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Background Roughly one third of cases of chronic heart failure (HF) are caused by genetic predisposition, metabolic stress and cardiac inflammation. Animal studies suggest that heart-reactive autoantibodies, most notably those directed against G-protein-coupled receptors (GPCR), could also play a pathogenetic role in the disease. However, so far, a causal link between humoral GPCR-autoimmunity and human non-ischemic heart failure other than Chagas' cardiomyopathy remains unclear. Purpose Here, we investigated possible associations of GPCR autoantibodies with inflammatory, hemodynamic, metabolic and functional parameters in patients with chronic non-ischemic HF unrelated to Chagas' disease. Methods We prospectively included 95 patients with newly diagnosed non-ischemic heart failure of unknown origin. Basic cardiac characterization comprised transthoracic echocardiography, cardiac magnetic resonance imaging, coronary angiography and right heart catheterization with endomyocardial biopsy. Mitochondrial oxidative phosphorylation capacity and coupling was measured using high-resolution respirometry in permeabilized myocardial fibers. A panel of candidate GPCR-autoantibodies was determined by validated and certified immune-assays in peripheral venous blood of the HF-patients and 60 matched healthy individuals. Results were normalized to total IgG. Results Among 10 candidate GPCR-autoantibodies determined, only autoantibodies for α1-adrenergic receptor (α1AR), β1-adrenergic receptor (β1AR), muscarinic receptor M5 (M5AR), angiotensin II receptor type 1 (AT1R) and type 2 (AT2R) exhibited HF-associated alterations: Autoantibodies against β1AR, M5R and AT2R were increased. Autoantibodies against α1AR and AT1R were decreased (Figure). These alterations were significant (p However, in HF-patients, increased AT2R autoantibodies were associated with improved myocardial mitochondrial coupling (r=−0.27, p=0.021), and decreased AT2R autoantibodies were associated with insulin resistance (r=−0.24 p=0.027). Conclusion(s) Some previously postulated alterations of GPCR autoantibodies were confirmed in thoroughly characterized HF-patients. However, association of these alterations with cardiac function was not traceable, which argues against a specific pathogenic role. Our data are compatible with multifaceted interactions of GPCR-autoantibodies with the myocardium and potentially with glucose metabolism, possibly indicating a disease-modifying or compensatory role. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Research comission of the Heinrich-Heine University Duesseldorf

Background/Introduction With the growing prevalence of prediabetes in developed countries, complications of this predecessor of diabetes mellitus type 2 become increasingly important for medical research and practice. Prediabetes is defined as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and may also incorporate elevated hemoglobin A1. While overt type 2 diabetes is a well-established risk factor and can even be the cause of cardiac failure, this is not yet proven for prediabetes. Mitochondrial impairment is a key pathomechanism in heart failure, but it remains uncertain, whether prediabetes impairs myocardial energy metabolism in humans just as type 2 diabetes does. Purpose We aimed to scrutinize the impact of prediabetes on myocardial mitochondrial metabolism and cardiac function. Methods We included 50 heart transplant recipients with normal glucose tolerance (GT, n=25), prediabetes (n=8, 3 IFG and 5 IGT) or type 2 diabetes mellitus (T2DM, n=17), who had received a healthy donor heart from a non-diabetic donor. In this cohort, the impact of the recipients' metabolism should be displayed in the donor heart after transplantation. We performed oral glucose tolerance tests to assess the diabetes status, and cardiac magnetic resonance imaging to assess cardiac systolic and diastolic function, circulating biomarkers of oxidative stress in serum samples (thiobarbituric acid reactive substances (TBARS) and redox potential), as well as global T2 relaxation times as a marker of myocardial inflammation. In transcatheter endomyocardial biopsies, we assessed myocardial mitochondrial oxidative capacity using high-resolution respirometry and myocardial mRNA expression of nuclear factor kappa B p105 subunit (NFKB1). Results GT and IFG/IGT patients exhibited comparable demographic and clinical characteristics, whereas T2DM had higher BMI, glycemia, triglycerides and creatine kinase (all p Conclusion Our findings point towards mitochondrial impairment as a predecessor of overt heart failure in prediabetes and may represent an early footprint of prediabetic cardiomyopathy. Funding Acknowledgement Type of funding sources: None.

Background Mitochondrial dysfunction is a driving factor in the development of heart failure (HF) and relates to poor cardiac function. Through elevated oxidative stress it is linked to myocardial inflammation. Both mechanisms promote the development of cardiac fibrosis, a key contributor to adverse outcomes in ischaemic and non-ischaemic HF. Differences in myocardial mitochondrial function and inflammation between patients with ischaemic and non-ischaemic HF have been indicated. While immunosuppression in non-ischaemic HF with myocardial inflammation has improved long-term results, little is known about possible benefits in ischaemic HF. Purpose We hypothesised that: 1. Myocardial lymphocytic inflammation and fibrosis differ in patients with HF due to ischaemic cardiomyopathy (ICM) compared to patients with dilated cardiomyopathy (DCM). 2. Inflammation and fibrosis are associated with markers of mitochondrial dysfunction. Methods Myocardial tissue specimens were obtained from the left ventricular (LV) apex of 65 patients (n[ICM] = 33, n[DCM] = 32) with HF requiring an LV assist device or heart transplantation. We assessed oxidative phosphorylation capacity (OXPHOS) via high resolution respirometry in saponine-permeabilised myocardial fibres (OROBOROS Oxygraph-2k). Reactive oxygen species (ROS) production was measured fluoroscopically via the Amplex Red method. Immunohistochemistry staining for CD3 was performed on snap-frozen tissue and digitally analysed. Azan staining was used for quantification of fibrotic area. Statistical analysis was conducted with GraphPad Prism v9.0 and IBM SPSS v27.0. Results ICM and DCM patients did not differ significantly regarding age (60.9±5.4 vs. 55.8±12.4 years, p=0.11), sex (91% vs. 90% male, p=0.93), BMI (27.6±5.1 vs. 26.5±6.0 kg/m2, p=0.82), or diabetic status (31% vs. 20% Type 2 Diabetes mellitus, p=0.31). Tissue specimens of ICM patients displayed about three times larger fibrotic areas compared to DCM (20.9±21.2 vs. 7.2±5.6%, p=0.001). Cellular inflammation (>14 CD3+ cells/mm2) was significantly more common in ICM than DCM patients. (27 vs. 6%, p=0.024). Inflammation and fibrosis did not correlate significantly (r=0.09, p=0.46). Fibrosis was not associated with OXPHOS capacity (r=−0.129, p=0.33). In patients with inflammation, OXPHOS capacity was lower compared to patients without inflammation (92.3±40.1 vs. 131.6±55.6 pmol/(s*mg), p=0.031) and inflammation was associated with lower OXPHOS capacity (r=−0.296, p=0.019). There was a trend towards lower electron transfer capacity in patients with inflammation (98.6±43.1 vs. 129.7±48.3 pmol/(s*mg), p=0.053). ROS production was not significantly different between tissue specimens with or without inflammation (0.51±0.21 vs. 0.67±0.33 pmol/(s*ml), p=0.17). Conclusions Myocardial cellular inflammation is prominent in ICM patients and relates to impaired mitochondria. Future studies may evaluate possible benefits from immunosuppression in ICM patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Research Foundation (DFG)

