Outcomes in patients with cardiac amyloidosis undergoing heart transplantation: the eurotransplant experience.

BACKGROUND: When advanced heart failure occurs in cardiac amyloidosis, prognosis is poor. In this setting heart transplantation (HTX) is a treatment option for selected patients. We here present the results of post-transplantation outcomes in cardiac amyloidosis within the Eurotransplant area, investigating possible predictors of survival. METHODS: Of 115 patients undergoing HTX due to cardiac amyloidosis in the Eurotransplant region between November 1987 and May 2020, detailed assessment prior to transplantation was available in 85 patients. The present study was conducted in a retrospective approach. Primary endpoint was mortality after HTX. Baseline variables were entered in a Cox proportional hazards model with the primary endpoint as a dependent variable. RESULTS: Median overall survival following HTX was 6.3 years in the overall collective and the subgroup. Univariate Cox proportional hazards model revealed a significant relationship between overall survival and the transplantation period (2008 to 2020 vs 1987 to 2007; median survival 9.7 years vs 1.8 years, hazard ratio 0.45, p = 0.01). Further predictors were albumin concentration (hazard ratio 0.92, p < 0.001), and systolic blood pressure (hazard ratio 0.96, p < 0.001). The transplant period as well as albumin concentration remained significant independent predictors in the AL sub cohort in a multivariate Cox proportional hazards model. CONCLUSIONS: HTX is a viable treatment option for patients at an advanced stage of cardiac amyloidosis as overall survival after transplantation has improved in the modern age. Patients at a very advanced stage of the disease, indicated by low serum albumin and blood pressure, show worse outcomes following HTX. Optimal timing and careful patient selection may therefore be particularly important to further improve post-HTX survival in amyloidosis patients.

Psychosocial Characteristics of Patients Evaluated for Kidney, Liver, or Heart Transplantation.

OBJECTIVE: Psychosocial parameters play a pivotal role in organ recipient evaluation before wait-listing for transplantation because of their impact on organ and patient outcome. Patients in need of heart (HTx), liver (LTx), or kidney transplantation (KTx) face distinct physical and psychological challenges. This study compares the psychosocial characteristics and preferences for additional therapy for patients undergoing assessment for these three types of organ transplantation to optimize patient-tailored psychological, social, and other supportive interventions. METHODS: We conducted a cross-sectional, observational study with 1110 potential transplantation candidates (LTx, n = 544; KTx, n = 330; HTx, n = 236), psychosocial status was determined for depressive symptoms (Patient Health Questionnaire Depression Scale), anxiety symptoms (seven-item Generalized Anxiety Disorder Screener), health-related quality of life (36-Item Short Form Health Survey), perceived social support (Perceived Social Support Questionnaire), sense of coherence (SoC; short form of the Sense of Coherence Scale), self-efficacy (General Self-Efficacy Short Scale), and body image (German Body Image Questionnaire-20). Preferences for additional supportive therapy were assessed dichotomously. Data were analyzed using multivariate analysis of covariance and χ2 tests. RESULTS: Patient groups differed significantly regarding depression ( F (2,1107) = 35.283, p < .001, partial η2 = 0.01), anxiety ( F (2,1107) = 15.027, p < .001, partial η2 = 0.03), health-related quality of life (physical: F (2,1107) = 96.772, p < .001, partial η2 = 0.15; mental: F (2,1107) = 11.442, p < .001, partial η2 = 0.02), perceived social support ( F (2,1107) = 20.813, p < .001, partial η2 = 0.04), SoC ( F (2,1107) = 12.920, p < .001, partial η2 = 0.02), self-efficacy ( F (2,1107) = 17.308, p < .001, partial η2 = 0.03), and body image (rejecting body evaluation: F (2,1107) = 5.006, p = .007, partial η2 = 0.01; vital body dynamics: F (2,1107) = 40.216, p < .001, partial η2 = 0.07). Patients evaluated for HTx showed the highest psychosocial impairment and the highest inclination regarding additional supportive therapy. CONCLUSIONS: Patients evaluated for HTx, LTx, and KTx have distinct psychosocial characteristics and treatment preferences. HTx patients display the highest psychosocial impairment. We suggest psychocardiological treatment structures for optimal outcome.

Mobile Access to Medical Records in Heart Transplantation Aftercare: Mixed-Methods Study Assessing Usability, Feasibility and Effects of a Mobile Application.

