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A high body mass index (BMI) is often associated with metabolic syndrome, which is accompanied by systemic low-grade chronic inflammation. Here, we analyzed whether BMI, other components of metabolic syndrome, and/or inflammatory markers correlate with left ventricular geometry, function, and infarct size as assessed by serial cardiac magnetic resonance imaging (MRI) after a first (clinically evident) ST-elevation MI (STEMI).Within the Etiology, Titre-Course, and effect on Survival (ETiCS) study, cardiac MRI conducted 7-9 days and 12 months after MI enabled longitudinal characterization of patients with a first STEMI along with serial routine blood counts and multiplex cytokine measurements.Of 91 locally included STEMI patients, 47% were overweight (25 kg/mBoth BMI and HbA1c correlated negatively with LVEF only early, but not late after STEMI. Peak CRP evolved as strongest predictor of cardiac function at all time points independent of the metabolic syndrome.

Cellular communication network factor 1 (CCN1) is an independent predictor of MACE after ACS and elevated levels correlated with infarct size after STEMI. We compared the prognostic accuracy of baseline levels of CCN1, NT-proBNP, hsTnT, and ST2 and changes in levels over time to predict the development of structural and functional alterations typical of LV remodelling.Serial 3-T cMRI scans were performed to determine LVEF, LVEDV, LVESV, infarct size, and relative infarct size, which were correlated with serial measurements of the four biomarkers. The prognostic significance of these biomarkers was assessed by multiple logistic regression analysis by examining their performance in predicting dichotomized cardiac MRI values 12 months after STEMI based on their median. For each biomarker three models were created using baseline (BL), the Δ value (BL to 6 months), and the two values together as predictors. All models were adjusted for age and renal function. Receiver operator curves were plotted with area under the curve (AUC) to discriminate the prognostic accuracy of individual biomarkers for MRI-based structural or functional changes.A total of 44 predominantly male patients (88.6%) from the ETiCS (Etiology, Titre-Course, and Survival) study were identified at a mean age of 55.5 ± 11.5 (SD) years treated by successful percutaneous coronary intervention (97.7%) at a rate of 95.5% stent implantation within a median pain-to-balloon time of 260 min (IQR 124-591). Biomarkers hsTnT and ST2 were identified as strong predictors (AUC 0.7) of LVEDV and LVEF. BL measurement to predict LVEF [hsTnT: AUC 0.870 (95% CI: 0.756-0.983), ST2: AUC 0.763 (95% CI: 0.615-0.911)] and the Δ value BL-6M [hsTnT: AUC 0.870 (95% CI: 0.756-0.983), ST2: AUC 0.809 (95% CI: 0.679-0.939)] showed a high prognostic value without a significant difference for the comparison of the BL model vs. the Δ-value model (BL-6M) for hsTnT (P = 1) and ST2 (P = 0.304). The combined model that included baseline and Δ value as predictors was not able to improve the ability to predict LVEF [hsTnT: AUC 0.891 (0.791-0.992), P = 0.444; ST2: AUC 0.778 (0.638-0.918), P = 0.799]. Baseline levels of CCN1 were closely associated with LVEDV at 12 months [AUC 0.708 (95% CI: 0.551-0.865)] and infarct size [AUC 0.703 (95% CI: 0.534-0.872)].Baseline biomarker levels of hsTnT and ST2 were the strongest predictors of LVEF and LVEDV at 12 months after STEMI. The association of CCN1 with LVEDV and infarct size warrants further study into the underlying pathophysiology of this novel biomarker.

Incidental research findings pose a considerable challenge to hospital-based research biobanks since they are acting as intermediaries between healthcare and research. In a joint action the centralized biobank ibdw (Interdisciplinary Bank of Biomaterials and Data Wuerzburg) together with local authorities drafted a coherent concept to manage incidental research findings in full compliance with relevant ethical and data privacy regulations. The concept was developed and elaborated in close collaboration with the German Biobank Alliance (GBA). Comprehensive documentation of all steps guarantees the traceability of the process. By a mandatory assessment of the findings prior to re-identification of the individual concerned, unnecessary measures can be avoided. The individual’s “right not to know” is respected according to the stipulations of the informed consent. As a general principle any communication with the individual occurs exclusively through the hospital and by competent physicians with appropriate knowledge and communication skills. We propose this scheme as a blueprint for reporting workflows for incidental research findings at hospital-based biobanks.

Incidental research findings pose a considerable challenge to clinical biobanks since they are acting as intermediaries between healthcare and research. In a joint action the centralized biobank ibdw (Interdisciplinary Bank of Biomaterials and Data Wuerzburg) together with local authorities drafted a coherent concept to manage incidental research findings in full compliance with ethical and data privacy regulations. The concept was developed and elaborated in close collaboration with the German Biobank Alliance (GBA). The first implementation was piloted and evaluated in a testbed. Comprehensive documentation of all steps guarantees the traceability of the process. By a mandatory assessment of the findings prior to re-identification of the individual concerned, unnecessary measures can be avoided. The individual's right to “not to know” is respected according to the stipulations of the informed consent. As a general principle any communication with the individual occurs exclusively through the hospital and by competent physicians with appropriate knowledge and communication skills. We propose this scheme as a blueprint for reporting workflows for incidental research findings at hospital-integrated biobanks.