ZusammenfassungTrotz großer Fortschritte in der Akutversorgung des Myokardinfarkts entwickelt ein relevanter Teil der Patienten eine chronische Herzinsuffizienz. Der durch den Infarkt verursachte myokardiale Schaden kann pathologische Umbauprozesse im Herzen wie linksventrikuläre Dilatation, Veränderung der ventrikulären Geometrie und die Ausbildung von Narbengewebe initiieren, die in einer progredienten Herzinsuffizienzsymptomatik und -letalität resultieren können. Verschiedene chirurgische und interventionelle Therapieverfahren zur Modulation der pathologischen Umbauprozesse im Herzmuskel wurden entwickelt. Sie erwiesen sich als sicher und effektiv in der Reduktion linksventrikulärer Volumina, einer Steigerung der linksventrikulären Ejektionsfraktion sowie im Hinblick auf klinische Parameter. Randomisierte prospektive Studien, die einen Überlebensvorteil durch interventionelle oder chirurgische linksventrikuläre Modulation nachweisen, liegen zurzeit nicht vor.

OBJECTIVES Primary graft dysfunction remains a serious problem after heart transplant. Pharmacological treatment with the calcium sensitizer levosimendan may be an additive treatment for primary graft dysfunction. MATERIALS AND METHODS Patients undergoing heart transplant between 2010 and 2020 were retrospectively reviewed and divided depending on postoperative treatment with (n = 41) or without (n = 109) levosimendan. Recipients who received levosi mendan were further divided with regard to timing of levosimendan application (early group: started ≤48 hours posttransplant [n = 23]; late group: started >48 hours posttransplant [n = 18]). RESULTS Patients who received levosimendan treatment displayed a remarkable incidence (87.8%) of postoperative primary graft dysfunction with need for venoarterial extracorporeal membrane oxygenation and therefore often presented with perioperative morbidity. Patient with early application of levosimendan showed significantly decreased duration of venoarterial extracorporeal membrane oxygenation support (5.1 ± 3.5 days vs 12.6 ± 9.3 days in those with late application; P < .01) and decreased mortality during venoarterial extracorporeal membrane oxygenation support (0.0% vs 33.3% in early vs late group; P < .01). In addition, compared with patients with late levosimendan application, patients with early application needed fewer blood transfusions (P < .05), had shorter ventilation times (279 ± 235 vs 428 ± 293 h; P = .03), and showed a trend of reduced incidence of postoperative renal failure (69.6% vs 94.4%; P = .06). Moreover, survival analyses indicated an increased survival for patients with early start of levosimendan therapy within the first 48 hours after heart transplant (P = .09). CONCLUSIONS Pharmacotherapy with levosimendan may be a promising additive in the treatment of primary graft dysfunction after heart transplant. With administration of levosimendan within the first 48 hours posttransplant, rates of successful weaning from venoarterial extracorporeal membrane oxygenation and outcomes after heart transplant were shown to increase.

Objective To evaluate the impact of severe tricuspid valve insufficiency (TVI) at the time of left ventricular assist device (LVAD) implantation on the hemodynamic and LVAD parameters in an acute ovine model. Methods Stable heart failure (HF) was induced in 10 ovines through the application of 3 ± 1 coronary ligations. Once stable HF was obtained (after 15 ± 5 days), the animals were supported with an LVAD. Hemodynamic data and pump parameters were obtained and compared in 2 settings; first with LVAD in place after weaning from the cardiopulmonary bypass machine (no TVI condition) and second following the induction of severe TVI through resection of the tricuspid valve (TVI condition). Results There were no statistically significant differences in the hemodynamic and pump parameters between TVI condition and no TVI conditions except for lower cardiac output in the TVI condition (2 [1.38-2.8] L/min vs 3.2 [1.55-3.7] L/min, P = .027) and the expected greater central venous pressure in the TVI condition (26 [24-31] mm Hg vs 15 [13-25] mm Hg, P = .020). A median pump flow of 2.8 (2.45-3.75) L/min versus 2.9 (2.75-3.8) L/min in the TVI condition and no TVI condition was documented (P = .160). Conclusions Results from this acute animal study suggest that severe TVI in HF with preserved right ventricular function does not have significant impact on the LVAD pump parameters. The observed reduction in cardiac output may warrant further investigations, especially under loading conditions.