BACKGROUND: Patient access to medical records can improve quality of care. The phellow application (app) was developed to provide patients access to selected content of their medical record. It was tested at a heart transplantation (HTx) outpatient clinic. The aims of this study were (1) to assess usability of phellow, (2) to determine feasibility of implementation in routine care, and (3) to study the effects app use had on patients' self-management. METHODS: Usability was measured quantitatively through the System Usability Scale (SUS). Furthermore, usability, feasibility, and effects on self-management were qualitatively assessed through interviews with users, non-users, and health care providers. RESULTS: The SUS rating (n = 31) was 79.9, indicating good usability. Twenty-three interviews were conducted. Although appreciation and willingness-to-use were high, usability problems such as incompleteness of record, technical issues, and complex registration procedures were reported. Improved technical support infrastructure, clearly defined responsibilities, and app-specific trainings were suggested for further implementation. Patients described positive effects on their self-management. CONCLUSIONS: To be feasible for implementation in routine care, usability problems should be addressed. Feedback on the effect of app use was encouraging. Accompanying research is crucial to monitor usability improvements and to further assess effects of app use on patients.

Heart transplantation across preformed donor-specific antibody barriers using a perioperative desensitization protocol.

Heart transplantation across preformed donor-specific HLA-antibody barriers is associated with impaired short- and long-term survival. Therefore, in recipients with preformed anti-HLA antibodies, waiting for crossmatch-negative donors is standard practice. As an alternative strategy, recipients with preformed anti-HLA donor specific antibodies have been managed at our institutions with a perioperative desensitization regimen. A retrospective analysis was performed comparing heart transplant recipients with preformed donor-specific HLA-antibodies to recipients without donor-specific antibodies. Recipients with a positive virtual crossmatch received a perioperative desensitization protocol including tocilizumab intraoperatively, plasma exchange and rituximab followed by a six-month course of IgGAM. Among the 117 heart-transplanted patients, 19 (16%) patients underwent perioperative desensitization, and the remaining 98 (84%) patients did not. Cold ischemic time, posttransplant extracorporeal life support for primary graft dysfunction, and intensive care unit stay time did not differ between groups. At 1-year follow-up, freedom from pulsed steroid therapy for presumed rejection and biopsy-confirmed acute cellular or humoral rejection did not differ between groups. One-year survival amounted to 94.7% in the treated patients and 81.4% in the control group. Therefore, heart transplantation in sensitized recipients undergoing a perioperative desensitization appears safe with comparable postoperative outcomes as patients with a negative crossmatch.

Impact of Percutaneous Mitral Valve Repair Using the MitraClipTM System on Ventricular Arrhythmias and ICD Therapies.

Transcatheter edge-to-edge repair (TEER) using the MitraClip™ device has been established as a suitable alternative to mitral valve surgery in patients with severe mitral regurgitation (MR) and high or prohibitive surgical risk. Only limited information regarding the impact of TEER on ventricular arrhythmias (VA) has been reported. The aim of the present study was to assess the impact of TEER using the MitraClipTM device on the burden of VA and ICD (Implantable Cardioverter Defibrillator) therapies. Among 600 MitraClipTM implantations performed in our clinic between September 2009 and October 2018, we identified 86 patients with successful TEER and an active implantable cardiac device (pacemaker, ICD, CRT-P/D (Cardiac Resynchronization Therapy-Pacemaker/Defibrillator)) eligible for retrospective VA analyses. These patients presented with mainly functional MR (81.4%) and severely reduced left ventricular ejection fraction (mean LVEF 22.1% ± 10.3%). The observation period comprised 456 ± 313 days before and 424 ± 287 days after TEER. The burden of ventricular arrhythmias (sustained ventricular tachycardia (sVT) and ventricular fibrillation (VF)) was significantly reduced after TEER (0.85 ± 3.47 vs. 0.43 ± 2.03 events per patient per month, p = 0.01). Furthermore, the rate of ICD therapies (anti-tachycardia pacing (ATP) and ICD shock) decreased significantly after MitraClipTM implantation (1.0 ± 3.87 vs. 0.32 ± 1.41, p = 0.014). However, reduction of VA burden did not result in improved two-year survival in this patient cohort with severely reduced LVEF. Mitral valve TEER using the MitraClip™ device was associated with a significant reduction of ventricular arrhythmias and ICD therapies.

[Drop in oxygen saturation and blood pressure as well as increase in central venous pressure during mitral valve clipping in an 81-year-old female patient]. / Abfall von Sauerstoffsättigung und Blutdruck sowie Anstieg des zentralen Venendrucks im Rahmen eines Mitralklappenclippings bei einer 81-Jährigen.

