Cardiac Amyloidosis (CA) remains highly underdiagnosed, especially among patients with causes of increased ventricular wall thickness, such as aortic stenosis (AS). The prevalence of CA throughout the spectrum of mild to severe AS is unknown and specific validated diagnostic parameters for this population are lacking. Here, we propose and prospectively evaluate a screening algorithm for CA among patients with mild to severe AS. In this prospective, single-center study (NCT05010980), we included patients ≥ 65 years with mild to severe AS, an interventricular septum thickness > 11 mm, and at least one of the following criteria: Sokolow-Lyon-Index to left ventricular mass index ratio < 1.6 or stroke volume index < 35 ml/m2. Participants were prospectively screened for CA according to current guideline recommendations. After screening 2126 patients of whom 187 were eligible, 57 participants were enrolled and completed the diagnostic work-up. Mean age was 83 ± 0.7 years and 71

BACKGROUND:Reduced mitochondrial respiratory function has been implicated in metabolic disorders like type 2 diabetes (T2D), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD), which are tightly linked to insulin resistance and impaired metabolic flexibility. However, the contribution of the ketone bodies (KBs) β-hydroxybutyrate (HBA) and acetoacetate (ACA) as substrates for mitochondrial oxidative phosphorylation (OXPHOS) in these insulin resistant states remains unclear. METHODS:Targeted high-resolution respirometry protocols were applied to detect the differential contribution of HBA and ACA to OXPHOS capacity in heart, skeletal muscle, kidney, and liver of distinct human or murine cohorts with T2D, obesity, and MASLD. FINDINGS:In humans with T2D, KB-driven mitochondrial OXPHOS capacity was ∼30% lower in the heart (p < 0.05) and skeletal muscle (p < 0.05) compared to non-diabetic controls. The relative contribution of KBs to maximal OXPHOS capacity in T2D was also lower in both the heart (∼25%, p < 0.05) and skeletal muscle (∼50%, p < 0.05). Similarly, in kidney cortex from high-fat diet-induced obese mice, both the absolute and relative contribution of KBs to OXPHOS capacity was ∼15% lower (p < 0.05). Finally, hepatic HBA-driven mitochondrial OXPHOS capacity was 29% lower (p < 0.05) in obese humans with hepatic steatosis compared to humans without. INTERPRETATION:Mitochondrial KB-driven OXPHOS capacity is impaired in insulin resistant states in various organs in absolute and relative terms, likely reflecting impaired mitochondrial metabolic flexibility. Our data suggest that KB respirometry can provide a sensitive readout of impaired mitochondrial function in diabetes, obesity, and MASLD. FUNDING:German Research Foundation, German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Center for Diabetes Research, German Heart Foundation, German Diabetes Society, Christiane-and-Claudia Hempel Foundation, European Community and Schmutzler Stiftung.

AIMS:Heart transplantation (HTX) is the treatment of choice for advanced heart failure. Still, long-term survival needs to be improved. Recent studies showed that obesity and type 2 diabetes (T2D) as well as impaired renal and liver function are associated with mortality post-HTX. There are many open questions including (i) optimal metabolic surveillance post-transplant, (ii) association of metabolic deterioration and cardiac function, (iii) association with hepatic and renal deterioration, and (iv) optimal timing and choice of treatment. The METAB-HTX trial will address these open questions, hypothesizing that metabolic deterioration post-HTX is associated with impaired cardiac function and survival. METHODS AND RESULTS:METAB-HTX is a prospective, longitudinal cohort study, enrolling 400 patients post-HTX in a period of 5 years. Time-series, deep cardiac, and metabolic phenotyping will be conducted. Cardiac function will be analysed by echocardiography as well as serial cardiac magnetic resonance imaging and spectroscopy (cMRI/MRS). Coronary angiography will be conducted to assess both macrovascular and microvascular coronary allograft vasculopathy (CAV). To evaluate allograft rejection, endomyocardial biopsies will be taken. Metabolic alterations will be investigated by (i) glucometabolic phenotyping including serial oral glucose tolerance tests, homeostasis model assessment, T2D endotyping, and muscle biopsies in selected cases; (ii) lipid disorders will be evaluated by classical lipid measurements in combination with evaluation of HDL function, plasma membrane lipid composition, fluidity analyses of circulating cells and MRI/MRS for adipose tissue distribution, and ectopic fat analysis. Kidney and liver function and structural alterations will be evaluated. Complex analyses will be conducted to evaluate (i) myocardial substrate utilization and energy metabolism by cardiac and circulating cell respirometry, (ii) impact of genetic (including immunogenetic) and transcriptomic factors by third- and fourth generation sequencing (short- and long-read sequencing), (iii) circulating signatures of future neoplasia by single-cell sequencing of circulating leucocytes, and (iv) evaluation of thromboinflammation in association with heart transplant events. The primary endpoint will be the incidence of heart transplant events, defined as worsening of systolic or diastolic left ventricular function, CAV, allograft rejection, worsening of kidney function, metabolic liver disease, infections, neoplasia, deterioration of glucose and lipid metabolism. Secondary outcomes include hospitalizations related to primary endpoints, re-HTX or ventricular assist device, cardiovascular mortality, and all-cause mortality. CONCLUSIONS:The METAB-HTX trial will identify early metabolic alterations potentially impairing cardiac function and outcome of HTX patients. This will identify patients at risk and allow precise planning of interventional trials to treat metabolic alterations post-HTX and improve outcome.