Introduction Establishing a chronic heart failure (HF) model is challenging, particularly in the sheep model. The aim of this study was to establish a reproducible model of HF in an ovine model. Methods Seventeen sheep were operated using the left thoracotomy approach. Chronic HF was induced through ligation of the diagonal and marginal branches only. Perioperative hemodynamic and echocardiographic parameters were compared. Results A total of (3 ± 1) coronary ligations were used. Thirteen animals survived the procedure and were followed up for (15 ± 5) days. The mean arterial pressure, heart rate (HR), mean pulmonary artery pressure (mPAP), central venous pressure and cardiac output at baseline and prior to animal sacrifice was (75 ± 14 mmHg) and (68 ± 16 mmHg) p = 0.261; (72 ± 9 b/min), (100 ± 28 b/min) p = 0.01; (15 ± 4 mmHg) and (18 ± 5 mmHg) p = 0.034; (10 ± 6 mmHg) and (8 ± 4 mmHg) p = 0.326; (3.4 ± 1 L/min) and (3.9 ± 1 L/min) p = 0.286 respectively. The LVEF, at baseline and prior to animal sacrifice was (63 ± 13 %) and (43 ± 6 %) p = 0.012. Twelve surviving animals were supported with LVAD in a follow-up procedure. Conclusions Chronic stable HF in sheep was successively established. Clinical symptoms and drastic increase in the mPAP and HR as well as echo findings were the most sensitive parameters of HF. This reproducible ovine model has proven to be highly promising for research regarding HF.

Background The number of patients waiting for heart transplantation (HTx) is exceeding the number of actual transplants. Subsequently, waiting times are increasing. One possible solution may be an increased acceptance of organs after rescue allocation. These organs had been rejected by at least three consecutive transplant centers due to medical reasons. Methods Between October 2010 and July 2019, a total of 139 patients underwent HTx in our department. Seventy (50.4%) of the 139 patients were transplanted with high urgency (HU) status and regular allocation (HU group); the remaining received organs without HU listing after rescue allocation (elective group, n = 69). Results Donor parameters were comparable between the groups. Thirty-day mortality was comparable between HU patients (11.4%) and rescue allocation (12.1%). Primary graft dysfunction with extracorporeal life support occurred in 26.9% of the elective group with rescue allocated organs, which was not inferior to the regular allocated organs (HU group: 35.7%). No significant differences were observed regarding the incidence of common perioperative complications as well as morbidity and mortality during 1-year follow-up. Conclusions Our data support the use of hearts after rescue allocation for elective transplantation of patients without HU status. We could show that patients with rescue allocated organs showed no significant disadvantages in the early perioperative morbidity and mortality as well at 1-year follow-up.

Background Diabetic cardiomyopathy is defined as Heart failure in patients with Type 2 Diabetes (T2DM) in absence of traditional risk factors. Following HTX, a substantial number of recipients develop insulin resistance or T2DM, associated with cardiac allograft vasculopathy and with increased mortality. Recently we have shown that endomyocardial biopsies of heart transplant (HTX) recipients with T2DM express reduced mitochondrial respiration. Purpose The current study analyses time depended impact of T2DM on myocardial mitochondrial respiration of a priorly non-diabetic heart. We hypothesized that myocardial mitochondrial oxidative phosphorylation capacity declines in patients with T2DM compared to glucose tolerant heart transplant recipients and that reduced mitochondrial respiration leads to impairment of cardiac function. Methods We included 101 HTX recipients who underwent routine endomyocardial biopsy. Patients with T1DM or a Donor with DM were excluded. Patients were classified according to criteria of the American Diabetes Association as non-diabetic (n=23), prediabetic (n=38) or T2DM (n=40), by either Fasting Plasma Glucose, 2h Plasma Glucose, HbA1c or intake of antidiabetic medication. We performed ex vivo high resolution respirometry on permeabilized fibres to assess myocardial mitochondrial respiration. Left ventricular ejection fraction (LV-EF) was assessed by cardiac-MRI or Echocardiography. Results Groups were of comparable age (p=0.06), sex (p=0.25) and time since HTX (p=0.91). Mean time since HTX was 29 months. Current rejection episodes (p=0.37) or corticoid pulse therapy (p=0.46) did not significantly differ between groups. Linear regression in T2DM patients revealed an inverse relationship between time since HTX and mitochondrial respiration at state III conditions supported by the substrates octanoyl-carnitine and ADP (R2=0.16, F(1,38)=6.97, p=0.01). Regression analyses for non-DM group and Prediabetes group revealed no significant relationship between time since HTX and mitochondrial function (non-DM: R2=0.04, F(1,21)=0.9, p=0.35; Prediabetes: R2=0.01, F(1,36)=0.27, p=0.61). Exclusion of patients with cellular allograft rejection (ISHLT ≥1) or of patients with recent corticoid pulse therapy did not alter these results. Linear correlation revealed a significant relationship (r=0.33, p=0.04) between declining mitochondrial state III respiration and left ventricular ejection fraction (n=39), suggesting associated functional consequences. Conclusions Our results suggest a T2DM associated decline of mitochondrial oxidative capacity in HTX recipients. Reduced mitochondrial respiration is associated to lower LV-EF. Targeting mitochondrial respiration might be a promising novel therapeutic approach to address T2DM associated mortality. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Research Counsil

Cancer therapy-related cardiotoxicity has been presenting a major problem in cancer survivors, who constitute a growing population caused by a significant improvement in cancer therapy during the past decades. Although some listing criteria have been defined for these patients, it is still a compelling decision to list patients with a complex cancer anamnesis. We describe herein a childhood cancer survivor after a cancer anamnesis with 2 different malignancies and an end-stage heart failure following chemoradiotherapy who was successfully treated with orthotopic heart transplant.