Acute ischemic cardiac injury predisposes one to cognitive impairment, dementia, and depression. Pathophysiologically, recent positron emission tomography data suggest astroglial activation after experimental myocardial infarction (MI). We analyzed peripheral surrogate markers of glial (and neuronal) damage serially within 12 months after the first ST-elevation MI (STEMI). Serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were quantified using ultra-sensitive molecular immunoassays. Sufficient biomaterial was available from 45 STEMI patients (aged 28 to 78 years, median 56 years, 11% female). The median (quartiles) of GFAP was 63.8 (47.0, 89.9) pg/mL and of NfL 10.6 (7.2, 14.8) pg/mL at study entry 0–4 days after STEMI. GFAP after STEMI increased in the first 3 months, with a median change of +7.8 (0.4, 19.4) pg/mL (p = 0.007). It remained elevated without further relevant increases after 6 months (+11.7 (0.6, 23.5) pg/mL; p = 0.015), and 12 months (+10.3 (1.5, 22.7) pg/mL; p = 0.010) compared to the baseline. Larger relative infarction size was associated with a higher increase in GFAP (ρ = 0.41; p = 0.009). In contrast, NfL remained unaltered in the course of one year. Our findings support the idea of central nervous system involvement after MI, with GFAP as a potential peripheral biomarker of chronic glial damage as one pathophysiologic pathway.

The secondary use of deidentified but not anonymized patient data is a promising approach for enabling precision medicine and learning health care systems. In most national jurisdictions (e.g., in Europe), this type of secondary use requires patient consent. While various ethical, legal, and technical analyses have stressed the opportunities and challenges for different types of consent over the past decade, no country has yet established a national consent standard accepted by the relevant authorities.A working group of the national Medical Informatics Initiative in Germany conducted a requirements analysis and developed a GDPR-compliant broad consent standard. The development included consensus procedures within the Medical Informatics Initiative, a documented consultation process with all relevant stakeholder groups and authorities, and the ultimate submission for approval via the national data protection authorities.This paper presents the broad consent text together with a guidance document on mandatory safeguards for broad consent implementation. The mandatory safeguards comprise i) independent review of individual research projects, ii) organizational measures to protect patients from involuntary disclosure of protected information, and iii) comprehensive information for patients and public transparency. This paper further describes the key issues discussed with the relevant authorities, especially the position on additional or alternative consent approaches such as dynamic consent.Both the resulting broad consent text and the national consensus process are relevant for similar activities internationally. A key challenge of aligning consent documents with the various stakeholders was explaining and justifying the decision to use broad consent and the decision against using alternative models such as dynamic consent. Public transparency for all secondary use projects and their results emerged as a key factor in this justification. While currently largely limited to academic medicine in Germany, the first steps for extending this broad consent approach to wider areas of application, including smaller institutions and medical practices, are currently under consideration.

Background Human biobanks are generally recognized as essential resources for effective biomedical research. All over the world biosamples and data from human subjects are collected in large biobanks. The biological material is stored long term for current and future (undetermined) research issues, which often require cross-border exchange of biosamples and related data. Content Commonly, the informed consent for research on human biospecimen is intended to cover only defined, specific research objectives. In June 2016, the biobank Task-Force of the Working Party of the German Medical Ethics Committees (WP-GMEC) updated its template for the broad use of human biological samples and related data. It complies with the current Organisation for Economic Co-operation and Development (OECD) and World Medical Association (WMA) recommendations and furnishes a framework that permits long-term storage and multi-purpose research use of human biological material and related data, including cross-border research. However, both (i) human biobanks storing and (ii) research projects requesting “broad consent” biological samples generally require an ethical approval; in addition, “broad consent” conditions should be reciprocated by making biobank processes transparent and by fostering both donor and public involvement. Outlook The broad consent template of the WP-GMEC clearly states that biological samples and data donated for medical research serve to address current and future research questions. It appears perfectly suited as a template for a Europe-wide harmonized broad consent facilitating biobank-based cross-border research.

Peptide mimicry breaks the heart Myocarditis, a prolonged chronic inflammation of heart muscle, can eventually progress to inflammatory cardiomyopathy, a serious condition associated with heart failure. Activated T helper (T H ) cells that recognize myosin heavy chain 6–derived peptides are thought to play a central role in this pathogenesis. Using a mouse model of myocarditis, Gil-Cruz et al. found that cardiac myosin–reactive T H cells are initially primed by myosin-peptide mimics derived from commensal Bacteroides species in the gut (see the Perspective by Epelman). Unlike heathy controls, human myocarditis patients also showed detectable immune reactivity to both Bacteroides and cardiac myosin antigens. Treatment with antibiotics dampened inflammatory responses and prevented lethal heart disease. Science , this issue p. 881 ; see also p. 806

About 20% of the German population have a migration background which might influence prevalence of preventable cardiovascular risk factors (CVRF).We report data of the prospective Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study investigating a representative sample of inhabitants of the City of Würzburg, Germany, aged 30 to 79 years. Individuals without migration background were defined as follows: German as native language, no other native language, and/or born in Germany. All other participants were defined as individuals with migration background.Of 2473 subjects (51% female, mean age 54 ± 12 years), 291 (12%) reported a migration background: n = 107 (37%) from a country within the EU, n = 117 (40%) from Russia, and n = 67 (23%) from other countries. Prevalence of hypertension, atherosclerotic disease, and diabetes mellitus was similar in individuals with and without migration background. By contrast, prevalence of obesity and metabolic syndrome was significantly higher in individuals with migration background, with the least favourable profile apparent in individuals from Russia (individuals without vs. with migration background: obesity 19 vs. 24%, p 0.05; odds ratio: EU: 1.6, Russia: 2.2*, other countries: 0.6; metabolic syndrome 18 vs. 21%, p 0.05; odds ratio: EU: 1.2, Russia: 1.7*, other countries: 1.5; *p 0.05).Individuals with migration background in Germany might exhibit a higher CVRF burden due to a higher prevalence of obesity and metabolic syndrome. Strategies for primary prevention of heart failure may benefit from deliberately considering the migration background.