Die orthotope Herztransplantation ist der therapeutische Goldstandard in der Behandlung der fortgeschrittenen Herzinsuffizienz. Eine bedeutende postoperative Komplikation ist die primäre Transplantatdysfunktion (PGD), welche sich als Funktionseinschränkung einer der beiden Herzkammern oder als biventrikuläre Dysfunktion manifestieren kann. In der Folge kann nach Ausschöpfung der medikamentösen Therapie eine Behandlung mit einem mechanischen Kreislaufunterstützungssystem (MCS) notwendig werden. Dabei ist nicht nur eine linksventrikuläre Einschränkung, sondern auch ein reines rechtsventrikuläres Versagen prognostisch von Bedeutung. In diesem Beitrag möchten wir daher anhand mehrerer Fälle eines primären Rechtsherzversagens nach Herztransplantation unter Berücksichtigung der komplexen Anatomie und Hämodynamik des rechten Herzens auf die zur Verfügung stehenden Therapieoptionen eingehen.

Abnormal mitochondrial oxidative phosphorylation (OXPHOS) is key to the pathogenesis of several cardiometabolic diseases. The ketone bodies (KBs), β-hydroxybutyrate (HBA) and acetoacetate (ACA), are critical for tissue-specific energy metabolism under various pathophysiological conditions. However, robust methods quantifying their contribution as substrates for OXPHOS are lacking. Here, we first established comprehensive high-resolution respirometry protocols for assessing the differential contributions of HBA, ACA, and related ketolytic enzymes to OXPHOS in translational studies in mice and humans. We then utilized these protocols to demonstrate (i) organ-specific differences in KB-driven mitochondrial respiration in mice, (ii) lower KB-driven mitochondrial respiration in liver of humans with steatosis, skeletal muscle of humans with diabetes and in kidney of diet-induced obese mice, as well as (iii) higher mitochondrial KB utilization capacity in mouse and human failing heart. These results highlight organ-specific roles of KB metabolism in cardiometabolic diseases and shall help to identify novel targets in these pathways. ### Competing Interest Statement AP receives research funding from Abiomed outside of this work. RaW is employed by Abiomed. RoW reports lecture fees from Novo Nordisk, Sanofi-Aventis, Boehringer Ingelheim and Eli Lilly, and served on the advisory board for Akcea Therapeutics, Daiichi Sankyo, Sanofi-Aventis, Eli Lilly, and NovoNordisk. MR is currently on scientific advisory boards of Astra Zeneca, Boehringer Ingelheim, Echosens, Eli Lilly, Madrigal, Merck-MSD, Novo Nordisk, and Target RWE, and has received support for investigator-initiated studies from Boehringer Ingelheim, Novo Nordisk and Nutricia/Danone. The other authors declare no competing interests.