Cardiac mitochondrial alterations are suspected to play a key role in the development of diabetes-related heart failure as reported in some animal and few human studies in type 2 diabetes (1). It is yet unclear whether these alterations are induced by diabetes-related metabolic changes or develop secondary to other factors underlying heart failure including micro- and macrovascular disease. We hypothesized that 1 ) exposure to type 2 diabetes provokes myocardial mitochondrial impairment prior to apparent left ventricular heart failure in humans and 2 ) these mitochondrial alterations are accompanied by increased oxidative stress, edema, and intracellular inflammation. The cohort of this cross-sectional clinical study (study number 5263R; ClinicalTrials.gov NCT03386864) comprised adult heart transplant recipients undergoing routine transcatheter ventricular endomyocardial biopsies (EMB) post-transplantation, who received heart transplants of donors without type 2 diabetes. Thus, time between transplantation and EMB (2.9 ± 2.4 years) corresponded to the exposure of the hearts to type 2 diabetes. The first post-transplantation visit was included; exclusion criteria comprised allograft rejection (>0R according to International Society for Heart and Lung Transplantation criteria) and coronary artery disease (assessed via coronary angiography). Participants underwent oral glucose tolerance tests to assess glucose tolerance and insulin sensitivity (oral glucose insulin sensitivity [OGIS]). Cardiac magnetic resonance imaging was conducted at 1.5T to determine ventricular volumes and function, left ventricular T2 relaxation time, global left ventricular longitudinal strain (GLS), and diastolic strain rate. EMBs were attained for assessment of allograft rejection, mRNA expression of nuclear factor κ-light-chain-enhancer of activated B cells p105 subunit (NF-κB1), Toll-like receptor 9 (TLR9), and mitochondrially encoded cytochrome c oxidase I (CO1) and mitochondrial function using high-resolution respirometry in permeabilized …

Purpose Representing a rare complication, antibody-mediated graft rejection (AMR), particularly caused by donor-specific antibodies (DSA), remains a serious problem after heart transplantation (HTx). Plasmapheresis, application of rituximab as well as intravenous immunoglobulins (IVIG) are widely established, however often insufficient treatments for AMR. IgM-enriched human intravenous immunoglobulin (IGM-IVIG) consists of IgM, IgA and IgG and provides a new multifactorial approach to the immunologic cascade of DSA-mediated AMR, however its efficiency is by now still not clear. Methods Between 2017 and 2020 four patients (P 1-4) developed DSA-mediated rejection (DSA-MR) after HTx in our department and were repetitively treated with 0.5-1.0 g/kg body weight IGM-IVIG (Pentaglobin®, Biotest AG, Dreieich, Germany) in combination with 3.0 mg/kg body weight anti-thymocyte globulin (ATG). Results Patients were transplanted at the age of 47 (P1), 57 (P2), 30 (P3) and 68 years (P4). Except P2, all patients were male. While in P1 and P4, DSA-MR occurred within the early postoperative interval after HTx, P2 and P3 developed DSA-MR one year after transplantation. In all patients donor-specific HLA-antibodies were found, however pathological examinations of right ventricular biopsies could only confirm AMR in P1-3 (pAMR1° to pAMR3°) but not in P4 (pAMR0). A severe impairment of biventricular function was observed in all patients with need for temporary veno-arterial extracorporeal membrane oxygenation (va-ECMO) in P4. Furthermore, P1 and P4 suffered from malign ventricular arrhythmias. After repetitive application of IGM-IVIG all patients could be stabilized, ventricular function recovered, and P1-3 could be discharged from hospital and are still alive today, whereas P4 has been transplanted quite recently and is still recovering in hospital. Conclusion DSA-MR provokes serious complications affecting the outcome after HTx. By application of IGM-IVIG, we were able to successfully treat all of our four patients suffering from severe graft failure caused by DSA-MR and no patient developed treatment-related adverse effects. As part of a multifactorial therapeutic approach, pharmacological treatment with IGM-IVIG seems to be a safe and effective strategy in order to address DSA-MR and offers promising results for the future.

Background Alterations of mitochondrial function have been identified to play a role in Heart Failure (HF) pathophysiology. Oxidative phosphorylation (OXPHOS) capacity of the myocardium was shown to be reduced in the failing heart. Ineffective mitochondrial function promotes formation of reactive oxygen species (ROS) that may affect remodelling in ischemia. Thus far, human mitochondrial function comparing dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) resembling the main aetiologies of heart failure with reduced ejection fraction (HFrEF) has not been investigated. Purpose We hypothesised that 1. ROS production is elevated in left ventricular myocardial tissue specimens of ICM patients compared to DCM. 2. Mitochondrial OXPHOS capacity is higher in left ventricular myocardial tissue specimens of DCM compared to ICM patients. Methods Myocardial tissue was obtained from the left ventricular apex from 63 patients (38 ICM, 25 DCM) with advanced HFrEF requiring implantation of a Left Ventricular Assist Device (LVAD). We performed high-resolution respirometry (HRR, OROBOROS Oxygraph-2k) in saponine-permeabilised myocardial fibres and measured ROS production fluoroscopically via the Amplex Red method. Statistical analysis was conducted using GraphPad Prism 7 and IBM SPSS v26.0. Results Groups were of comparable age (61.5±1.2 vs. 59.3±2.4 years, p=n.s.), sex (87% vs 85% male, p=n.s.), diabetic status (32% vs 38.4% type 2 diabetes mellitus, p=n.s.), and body mass index (28.1±0.8 vs. 26.3±1.1 kg/m2, p=n.s.). We detected reduced myocardial mitochondrial OXPHOS capacity in ICM under state 3 conditions by about 15% (68.7±34.0 vs. 80.9±30.5 pmol/(s*mg), p Conclusion This is the first human study deciphering distinct alterations in mitochondrial function (OXPHOS capacity) in ventricular myocardium of HFrEF patients. Future studies may address how distinct metabolic patterns at the time of implantation may relate to long-term outcome of HFrEF in terms of remodelling and recovery. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): DFG (German Research Foundation)