PurposeCardiotoxic adverse events (AE) are challenging in the field of oncologic therapy. Age-related prevalence of cardiovascular disease and cancer itself may contribute to an increased risk of cardiac morbidity. Cardiac dysfunction impacts cardiac morbidity, survival and quality of life in cancer patients. This study established a cardio-oncological monitoring for the early detection of cardiovascular complications during experimental anti-tumour therapy. MethodsNinety patients referred to experimental anti-tumour therapy underwent prospective monitoring including repeat-electrocardiogram (ECG), echocardiography with speckle tracking imaging (STI), and determination of cardiac biomarkers. Changes in cardiac function were evaluated according to the Common Terminology Criteria of Adverse Events (CTCAE Version 4.03). ResultsConventional ECG, high-sensitive troponin T, echocardiography including STI-analysis, and 24-hour Holter ECG were identified as relevant diagnostic tools. Early signs of cardiotoxicity appeared within the first 3 months after initiating anti-tumour therapy. Most frequent AEs were mitral valve disease (22%), diastolic dysfunction (15.7%), sinus tachycardia (13.8%), and increased hs-TnT (13.8%). ConclusionProspective cardiac monitoring allowed early detection of cardiac dysfunction during experimental anti-tumour therapy. A multi­disciplinary work-up and decision-making during cancer treatment is warranted to foster a deeper understanding of the underlying mechanisms of cardiac AEs and particularly to early detect and counteract cardiotoxicity.

European journal of human genetics (2021). doi:10.1038/s41431-021-00905-x, Published by Stockton Press, Basingstoke

PURPOSE Cardiac T1 mapping has become an increasingly important imaging technique, contributing novel diagnostic options. However, currently utilized methods are often associated with accuracy problems because of heart rate variations and cardiac arrhythmia, limiting their value in clinical routine. This study aimed to introduce an improved arrhythmia-related robust T1 mapping sequence called RT-TRASSI (real-time Triggered RAdial Single-Shot Inversion recovery). METHODS All measurements were performed on a 3.0T whole-body imaging system. A real-time feedback algorithm for arrhythmia detection was implemented into the previously described pulse sequence. A programmable motion phantom was constructed and measurements with different simulated arrhythmias arranged. T1 mapping accuracy and susceptibility to artifacts were analyzed. In addition, in vivo measurements and comparisons with 3 prevailing T1 mapping sequences (MOLLI, ShMOLLI, and SASHA) were carried out to investigate the occurrence of artifacts. RESULTS In the motion phantom measurements, RT-TRASSI showed excellent agreement with predetermined reference T1 values. Percentage scattering of the T1 values ranged from -0.6% to +1.9% in sinus rhythm and -1.0% to +3.1% for high-grade arrhythmias. In vivo, RT-TRASSI showed diagnostic image quality with only 6% of the acquired T1 maps including image artifacts. In contrast, more than 40% of the T1 maps acquired with MOLLI, ShMOLLI, or SASHA included motion artifacts. CONCLUSION Accuracy issues because of heart rate variability and arrhythmia are a prevailing problem in current cardiac T1 mapping techniques. With RT-TRASSI, artifacts can be minimized because of the short acquisition time and effective real-time feedback, avoiding potential data acquisition during systolic heart phase.

Patients suffering from chronic heart failure (CHF) caused or promoted by autoantibodies against cardiac beta1-adrenergic receptors (beta1AR) could benefit from specific therapies aimed at tolerance induction, removal or neutralisation of beta1AR autoantibodies, provided the patients can be selected for these therapies by reliable detection and quantitation of beta1AR autoantibodies in their circulation and by a valid assessment of the autoantibodies's putative cardio-pathogenic potential. Here, we discuss the current state of knowledge regarding the effects of CHF-associated (auto)antibodies on beta1AR function and beta1AR-mediated signal tranduction and discuss the presumed role of these effects in the development and progression of CHF. Identification of disease-relevant functional autoantibody effects and their specific assessment in medical diagnostic will be a prerequesite for the implementation of novel specific therapies not only for CHF caused or promoted by beta1AR autoantibodies but alos for most other diseases involving autoantibodies that target G-protein coupled receptors.

Aims Chronic heart failure (CHF) can be caused by autoantibodies stimulating the heart via binding to first and/or second extracellular loops of cardiac β1‐adrenoceptors. Allosteric receptor activation depends on conformational features of the autoantibody binding site. Elucidating these features will pave the way for the development of specific diagnostics and therapeutics. Our aim was (i) to fine‐map the conformational epitope within the second extracellular loop of the human β1‐adrenoceptor (β1ECII) that is targeted by stimulating β1‐receptor (auto)antibodies and (ii) to generate competitive cyclopeptide inhibitors of allosteric receptor activation, which faithfully conserve the conformational auto‐epitope. Methods and results Non‐conserved amino acids within the β1ECII loop (compared with the amino acids constituting the ECII loop of the β2‐adrenoceptor) were one by one replaced with alanine; potential intra‐loop disulfide bridges were probed by cysteine–serine exchanges. Effects on antibody binding and allosteric receptor activation were assessed (i) by (auto)antibody neutralization using cyclopeptides mimicking β1ECII ± the above replacements, and (ii) by (auto)antibody stimulation of human β1‐adrenoceptors bearing corresponding point mutations. With the use of stimulating β1‐receptor (auto)antibodies raised in mice, rats, or rabbits and isolated from exemplary dilated cardiomyopathy patients, our series of experiments unmasked two features of the β1ECII loop essential for (auto)antibody binding and allosteric receptor activation: (i) the NDPK211–214 motif and (ii) the intra‐loop disulfide bond C209↔C215. Of note, aberrant intra‐loop disulfide bond C209↔C216 almost fully disrupted the functional auto‐epitope in cyclopeptides. Conclusions The conformational auto‐epitope targeted by cardio‐pathogenic β1‐receptor autoantibodies is faithfully conserved in cyclopeptide homologues of the β1ECII loop bearing the NDPK211–214 motif and the C209↔C215 bridge while lacking cysteine C216. Such molecules provide promising tools for novel diagnostic and therapeutic approaches in β1‐autoantibody‐positive CHF.