AbstractAimsMyocardial inflammation and impaired mitochondrial oxidative capacity are hallmarks of heart failure (HF) pathophysiology. The extent of myocardial inflammation in patients suffering from ischaemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) and its association with mitochondrial energy metabolism are unknown. We aimed at establishing a relevant role of cardiac inflammation in the impairment of mitochondrial energy production in advanced ischaemic and non‐ischaemic HF.MethodsWe included 81 patients with stage D HF (ICM, n = 44; DCM, n = 37) undergoing left ventricular assist device implantation (n = 59) or heart transplantation (n = 22) and obtained left ventricular tissue samples during open heart surgery. We quantified mitochondrial oxidative capacity, citrate synthase activity (CSA) and fibrosis and lymphocytic infiltration. We considered infiltration of >14 CD3+ cells/mm2 relevant inflammation.ResultsPatients with ICM or DCM did not differ regarding age (61.5 ± 5.7 vs. 56.5 ± 12.7 years, P = 0.164), sex (86% vs. 84% male, P = 0.725), type 2 diabetes mellitus (34% vs. 18%, P = 0.126) or chronic kidney disease (8% vs. 11%, P = 0.994). ICM exhibited oxidative capacity reduced by 23% compared to DCM (108.6 ± 41.4 vs. 141.9 ± 59.9 pmol/(s*mg), P = 0.006). Maximum production of reactive oxygen species was not significantly different between ICM and DCM (0.59 ± 0.28 vs. 0.69 ± 0.36 pmol/(s*ml), P = 0.196). Mitochondrial content, detected by CSA, was lower in ICM (359.6 ± 164.1 vs. 503.0 ± 198.5 nmol/min/mg protein, P = 0.002). Notably, relevant inflammation was more common in ICM (27% vs. 6%, P = 0.024), and the absolute number of infiltrating leucocytes correlated with lower oxidative capacity (r = −0.296, P = 0.019). Fibrosis was more prevalent in ICM (20.9 ± 21.2 vs. 7.2 ± 5.6% of area, P = 0.002), but not associated with oxidative capacity (r = −0.13, P = 0.327).ConclusionsMore than every fourth ICM patient with advanced HF displays myocardial inflammation in the range of inflammatory cardiomyopathy associated with reduced mitochondrial oxidative capacity. Future studies may evaluate inflammation in ICM at earlier stages in standardised fashion to explore the therapeutic potential of immunosuppression to influence trajectories of HF in ICM.

Abstract Aims Cancer therapy-related cardiac dysfunction (CTRCD) is a dreaded complication of anthracycline therapy. CTRCD most frequently appears in patients with cardiovascular risk factors (CVR) or known cardiovascular disease. However, limited data exist on incidence and course of anthracycline-induced CTRCD in patients without preexisting risk factors. We therefore aimed to longitudinally investigate a cohort of young women on anthracycline treatment due to breast cancer without cardiovascular risk factors or known cardiovascular disease (NCT03940625). Methods and results We enrolled 59 women with primary breast cancer and scheduled anthracycline-based therapy, but without CVR or preexisting cardiovascular disease. We conducted a longitudinal assessment before, immediately and 12 months after cancer therapy with general laboratory, electrocardiograms, echocardiography and cardiovascular magnetic resonance (CMR), including myocardial relaxometry with T1, T2 and extracellular volume mapping. Every single patient experienced a drop in CMR-measured left ventricular ejection fraction (LVEF) of 6 ± 3% immediately after cancer therapy. According to the novel definition 32 patients (54.2%) developed CTRCD after 12 months defined by reduction in LVEF, global longitudinal strain (GLS) and/or biomarkers elevation, two of them were symptomatic. Global myocardial T2 relaxation times as well as myocardial mass increased coincidently with a decline in wall-thickening. While T2 values and myocardial mass normalized after 12 months, LVEF and GLS remained impaired. Conclusion In every single patient anthracyclines induce a decline of myocardial contractility, even among patients without pre-existing risk factors for CTRCD. Our data suggest to thoroughly evaluate whether this may lead to an increased risk of future cardiovascular events. Graphical Abstract Reduced myocardial contractility in low-risk patients receiving anthracycline-based cancer therapy. This study included 59 otherwise healthy women with primary breast cancer undergoing anthracycline-based chemotherapy. CMR was performed at baseline, directly and 12 months after cancer therapy. A decline in left ventricular function was observed in every single patient accompanied by transient edema. More than 50% were diagnosed with cancer therapy related cardiovascular dysfunction. LVEF: left ventricular function, CTRCD: cancer therapy related cardiovascular dysfunction, GLS = Global longitudinal strain, hs-TnT = high sensitive Troponin T, NT-pro BNP = NT-pro brain natriuretic peptide

Purpose: Cardiac amyloidosis is a common cause of heart failure with preserved ejection fraction and increasingly recognized since new diagnostic algorithms and therapeutic approaches were established during recent years. Mitochondrial dysfunction is known to play a key role in different etiologies of human heart failure but its role in cardiac amyloidosis remains unclear. Here we investigated myocardial mitochondrial function in endomyocardial biopsies from humans with different types of cardiac amyloidosis.