Type 2 Diabetes Mellitus (T2DM) is a major risk factor for chronic heart failure, even independent of coronary artery disease. Various underlying mechanisms worsening ventricular function in T2DM have been postulated based on data from animal studies, including mitochondrial abnormalities, alterations of Nuclear factor kappa-B (NfκB) expression, increased oxidative stress and inflammation and cardiac fibrosis and diastolic impairment. However, evidence in humans for these mechanisms is currently lacking. Especially early T2DM-related alterations and the impact of T2DM in the absence of coronary artery disease remain unclear. We hypothesize that T2DM (I) leads to distinct changes in diastolic cardiac function, (II) impairs mitochondrial function of the ventricular myocardium, and (III) increases ventricular myocardial NfκB expression. Heart transplant recipients with T2DM (“T2DM”, n=17) and without (“Non-DM”, n=32) T2DM (as determined by oral glucose tolerance tests) were included, if they had received their heart from a donor without Diabetes Mellitus. Thus, diabetes-exposure of the transplanted hearts exactly corresponded to the time since transplantation. Magnetic resonance imaging was performed to assess left ventricular ejection fraction, global longitudinal strain (GLS), diastolic strain, and T2 relaxation times, a marker of myocardial edema. We assessed NfκB p105 subunit (NfκB1) mRNA expression using real-time PCR and myocardial mitochondrial respiration using high-resolution respirometry in ventricular endomyocardial biopsies. All participants had normal left ventricular ejection fraction (LVEF) without angiographic signs of coronary artery disease post transplantation (average 2.9±2.4 years). Age, sex distribution and LVEF were comparable between T2DM and Non-DM participants (p=0.50, 0.40 and 0.36, respectively). While GLS was not different (p=0.34), T2DM exhibited lower diastolic strain (1.0±0.4 vs. 1.4±0.4s-1, p Exposure to T2DM diminishes mitochondrial function in ventricular myocardium, which relates to hyperglycemia, insulin resistance, oxidative stress, inflammation, and ventricular diastolic dysfunction and edema. These changes appear within short-term overt diabetes and might precede T2DM-related heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was supported by funding from the German Research Council (SFB1116) and a grant provided by the research commission of the Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.

Background Right ventricular (RV) dysfunction is a predictor of poor clinical outcome in patients with heart failure and valvular heart disease. However, in patients undergoing MitraClip implantation, only limited data exist regarding the prognostic role of RV function and dimensions on outcomes. Previous studies suggested that RV dysfunction may be associated with poor clinical outcome following MitraClip, while other studies demonstrated contractionary results. Purpose The purpose of this study was to assess whether cardiac magnetic resonance (CMR) imaging derived RV assessment can facilitate risk stratification among patients undergoing transcatheter mitral valve repair with the MitraClip. Methods Sixty-one patients (mean age 77±9 years; 72% functional MR; logistic EuroScore 24±15) with severe mitral regurgitation (MR) were included and underwent CMR imaging and right heart catheterization prior MitraClip procedure. We divided patients into groups according to the presence of RV systolic dysfunction defined by RV ejection fraction (RVEF) Results Patients with RV systolic dysfunction displayed increased left and right ventricular volumes as well as reduced LVEF (all p Conclusion The assessment of RV volumes and function by CMR imaging yields important prognostic information that enable an estimation of heart failure severity and prognosis. In this regard, not only RV systolic dysfunction, but also RV dilatation was associated with increased 1-year mortality, while patients presenting with both exhibit additive high mortality risk. Therefore, current criteria for patient selection that are mainly based on mitral valve characteristics only, should also consider RV volumes and function as can be accurately assessed by CMR. Funding Acknowledgement Type of funding source: None

Background Heart transplantation (HTx) is the best therapy for end-stage heart failure. Unfortunately, death on the waiting list remains a problem. Decreasing the number of rejected organs could increase the donor pool. Methods A total of 144 patients underwent HTx at our department between 2010 and 2019. Of them, 27 patients received organs of donors with cardiopulmonary resuscitation (CPR) prior to organ donation (donor CPR) and were compared with patients who received organs without CPR (control; n = 117). Results We did not observe any disadvantage in the outcome of the donor CPR group compared with the control group. Postoperative morbidity and 1-year survival (control: 72%; donor CPR: 82%; p = 0.35) did not show any differences. We found no impact of the CPR time as well as the duration between CPR and organ donation, but we found an improved survival rate for donors suffering from anoxic brain injury compared with cerebral injury (p = 0.04). Conclusions Donor organs should not be rejected for HTx due to resuscitation prior to donation. The need for CPR does not affect the graft function after HTx in both short- and mid-term outcomes. We encourage the use of these organs to increase the donor pool and preserve good results.

Nuclear factor kappa-B (NFkB) has been postulated to induce cardiac fibrosis and dysfunction in heart failure and triggers inflammatory pathways. NFkB can be induced by damaged mitochondria. Its association with myocardial mitochondrial respiratory function in non-ischemic diabetes-related heart failure in humans is yet unclear. We hypothesized that human ventricular myocardial NFkB expression (i) is increased by type 2 diabetes mellitus (T2DM), and (ii) relates to reduced myocardial mitochondrial respiration. Heart transplant recipients with or without T2DM (as determined by oral glucose tolerance test), about to undergo post-transplant surveillance endomyocardial biopsies, were included, if they had received hearts from donors without T2DM. Thus, time since transplantation equaled diabetes-exposure of the transplanted hearts (2.9±2.4 years). We assessed normalized NFkB p105 subunit (NFkB1) mRNA expression using real-time PCR and myocardial mitochondrial respiration using high-resolution respirometry. Study participants (T2DM: n=17, Non-DM: n=32) had no histological signs of allograft rejection, heart failure (left ventricular ejection fraction 66.2±6.5%) or coronary artery disease. Age and sex distribution were similar between Non-DM and T2DM (p=0.50; p=0.40, respectively). Myocardial NFkB1 expression was 60% higher in T2DM than in Non-DM (0.28 [0.21-0.44] vs. 0.45 [0.29-0.71] arbitrary units, p Disclosure E. Zweck: None. D. Scheiber: None. T. Jelenik: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. P. Horn: None. D. Pesta: None. D. Lassner: None. H. Schultheiss: None. U. Boeken: None. P. AKhyari: None. A. Lichtenberg: None. M. Kelm: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. R. Westenfeld: None. J. Szendroedi: None. Funding German Research Council (SFB1116); Heinrich-Heine University

