Publications by authors named "Thomas Thum"

366 Publications

ERBB4 and Multiple MicroRNAs That Target ERBB4 Participate in Pregnancy-Related Cardiomyopathy.

Circ Heart Fail 2021 Jul 12;14(7):e006898. Epub 2021 Jul 12.

Department of Pharmaceutical, Biomedical and Veterinary Sciences, Laboratory of Physiopharmacology, University of Antwerp, Wilrijk, Belgium (E.F., J.V.f., Z.V., L.D., T.B., V.F.M.S., G.W.D.K.).

Background: Peripartum cardiomyopathy (PPCM) is a life-threatening disease in women without previously known cardiovascular disease. It is characterized by a sudden onset of heart failure before or after delivery. Previous studies revealed that the generation of a 16-kDa PRL (prolactin) metabolite, the subsequent upregulation of miR-146a, and the downregulation of the target gene is a common driving factor of PPCM.

Methods: miRNA profiling was performed in plasma of PPCM patients (n=33) and postpartum-matched healthy CTRLs (controls; n=36). Elevated miRNAs in PPCM plasma, potentially targeting ERBB4 (erythroblastic leukemia viral oncogene homolog 4), were overexpressed in cardiomyocytes using lentiviral vectors. Next, cardiac function, cardiac morphology, and PPCM phenotype were investigated after recurrent pregnancies of HZ (heterozygous) cardiomyocyte-specific mice (, n=9) with their age-matched nonpregnant CTRLs (n=9-10).

Results: Here, we identify 9 additional highly conserved miRNAs (miR-199a-5p and miR-199a-3p, miR-145a-5p, miR-130a-3p, miR-135a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, and miR19b-3p) that target tyrosine kinase receptor ERBB4 and are over 4-fold upregulated in plasma of PPCM patients at the time of diagnosis. We confirmed that miR-146a, miR-199a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, miR-130a-5p, and miR-135-3p overexpression decreases ERBB4 expression in cardiomyocytes (-29% to -50%; <0.05). In addition, we demonstrate that genetic cardiomyocyte-specific downregulation of during pregnancy suffices to induce a variant of PPCM in mice, characterized by left ventricular dilatation (postpartum second delivery: left ventricular internal diameter in diastole, +19±7% versus HZ-CTRL; <0.05), increased atrial natriuretic peptide (ANP) levels (4-fold increase versus HZ-CTRL mice, <0.001), decreased VEGF (vascular endothelial growth factor) and VE-cadherin levels (-33±17%, =0.07; -27±20%, <0.05 versus HZ-CTRL), and histologically enlarged cardiomyocytes (+20±21%, versus HZ-CTRL, <0.05) but without signs of myocardial apoptosis and inflammation.

Conclusions: ERBB4 is essential to protect the maternal heart from peripartum stress. Downregulation of ERBB4 in cardiomyocytes induced by multiple miRNAs in the peripartum period may be crucial in PPCM pathophysiology. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00998556.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.006898DOI Listing
July 2021

Identification of sex-specific biomarkers predicting new-onset heart failure.

ESC Heart Fail 2021 Jun 22. Epub 2021 Jun 22.

Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, P. Debyelaan 25, Maastricht, 6229 HX, The Netherlands.

Aims: Heart failure (HF) is common in both men and women, yet disease pathophysiology, presentation, and progression differ between sexes. Studies addressing whether biomarkers predict new onset HF sex-specifically are scarce. This study therefore aims to test the sex-specificity of 252 protein biomarkers for new-onset HF.

Methods And Results: A matched case-control design in patients selected from cohorts within the HOMAGE consortium was used. Cases (new-onset HF, n = 562) and controls (n = 780) were matched for cohort (PREDICTOR, HEALTH-ABC, & PROSPER), follow-up time (defined as time from entry to incident HF), and age. Incident HF was defined as first hospitalization for HF. Targeted plasma proteins (n = 252) were measured using Proximity Extension Assay technology from O-link. To look for sex differences for new onset HF, we adjusted for cohort, age, and baseline clinical parameters. At baseline, women had a biomarker profile reflecting activated metabolism and immune responses. However, none of the biomarkers had a significant interaction with sex in predicting new onset HF, but four biomarkers had a trend towards sex-specificity (P < 0.013). E-selectin and interleukin 1 receptor antagonist were more female-specific, whereas IL17A and CHIT1 tended to be male sex-specific for incident HF.