Heart failure (HF) is the leading cause of mortality and morbidity in Western countries. In the past two decades, evidence for the clinical relevance of GPCR-autoimmunity in human HF has substantially increased. Stimulating autoantibodies targeting the second extracellular loop (ECII) of the cardiac beta1-adrenoceptor (beta1-aabs) have been claimed to be involved in the pathogenesis of HF and to increase the risk of cardiovascular death by three-fold. Still, the events triggering the formation of beta1-aabs and their impact on HF-progression are unknown. Methods In total 13 University Hospitals (12 German, 1 Serbian) prospectively recruited 226 patients (pts.) with a first acute myocardial infarction (FAMI), and 140 pts with acute (biopsy- or cMRI-proven) myocarditis (AMitis) into the Etiology, Titer-Course and effect on Survival of cardiac autoantibodies-study (ETiCS-study). This study aimed to investigate whether the presentation of cardiac membrane antigens (e.g., the beta1-adrenoceptor) following cardiac necrosis/inflammation triggers the formation of beta1-aabs. At baseline (BL) and three follow-ups (Fup1–3), blood was sampled to analyze the time-course of beta1-aabs. Beta1-aab titers were measured by FACS using Dyna-beads® M-270-Epoxy coated with increasing amounts of beta1-ECII-peptides (2.5–100 μg/ml), checked versus scrambled peptides (a mixture of same amino-acids). After reacting, the samples were measured by FACScan flow-cytometry; obtained data were analyzed with FlowJo (Treestar). When half-maximal binding was calculable the serum was classified beta1-aab-positive. Results From n=366 pts (226 FAMI/140 AMitis) recruited into the ETiCS-study 45 pts had to be excluded because of unperformed cMRI's; 46 pts stopped the study before Fup-1 (month 3). Only 180/226 FAMI- and 98/140 AMitis-pts had complete Fup1–3 (after 3, 6, and 12 months with clinical assessment, echocardiograms, and cMRI's at BL and Fup-3). In all valid ETiCS-pts (197 FAMI-/123 AMitis-pts) the titer-course of beta1-aabs was compared with the development of echo-LVEF. Relevant (high-affinity) beta1-aab-titers were detected in ∼31% (37/123) of the AMitis-pts compared to only ∼21% (42/197) of the FAMI-pts. In aab-positive AMitis-pts echo-LVEF did not recover and was always significantly inferior to aab-negative AMitis-pts (BL: 38 vs. 49% LVEF; Fup-3: 49 vs. 64% LVEF) whereas such a difference was not noted in FAMI-pts. In addition, aab-positive AMitis-pts had higher NT pro-BNP-, renin-, and aldosterone-levels than aab-negative AMitis-pts. Conclusion The first evaluation of the completed ETiCS-study clearly suggests that acute microbial-induced rather than post-infarction myocardial inflammation triggers the formation of clinically relevant beta1-aabs. AAb-positive AMitis-patients might profit from early intensification of standard HF-therapy (including early beta-blockade) and/or novel antibody-directed experimental therapies which are currently developed. Acknowledgement/Funding BMBF Grant FKZ 01ES0816

Circulating AT1R autoantibodies (AT1R-aabs) directed against the ECL2 of the AT1R with agonist-like activity are supposed to play a pathophysiological role in diseases associated with vascular and renal damage, such as preeclampsia and severehypertension (HT), but they are also thought to be involved in heart failure and primary hyperaldosteronism (PHA). Methods High-throughput screening assays aiming at a reliable detection of AT1R-aabs in sera from patients with HT and PHA were established. The agonist-like activity of AT1R-aabs was assessed by changes in intracellular calcium-levels using Fura2-QBT dye; the AlphaLISA Assay was used to assess induction of ERK1/2-phosphorylation in stably transfected AT1R-HEK-cells or in adrenocortical NCI-H295R cells. Results IgG isolated from sera of n=60 patients with PHA and n=164 with HT were screened for their capacity to increase [Ca2+]i or to activate ERK1/2. Sixteen out of 60 PHA-patients increased [Ca2+]i compared to none of the HT-patients, whereas in both disease-entities we detected AT1R-aabs inducing ERK1/2-activation with a similar prevalence (PHA: 41%, HT: 42%), indicating the existence of differentially acting AT1R-aabs. PHA-patients positive for ERK1/2-activating AT1R-aabs have significantly lower serum potassium- (3,8±0,1 vs. 4,1±0,1 mmol/l, p In addition, ERK1/2-activation induced by either angiotensin II or by IgG isolated from patients with PHA or HT could be differentially blocked by the use of various signaling inhibitors. In order to elucidate if stimulating AT1R-aabs could be involved in an over-secretion of aldosterone due to sustained receptor-activation, we investigatedtheir effects on NCI-H295R-cells. At the transcriptional level, AT1R-aabs were able to induce a time-dependent upregulation of the key steroidogenic enzymes involved in aldosterone biosynthesis CYP21A1-, HSD3B2-, CYP11B1-, and in particular CYP11B2-mRNA (2fold over basal), with the maximum level achieved after 8 to 12 hours. Concordant withan agonist-stimulated internalization of AT1R,AT1R-mRNA was downregulated by AT1R-aabs (up to 25% of basal) providing direct evidence of a chronic receptor-stimulation by AT1R-aabs. Conclusion Functional assays based on AT1R-activation (Ca2+ measurements & ERK1/2-phosphorylation) are able to detect AT1R-aabs in 41% or 42% of patients with HT or PHA, respectively. Moreover, our data provide evidence that AT1R-aabs stabilize a specific AT1R-conformation distinct from that induced by angiotensin II thereby triggering a different intracellular signaling pattern resulting in chronic aldosterone production. Acknowledgement/Funding BMBF grant

