donation to address the myths about heart transplantation and promote heart donation. With these, African countries can improve access to heart transplantation, enhance patient outcomes, save lives in the region, and ultimately reduce the mortality rate in Africa.

Prognosis Communication in Heart Failure: Experiences and Preferences of End-Stage Heart Failure Patients and Care Partners.

Patients with heart failure (HF) overestimate survival compared with model-predicted estimates, but the reasons for this discrepancy are poorly understood. We characterized how patients with end-stage HF and their care partners understand prognosis and elicited their preferences around prognosis communication. We conducted in-depth, semistructured interviews with patients with end-stage HF and their care partners between 2021 and 2022 at a tertiary care center in Michigan. Participants were asked to describe barriers they faced to understanding prognosis. All interviews were coded and analyzed using an iterative content analysis approach. Fifteen patients with end-stage HF and 15 care partners participated, including 7 dyads. The median patient age was 66.5 years (range, 31-80) and included 9 of 15 (60%) White participants and 9 of 15 (60%) were males. Care partners included 10 of 15 (67%) White participants and 6 of 15 (40%) were males. Care partners were partners (n=7, 47%), siblings (n=4, 27%), parents (n=2, 13%), and children (n=2, 13%). Most patients demonstrated a poor understanding of their prognosis. In contrast, care partners commonly identified the patient's rapidly declining trajectory. Patients and care partners described ineffective prognosis communication with clinicians, common barriers to understanding prognosis, and similar suggestions on improving prognosis communication. Barriers to understanding prognosis included (1) conversation avoidance by physicians, (2) information inconsistency across different physicians, (3) distractions during prognosis communication due to emphasis on other conditions, and (4) confusion related to the use of medical jargon. Most patients and care partners wanted discussions around prognosis to begin early in the course of the disease, repeated routinely using layperson's terms, incorporating both quality of life and survival assessments, and involving care partners. Both patients and care partners did not expect precise survival estimates. Patients with end-stage HF demonstrate a poor understanding of their prognosis compared with their care partners. Patients and care partners are open to discussing prognosis early, using direct and patient-centered language.

Modeling doxorubicin-induced cardiotoxicity with human myocardial tissue slices: insights on genetic susceptibility and cardioprotection

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): PSIDER and HARVEY (ZonMW) Introduction Cardiotoxicity poses a significant challenge in drug development, often leading to the 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 imperative for animal-free preclinical testing, this study aimed to develop a novel model using human myocardial tissue slices to get a deeper understanding and potential prevention of doxorubicin-Induced cardiotoxicity. Methods Human myocardial tissue slices of 300 μm thick were derived from end-stage heart failure patients explanted hearts, including those harbouring likely or pathogenic cardiovascular mutations (class 4 and 5) (N=3) and non-genetic cardiovascular etiology (N=3). Myocardial tissue slices were cultured under physiological mechanical and electrical conditions. Slices were exposed to doxorubicin (1 µM) over a 10-day culture period, and their responses were compared to DMSO-vehicle controls, by recording contractile force and Ca2+ transients. Additionally, a subset of slices was treated with a cardioprotective agent, dexrazoxane (100 µM), 1 day prior to and during doxorubicin exposure to assess potential cardioprotection. Results Doxorubicin-exposed slices with a pathogenic mutation exhibited reduced mechanical force, increased threshold potential, and impaired ability to follow pacing at higher frequencies. Additionally, aberrations in calcium handling, manifested as arrhythmia-like disconnection of muscle fibers, were notably observed in these slices. Instead, slices from patients without pathogenic mutations showed minimal cardiotoxicity when exposed to doxorubicin. Encouragingly, pretreatment with dexrazoxane demonstrated a protective effect against doxorubicin-induced cardiotoxicity in the genetically susceptible group. Our functional findings corroborated our structural data, highlighting the breakdown of sarcomere structure and cell-cell connections and increased DNA damage, particularly in patients harbouring a genetic cardiovascular mutation. Conclusion In summary, human myocardial tissue slices faithfully recapitulate doxorubicin-induced cardiotoxicity. Importantly, our data suggests the utility of employing genetic testing for known cardiovascular mutations as a valuable step before initiating doxorubicin treatment. Additionally, we demonstrate for the first time the in vitro cardioprotective potential of dexrazoxane in a human tissue model. These findings pave the way for using ex vivo myocardial tissue slices to evaluate cardiotoxicity and their value as a powerful tool for evaluating the efficacy and delivery approaches.