Conclusions: The majority of biomarkers associated with incident HF did not significantly differ between women and men, despite clear differences in biomarkers at baseline.
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http://dx.doi.org/10.1002/ehf2.13476DOI Listing
June 2021

Circulating microRNAs predispose to takotsubo syndrome following high-dose adrenaline exposure.

Cardiovasc Res 2021 Jun 22. Epub 2021 Jun 22.

National Heart and Lung Institute, Imperial College London, UK.

Aims: Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and absence of coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS.

Methods And Results: miR-16 and miR-26a were co-overexpressed in rats with AAV and TTS induced with an adrenaline bolus. Untreated isolated rat cardiomyocytes were transfected with pre-/anti-miRs and functionally assessed. Ventricular basal hypercontraction and apical depression were accentuated in miR-transfected animals after induction of TTS. In vitro miR-16 and/or miR-26a overexpression in isolated apical (but not basal) cardiomyocytes produced strong depression of contraction, with loss of adrenaline sensitivity. They also enhanced the initial positive inotropic effect of adrenaline in basal cells. Decreased contractility after TTS-miRs was reproduced in non-failing human apical cardiomyocytes. Bioinformatic profiling of miR targets, followed by expression assays and functional experiments, identified reductions of CACNB1 (L-type calcium channel Cavβ subunit), RGS4 (regulator of G-protein signalling 4) and G-protein subunit Gβ (GNB1) as underlying these effects.

Conclusion: miR-16 and miR-26a sensitise the heart to TTS-like changes produced by adrenaline. Since these miRs have been associated with anxiety and depression, they could provide a mechanism whereby priming of the heart by previous stress causes an increased likelihood of TTS in the future.

Translational Perspective: TTS-associated miRs have the potential to be active players predisposing to TTS. Feasibly, their measurement in recovered TTS patients during subsequent periods of stress could be used to predict likelihood of recurrence, a significant risk in this population, and allow preventative action. Since they have been reported as raised in anxiety and depression, they could be part of a priming mechanism where chronic stress predisposes to an acute episode. Understanding the mechanistic basis for the sensitisation may also allow design of other prophylactic pharmacological therapies, including the pre/anti-miR constructs which are now starting to reach the clinic.
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http://dx.doi.org/10.1093/cvr/cvab210DOI Listing
June 2021

Reconstruction of the miR-506-Quaking axis in Idiopathic Pulmonary Fibrosis using integrative multi-source bioinformatics.

Sci Rep 2021 Jun 14;11(1):12456. Epub 2021 Jun 14.

Chair of Medical Informatics, Friedrich-Alexander University (FAU) of Erlangen-Nürnberg, Erlangen, Germany.

The family of RNA-binding proteins (RBP) functions as a crucial regulator of multiple biological processes and diseases. However, RBP function in the clinical setting of idiopathic pulmonary fibrosis (IPF) is still unknown. We developed a practical in silico screening approach for the characterization of RBPs using multi-sources data information and comparative molecular network bioinformatics followed by wet-lab validation studies. Data mining of bulk RNA-Sequencing data of tissues of patients with IPF identified Quaking (QKI) as a significant downregulated RBP. Cell-type specific expression was confirmed by single-cell RNA-Sequencing analysis of IPF patient data. We systematically analyzed the molecular interaction network around QKI and its functional interplay with microRNAs (miRs) in human lung fibroblasts and discovered a novel regulatory miR-506-QKI axis contributing to the pathogenesis of IPF. The in silico results were validated by in-house experiments applying model systems of miR and lung biology. This study supports an understanding of the intrinsic molecular mechanisms of IPF regulated by the miR-506-QKI axis. Initially applied to human lung disease, the herein presented integrative in silico data mining approach can be adapted to other disease entities, underlining its practical relevance in RBP research.
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http://dx.doi.org/10.1038/s41598-021-89531-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203802PMC
June 2021

AntimiR-132 Attenuates Myocardial Hypertrophy in an Animal Model of Percutaneous Aortic Constriction.