The scientific impact of translational biomedical research largely depends on the availability of high-quality biomaterials. However, evidence-based and robust quality indicators (QIs) covering the most relevant preanalytical variations are still lacking. The aim of this study was to identify and validate a QI suitable for assessing time-to-centrifugation (TTC) delays in human liquid biospecimens originating from both healthy and diseased individuals. Serum and plasma samples with varying TTCs were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in a pilot cohort of healthy individuals to identify a suitable QI candidate. Taurine (TAU), as a TTC QI candidate, was validated in healthy individuals and patients with rheumatologic and cardiologic diseases, considering the (1) preanalytical handling temperature, (2) platelet count, and (3) postcentrifugation delay. For discrimination of high TTC (TTC60 minutes) from low TTC serum specimens, a probability calculation tool was developed (Triple-T-cutoff-model). TTC-dependent changes in healthy individuals were observed for amino acids, particularly TAU. Validation of the TAU levels in an independent cohort of healthy individuals revealed a time-dependent increase in serum, but not in plasma, for a TTC delay of 30-240 minutes. TAU increases were dependent on the handling temperature and platelet count and volume. By contrast, no changes in TAU concentrations were observed for additional postcentrifugation delays. Validation of TAU and the Triple-T-cutoff-model, in rheumatologic/cardiologic patient collectives, allowed the discrimination of samples with TTC ≤60 min/60 min with estimated AUROC (area under the receiver operating characteristic curve) values of 89% [78%-100%]/86% [71%-100%] and 91% [79%-100%]/84% [68%-100%], respectively. Considering the preanalytical handling temperature and platelet count and volume, TAU and the Triple-T-cutoff-model represent reliable QIs for TTC60 minutes in serum samples from healthy individuals and selected rheumatologic/cardiologic patients. However, further studies in larger patient collectives with various diseases are needed to assess the robustness and potential of the QIs presented in this article as biobanking quality assurance/quality control tools to support high-quality biomedical research.

Under the umbrella of the German Biobank Node (GBN), 11 biobanks and two IT development centers are funded by the Federal Ministry of Education and Research (BMBF) to work together in the German Biobank Alliance (GBA). Their common aim is to make existing biomaterials hosted by different biobanks nationally and internationally available for biomedical research. This position article reflects and summarizes contributions and comments made during a GBA workshop, on the cooperation between academic biobanks and pharmaceutical and diagnostics companies that took place in Leipzig on the 21st of June 2018. It documents key points agreed on by all participating biobanks during the workshop thereby addressing several of the challenges identified. Although there are various possibilities for cooperation between academic biobanks and industry, this position article focuses exclusively on projects where academic biobanks give access to their biosamples and related data to industry partners. In doing so it considers the general conditions/framework and procedures in the German biobanking environment and raises ethical, legal, and procedural issues to be addressed when initiating such collaborations. It intends to furnish a basis for further activities to foster cooperation with industry and to push an overarching national coordination process. The final aim is to develop GBN-recommendations. Of course, many hospitals already have clear regulations on collaboration(s) with industry partners. These naturally take precedence for the GBA biobanks. However, where interest exists, GBN/GBA recommendations could help to induce changes to existing local policies nonetheles peerReviewed

Myocarditis represents a major cause of dilated cardiomyopathy and sudden cardiac death in younger adults. Currently, definitive diagnosis of myocarditis requires endomyocardial biopsy, which is highly invasive and has the drawback of variable sensitivity due to inherent sampling error. Therefore, reliable noninvasive methods to detect and monitor cardiac inflammation are clinically relevant. In this study, we explored the potential of radiolabeled methionine to assess myocardial inflammatory activity in a rat model of experimental autoimmune myocarditis (EAM). Methods: Autoimmune myocarditis was induced by immunizing Lewis rats twice with porcine cardiac myosin and Freund complete adjuvant. Control animals were treated with adjuvant alone. Dual-tracer autoradiography was performed to assess 14C-methionine uptake and to compare the distributions of 14C-methionine versus 18F-FDG. Hematoxylin and eosin staining and anti-CD68 macrophage staining were performed for histologic analysis. Additionally, cardiac 11C-methionine PET was performed to evaluate the feasibility of in vivo imaging. 18F-FDG PET was also conducted to compare the in vivo uptake of 11C-methionine and 18F-FDG. Results: Multiple focal cardiac inflammatory lesions were histologically identified in myosin-immunized rats, whereas no cardiac lesions were observed in the controls. Autoradiographic images clearly showed a high-density accumulation of 14C-methionine in inflammatory lesions of EAM rats, whereas no significant uptake was observed in the control animals. 14C-methionine uptake was significantly higher in inflammatory lesions than in remote noninflammatory areas and control rat hearts. The distribution of 14C-methionine correlated well with that of 18F-FDG and with macrophage density. The contrast between inflammatory and noninflammatory areas was higher for 18F-FDG than for 14C-methionine (3.45 ± 0.68 vs. 2.07 ± 0.21, respectively; P

Background Biobanks increasingly presume long-term storage of biomaterials and data that shall be used for future research projects which are today unspecified. Appropriate consent documents for sample donors must therefore explain the breadth of consent and other elements of the biobank governance framework. Recent reviews demonstrated high variability in what issues these documents mention or not and how the issues are explained. This might undermine the protection of sample donors, complicate networked biobank research, create research waste and impact on public trust. Methods A systematic analysis of international research guidelines and existing broad consent templates was performed. Based on this information an interdisciplinary expert group from the AKMEK (Permanent Working Party of German RECs) developed a draft template and organized a comprehensive stakeholder consultation. After revision the final template was consented by all 53 German RECs. Results This paper briefly explores the spectrum of potentially relevant issues for broad consent forms. It then elaborates the template and how it was designed to be applicable in different types of biobanks. Discussion To further improve the validity and applicability of broad consent forms in biobank and other big data research, practice evaluations are needed. We hope that in this regard the presented template supports the development of new consent forms as well as the evaluation and revision of existing ones.