BACKGROUND: Atrial septal defects (ASD) following endovascular mitral valve clipping are potentially hemodynamically relevant complications. Immediate closure with an occluder can represent a safe and effective treatment. An 81-year-old female patient suffering from severe dyspnea due to previously known severe mitral valve regurgitation was scheduled for elective mitral valve clipping. The clip was successfully implanted. Removal of the transseptal cannula resulted in a sudden drop in oxygen saturation and systolic blood pressure as well as an immediate increase in central venous pressure. An iatrogenic left-right shunt was observed at the atrial level with a relevant shunt volume. Immediate closure using an atrial septal occluder successfully restored the oxygen saturation and hemodynamic parameters. CONCLUSION: An increase in central venous pressure, reduction of systolic blood pressure or oxygen saturation after withdrawal of the transseptal cannula during mitral valve clipping should always be further investigated regarding a possible ASD.

Histone deacetylase 4 deletion broadly affects cardiac epigenetic repression and regulates transcriptional susceptibility via H3K9 methylation.

Histone deacetylase 4 (HDAC4) is a member of class IIa histone deacetylases (class IIa HDACs) and is believed to possess a low intrinsic deacetylase activity. However, HDAC4 sufficiently represses distinct transcription factors (TFs) such as the myocyte enhancer factor 2 (MEF2). Transcriptional repression by HDAC4 has been suggested to be mediated by the recruitment of other chromatin-modifying enzymes, such as methyltransferases or class I histone deacetylases. However, this concept has not been investigated by an unbiased approach. Therefore, we studied the histone modifications H3K4me3, H3K9ac, H3K27ac, H3K9me2 and H3K27me3 in a genome-wide approach using HDAC4-deficient cardiomyocytes. We identified a general epigenetic shift from a 'repressive' to an 'active' status, characterized by an increase of H3K4me3, H3K9ac and H3K27ac and a decrease of H3K9me2 and H3K27me3. In HDAC4-deficient cardiomyocytes, MEF2 binding sites were considerably overrepresented in upregulated promoter regions of H3K9ac and H3K4me3. For example, we identified the promoter of Adprhl1 as a new genomic target of HDAC4 and MEF2. Overexpression of HDAC4 in cardiomyocytes was able to repress the transcription of the Adprhl1 promoter in the presence of the methyltransferase SUV39H1. On a genome-wide level, the decrease of H3K9 methylation did not change baseline expression but was associated with exercise-induced gene expression. We conclude that HDAC4, on the one hand, associates with activating histone modifications, such as H3K4me3 and H3K9ac. A functional consequence, on the other hand, requires an indirect regulation of H3K9me2. H3K9 hypomethylation in HDAC4 target genes ('first hit') plus a 'second hit' (e.g., exercise) determines the transcriptional response.

Risk Factors, Treatment and Prognosis of Patients with Lung Cancer after Heart Transplantation.

Long-term survival after heart transplantation (HTX) is impacted by adverse effects of immunosuppressive pharmacotherapy, and post-transplant lung cancer is a common occurrence. This study aimed to examine the risk factors, treatment, and prognosis of patients with post-transplant lung cancer. We included 625 adult patients who received HTX at Heidelberg Heart Center between 1989 and 2018. Patients were stratified by diagnosis and staging of lung cancer after HTX. Analysis comprised donor and recipient characteristics, medications including immunosuppressive drugs, and survival after diagnosis of lung cancer. A total of 41 patients (6.6%) were diagnosed with lung cancer after HTX, 13 patients received curative care and 28 patients had palliative care. Mean time from HTX until diagnosis of lung cancer was 8.6 ± 4.0 years and 1.8 ± 2.7 years from diagnosis of lung cancer until last follow-up. Twenty-four patients (58.5%) were switched to an mTOR-inhibitor after diagnosis of lung cancer. Multivariate analysis showed recipient age (HR: 1.05; CI: 1.01-1.10; p = 0.02), COPD (HR: 3.72; CI: 1.88-7.37; p < 0.01), and history of smoking (HR: 20.39; CI: 2.73-152.13; p < 0.01) as risk factors for post-transplant lung cancer. Patients in stages I and II had a significantly better 1-year (100.0% versus 3.6%), 2-year (69.2% versus 0.0%), and 5-year survival (53.8% versus 0.0%) than patients in stages III and IV (p < 0.01). Given the poor prognosis of late-stage post-transplant lung cancer, routine reassessment of current smoking status, providing smoking cessation support, and intensified lung cancer screening in high-risk HTX recipients are advisable.

Re-do MitraClip in patients with functional mitral valve regurgitation and advanced heart failure.