J Am Coll Cardiol 2021 Jun;77(23):2923-2935

Klinik und Poliklinik für Innere Medizin I, University Clinic rechts der Isar, Technical University of Munich, Munich, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany. Electronic address:

Background: Pathological cardiac hypertrophy is a result of afterload-increasing pathologies including untreated hypertension and aortic stenosis. It features progressive adverse cardiac remodeling, myocardial dysfunction, capillary rarefaction, and interstitial fibrosis often leading to heart failure.

Objectives: This study aimed to establish a novel porcine model of pressure-overload-induced heart failure and to determine the effect of inhibition of microribonucleic acid 132 (miR-132) on heart failure development in this model.

Methods: This study developed a novel porcine model of percutaneous aortic constriction by implantation of a percutaneous reduction stent in the thoracic aorta, inducing progressive remodeling at day 56 (d56) after pressure-overload induction. In this study, an antisense oligonucleotide specifically inhibiting miR-132 (antimiR-132), was regionally applied via intracoronary injection at d0 (percutaneous transverse aortic constriction induction) and d28.

Results: At d56, antimiR-132 treatment diminished cardiomyocyte cross-sectional area (188.9 ± 2.8 vs. 258.4 ± 9.0 μm in untreated hypertrophic hearts) and improved global cardiac function (ejection fraction 48.9 ± 1.0% vs. 36.1 ± 1.7% in control hearts). Moreover, at d56 antimiR-132-treated hearts displayed less increase of interstitial fibrosis compared with sham-operated hearts (Δsham 1.8 ± 0.5%) than control hearts (Δsham 10.8 ± 0.6%). Of note, cardiac platelet and endothelial cell adhesion molecule 1 capillary density was higher in the antimiR-132-treated hearts (647 ± 20 cells/mm) compared with in the control group (485 ± 23 cells/mm).

Conclusions: The inhibition of miR-132 is a valid strategy in prevention of heart failure progression in hypertrophic heart disease and may be developed as a treatment for heart failure of nonischemic origin.
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http://dx.doi.org/10.1016/j.jacc.2021.04.028DOI Listing
June 2021

Heart Failure Association, Heart Failure Society of America, and Japanese Heart Failure Society Position Statement on Endomyocardial Biopsy.

J Card Fail 2021 Jul 19;27(7):727-743. Epub 2021 May 19.

Cleveland Clinic, Cleveland Ohio.

Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumors. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples has significantly improved the diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (1) an overview of the practical approach to EMB, (2) an update on indications for EMB, (3) a revised plan for heart transplant rejection surveillance, (4) the impact of multimodality imaging on EMB, and (5) the current clinical practice in the worldwide use of EMB.
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http://dx.doi.org/10.1016/j.cardfail.2021.04.010DOI Listing
July 2021

Heart Failure Association of the ESC, Heart Failure Society of America and Japanese Heart Failure Society Position statement on endomyocardial biopsy.

Eur J Heart Fail 2021 Jun 19;23(6):854-871. Epub 2021 May 19.

Cleveland Clinic, Cleveland, OH, USA.

Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant (HTx) rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumours. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples have significantly improved diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (i) an overview of the practical approach to EMB, (ii) an update on indications for EMB, (iii) a revised plan for HTx rejection surveillance, (iv) the impact of multimodality imaging on EMB, and (v) the current clinical practice in the worldwide use of EMB.
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http://dx.doi.org/10.1002/ejhf.2190DOI Listing
June 2021

Propelling Healthcare with Advanced Therapy Medicinal Products: A Policy Discussion.

Biomed Hub 2020 Sep-Dec;5(3):130-152. Epub 2020 Dec 3.

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.