Gerade im letzten, wesentlich von den Bemuhungen um eine immer weitergehende Individualisierung/Personalisierung der Medizin gepragten Jahrzehnt ist der Bedarf an gut charakterisierten und qualitativ hochwertigen humanen Biomaterialien signifikant gestiegen. Bei der Errichtung und dem Betrieb von Humanbiobanken sind grundsatzlich die Interessen der medizinischen Forschung und die Wahrung der Forschungsfreiheit mit den Rechten und Interessen der Patienten bzw. Spender in Einklang zu bringen und immer auch unter ethischen Gesichtspunkten abzuwagen. Daruber hinaus spielen Qualitatskontrolle und -sicherung fur heutige Biobanken sowohl aus wissenschaftlichen, aber v. a. auch aus ethischen Grunden eine immer wichtigere Rolle, da die gespendeten Biomaterialien z. T. uber Jahrzehnte und somit auch fur gegenwartig noch nicht absehbare medizinische Forschungszwecke eingelagert und (bei Bedarf) bereitgestellt werden. Daruber hinaus gewinnt die Kompatibilitat nationaler Humanbiobanken mit internationalen Biobanknetzwerken immer mehr an Bedeutung.

Rationale Despite advances in pharmacotherapy, heart failure still incurs significant morbidity and mortality. Stimulating antibodies directed against the secondextracellular loop of the human s1-adrenergic receptor (anti-s1EC2) cause myocyte damage and heart failure in rats. This receptor domain is 100% homologous between rats and humans. Objective s1EC2-mimicking cyclopeptides (25-meric) markedly improved the development and/or course of anti-s1EC2-mediated cardiomyopathy. Further developments should be investigated. Methods and results The shortened 18-meric cyclic peptide COR-1, in which one of the two disulphide bonds was removed to enable reproducible GMP production, can also be used to treat cardiomyopathic rats. Echocardiography, catheterization and histopathology of the rat hearts revealed that monthly intravenous administrations of COR-1 almost fully reversed the cardiomyopathic phenotype within 6 months at doses of 1 to 4 mg/kg body weight. Administration of COR-1 resulted in markedly reduced anti-s1EC2-expressing memory B lymphocytes in the spleen despite continued antigenic boosts, but did not significantly decrease overall peripheral anti-s1EC2 titers. COR-1 did not induce any anti-s1EC2 or other immune response in naive rats (corresponding to findings in healthy human volunteers). It did not cause any toxic side effects in GLP studies in dogs, rats or mice, and the “no observed adverse effect level” (NOAEL) exceeded the therapeutic doses by 100-fold. Conclusion The second generation immunomodulating epitope-mimicking cyclopeptide COR-1 (also termed JNJ-5442840) offers promise to treat immune-mediated cardiac diseases.

Patients suffering from chronic heart failure (CHF) caused or promoted by autoantibodies against cardiac beta

Human biological materials and related data stored in biobanks are valuable resources for biomedical research. Transparent, effective, and efficient governance structures and procedures for access, compensation, and priority setting are needed, but recent debates indicate challenges in the practical application of such governance processes. This study aimed to assess the practical experiences and attitudes of biobank experts regarding the governance of biosample access, prioritization, and compensation. Qualitative, semi-structured telephone interviews were conducted with 20 biobank directors from eight countries. Respondents highlighted the need for sound governance structures in order to ensure acceptance by all stakeholders (patients/donors, researchers, research funders, public, and others). They stressed practical difficulties in trying to make best use of biomaterials. As biobanks often form part of larger academic and clinical settings, the different and sometimes conflicting interests of researchers, clinicians, patients, funders, and biobank staff currently affect the governance of access decisions. Investments such as intellectual input, financial, and human resources need to be compensated adequately. Biobanks thereby have a dual role stewarding the hosted biosamples and acting as a service provider for local researchers from universities or hospitals. In order to facilitate efficient use of human biological materials, greater harmonization of at least minimum standards for access and compensation are required at both a national and an international level.

Aims: Although mortality rate is very high, diagnosis of acute myocarditis remains challenging with conventional tests. We aimed to elucidate the potential role of longitudinal 2-Deoxy-2-\(^{18}\)F-fluoro-D-glucose (\(^{18}\)F-FDG) positron emission tomography (PET) inflammation monitoring in a rat model of experimental autoimmune myocarditis. Methods and results: Autoimmune myocarditis was induced in Lewis rats by immunizing with porcine cardiac myosin emulsified in complete Freund’s adjuvant. Time course of disease was assessed by longitudinal \(^{18}\)F-FDG PET imaging. A correlative analysis between in- and ex vivo \(^{18}\)F-FDG signalling and macrophage infiltration using CD68 staining was conducted. Finally, immunohistochemistry analysis of the cell-adhesion markers CD34 and CD44 was performed at different disease stages determined by longitudinal \(^{18}\)F-FDG PET imaging. After immunization, myocarditis rats revealed a temporal increase in 18F-FDG uptake (peaked at week 3), which was followed by a rapid decline thereafter. Localization of CD68 positive cells was well correlated with in vivo \(^{18}\)F-FDG PET signalling (R\(^2\) = 0.92) as well as with ex vivo 18F-FDG autoradiography (R\(^2\) = 0.9, P < 0.001, respectively). CD44 positivity was primarily observed at tissue samples obtained at acute phase (i.e. at peak 18F-FDG uptake), while CD34-positive staining areas were predominantly identified in samples harvested at both sub-acute and chronic phases (i.e. at \(^{18}\)F-FDG decrease). Conclusion: \(^{18}\)F-FDG PET imaging can provide non-invasive serial monitoring of cardiac inflammation in a rat model of acute myocarditis.