AIM: Percutaneous mitral valve repair (PMVR) via MitraClip implantation is a therapeutic option for severe mitral regurgitation (MR) in advanced stages of heart failure (HF). However, progressive left ventricular dilation in these patients may lead to recurrent MR after PMVR and consequent re-do MitraClip implantation. Here, we describe the characteristics and outcomes of this clinical scenario. METHODS AND RESULTS: Patients with systolic HF and functional MR undergoing a re-do MitraClip procedure were retrospectively analysed. Inclusion criteria were age ≥18 years, technical, device and procedural success at first MitraClip procedure, functional MR and systolic HF with an ejection fraction (EF) of <45%. Seventeen out of 684 patients undergoing PMVR with the MitraClip device at our institution between September 2009 and July 2019 were included. All patients displayed advanced HF with an EF of 20% (±9.9) and highly elevated N-terminal pro-brain natriuretic peptide. Technical success of the re-do MitraClip procedure was 100%, whereas procedural and device success were only achieved in 11 patients (65%). Unsuccessful re-do procedures were related to lower EF and implantation of more than one clip at initial procedure. However, despite reduction in MR grade and no occurrence of significant mitral stenosis after the procedure, the mortality during 12 months follow-up remained high (8 of 17; 47%). CONCLUSIONS: In a cohort of patients with advanced HF undergoing PMVR, re-do MitraClip procedure was feasible, but procedural success was unsatisfactory and morbidity and mortality remained high, possibly reflecting the advanced stage of HF in these patients.

Atrial fibrillation before heart transplantation is a risk factor for post-transplant atrial fibrillation and mortality.

AIMS: Atrial fibrillation (AF) after heart transplantation (HTX) is associated with worse clinical outcomes. The current study aimed to analyse the association between AF before HTX and AF within 30 days after HTX. METHODS AND RESULTS: This study included 639 adults who received HTX at Heidelberg Heart Center. Patients were subdivided into four groups depending on the status of AF before and after HTX. Analyses comprised recipient and donor data, medication, echocardiographic features, permanent pacemaker implantation, stroke, and mortality after HTX. Three hundred thirty-two patients (52.0%) had neither AF before nor after HTX, 15 patients (2.3%) had no AF before HTX but showed AF after HTX, 219 patients (34.3%) showed AF before HTX but had no AF after HTX, and 73 patients (11.4%) had AF before and after HTX. Patients with AF before and after HTX had a higher 1 year post-transplant mortality (39.7%) than patients without AF before or after HTX (18.1%, P < 0.01). Secondary outcomes showed a higher percentage of enlarged atria, ventricular dysfunction, mitral regurgitation, 1-year stroke, and 1-year permanent pacemaker implantation in patients with AF before and after HTX. Multivariate analysis revealed a six-fold elevated risk for post-transplant AF in patients with AF before HTX (hazard ratio: 6.59, confidence interval: 3.72-11.65; P < 0.01). Further risk factors for post-transplant AF were higher donor age and prolonged ischaemic time, whereas total orthotopic HTX was associated with a two-fold lower risk for post-transplant AF. CONCLUSIONS: Atrial fibrillation before HTX is a risk factor for post-transplant AF, permanent pacemaker implantation, and mortality after HTX.

PASCAL-based mitral valve repair in an all-comer population: acute and mid-term clinical results.

AIMS: We investigated short and mid-term safety and efficacy of the PASCAL system for percutaneous mitral valve repair (PMVr) in severe mitral regurgitation (MR) in an all-comer population. METHODS AND RESULTS: In the first consecutive 41 patients undergoing PMVr using the PASCAL system in our centre, procedural success and safety were assessed. Efficacy in improving MR and functional class were evaluated. Median patient age was 74 years, 58.5% were male patients, and median European System for Cardiac Operative Risk Evaluation Score II was 5.1%. All patients suffered from severe MR with 59% functional MR, 29% degenerative MR, and 12% of mixed aetiology MR. The technical success rate was 90%, limited by four cases where PASCAL implantation was aborted due to a prohibitive mitral gradient. On average, 1.16 PASCAL devices per patient were implanted. All patients successfully implanted with a PASCAL device were discharged with MR grade ≤ 2 and 79% with MR grade ≤ 1. Mean follow-up was 8.7 ± 4.9 months. Ninety-seven per cent of patients remained at MR ≤ 2 at follow-up, which translated into a significantly improved New York Heart Association functional class as well as a significant reduction of systolic pulmonary artery pressure and brain natriuretic peptide levels. The procedure-related rate for major adverse events was 3%. Neither early nor late single-leaflet detachment was found. In one patient, air embolism occurred, resulting in modification of the PASCAL instructions for use. CONCLUSIONS: Percutaneous mitral valve repair using PASCAL in a real-world, all-comer population was feasible and safe, resulting in a significant mid-term reduction of MR with persistent clinical improvement.

Newly acquired complete right bundle branch block early after heart transplantation is associated with lower survival.