Aims: Identifying patients who may benefit from mechanical circulatory support (MCS) after out-of-hospital cardiac arrest (OHCA) and return of spontaneous circulation (ROSC) remains challenging; thus, a search for helpful biomarkers is warranted. We aimed to evaluate phosphate and lactate levels on admission regarding their associations with survival with and without MCS. Methods: In 224 OHCA patients who achieved ROSC, the initial phosphate and lactate levels were investigated to discriminate in-hospital mortality by receiver operating characteristic (ROC) curves. According to the Youden Index (YI) from the respective ROC, the groups were risk stratified by both biomarkers, and 30-day mortality was analyzed in patients with and without MCS. Results: Within the entire collective, MCS was not associated with a better chance of survival. Both phosphate and lactate level elevations showed good yet comparable discriminations to predict mortality (areas under the curve: 0.80 vs. 0.79, p = 0.74). In patients with initial phosphate values > 2.2 mmol/L (>YI), 30-day mortality within the MCS cohort was lower (HR 2.3, 95% CI: 1.4–3.7; p = 0.0037). In patients with lower phosphate levels and groups stratified by lactate, 30-day mortality was similar in patients with and without MCS. Conclusions: We found a significant association between survival and MCS therapy in patients with phosphate levels above 2.2 mmol/L (Youden Index), and a similar discrimination of patient overall survival by lactate and phosphate. Prospective studies should assess the possible independent prognostic value of phosphate and its clearance for MCS efficiency.

BACKGROUND:Out-of-hospital cardiac arrest (OHCA) remains a frequent medical emergency with low survival rates even after a return of spontaneous circulation (ROSC). Growing evidence supports formation of dedicated teams in scenarios like cardiogenic shock to improve prognosis. Thus, the European Resuscitation Council (ERC) recommended introduction of Cardiac Arrest Centers (CAC) in their 2015 guidelines. Here, we aimed to elucidate the effects of newly introduced CACs in Germany regarding survival rate and neurological outcome. METHODS:A multicenter retrospective observational cohort study was performed at three university hospitals and outcomes after OHCA were compared before and after CAC accreditation. Primary outcomes were survival until discharge and favorable neurological status (CPC 1 or 2) at discharge. RESULTS:In total 784 patients (368 before and 416 after CAC accreditation) were analyzed. Rates of immediate percutaneous coronary intervention (40 vs. 52%, p = 0.01) and implementation of extracorporeal CPR (8 vs. 13%, p < 0.05) increased after CAC accreditation. Likelihood of favorable neurological status at discharge was higher after CAC accreditation (71 vs. 87%, p < 0.01), whereas overall survival remained similar (35 vs. 35%, p > 0.99). CONCLUSION:CAC accreditation is linked to higher rates of favorable neurological outcome and unchanged overall survival.

Myat Soe Thet et al. published a letter [...].

Since March 2020, the COVID‐19 pandemic has tremendously impacted health care all around the globe. We analyzed the impact of the pandemic on donors, recipients, and outcome of heart transplantation (HTx).

Background Orthotopic heart transplantation (HTX) is the gold standard to treat end-stage heart failure. Numerous risk stratification tools have been developed in the past years. However, their clinical utility is limited by their poor discriminative ability. High sensitivity troponin T (hsTnT) is the most specific biomarker to detect myocardial cell injury. However, its prognostic relevance after HTX is not fully elucidated. Thus, this study evaluated the predictive value of postoperative hsTnT for 1-year survival and days alive and out of hospital (DAOH) after HTX. Methods This retrospective cohort study included patients who underwent HTX at the University Hospital Duesseldorf, Germany between 2011 and 2021. The main exposure was hsTnT concentration at 48 h after HTX. The primary endpoints were mortality and DAOH within 1 year after surgery. Receiver operating characteristic (ROC) curve analysis, logistic regression model and linear regression with adjustment for risk index for mortality prediction after cardiac transplantation (IMPACT) were performed. Results Out of 231 patients screened, 212 were included into analysis (mean age 55 ± 11 years, 73% male). One-year mortality was 19.7% (40 patients) and median DAOH was 298 days (229–322). ROC analysis revealed strongest discrimination for mortality by hsTnT at 48 h after HTX [AUC = 0.79 95% CI 0.71–0.87]. According to Youden Index, the cutoff for hsTnT at 48 h and mortality was 1640 ng/l. After adjustment for IMPACT score multivariate logistic and linear regression showed independent associations between hsTnT and mortality/DAOH with odds ratio of 8.10 [95%CI 2.99–21.89] and unstandardized regression coefficient of −1.54 [95%CI −2.02 to −1.06], respectively. Conclusion Postoperative hsTnT might be suitable as an early prognostic marker after HTX and is independently associated with 1-year mortality and poor DAOH.