Recent advances in biomedicine are opening the door to new approaches, and treatment and prevention are being transformed by novel medicines based on genetic engineering, innovative cell-based therapies and tissue-engineered products, and combinations of a medical device with embedded cell or tissue components. These advanced therapy medicinal products (ATMPs) hold one of the keys to making a reality of genuinely personalised medicine. There are an estimated 450 companies across the globe working on the development of gene therapies and more than 1,000 clinical trials underway worldwide, and some 20-30 new ATMPs filings are expected in Europe annually over the next 5 years. But challenges confront the sector, complicating the translation from research into patient access. Scientific, clinical development and regulatory issues are compounded by limited experience with clinical and commercial use, limited manufacturing know-how, high costs, and difficulties in accessing development funding and investment. Pricing and reimbursement and market access issues are an additional challenge, particularly in Europe, where unfamiliarity with the technology and uncertainty over the use of real-world evidence induce caution among clinicians, health technology assessment bodies and payers. There is a need for a review of the suitability of the regulatory and market access framework for these products, focused development of data, public/private partnerships, and fuller collaboration governments, doctors, insurers, patients, and pharmaceutical companies. This paper makes specific recommendations for all stakeholders, ranging from early dialogue on potential products, linking of clinical data and patient registries or standardisation of control frameworks, to a comprehensive approach to evidence generation, assessment, pricing, and payment for ATMPs.
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http://dx.doi.org/10.1159/000511678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101061PMC
December 2020

Leveraging clinical epigenetics in heart failure with preserved ejection fraction: a call for individualized therapies.

Eur Heart J 2021 05;42(20):1940-1958

Center for Molecular Cardiology, University of Zürich, Wagistrasse 12, Schlieren CH-8952, Switzerland.

Described as the 'single largest unmet need in cardiovascular medicine', heart failure with preserved ejection fraction (HFpEF) remains an untreatable disease currently representing 65% of new heart failure diagnoses. HFpEF is more frequent among women and associates with a poor prognosis and unsustainable healthcare costs. Moreover, the variability in HFpEF phenotypes amplifies complexity and difficulties in the approach. In this perspective, unveiling novel molecular targets is imperative. Epigenetic modifications-defined as changes of DNA, histones, and non-coding RNAs (ncRNAs)-represent a molecular framework through which the environment modulates gene expression. Epigenetic signals acquired over the lifetime lead to chromatin remodelling and affect transcriptional programmes underlying oxidative stress, inflammation, dysmetabolism, and maladaptive left ventricular remodelling, all conditions predisposing to HFpEF. The strong involvement of epigenetic signalling in this setting makes the epigenetic information relevant for diagnostic and therapeutic purposes in patients with HFpEF. The recent advances in high-throughput sequencing, computational epigenetics, and machine learning have enabled the identification of reliable epigenetic biomarkers in cardiovascular patients. Contrary to genetic tools, epigenetic biomarkers mirror the contribution of environmental cues and lifestyle changes and their reversible nature offers a promising opportunity to monitor disease states. The growing understanding of chromatin and ncRNAs biology has led to the development of several Food and Drug Administration approved 'epidrugs' (chromatin modifiers, mimics, anti-miRs) able to prevent transcriptional alterations underpinning left ventricular remodelling and HFpEF. In the present review, we discuss the importance of clinical epigenetics as a new tool to be employed for a personalized management of HFpEF.
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http://dx.doi.org/10.1093/eurheartj/ehab197DOI Listing
May 2021

Patient profiling in heart failure for tailoring medical therapy. A consensus document of the Heart Failure Association of the European Society of Cardiology.

Eur J Heart Fail 2021 Jun 20;23(6):872-881. Epub 2021 May 20.

Department Faculty of Medicine, University of Belgrade, Belgrade, Serbia.