AIMS: Right bundle branch block (RBBB) after heart transplantation (HTX) is a common finding, but its impact on post-transplant survival remains uncertain. This study investigated the post-transplant outcomes of patients with complete RBBB (cRBBB) ≤ 30 days after HTX. METHODS: This registry study analysed 639 patients receiving HTX at Heidelberg Heart Center between 1989 and 2019. Patients were stratified by diagnosis of cRBBB ≤ 30 days after HTX. Analysis included recipient and donor data, medication, echocardiographic features, graft rejections, atrial fibrillation, heart rates, permanent pacemaker implantation and mortality after HTX including causes of death. RESULTS: One hundred thirty-nine patients showed cRBBB ≤ 30 days after HTX (21.8%), 20 patients with pre-existing cRBBB in the donor heart (3.2%) and 119 patients with newly acquired cRBBB (18.6%). Patients with newly acquired cRBBB had a worse 1-year post-transplant survival (36.1%, P < 0.01) compared with patients with pre-existing cRBBB (85.0%) or without cRBBB (86.4%), along with a higher percentage of death due to graft failure (P < 0.01). Multivariate analysis indicated cRBBB ≤ 30 days after HTX as significant risk factor for 1-year mortality after HTX (HR: 2.20; 95% CI: 1.68-2.87; P < 0.01). Secondary outcomes showed a higher rate of an enlarged right atrium (P = 0.01), enlarged right ventricle (P < 0.01), reduced right ventricular function (P < 0.01), 30-day atrial fibrillation (P < 0.01) and 1-year permanent pacemaker implantation (P = 0.02) in patients with cRBBB after HTX. CONCLUSIONS: Newly acquired cRBBB early after HTX is associated with increased post-transplant mortality.

Initial experience with percutaneous mitral valve repair in patients with cardiac amyloidosis.

BACKGROUND: Percutaneous mitral valve repair (PMVR) is a therapeutic option for severe mitral regurgitation (MR) in patients with heart failure due to differential aetiologies. However, only little is known about the safety and efficacy of this procedure in patients with amyloid cardiomyopathy. METHODS: Five patients with cardiac amyloidosis and moderate to severe or severe MR undergoing PMVR were analysed retrospectively and compared to seven patients with cardiac amyloidosis and severe MR without intervention. Clinical and functional data, renal function and cardiac biomarkers as well as established risk scores for cardiac amyloidosis were assessed. Primary endpoint was the reduction in MR one year after PMVR. Secondary endpoints were safety, overall mortality after 12 months compared with the control group, as well as changes in clinical and functional parameters. RESULTS: Amyloidosis risk assessment documented amyloid cardiomyopathy at an advanced stage in all patients. Procedural, technical and device success of PMVR were all 100% and residual MR remained mild to moderate at 12 months follow-up (P = .038 vs before PMVR). Differences in survival compared with the control (no PMVR) group pointed to a possible survival benefit in the PMVR group (P = .02). CONCLUSION: PMVR is a feasible and safe procedure in patients with cardiac amyloidosis and might carry a possible survival benefit in this patient group.

MitraClip implantation followed by insertion of a left ventricular assist device in patients with advanced heart failure.

AIMS: Mitral valve regurgitation (MR) is common in patients with advanced heart failure (HF). Percutaneous mitral valve repair (PMVR) via MitraClip (MC) has emerged as a feasible treatment strategy for these high-risk patients. However, as HF often further progresses, there is a frequent need for left ventricular assist device (LVAD) implantation in these patients. We aimed to investigate whether prior MC implantation affects the subsequent LVAD implantation and outcome. METHODS AND RESULTS: Thirty-seven patients with advanced HF and significant MR who underwent LVAD implantation were retrospectively analysed. Follow-up data were collected at 1 year after LVAD implantation. Primary endpoint was all-cause mortality. Secondary endpoint included peri-operative parameters and clinical development depicted as New York Heart Association (NYHA) class and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level. Seventeen patients initially received a MC device (MC group), resulting in a significant reduction in MR grade. After MC, NYHA class and INTERMACS level further worsened, leading to subsequent LVAD implantation after a median time of 475 days in the MC group. At LVAD implantation, overall characteristics were comparable with those of the patients undergoing LVAD implantation without prior MC placement (no-MC group). Procedural data revealed a higher incidence of right ventricular (RV) failure needing mechanical RV assistance and a longer need for nitric oxide ventilation in the MC group after LVAD implantation. One-year survival was slightly better in the no-MC group compared with the MC group [41% (n = 7/17) vs. 65% (n = 13/20); P = 0.15], albeit event-free survival was comparable between both groups, MC and no-MC. CONCLUSIONS: LVAD implantation after MC is feasible and safe. However, in patients with advanced HF and severe MR, PMVR may only delay a needed LVAD implantation and thereby lead to poorer peri-operative RV function and impaired outcome. Arguably, these patients might benefit from the timely management of advanced HF by the means of early LVAD implantation or heart transplantation.