A causal link between non-ischaemic heart failure (HF) and humoral autoimmunity against G-protein-coupled receptors (GPCR) remains unclear except for Chagas' cardiomyopathy. Uncertainty arises from ambiguous reports on incidences of GPCR autoantibodies, spurious correlations of autoantibody levels with disease activity, and lack of standardization and validation of measuring procedures for putatively cardio-pathogenic GPCR autoantibodies. Here, we use validated and certified immune assays presenting native receptors as binding targets. We compared candidate GPCR autoantibody species between HF patients and healthy controls and tested associations of serum autoantibody levels with serological, haemodynamic, metabolic, and functional parameters in HF. Ninety-five non-ischaemic HF patients undergoing transcatheter endomyocardial biopsy and 60 healthy controls were included. GPCR autoantibodies were determined in serum by IgG binding to native receptors or a cyclic peptide (for β1AR autoantibodies). In patients, cardiac function, volumes, and myocardial structural properties were assessed by cardiac magnetic resonance imaging; right heart catheterization served for determination of cardiac haemodynamics; endomyocardial biopsies were used for histological assessment of cardiomyopathy and determination of cardiac mitochondrial oxidative function by high-resolution respirometry. Autoantibodies against β 1 adrenergic (β 1 AR ) , M5-muscarinic (M5AR), and angiotensin II type 2 receptors (AT2R) were increased in HF (all P  < 0.001). Autoantibodies against α 1 -adrenergic (α 1 AR) and angiotensin II type 1 receptors (AT1R) were decreased in HF (all P  < 0.001). Correlation of alterations of GPCR autoantibodies with markers of cardiac or systemic inflammation or cardiac damage, haemodynamics, myocardial histology, or left ventricular inflammation (judged by T2 mapping) were weak, even when corrected for total IgG. β 1 AR autoantibodies were related inversely to markers of left ventricular fibrosis indicated by T1 mapping (r = −0.362, P  < 0.05) and global longitudinal strain (r = −0.323, P  < 0.05). AT2R autoantibodies were associated with improved myocardial mitochondrial coupling as measured by high-resolution respirometry in myocardial biopsies (r = −0.352, P  < 0.05). In insulin-resistant HF patients, AT2R autoantibodies were decreased (r = −.240, P  < 0.05), and AT1R autoantibodies were increased (r = 0.212, P  < 0.05). GPCR autoantibodies are markedly altered in HF. However, they are correlated poorly or even inversely to haemodynamic, metabolic, and functional markers of disease severity, myocardial histology, and myocardial mitochondrial efficiency. These observations do not hint towards a specific cardio-pathogenic role of GPCR autoantibodies and suggest that further investigations are required before specific therapies directed at GPCR autoantibodies can be clinically tested in non-ischaemic HF.