Despite guideline recommendations and available evidence, implementation of treatment in heart failure (HF) is poor. The majority of patients are not prescribed drugs at target doses that have been proven to positively impact morbidity and mortality. Among others, tolerability issues related to low blood pressure, heart rate, impaired renal function or hyperkalaemia are responsible. Chronic kidney disease plays an important role as it affects up to 50% of patients with HF. Also, dynamic changes in estimated glomerular filtration rate may occur during the course of HF, resulting in inappropriate dose reduction or even discontinuation of decongestive or neurohormonal modulating therapy in clinical practice. As patients with HF are rarely naïve to pharmacologic therapies, the challenge is to adequately prioritize or select the most appropriate up-titration schedule according to patient profile. In this consensus document, we identified nine patient profiles that may be relevant for treatment implementation in HF patients with a reduced ejection fraction. These profiles take into account heart rate (<60 bpm or >70 bpm), the presence of atrial fibrillation, symptomatic low blood pressure, estimated glomerular filtration rate (<30 or >30 mL/min/1.73 m ) or hyperkalaemia. The pre-discharge patient, frequently still congestive, is also addressed. A personalized approach, adjusting guideline-directed medical therapy to patient profile, may allow to achieve a better and more comprehensive therapy for each individual patient than the more traditional, forced titration of each drug class before initiating treatment with the next.
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http://dx.doi.org/10.1002/ejhf.2206DOI Listing
June 2021

Cardiovascular RNA markers and artificial intelligence may improve COVID-19 outcome: a position paper from the EU-CardioRNA COST Action CA17129.

Cardiovasc Res 2021 07;117(8):1823-1840

Cardiovascular Research Unit, Department of Population Health, Luxembourg Institute of Health, 1A-B rue Edison, L-1445 Strassen, Luxembourg.

The coronavirus disease 2019 (COVID-19) pandemic has been as unprecedented as unexpected, affecting more than 105 million people worldwide as of 8 February 2020 and causing more than 2.3 million deaths according to the World Health Organization (WHO). Not only affecting the lungs but also provoking acute respiratory distress, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is able to infect multiple cell types including cardiac and vascular cells. Hence a significant proportion of infected patients develop cardiac events, such as arrhythmias and heart failure. Patients with cardiovascular comorbidities are at highest risk of cardiac death. To face the pandemic and limit its burden, health authorities have launched several fast-track calls for research projects aiming to develop rapid strategies to combat the disease, as well as longer-term projects to prepare for the future. Biomarkers have the possibility to aid in clinical decision-making and tailoring healthcare in order to improve patient quality of life. The biomarker potential of circulating RNAs has been recognized in several disease conditions, including cardiovascular disease. RNA biomarkers may be useful in the current COVID-19 situation. The discovery, validation, and marketing of novel biomarkers, including RNA biomarkers, require multi-centre studies by large and interdisciplinary collaborative networks, involving both the academia and the industry. Here, members of the EU-CardioRNA COST Action CA17129 summarize the current knowledge about the strain that COVID-19 places on the cardiovascular system and discuss how RNA biomarkers can aid to limit this burden. They present the benefits and challenges of the discovery of novel RNA biomarkers, the need for networking efforts, and the added value of artificial intelligence to achieve reliable advances.
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http://dx.doi.org/10.1093/cvr/cvab094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083253PMC
July 2021

Therapeutic and Diagnostic Translation of Extracellular Vesicles in Cardiovascular Diseases: Roadmap to the Clinic.

Circulation 2021 Apr 5;143(14):1426-1449. Epub 2021 Apr 5.

Institute of Molecular and Translational Therapeutic Strategies (IMTTS) (F.K., S.K-K., T.T.), Hannover Medical School, Germany.

Exosomes are small membrane-bound vesicles of endocytic origin that are actively secreted. The potential of exosomes as effective communicators of biological signaling in myocardial function has previously been investigated, and a recent explosion in exosome research not only underscores their significance in cardiac physiology and pathology, but also draws attention to methodological limitations of studying these extracellular vesicles. In this review, we discuss recent advances and challenges in exosome research with an emphasis on scientific innovations in isolation, identification, and characterization methodologies, and we provide a comprehensive summary of web-based resources available in the field. Importantly, we focus on the biology and function of exosomes, highlighting their fundamental role in cardiovascular pathophysiology to further support potential applications of exosomes as biomarkers and therapeutics for cardiovascular diseases.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021236PMC
April 2021

Remodelling of adult cardiac tissue subjected to physiological and pathological mechanical load in vitro.