Temporary right ventricular circulatory support following right ventricular infarction: results of a groin-free approach.

AIMS: Acute right heart failure (RHF) is a severe complication of right ventricular infarction. The management of acute RHF poses a number of challenges, such as providing haemodynamic support. Temporary circulatory support (TCS) may be required upon failing medical therapy. The ProtekDuo® dual lumen cannula provides a minimally invasive option for (TCS) through a groin-free internal jugular vein approach. We present the largest patient series to date using the ProtekDuo® cannula as temporary right ventricular assist device (t-RVAD) in RHF after acute myocardial infarction (MI). METHODS AND RESULTS: From July 2016 to November 2019, 10 patients underwent t-RVAD implantation for RHF following acute MI. Transthoracic and transoesophageal echocardiography were performed in all patients to assess cardiac function, with a particular focus on RV function. Cumulative 30-day survival was 60%. Mean TAPSE was 6.4 ± 3.1 mm, mean fractional area change was 12.1 ± 4.2%, and mean right ventricular end diastolic area was 19.8 ± 2.7 cm2 . Mean implantation time was 32.8 ± 8.3 min. Mean interval after first cardiac intervention was 4.6 ± 5.8 days. Mean t-RVAD time was 10.0 ± 7.4 days with a significant reduction in central venous pressure 19.3 ± 2.7 vs. 8.2 ± 2.6 mmHg, P < 0.001 and a significant increase in central venous saturation 52.8 ± 15.6 vs. 80.0 ± 6.0%, P < 0.001. Mean intensive care unit stay was 18.6 ± 12.2 days. Four patients were weaned from TCS. Two patients were bridged to a long-term paracorporeal RVAD. There were no t-RVAD associated complications. Causes of death (n = 4) were multiorgan failure, electromechanical dissociation, and haemorrhagic stroke. Mean follow-up time was 96.0 ± 107.6 days. No independent predictors of mortality were identified in univariate analysis. CONCLUSIONS: We show that groin-free, percutaneous implantation of the ProtekDuo® cannula is a feasible and safe tool for TCS in acute RHF post-MI. This approach provides the advantages of percutaneous implantation including complete mobilization and non-surgical bedside explantation, as well as the option for adding an oxygenator to the t-RVAD circuit.

COVID-19 among heart transplant recipients in Germany: a multicenter survey.

AIMS: Heart transplantation may represent a particular risk factor for severe coronavirus infectious disease 2019 (COVID-19) due to chronic immunosuppression and frequent comorbidities. We conducted a nation-wide survey of all heart transplant centers in Germany presenting the clinical characteristics of heart transplant recipients with COVID-19 during the first months of the pandemic in Germany. METHODS AND RESULTS: A multicenter survey of all heart transplant centers in Germany evaluating the current status of COVID-19 among adult heart transplant recipients was performed. A total of 21 heart transplant patients with COVID-19 was reported to the transplant centers during the first months of the pandemic in Germany. Mean patient age was 58.6 ± 12.3 years and 81.0% were male. Comorbidities included arterial hypertension (71.4%), dyslipidemia (71.4%), diabetes mellitus (33.3%), chronic kidney failure requiring dialysis (28.6%) and chronic-obstructive lung disease/asthma (19.0%). Most patients received an immunosuppressive drug regimen consisting of a calcineurin inhibitor (71.4%), mycophenolate mofetil (85.7%) and steroids (71.4%). Eight of 21 patients (38.1%) displayed a severe course needing invasive mechanical ventilation. Those patients showed a high mortality (87.5%) which was associated with right ventricular dysfunction (62.5% vs. 7.7%; p = 0.014), arrhythmias (50.0% vs. none; p = 0.012), and thromboembolic events (50.0% vs. none; p = 0.012). Elevated high-sensitivity cardiac troponin T- and N-terminal prohormone of brain natriuretic peptide were significantly associated with the severe form of COVID-19 (p = 0.017 and p < 0.001, respectively). CONCLUSION: Severe course of COVID-19 was frequent in heart transplanted patients. High mortality was associated with right ventricular dysfunction, arrhythmias, thromboembolic events, and markedly elevated cardiac biomarkers.

Benefits of peritoneal ultrafiltration in HFpEF and HFrEF patients.