Background Acute myocarditis as well as post-ischemic myocardial inflammation are generally associated with a profound activation of the immune system. Current established imaging techniques such as cardiac MRI reliably demonstrate signs of acute myocardial injury. However, detection of mediating cells such as macrophages is currently limited to experimental settings. We aimed to investigate the feasibility of somatostatin receptor (SSTR) based positron emission tomography/computed tomography (PET/CT) for detecting inflammatory lesions in patients after acute myocardial infarction or acute peri-/myocarditis. Methods 12 patients with active peri-/myocarditis (n=6) or sub-acute myocardial infarction (n=6) underwent SSTR-PET/CT and cardiac MRI within 3–10days after onset of symptoms. The AHA 17-segment model of the left myocardium was used for visual localization of inflamed myocardium for both imaging modalities. Tracer uptake of infarcted/inflamed myocardium was assessed as mean and maximum standardized uptake value (SUV mean and SUV max ) and compared with both remote myocardium and left ventricular (LV) cavity. Results SSTR-PET/CT revealed areas with increased cardiac tracer uptake in all patients. In the 17-segment model, PET/CT yielded 55 and MRI 47 positive segments. Overall, concordance of the 2 modalities was 85.3% (174/204 segments analyzed). In 9.3% (19/204), more positive segments were identified by PET/CT, whereas in 5.4% (11/204), MRI detected more positive segments. Conclusions The imaging patterns of SSTR-directed radiotracers and MRI in vivo show a close spatial relation of macrophage concentration and structural changes. This suggests the possibility of a new potential biomarker that predicts cardiac remodeling and, hence, progression towards heart failure. Prospective trials are warranted.

Objective Acute and chronic forms of myocarditis are mainly induced by virus infections. As a consequence of myocardial damage and inflammation dilated cardiomyopathy and chronic heart failure may develop. The gold standard for the diagnosis of myocarditis is endomyocardial biopsies which are required to determine the etiopathogenesis of cardiac inflammatory processes. However, new non-invasive MRI techniques hold great potential in visualizing cardiac non-ischemic inflammatory lesions at high spatial resolution, which could improve the investigation of the pathophysiology of viral myocarditis. Results Here we present the discovery of a novel endogenous T2* MRI contrast of myocardial lesions in murine models of acute and chronic CVB3 myocarditis. The evaluation of infected hearts ex vivo and in vivo by 3D T2w and T2*w MRI allowed direct localization of virus-induced myocardial lesions without any MRI tracer or contrast agent. T2*w weighted MRI is able to detect both small cardiac lesions of acute myocarditis and larger necrotic areas at later stages of chronic myocarditis, which was confirmed by spatial correlation of MRI hypointensity in myocardium with myocardial lesions histologically. Additional in vivo and ex vivo MRI analysis proved that the contrast mechanism was due to a strong paramagnetic tissue alteration in the vicinity of myocardial lesions, effectively pointing towards iron deposits as the primary contributor of contrast. The evaluation of the biological origin of the MR contrast by specific histological staining and transmission electron microscopy revealed that impaired iron metabolism primarily in mitochondria caused iron deposits within necrotic myocytes, which induces strong magnetic susceptibility in myocardial lesions and results in strong T2* contrast. Conclusion This T2*w MRI technique provides a fast and sensitive diagnostic tool to determine the patterns and the severity of acute and chronic enteroviral myocarditis and the precise localization of tissue damage free of MR contrast agents.

Growing evidence indicates a cardio-pathogenic role of autoantibodies against β1-adrenergic receptors (β1AR). In particular autoantibodies stimulating β1AR-mediated cAMP-production (i.e. agonistic β1AR autoantibodies) play a paramount role in chronic heart failure. When induced by immunisation, such autoantibodies cause heart failure in rodents; when present in patients they negatively affect survival in heart failure. However, the true prevalence and clinical impact of agonistic β1AR autoantibodies in human heart disease are still unclear, as are the events triggering their production, and the inter-relationship between autoantibody level and disease activity. β1AR autoantibodies can be removed by extracorporeal absorption or neutralised by systemic administration of synthetic epitope mimics. Only patients bearing agonistic β1AR autoantibodies in their bloodstream will benefit from these approaches. Therefore, reliable detection of agonistic β1AR autoantibodies is a key pre-requisite for the future implementation of these strategies. β1AR autoantibodies impact on conformation and down-stream signalling of the receptor by binding a conformational epitope, which is poorly represented by synthetic mimics and readily destroyed by fixation. Consequently, β1AR autoantibodies can reliably be detected only by assays utilising the native β1AR as a test antigen. To provide a sufficient basis for diagnostic predictions or therapeutic decisions, one must also determine whether β1AR autoantibodies stimulate the receptor, which again requires native, cell-based reporter systems. Translation of these procedures into versatile diagnostic tests fitting the requirements of general health care is a challenge for future development. Here, we will review the state of diagnostic and therapeutic efforts in the field of β1AR-directed autoimmunity, thereby aiming to furnish a conceptual frame for the further development of novel, more reliable diagnostic tools and more specific antibody-targeted therapeutic concepts.

Background— Monocytes and macrophages are indispensable in the healing process after myocardial infarction (MI); however, the spatiotemporal distribution of monocyte infiltration and its correlation to prognostic indicators of reperfused MI have not been well described. Methods and Results— With combined fluorine 19/proton ( 1 H) magnetic resonance imaging, we noninvasively visualized the spatiotemporal recruitment of monocytes in vivo in a rat model of reperfused MI. Blood monocytes were labeled by intravenous injection of 19 F-perfluorocarbon emulsion 1 day after MI. The distribution patterns of monocyte infiltration were correlated to the presence of microvascular obstruction (MVO) and intramyocardial hemorrhage. In vivo, 19 F/ 1 H magnetic resonance imaging performed in series revealed that monocyte infiltration was spatially inhomogeneous in reperfused MI areas. In the absence of MVO, monocyte infiltration was more intense in MI regions with serious ischemia-reperfusion injuries, indicated by severe intramyocardial hemorrhage; however, monocyte recruitment was significantly impaired in MVO areas accompanied by severe intramyocardial hemorrhage. Compared with MI with isolated intramyocardial hemorrhage, MI with MVO resulted in significantly worse pump function of the left ventricle 28 days after MI. Conclusions— Monocyte recruitment was inhomogeneous in reperfused MI tissue. It was highly reduced in MVO areas defined by magnetic resonance imaging. The impaired monocyte infiltration in MVO regions could be related to delayed healing and worse functional outcomes in the long term. Therefore, monocyte recruitment in MI with MVO could be a potential diagnostic and therapeutic target that could be monitored noninvasively and longitudinally by 19 F/ 1 H magnetic resonance imaging in vivo.