The lifetime risk of developing heart failure is approximately 20%, and survival rates remain poor. Myocardial mitochondrial function has been suggested to play a pivotal role in heart failure pathophysiology. Human studies on ex vivo mitochondrial function have mostly been limited to atrial tissue obtained during open heart surgery and have provided contradictory results. This study aimed at measuring myocardial mitochondrial function in transcatheter ventricular endomyocardial biopsies and assessing the relationship between oxidative capacity and heart function. We enrolled 40 heart failure patients undergoing ventricular assist device surgery or heart transplantation (34 males, age 57 ± 11 years, body mass index 26.6 ± 4.8 kg/m2) and 29 heart transplant recipients of comparable age and body mass index with normal left ventricular function undergoing surveillance biopsies (23 males, 57 ± 12 years, body mass index 26.2 ± 4.1 kg/m2). High-resolution respirometry was established in the myocardium to measure oxidative capacity ex vivo. The mitochondrial oxidative capacity was 90% higher in ventricular compared to atrial tissues (n = 11, p, Heart failure: Energy metabolism reflects cardiac function The capacity of mitochondria in heart muscle cells to use oxygen to produce energy correlates with cardiac function. Julia Szendroedi at Heinrich-Heine University, Düsseldorf, Germany, and colleagues have established a technique to reliably evaluate mitochondrial energy metabolism in patients with or recovering from heart failure. They showed that the mitochondrial oxidative capacity of cells in the lower heart chambers (ventricles) was significantly higher than in the upper heart chambers (atria). Moreover, they found that mitochondrial oxidative capacity was reduced by 44% in heart muscle biopsies from patients with heart failure compared with biopsies from heart transplant recipients with normal ventricular function. Stimulating the respiration rate of mitochondria in ventricular heart cells could be a promising strategy for improving cardiac function.

Background Primary graft dysfunction (PGD) is a common cause of early death after heart transplantation (htx). The use of extracorporeal life support (ECLS) after htx has increased during the last years. It is still discussed controversially whether peripheral cannulation is favorable compared to central cannulation. We aimed to compare both cannulation techniques. Methods Ninety patients underwent htx in our department between 2010 and 2017. Twenty-five patients were treated with ECLS due to PGD (10 central extracorporeal membrane oxygenator [cECMO] and 15 peripheral extracorporeal membrane oxygenator [pECMO] cannulation). Pre- and intraoperative parameters were comparable between both groups. Results Thirty-day mortality was comparable between the ECLS-groups (cECMO: 30%; pECMO: 40%, p = 0.691). Survival at 1 year (n = 18) was 40 and 30.8% for cECMO and pECMO, respectively. The incidence of postoperative renal failure, stroke, limb ischemia, and infection was comparable between both groups. We also did not find significant differences in duration of mechanical ventilation, intensive care unit stay, or in-hospital stay. The incidence of bleeding complications was also similar (cECMO: 60%; pECMO: 67%). Potential differences in support duration in pECMO group (10.4 ± 9.3 vs. 5.7 ± 4.7 days, p = 0.110) did not reach statistical significance. Conclusions In patients supported for PGD, peripheral and central cannulation strategies are safe and feasible for prolonged venoarterial ECMO support. There was no increase in bleeding after central implantation. With regard to the potential complications of a pECMO, we think that aortic cannulation with tunneling of the cannula and closure of the chest could be a good option in patients with PGD after htx.

BACKGROUND Orthotopic heart transplantation (HTx) is the gold standard treatment for patients with terminal heart failure. As donor organs are limited, patients are often on ventricular assist device (VAD) support before receiving HTx. We aimed to compare the outcome after HTx in patients with and without preoperative VADs as well as in patients who underwent different VAD implantation techniques. METHODS A total of 126 patients underwent HTx at our department between 2010 and 2019 and were retrospectively analyzed. While 47 patients underwent primary transplantation (No VAD), 79 were on VAD support. The preoperative and intraoperative parameters were comparable between the two groups. RESULTS VAD support significantly increased the HTx operation time (

Background Impairment of myocardial mitochondrial function is regarded as an established pathomechanism in heart failure. Enhanced oxidation of ketone bodies may potentially exert protective effects on myocardial function. High-resolution respirometry (HRR) resembles a gold-standard methodology to determine myocardial mitochondrial metabolism and oxidative function but has not been validated for ketone substrates yet. Purpose We hypothesized that (1) quantification of ketone body oxidative capacity (OC) in myocardium utilizing ex-vivo HRR is feasible and that (2) ketone-associated OC is elevated after fasting and under conditions of chronic mechanical ventricular unloading. Methods We established new HRR (Oxygraph-2k) protocols, measuring oxygen flux generated by oxidation of the ketone substrates beta-hydroxybutyrate (HBA) and acetoacetate (ACA). Ketone protocols were then applied to twelve C57BL/6 mice' (of which six were fasted for 16h) left ventricular and right liver lobe tissue, as well as to eleven terminal heart failure patients' left ventricular tissue, harvested at heart transplantation. Heart transplant recipients were subdivided into patients with left ventricular assist device prior to transplantation (LVAD group, n=6) or no unloading prior to transplantation (HTX group, n=5). Results In non-fasted rodent hearts, HBA yielded an OC of 25±4 pmol/(s*mg tissue) above basal respiration, when applied as sole substrate (21±11 pmol/(s*mg) in liver). ACA alone did not induce oxygen flux, but ACA+succinate yielded 229% higher oxygen flux than succinate alone in state III (146±32 vs 44±12 pmol/(s*mg); p=0.0003). When titrated after succinate, ACA increased OC by 93±25 pmol/(s*mg) (p=0.0003). In 16h-fasted rodent hearts, HBA-supported OC was 27% higher (41±3 vs 52±9 pmol/(s*mg); p=0.04), while OC with ACA+succinate was unchanged (p=0.60). In rodent liver, no oxygen flux was induced by ACA, reflecting absence of 3-oxoacid CoA-transferase. However, HBA-supported OC was 118% higher in fasted liver (37±13 vs 57±13 pmol/(s*mg); p=0.03). In humans, left ventricular unloading was not associated with altered myocardial OC for fatty acids and glycolytic substrates (standard protocol, p=0.13), but HBA-supported OC was 39% higher in the LVAD group compared to the HTX group (54±12 vs 39±9 pmol/(s*mg), p=0.04). Conclusion Quantification of ketone body OC with HRR is feasible in permeabilized myocardial fibers. Applying this novel method revealed increased HBA-supported myocardial mitochondrial respiration after fasting and chronic left ventricular unloading. These data support a concept of enhanced ketone oxidation following ventricular unloading in myocardial mitochondria. Our findings facilitate new studies on myocardial ketone turnover and the interaction of mitochondrial ketone metabolism with cardiac performance. Acknowledgement/Funding CRC 1116, Research commission of the University Hospital Düsseldorf