BACKGROUND: Peritoneal ultrafiltration (pUF) in refractory heart failure (HF) reduces the incidence of decompensation episodes, which is of particular significance as each episode incrementally adds to mortality. Nevertheless, there are insufficient data about which patient cohort benefits the most. The objective of this study was to compare pUF in HFrEF and HFpEF, focusing on functional status, hospitalizations, surrogate endpoints and mortality. METHODS: This study involves 143 patients, who could be classified as either HFpEF (n = 37, 25.9%) or HFrEF (n = 106, 74.1%) and who received pUF due to refractory HF. RESULTS: Baseline eGFR was similar in HFrEF (23.1 ± 10.6 mg/dl) and HFpEF (27.8 ± 13.2 mg/dl). Significant improvements in NYHA class were found in HFpEF (3.19 ± 0.61 to 2.72 ± 0.58, P <  0.001) and HFrEF (3.45 ± 0.52 to 2.71 ± 0.72, P <  0.001). CRP decreased in HFrEF (19.4 ± 17.6 mg/l to 13.7 ± 21.4 mg/l, P = 0.018) and HFpEF (33.7 ± 52.6 mg/l to 17.1 ± 26.3 mg/l, P = 0.004). Body weight was significantly reduced in HFrEF (81.1 ± 14.6 kg to 77.2 ± 15.6 kg, P = 0.003) and HFpEF (86.9 ± 15.8 kg to 83.1 ± 15.9 kg, P = 0.005). LVEF improved only in HFrEF (25.9 ± 6.82% to 30.4 ± 12.2%, P = 0.046). BCR decreased significantly in HFrEF and HFpEF (55.7 ± 21.9 to 34.3 ± 17.9 P > 0.001 and 50.5 ± 68.9 to 37.6 ± 21.9, P = 0.006). Number of hospitalization episodes as well as number of hospitalization days decreased significantly only in HFpEF (total number 2.88 ± 1.62 to 1.25 ± 1.45, P <  0.001, days 40.4 ± 31.7 to 18.3 ± 22.5 days, P = 0.005). CONCLUSIONS: pUF offers various benefits in HFpEF and HFrEF, but there are also substantial differences. In particular, hospitalization rates were found to be significantly reduced in HFpEF patients, indicating a greater medical and economical advantage. However, LVEF was only found to be improved in HFrEF patients. While pUF can now be regarded as an option to supplement classical HF therapy, further studies are desirable to obtain specifications about pUF in HFpEF, HFmEF and HFrEF patients.

CaMKII activity contributes to homeometric autoregulation of the heart: A novel mechanism for the Anrep effect.

KEY POINTS: The Anrep effect represents the alteration of left ventricular (LV) contractility to acutely enhanced afterload in a few seconds, thereby preserving stroke volume (SV) at constant preload. As a result of the missing preload stretch in our model, the Anrep effect differs from the slow force response and has a different mechanism. The Anrep effect demonstrated two different phases. First, the sudden increased afterload was momentary equilibrated by the enhanced LV contractility as a result of higher power strokes of strongly-bound myosin cross-bridges. Second, the slightly delayed recovery of SV is perhaps dependent on Ca2+ /calmodulin-dependent protein kinase II activation caused by oxidation and myofilament phosphorylation (cardiac myosin-binding protein-C, myosin light chain 2), maximizing the recruitment of available strongly-bound myosin cross-bridges. Short-lived oxidative stress might present a new facet of subcellular signalling with respect to cardiovascular regulation. Relevance for human physiology was demonstrated by echocardiography disclosing the Anrep effect in humans during handgrip exercise. ABSTRACT: The present study investigated whether oxidative stress and Ca2+ /calmodulin-dependent protein kinase II (CaMKII) activity are involved in triggering the Anrep effect. LV pressure-volume (PV) analyses of isolated, preload controlled working hearts were performed at two afterload levels (60 and 100 mmHg) in C57BL/6N wild-type (WT) and CaMKII-double knockout mice (DKOCaMKII ). In snap-frozen WT hearts, force-pCa relationship, H2 O2 generation, CaMKII oxidation and phosphorylation of myofilament and Ca2+ handling proteins were assessed. Acutely raised afterload showed significantly increased wall stress, H2 O2 generation and LV contractility in the PV diagram with an initial decrease and recovery of stroke volume, whereas end-diastolic pressure and volume, as well as heart rate, remained constant. Afterload induced increase in LV contractility was blunted in DKOCaMKII -hearts. Force development of single WT cardiomyocytes was greater with elevated afterload at submaximal Ca2+ concentration and associated with increases in CaMKII oxidation and phosphorylation of cardiac-myosin binding protein-C, myosin light chain and Ca2+ handling proteins. CaMKII activity is involved in the regulation of the Anrep effect and associates with stimulation of oxidative stress, presumably starting a cascade of CaMKII oxidation with downstream phosphorylation of myofilament and Ca2+ handling proteins. These mechanisms improve LV inotropy and preserve stroke volume within few seconds.