Particularly in the past decade which has been marked by efforts to foster individualized/personalized medicine the need for well-characterized high-quality collections of human biological material has significantly increased. When establishing and operating a human biobank the interests and the "freedom" of biomedical research must always be weighed against the interests and rights of patients and/or donors; in this process ethical aspects should be considered systematically. In addition, the importance of quality control and quality assurance has largely increased in human biobanking, both from a scientific and even more from an ethical point of view, because donated biological materials are potentially stored for decades and (on request) might serve for currently not foreseeable biomedical research purposes. In addition, the compatibility of national human biobanks with international biobank networks becomes increasingly important.

Aims A novel concept for the treatment of heart failure is the neutralization of antibodies against the β1-adrenergic receptor (anti-β1AR-ab). In a rat model of autoimmune cardiomyopathy, the cyclic peptide COR-1 (given i.v. once monthly) neutralized anti-β1AR-abs and prevented anti-β1AR-ab-induced myocardial damage, and completely reverted cardiac dysfunction over 3–6 months. Methods and results A clinical phase I trial was designed as a single-blinded, placebo-controlled study. Fifty human volunteers received COR-1 or matching placebo as a single i.v. administration with ascending doses (10–240 mg). Primary endpoints were safety and tolerability, while the pharmacokinetic profile of COR-1 was assessed as a secondary endpoint. All five investigated dose groups were well tolerated; no drug-related side effects occurred. Pharmacokinetics revealed a favourable profile with an almost complete plasma clearance within 60 min after administration. Pharmacodynamic investigation showed dose-dependent efficacy with almost complete scavenging of pathological anti-β1AR-abs ex vivo at the two highest doses. No anti-COR-1 autoantibodies occurred. No other effects on the immune system (such as an increase of crucial cytokines) were observed up to 43 days after drug administration, nor upon incubation of anti-β1AR-ab-positive patient blood samples with COR-1 ex vivo. Conclusions COR-1 was shown to be safe after i.v. administration in vivo; no relevant side effects occurred. Efficacy was estimated from ex vivo investigation of the potency to neutralize specific anti-β1-AR-abs. Trial registration: NCT 01043146, Eudra CT 2008-07745-31.

Rationale: Autoantibodies directed against the second extracellular loop of the cardiac β1-adrenergic receptor (β1-AR) are thought to contribute to the pathogenesis of dilated cardiomyopathy (DCM) and Chagas heart disease. Various approaches have been used to detect such autoantibodies; however, the reported prevalence varies largely, depending on the detection method used. Objective: We analyzed sera from 167 DCM patients (ejection fraction Methods and Results: The novel assay was designed according to the currently most reliable anti-TSH receptor antibody-ELISA used to diagnose Graves disease (“third-generation assay”) and also detects the target antibodies by competition with a specific monoclonal anti–β1-AR antibody (β1-AR MAb) directed against the functionally relevant β1-AR epitope. Anti–β1-AR antibodies were detected in ≈60% of DCM patients and in ≈8% of healthy volunteers using the same cutoff values. The prevalence of these antibodies was 17% in patients with hypertensive heart disease. Anti–β1-AR antibody titers (defined as inhibition of β1-AR MAb-binding) were no longer detected after depleting sera from IgG antibodies by protein G adsorption. In contrast, a previously used ELISA conducted with a linear 26-meric peptide derived from the second extracellular β1-AR loop yielded a high number of false-positive results precluding any specific identification of DCM patients. Conclusions: We established a simple and efficient screening assay detecting disease-relevant β1-AR autoantibodies in patient sera yielding a high reproducibility also in high throughput screening. The assay was validated according to “good laboratory practice” and can serve as a companion biodiagnostic assay for the development and evaluation of antibody-directed therapies in antibody-positive heart failure.

Background— Trials investigating efficacy of disease management programs (DMP) in heart failure reported contradictory results. Features rendering specific interventions successful are often ill defined. We evaluated the mode of action and effects of a nurse-coordinated DMP (HeartNetCare-HF, HNC). Methods and Results— Patients hospitalized for systolic heart failure were randomly assigned to HNC or usual care (UC). Besides telephone-based monitoring and education, HNC addressed individual problems raised by patients, pursued networking of health care providers and provided training for caregivers. End points were time to death or rehospitalization (combined primary), heart failure symptoms, and quality of life (SF-36). Of 1007 consecutive patients, 715 were randomly assigned (HNC: n=352; UC: n=363; age, 69±12 years; 29% female; 40% New York Heart Association class III-IV). Within 180 days, 130 HNC and 137 UC patients reached the primary end point (hazard ratio, 1.02; 95% confidence interval, 0.81–1.30; P =0.89), since more HNC patients were readmitted. Overall, 32 HNC and 52 UC patients died (1 UC patient and 4 HNC patients after dropout); thus, uncensored hazard ratio was 0.62 (0.40–0.96; P =0.03). HNC patients improved more regarding New York Heart Association class ( P =0.05), physical functioning ( P =0.03), and physical health component ( P =0.03). Except for HNC, health care utilization was comparable between groups. However, HNC patients requested counseling for noncardiac problems even more frequently than for cardiovascular or heart-failure–related issues. Conclusions— The primary end point of this study was neutral. However, mortality risk and surrogates of well-being improved significantly. Quantitative assessment of patient requirements suggested that besides (tele)monitoring individualized care considering also noncardiac problems should be integrated in efforts to achieve more sustainable improvement in heart failure outcomes. Clinical Trial Registration— URL: http://www.controlled-trials.com . Unique identifier: ISRCTN23325295.

Recently, Nagatomo et al. [(1)][1] reported on the predictive value of β1-adrenergic receptor autoantibodies (β1AAbs) for recovery from acute cardiac failure (HF). The investigators found a much lower prevalence of β1AAbs in HF than those in comparable studies [(2)][2]. Moreover