Hyperinsulinemia and impaired insulin secretion are potential contributors to the development of diabetes-related heart failure. Interference with ventricular myocardial mitochondria might play a key pathogenic role, but human data confirming these connections are limited. We hypothesized that ventricular myocardial mitochondrial function is impaired in hyperinsulinemia but is positively related to insulin secretion capacity. We recruited 32 heart transplant recipients without heart failure or antihyperglycemic treatment (age: 53.5±13.3years; BMI: 24.8±2.9kg/m²; HbA1c: 5.9±0.7%). We measured serum insulin levels and blood glucose every 30 minutes for three hours after an oral 75g glucose uptake. Seven patients were newly diagnosed with type 2 diabetes and six had impaired glucose tolerance. High-resolution respirometry was performed on transcatheter ventricular endomyocardial biopsies to determine mitochondrial oxidative capacity, coupling efficiency (respiratory control ratio, RCR) and intrinsic uncoupling (leak control ratio, LCR). Fasting serum insulin, a marker of insulin resistance, was inversely associated with ventricular myocardial mitochondrial RCR (r=-0.39; p=0.02) and positively with LCR (r=0.42; p=0.02), but not with oxidative capacity (p=0.34). Maximum increase of insulin in proportion to fasting levels strongly related to ventricular myocardial mitochondrial RCR (r=0.62; p=0.0001) and inversely to LCR (r=-0.46; p=0.01). This insulin secretory response related to fatty acid-dependent respiration (r=0.35; p=0.05) and tended to relate to combined oxidative capacity from fatty acid and glycolytic substrates (r=0.31; p=0.09). Maximum insulin response following glucose ingestion relates to cardiac mitochondrial efficiency and oxidative capacity, while insulin resistance might affect cardiac energy metabolism. These data suggest a pathogenic role of hyperinsulinemia as well as beta cell failure in diabetes-related heart failure. Disclosure E. Zweck: None. D. Scheiber: None. S. Albermann: None. J. Borger: None. T. Jelenik: None. D. Pesta: None. P. Horn: None. U. Boeken: None. P. AKhyari: Research Support; Self; Abbott, Edwards Lifesciences Corporation, Medtronic. M. Kelm: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. R. Westenfeld: None. J. Szendroedi: None. Funding German Research Foundation (CRC1116); Heinrich-Heine University

Background In secondary MR, data on left ventricular (LV) remodeling after MitraClip procedure are rare, even this information may impact patient selection. This study investigated changes in LV structure and function by cardiovascular magnetic resonance (CMR) following MitraClip implantation for secondary mitral regurgitation (MR) in order to assess extent and predictors of LV reverse remodeling (LVRR). Methods and Results Twenty-nine patients underwent CMR imaging prior to and six months after MitraClip procedure. LVRR was defined by a decrease of LV end-diastolic volume index (LVEDVi) > 15% compared to baseline. According to the definition of LVRR, 34% of patients displayed LVRR at follow-up CMR. Baseline LV stroke volume index (LVSVi), LV ejection fraction (LVEF), LV circumferential strain and MR volume at baseline were predictors of LVRR at follow-up. At second CMR, we detected an improvement in hemodynamic status as illustrated by an increase in effective LVSVi (28 ± 8 ml/m2 vs. 33 ± 8 ml/m2; p = 0.053) and cardiac index (2.0 ± 0.5 vs. 2.3 ± 0.5 l/min; p = 0.016), while LVEF and LV strain parameters did not change (p > 0.05). Improvements in effective LVSVi were associated with the decrease of MR volume (r = 0.509; p = 0.018) and MR fraction (r = 0.629; p = 0.002) by MitraClip. Conclusions Together, MitraClip implantation is associated with LVRR in one third of patients. Baseline LV function and magnitude of MR are important predictors of LVRR. Improvement of hemodynamic status may be assessed by effective stroke volume index and correlates with the reduction of MR by MitraClip implantation, rather than an increase in LV contractility.

Purpose Representing a rare complication, antibody-mediated graft rejection (AMR), particularly caused by donor-specific antibodies (DSA), remains a serious problem after heart transplantation (HTx). Plasmapheresis, application of rituximab as well as intravenous immunoglobulins (IVIG) are widely established, however often insufficient treatments for AMR. IgM-enriched human intravenous immunoglobulin (IGM-IVIG) consists of IgM, IgA and IgG and provides a new multifactorial approach to the immunologic cascade of DSA-mediated AMR, however its efficiency is by now still not clear. Methods Between 2017 and 2020 four patients (P 1-4) developed DSA-mediated rejection (DSA-MR) after HTx in our department and were repetitively treated with 0.5-1.0 g/kg body weight IGM-IVIG (Pentaglobin®, Biotest AG, Dreieich, Germany) in combination with 3.0 mg/kg body weight anti-thymocyte globulin (ATG). Results Patients were transplanted at the age of 47 (P1), 57 (P2), 30 (P3) and 68 years (P4). Except P2, all patients were male. While in P1 and P4, DSA-MR occurred within the early postoperative interval after HTx, P2 and P3 developed DSA-MR one year after transplantation. In all patients donor-specific HLA-antibodies were found, however pathological examinations of right ventricular biopsies could only confirm AMR in P1-3 (pAMR1° to pAMR3°) but not in P4 (pAMR0). A severe impairment of biventricular function was observed in all patients with need for temporary veno-arterial extracorporeal membrane oxygenation (va-ECMO) in P4. Furthermore, P1 and P4 suffered from malign ventricular arrhythmias. After repetitive application of IGM-IVIG all patients could be stabilized, ventricular function recovered, and P1-3 could be discharged from hospital and are still alive today, whereas P4 has been transplanted quite recently and is still recovering in hospital. Conclusion DSA-MR provokes serious complications affecting the outcome after HTx. By application of IGM-IVIG, we were able to successfully treat all of our four patients suffering from severe graft failure caused by DSA-MR and no patient developed treatment-related adverse effects. As part of a multifactorial therapeutic approach, pharmacological treatment with IGM-IVIG seems to be a safe and effective strategy in order to address DSA-MR and offers promising results for the future.