Validation of the Castle HTx data in a real world scenario

Abstract Background Pulmonary vein isolation (PVI) is recommended in patients with symptomatic atrial fibrillation (AF) and reduced left ventricular ejection fraction (LVEF). Recently the Castle HTx (CHTx) trial showed a significant mortality reduction in end stage heart failure patients undergoing PVI in addition to optimized medical therapy (OMT) compared to OMT only. Aim Objective of this analysis is to validate results of Castle HTx study in a real world scenario. Methods All patients between September 2021 und September 2023 referred for PVI at our center with symptomatic AF und LVEF ≤35% were included in this retrospective analysis at the University Hospital Cologne. Results A total of 119 PVI in patients with LVEF≤35% were successfully performed (mean age 63.3±10.1 years, 96 patients (81%) male, 43 (36%) paroxysmal AF, 76 (64%) persistent AF) matching inclusion criteria used in CHTx. Cryo-PVI was used in 50 (42%), RF-PVI in 60 (50%) and PFA in 9 (8%) patients. Complete follow-up (FU) with a mean of 549.6±430.2 days was obtained in 108 patients, comparable to CHtx (540 days). During FU 11 patients (10%) died from any cause (CHTx 8 patients (8%)), 2 patients (2%) received a left ventricular assist device (CHTx 1 patient (1%)) and no patient had urgent heart transplantation (CHTx 1 patient (1%)). For 30 patients (28%) recurrence of AF was detected and 72% remained in sinus rhythm. In 6 patients (5%) post-procedural complications occurred: 5 inguinal hematoma, 1 decompensation. During FU LVEF was statistically significantly improved (EF initial 26.9±6.5%, EF FU (n=80) 37.1±12.8%, p&amp;lt;0.001) (CHTx EF initial 29.0±6.4%, EF FU (n=92) 37.2±9.1%). Conclusion The findings of the Castle HTx patients have been validated in a real-world setting. PVI for rhythm control in end stage heart failure patients is safe and highly effective. Our patient cohort, matched to the Castle HTx ablation group, showed freedom from AF rate of 72% after mean FU time of 550 days. Furthermore, LVEF was improved significantly in our cohort echoing the results from CHTx.

Characterization of ventricular tachycardia ablation in end-stage heart failure patients with left ventricular assist device (CHANNELED-Registry)

Abstract Background Left-ventricular-assist-devices (LVAD) are an established therapy for patients with end-stage heart failure. These patients are at high risk for ventricular tachycardia (VT) and ICD-shocks due to the arrhythmogenic substrate of the underlying cardiomyopathy itself and as the LVAD cannula might be arrhythmogenic, too. Purpose Data on catheter ablation of VT in LVAD patients are scarce and current evidence predominantly consists of case reports and small single-center series. This multicenter registry seeks to systematically assess the mechanism and origin of VA in LVAD patients and to evaluate procedural parameters and outcome of VT ablation in this special subset of patients. Methods Retrospective data of LVAD patients referred for VT ablation at 11 tertiary care centers between January 2017 and August 2023 were included in this multicenter registry. VT mechanisms, procedural data, clinical follow-up, and outcome were assessed. Results We report 49 patients (88% male, age 61±8 years) undergoing 51 ablation procedures included in this ongoing registry. The underlying cardiomyopathy was ischemic in 25/49 patients (51%) and nonischemic in 24/49 patients (49%) with a mean left ventricular ejection fraction of 21%±6% before LVAD implantation. Most catheter ablations were conducted after prior antiarrhythmic drug (AAD) treatment (15/51 on amiodarone, 13/51 on prior intensification of amiodarone treatment, 18/51 on prior combination of two or more AADs). A total of 75 VTs were targeted (39/51 transseptal, 3/51 retrograde aortic, 9/51 combined approaches) and 13/49 patients required VT ablation less than 1 month after LVAD implantation. Of the targeted VTs the majority (69%) were cardiomyopathy related and only 31% of the targeted VTs were related to the LVAD cannula. In 5/51 procedures access site complications and in 1/51 procedures a pericardial effusion occurred; one patient showed a post procedural oxygen desaturation; despite immediate intubation the patient deceased from hypoxic brain injury. No LVAD related complications were observed. A follow-up was available for 35/49 patients. During a median follow-up of 277 days (IQR 78-625 days), 5/35 patients were transplanted and 13/35 died. Patients died after a median time of 124 days (IQR 34-952 days) primarily from heart failure, sepsis, or intracranial bleeding. Of the remaining 17/35 patients, 7/17 patients were arrhythmia-free at a median follow-up of 212 days (IQR 78-639 days). Conclusion Although often chosen as last resort, catheter ablation of VT in LVAD patients is feasible and can be performed safely in this critically ill subset of heart failure patients in experienced centers. Intrinsic myocardial scar seems to be the dominant substrate in these patients but LVAD cannulae contribute to a significant number of VTs. In the presence of severely reduced LV function the VT recurrence remains high despite maximal therapy and prognosis of these patients is limited.