CaMKII does not control mitochondrial Ca2+ uptake in cardiac myocytes.

KEY POINTS: Mitochondrial Ca2+ uptake stimulates the Krebs cycle to regenerate the reduced forms of pyridine nucleotides (NADH, NADPH and FADH2 ) required for ATP production and reactive oxygen species (ROS) elimination. Ca2+ /calmodulin-dependent protein kinase II (CaMKII) has been proposed to regulate mitochondrial Ca2+ uptake via mitochondrial Ca2+ uniporter phosphorylation. We used two mouse models with either global deletion of CaMKIIδ (CaMKIIδ knockout) or cardiomyocyte-specific deletion of CaMKIIδ and γ (CaMKIIδ/γ double knockout) to interrogate whether CaMKII controls mitochondrial Ca2+ uptake in isolated mitochondria and during ß-adrenergic stimulation in cardiac myocytes. CaMKIIδ/γ did not control Ca2+ uptake, respiration or ROS emission in isolated cardiac mitochondria, nor in isolated cardiac myocytes, during ß-adrenergic stimulation and pacing. The results of the present study do not support a relevant role of CaMKII for mitochondrial Ca2+ uptake in cardiac myocytes under physiological conditions. ABSTRACT: Mitochondria are the main source of ATP and reactive oxygen species (ROS) in cardiac myocytes. Furthermore, activation of the mitochondrial permeability transition pore (mPTP) induces programmed cell death. These processes are essentially controlled by Ca2+ , which is taken up into mitochondria via the mitochondrial Ca2+ uniporter (MCU). It was recently proposed that Ca2+ /calmodulin-dependent protein kinase II (CaMKII) regulates Ca2+ uptake by interacting with the MCU, thereby affecting mPTP activation and programmed cell death. In the present study, we investigated the role of CaMKII under physiological conditions in which mitochondrial Ca2+ uptake matches energy supply to the demand of cardiac myocytes. Accordingly, we measured mitochondrial Ca2+ uptake in isolated mitochondria and cardiac myocytes harvested from cardiomyocyte-specific CaMKII δ and γ double knockout (KO) (CaMKIIδ/γ DKO) and global CaMKIIδ KO mice. To simulate a physiological workload increase, cardiac myocytes were subjected to ß-adrenergic stimulation (by isoproterenol superfusion) and an increase in stimulation frequency (from 0.5 to 5 Hz). No differences in mitochondrial Ca2+ accumulation were detected in isolated mitochondria or cardiac myocytes from both CaMKII KO models compared to wild-type littermates. Mitochondrial redox state and ROS production were unchanged in CaMKIIδ/γ DKO, whereas we observed a mild oxidation of mitochondrial redox state and an increase in H2 O2 emission from CaMKIIδ KO cardiac myocytes exposed to an increase in workload. In conclusion, the results obtained in the present study do not support the regulation of mitochondrial Ca2+ uptake via the MCU or mPTP activation by CaMKII in cardiac myocytes under physiological conditions.

ECPELLA 2.0-Minimally invasive biventricular groin-free full mechanical circulatory support with Impella 5.0/5.5 pump and ProtekDuo cannula as a bridge-to-bridge concept: A first-in-man method description.

BACKGROUND: Cardiogenic shock (CS) from biventricular heart failure that requires acute mechanical circulatory support (MCS) is associated with high mortality. Different MCS methods and techniques have emerged as a standard of care in CS. Nevertheless, the routine MCS approach carries multiple limitations such as limb ischemia, missing of left ventricular unloading and immobilization. We describe a method to establish a groin-free full support MCS in patients with CS without the need for thoracotomy. This is the first report of the ECPELLA 2.0 concept, a peripheral groin-free biventricular MCS in patients with acute CS. METHODS AND RESULTS: We discuss two patients in acute CS (INTERMACS I) treated with two peripheral MCS devices (Impella 5.0 or 5.5 surgically via an axillary artery and ProtekDuo cannula percutaneously via a right internal jugular vein) as a bridge before the implantation of a durable left ventricular assist device (LVAD). Biventricular assist device (BIVAD)-support duration was 9 and 15 days and both of the patients were successfully bridged to a durable LVAD. As our BIVAD-concept is groin-free, the patients started full mobilization as early as they were weaned from the respirator 2 days after the BIVAD-implantation. ECPELLA 2.0 provides a high cardiac output, right and left ventricular unloading with end-organ recovery and a possibility of administration of a membrane oxygenator. There were no device-related complications. CONCLUSION: The ECPELLA 2.0 biventricular support concept for patients suffering from an acute CS. Allows for rapid extubation, mobilization, and physical exercise while on full support. Additional application of a membrane oxygenator is easily feasible if required.