Background: Hysteroscopic morcellation removes uterine pathology under direct visualization with continuous real-time tissue fragment removal. Objective: The aim of this study was to explore the feasibility of hysteroscopic morcellation across a diverse set of facilities, including both surgical and office-based settings. Design: This was a prospective, single-arm, multicenter registry development (Canadian Task Force classification II-3). Materials and Methods: Thirty-four U.S. obstetrics and gynecology facilities enrolled subjects into the registry. Inclusion criteria were women ages 18–65 with indications for hysteroscopic myomectomy and/or polypectomy who were treated with the MyoSure® Hysteroscopic Tissue Removal System (Hologic Inc., Marlborough, MA). Intrauterine lesion type/size and removal parameters, adverse events (AEs), and physician satisfaction ratings were recorded. Results: A total of 559 pathologies (187 fibroids; 372 polyps) were removed from 278 registered subjects (mean age: 43.9 ± 9.0 years), with 250 procedures (89.9%) performed in an ambulatory surgery center or hospital outpatient setting and 28 (10.1%) in a gynecologic office setting. Most patients (n = 206, 74.1%) were treated for abnormal uterine bleeding, and 42 (15.1%) were treated for infertility. Mean fibroid diameter was 2.2 ± 1.2 cm. Mean polyp diameter was 1.3 ± 1.0 cm. Overall mean percentage of pathology removed was 95.4% (polyps 99.3%, fibroids 86.8%). Five AEs included four incidents of blunt cervical trauma and a single postoperative case of pedal edema; all were considered mild and resolved spontaneously. Postprocedure surveys indicated that 95% of reporting physicians were “satisfied” or “highly satisfied” with device performance. Conclusions: Hysteroscopic morcellation of intrauterine pathology was accomplished safely with a high degree of physician satisfaction in 278 patients treated in diverse healthcare settings that are reflective of general community practice in the United States. (J GYNECOL SURG 32:318)

Aims To evaluate whether CMR-derived RV assessment can facilitate risk stratification among patients undergoing transcatheter mitral valve repair (TMVR). Background In patients undergoing TMVR, only limited data exist regarding the role of RV function. Previous studies assessed the impact of pre-procedural RV dysfunction stating that RV failure may be associated with increased cardiovascular mortality after the procedure. Methods Sixty-one patients underwent CMR, echocardiography and right heart catheterization prior TMVR. All-cause mortality and heart failure hospitalizations were assessed during 2-year follow-up. Results According to RV ejection fraction (RVEF) Conclusion In patients undergoing TMVR, pre-existing RV dysfunction and RV dilatation are associated with reduced survival, in progressive additive fashion. The assessment of RV volumes and function by CMR may aid in risk stratification prior TMVR in these high-risk patients.

Hepatic and myocardial ectopic lipid deposition has been associated with insulin resistance (IR) and cardiovascular risk. Lipid overload promotes increased hepatic oxidative capacity, oxidative stress, and impaired mitochondrial efficiency, driving the progression of nonalcoholic fatty liver disease (NAFLD). We hypothesized that higher lipid availability promotes ischemia-induced cardiac dysfunction and decreases myocardial mitochondrial efficiency. Mice with adipose tissue–specific overexpression of sterol element–binding protein 1c as model of lipid overload with combined NAFLD-IR and controls underwent reperfused acute myocardial infarcts (AMIs). Whereas indexes of left ventricle (LV) contraction were similar in both groups at baseline, NAFLD-IR showed severe myocardial dysfunction post-AMI, with prominent LV reshaping and increased end-diastolic and end-systolic volumes. Hearts of NAFLD-IR displayed hypertrophy, steatosis, and IR due to 18:1/18:1-diacylglycerol–mediated protein kinase Cε (PKCε) activation. Myocardial fatty acid–linked respiration and oxidative stress were increased, whereas mitochondrial efficiency was decreased. In humans, decreased myocardial mitochondrial efficiency of ventricle biopsies related to IR and troponin levels, a marker of impaired myocardial integrity. Taken together, increased lipid availability and IR favor susceptibility to ischemia-induced cardiac dysfunction. The diacylglycerol-PKCε pathway and reduced mitochondrial efficiency both caused by myocardial lipotoxicity may contribute to the impaired LV compensation of the noninfarcted region of the myocardium.

Mechanical ventricular unloading in advanced heart failure (HF) has been shown to induce reverse remodeling in myocardial tissues. Little is known about the impact of ventricular unloading on myocardial energy metabolism. We hypothesized that left ventricular unloading reduces myocardial mitochondrial reactive oxygen species (ROS) production and improves mitochondrial coupling efficiency in patients suffering from advanced HF. Left ventricular tissue specimens were harvested from explanted hearts at the time of transplantation. We compared myocardial metabolism in explanted hearts supported with an unloading ventricular assist device prior to transplantation (LVAD-HTX; n = 9) with tissue specimens of unsupported failing hearts (HTX; n = 6). Myocardial mitochondrial ROS production was decreased by 40% in LVAD-HTX compared to HTX patients (1.5 ± 0.3 vs. 0.9 ± 0.1 pmol/(s/mg); p