Purpose It was reported that mRNA-based Covid-19 vaccines rarely cause myocarditis. Although endomyocardial biopsy (EMB) is considered the gold standard for diagnosing myocarditis, no standardized study has been performed after Covid-19 vaccination in humans. Because routine EMB is frequently performed in heart transplant recipients (HTX), we aimed here to investigate effects of Covid-19 vaccination by analyzing myocardial inflammation with state-of-the-art quantitative immunohistochemistry. Methods Consecutive patients after HTX who underwent routine EMB at a median of 167 days before and 136 days after the first Covid 19 vaccination with an mRNA vaccine were included and divided into groups with and without postvaccination inflammatory response, defined as increased CD3+ lymphocyte count >14/ mm2. Patients with evidence of rejection (ISHLT grade >1) or >14 CD3+ lymphocytes/mm2 at baseline were excluded. Results The final analysis included 46 patients with a mean age of 63 years and a time after HTX of 2.4 years. Thirty-six (78%) patients remained below the threshold of 14 CD3+ lymphocytes/mm2. However, in 10 (22%) recipients, we detected significant leukocyte infiltration by quantitative analysis of EMB after vaccination (4 vs. 33.7 leukocytes/ mm2, p=0.001). The groups did not differ with respect to age (63 vs. 57 years, p=0.21), body mass index (25 vs. 24 kg/m2, p=0.24), NYHA class (≥2 at 19 vs. 10%, p=0.4), NT-ProBNP levels (592 vs. 514 ng/l, p=0.55) or myocardial CD3+ cell count (4.9 vs. 2.6 cells/mm2, p=0.07) before vaccination. Patients with leukocyte infiltration remained clinically inapparent with stable NYHA class (≥2 in 10 vs. 20%, p=0.99) and did not have increased NT-ProBNP levels (514 vs. 478 ng/l, p=0.03). No hospitalizations for suspected myocarditis were reported. Conclusion For the first time, we report subclinical myocardial leukocyte infiltration after Covid-19 mRNA vaccination in one in five patients without clinical sequelae during the short observation period.

HomeCirculationVol. 146, No. 15Impaired Myocardial Mitochondrial Respiration in Humans With Prediabetes: A Footprint of Prediabetic Cardiomyopathy No AccessLetterRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessLetterRequest AccessFull TextImpaired Myocardial Mitochondrial Respiration in Humans With Prediabetes: A Footprint of Prediabetic Cardiomyopathy Elric Zweck, MD, Daniel Scheiber, MD, Heinz-Peter Schultheiss, MD, Oliver Kuss, PhD, Malte Kelm, MD, Michael Roden, MD, Ralf Westenfeld, MD and Julia Szendroedi, MD, PhD Elric ZweckElric Zweck https://orcid.org/0000-0001-6739-476X Division of Cardiology, Pulmonology and Vascular Medicine (E.Z., D.S., M.K., R.W.), Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany Institute for Clinical Diabetology (E.Z., D.S., M.R., J.S.), German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Düsseldorf. Institute for Biometrics and Epidemiology (O.K.), German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Düsseldorf. , Daniel ScheiberDaniel Scheiber https://orcid.org/0000-0002-6352-2565 Division of Cardiology, Pulmonology and Vascular Medicine (E.Z., D.S., M.K., R.W.), Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany Institute for Clinical Diabetology (E.Z., D.S., M.R., J.S.), German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Düsseldorf. Institute for Biometrics and Epidemiology (O.K.), German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Düsseldorf. , Heinz-Peter SchultheissHeinz-Peter Schultheiss Heinrich-Heine University, Düsseldorf, Germany (H-P.S.). , Oliver KussOliver Kuss https://orcid.org/0000-0003-3301-5869 Institute for Biometrics and Epidemiology (O.K.), German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Düsseldorf. , Malte KelmMalte Kelm https://orcid.org/0000-0003-0060-1052 Division of Cardiology, Pulmonology and Vascular Medicine (E.Z., D.S., M.K., R.W.), Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany Cardiovascular Research Institute Düsseldorf (M.K., M.R.), Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany , Michael RodenMichael Roden Institute for Clinical Diabetology (E.Z., D.S., M.R., J.S.), German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Düsseldorf. German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg (E.Z., D.S., M.R., J.S.). Cardiovascular Research Institute Düsseldorf (M.K., M.R.), Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany Division of Endocrinology and Diabetology (M.R.), Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany , Ralf WestenfeldRalf Westenfeld Division of Cardiology, Pulmonology and Vascular Medicine (E.Z., D.S., M.K., R.W.), Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany and Julia SzendroediJulia Szendroedi Correspondence to: Julia Szendroedi, MD, PhD, Department of Endocrinology, Diabetology, Metabolism, and Clinical Chemistry, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Email E-mail Address: [email protected] https://orcid.org/0000-0002-7296-7152 Department of Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, Heidelberg; Institute for Diabetes and Cancer; and Joint Heidelberg-IDC Translational Diabetes Program, Helmholtz Center Munich, München-Neuherberg, Germany (J.S.). Institute for Clinical Diabetology (E.Z., D.S., M.R., J.S.), German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Düsseldorf. German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg (E.Z., D.S., M.R., J.S.). Originally published10 Oct 2022https://doi.org/10.1161/CIRCULATIONAHA.122.058995Circulation. 2022;146:1189–1191FootnotesCirculation is available at www.ahajournals.org/journal/circFor Sources of Funding and Disclosures, see page 1191.Correspondence to: Julia Szendroedi, MD, PhD, Department of Endocrinology, Diabetology, Metabolism, and Clinical Chemistry, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Email Julia.[email protected]uni-heidelberg.deReferences1. Wu JD, Liang D, Xie Y. Prediabetes and risk of heart failure: the link grows stronger.Cardiovasc Diabetol. 2021; 20:112. doi: 10.1186/s12933-021-01302-wCrossrefMedlineGoogle Scholar2. Nunes S, Soares E, Fernandes J, Viana S, Carvalho E, Pereira FC, Reis F. Early cardiac changes in a rat model of prediabetes: brain natriuretic peptide overexpression seems to be the best marker.Cardiovasc Diabetol. 2013; 12:44. doi: 10.1186/1475-2840-12-44CrossrefMedlineGoogle Scholar3. Zweck E, Scheiber D, Jelenik T, Bonner F, Horn P, Pesta D, Schultheiss HP, Boeken U, Akhyari P, Lichtenberg A, et al. Exposure to type 2 diabetes provokes mitochondrial impairment in apparently healthy human hearts.Diabetes Care. 2021; 44:e82–e84. doi: 10.2337/dc20-2255CrossrefMedlineGoogle Scholar4. Scheiber D, Jelenik T, Zweck E, Horn P, Schultheiss HP, Lassner D, Boeken U, Saeed D, Kelm M, Roden M, et al. High-resolution respirometry in human endomyocardial biopsies shows reduced ventricular oxidative capacity related to heart failure.Exp Mol Med. 2019; 51:116–110. doi: 10.1038/s12276-019-0214-6CrossrefGoogle Scholar5. Tura A, Chemello G, Szendroedi J, Gobl C, Faerch K, Vrbikova J, Pacini G, Ferrannini E, Roden M. Prediction of clamp-derived insulin sensitivity from the oral glucose insulin sensitivity index.Diabetologia. 2018; 61:1135–1141. doi: 10.1007/s00125-018-4568-4CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails October 11, 2022Vol 146, Issue 15 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.058995PMID: 36214134 Originally publishedOctober 10, 2022 Keywordscardiomyopathiesprediabetic statemitochondriatransplantsdiabetes mellitus, type 2PDF download Advertisement SubjectsHeart FailureMetabolic SyndromeMetabolismPhysiology