Performance of risk scores in predicting major bleeding in left ventricular assist device recipients: a comparative external validation

BackgroundImplantation of a left ventricular assist device (LVAD) is a crucial therapeutic option for selected end-stage heart failure patients. However, major bleeding (MB) complications postimplantation are a significant concern. ObjectivesWe evaluated current risk scores’ predictive accuracy for MB in LVAD recipients. MethodsWe conducted an observational, single-center study of LVAD recipients (HeartWare or HeartMate-3, November 2010-December 2022) in the Netherlands. The primary outcome was the first post-LVAD MB (according to the International Society on Thrombosis and Haemostasis [ISTH] and Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS], and INTERMACS combined with intracranial bleeding [INTERMACS+] criteria). Mortality prior to MB was considered a competing event. Discrimination (C-statistic) and calibration were evaluated for the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly score, Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke score, Anticoagulation and Risk Factors in Atrial Fibrillation score, Outpatient Bleeding Risk Index, venous thromboembolism score, atrial fibrillation score, and Utah Bleeding Risk Score (UBRS). ResultsOne hundred four patients were included (median age, 64 years; female, 20.2%; HeartWare, 90.4%; HeartMate-3, 9.6%). The cumulative MB incidence was 75.7% (95% CI 65.5%-85.9%) by ISTH and INTERMACS+ criteria and 67.0% (95% CI 56.0%-78.0%) per INTERMACS criteria over a median event-free follow-up time of 1916 days (range, 59-4521). All scores had poor discriminative ability on their intended prediction timeframe. Cumulative area under the receiving operator characteristic curve ranged from 0.49 (95% CI 0.35-0.63, venous thromboembolism-BLEED) to 0.56 (95% CI 0.47-0.65, UBRS) according to ISTH and INTERMACS+ criteria and from 0.48 (95% CI 0.40-0.56, Anticoagulation and Risk Factors in Atrial Fibrillation) to 0.56 (95% CI 0.47-0.65, UBRS) per INTERMACS criteria. All models showed poor calibration, largely underestimating MB risk. ConclusionCurrent bleeding risk scores exhibit inadequate predictive accuracy for LVAD recipients. There is a need for an accurate risk score to identify LVAD patients at high risk of MB who may benefit from patient-tailored antithrombotic therapy.

Post–COVID-19 Era In Heart Transplantation and Its Impact on the Early Postoperative Period After Surgery

End-stage heart failure patients were at increased risk for acquiring COVID-19 infection and progression to severe disease, given multiple health care contacts and underlying health conditions. Understanding the outcomes of such patients will help risk-stratify and guide optimization before heart transplant surgery. The aim of this study was to evaluate the impact of the COVID-19 pandemic on heart transplantation activity and outcomes in the early postoperative period. Retrospective data analysis of patients undergoing orthotopic heart transplantation in our institution from March 2020 to July 2023. The patient population (N = 208) included 176 (84.6%) men and 32 (15.4%) women. The perioperative data of the pandemic group, March 2020 to February 2022 (N = 151), and the post-pandemic group, March 2022 to July 2023 (N = 57), were compared. The number of patients requiring inotropic support increased during the post-COVID-19 era (N = 48 [84.2%], vs N = 72 [47.7%], P < .001). There were no differences in renal complications. Duration of mechanical ventilation was longer in the post-pandemic group (19 hours [14-24] vs 14 hours [9-28], P < .05). The extended duration of mechanical ventilation in the post-pandemic group may be related to the patient's preoperative condition. The number of heart transplant recipients with end-stage heart failure requiring inotropic support increased in the post-COVID-19 era. Although some efforts have been made to reduce the impact of the pandemic, more research is required.

Long-term outcomes of a novel fully magnetically levitated ventricular assist device for the treatment of advanced heart failure in China

PurposeLeft ventricular assist devices (LVADs) are well-established for treating end-stage heart failure, but this therapy is only available to Chinese patients in recent years. The CH-VAD is the first used fully magnetically levitated pump and the most widely used device in China. This study reports the long-term outcomes of a cohort supported by the CH-VAD for the first time. MethodsFrom June 2017 to August 2023, 50 consecutive patients received CH-VAD implantation in Fuwai Hospital. Clinical data were collected during follow-up and retrospectively analyzed. ResultsBaseline characteristics included a mean age of 47.9±13.9 years, 90% male, and 26% ischemic etiology. The INTERMACS profile revealed 12% Profile 1, 56% Profile 2, 26% Profile 3 and 6% Profile 4. Mean support duration was 868 ± 630 days (range 33 days-6.4 years). Kaplan-Meier survival rate was 96% (95% confidence interval [CI], 85 to 99) at 6 months, 93% (95% CI, 79-98) at 1 year, 93% (95% CI, 79-98) at 2 years and 89% (95% CI, 71-96) at 3 years. 40 patients (80%) currently remain on support, 3 were bridged to recovery, 2 received transplant, and 5 expired during support. Major adverse events included right heart failure (10%), surgical related bleeding (8%), arrhythmia (8%) and driveline infection (16%). Major hemocompatibility-related adverse events were limited to 3 non-disabling strokes and 1 gastrointestinal bleeding. There was no major device malfunction during the follow-up period. ConclusionsThe largest single-center experience with the leading LVAD in China shows high survival with low complication rates, demonstrating the CH-VAD is safe and efficient in providing long-term support for end-stage heart failure patients.