Objective: Although the application of higher doses of norepinephrine (NE) in potential organ donors is a frequent reason for heart decline, its associations with outcomes after heart transplantation (HTx) are discussed controversially. Therefore, we aimed to explore donor NE support’s potential impact on outcomes in our single-center heart transplant cohort. Methods: All patients who had undergone HTx in our center between September 2010 and April 2022 (n = 241) were screened for eligibility. From those, all patients with complete data on donor NE support (n = 238) were included. Recipients were divided into three groups according to their donor NE support: without support (n = 26), with low support of 0.01–0.2 µg/kg/min (n = 132), and with high support of > 0.2 µg/kg/min (n = 80). Receiver operating characteristics (ROC) and Kaplan Meier analysis was used to investigate the association of donor NE support and mortality after heart transplantation. Recipient and donor variables, including peri- and postoperative characteristics, were reviewed and compared. Results: NE support in donors ranged between 0 and 2.94 µg/kg/min (median 0.13 µg/kg/min, IQR 0.05–0.26 µg/kg/min). No association between donor NE support and mortality after HTx was observed (AUC for overall survival 0.494). Neither Kaplan-Meier analysis in survival up to 5 years after transplantation (Log Rank p = 0.284) nor group comparisons showed significant differences between the groups. With few exceptions, baseline characteristics in recipients and donors were comparable between the groups. Regarding peri- and postoperative parameters, increasing donor NE support was associated with a longer duration of mechanical ventilation (68 h and 95 h vs. 47 h), longer postoperative IMC/ICU stay (14 vs. 15 vs. 19 days), and a higher need for mechanical life support post-HTx (26% and 39% vs. 12%). Conclusion: In this retrospective analysis, NE support in donors prior to heart transplantation was unrelated to differing survival after heart transplantation. However, higher doses of donor NE were associated with prolonged ventilation, longer duration on IMC/ICU, and a higher need for extracorporeal life support in recipients post-HTx.