Cardiovasc Res 2021 Mar 16. Epub 2021 Mar 16.

National Heart and Lung Institute, Imperial College London, UK.

Aims: Cardiac remodelling is the process by which the heart adapts to its environment. Mechanical load is a major driver of remodelling. Cardiac tissue culture has been frequently employed for in vitro studies of load-induced remodelling; however, current in vitro protocols (e.g. cyclic stretch, isometric load, auxotonic load) are oversimplified and do not accurately capture the dynamic sequence of mechanical conformational changes experienced by the heart in vivo. This limits translational scope and relevance of findings.

Methods And Results: We developed a novel methodology to study chronic load in vitro. We first developed a bioreactor that can recreate the electromechanical events of in vivo pressure-volume loops as in vitro force-length loops. We then used the bioreactor to culture rat living myocardial slices (LMS) for 3 days. The bioreactor operated on the basis of a 3-Element Windkessel circulatory model enabling tissue mechanical loading based on physiologically relevant parameters of afterload and preload. LMS were continuously stretched/relaxed during culture simulating conditions of physiological load (normal preload & afterload), pressure-overload (normal preload & high afterload), or volume-overload (high preload & normal afterload). At the end of culture, functional, structural, and molecular assays were performed to determine load-induced remodelling.Both pressure- and volume-overloaded LMS showed significantly decreased contractility that was more pronounced in the latter compared with physiological load p < 0.0001). Overloaded groups also showed cardiomyocyte hypertrophy; RNAseq identified shared and unique genes expressed in each overload group. The PI3K-Akt pathway was dysregulated in volume-overload while inflammatory pathways were mostly associated with remodelling in pressure-overloaded LMS.

Conclusion: We have developed a proof-of-concept platform and methodology to recreate remodelling under pathophysiological load in vitro. We show that LMS cultured in our bioreactor remodel as a function of the type of mechanical load applied to them.
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http://dx.doi.org/10.1093/cvr/cvab084DOI Listing
March 2021

Alternative strategies in cardiac preclinical research and new clinical trial formats.

Cardiovasc Res 2021 Mar 8. Epub 2021 Mar 8.

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.

An efficient and safe drug development process is crucial for the establishment of new drugs on the market aiming to increase quality of life and life-span of our patients. Despite technological advances in the past decade, successful launches of drug candidates per year remain low. We here give an overview about some of these advances and suggest improvements for implementation to boost preclinical and clinical drug development with a focus on the cardiovascular field. We highlight advantages and disadvantages of animal experimentation and thoroughly review alternatives in the field of three-dimensional cell culture as well as preclinical use of spheroids and organoids. Microfluidic devices and their potential as organ-on-a-chip systems, as well as the use of living animal and human cardiac tissues are additionally introduced. In the second part, we examine recent gold standard randomized clinical trials and present possible modifications to increase lead candidate throughput: adaptive designs, master protocols and drug repurposing. In silico and N-of-1 trials have the potential to redefine clinical drug candidate evaluation. Finally, we briefly discuss clinical trial designs during pandemic times.
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http://dx.doi.org/10.1093/cvr/cvab075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989574PMC
March 2021

Serum microRNAs and antifibrotic response to eplerenone in acute myocardial infarction complicated by systolic dysfunction.

Int J Cardiol 2021 06 5;332:35-37. Epub 2021 Mar 5.

Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, INSERM U1116, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France. Electronic address:

Background: After myocardial infarction (MI) complicated by heart failure (HF), eplerenone reduced serum concentrations of amino-terminal propeptide of type III collagen (PIIINP) and carboxy-terminal propeptide of type I collagen (PICP). Determining a subgroup who are more prone to decrease their collagen content and to respond better to the antifibrotic effects of mineralocorticoid receptor antagonists (MRA) may be relevant for a personalized treatment approach. Whether circulating microRNAs may identify a subgroup that have experienced a more pronounced antifibrotic effect of eplerenone as measured by a PICP and PIIINP decrease is unclear.

Methods: A set of circulating microRNAs linked to cardiac fibrosis (mir-1, mir-21, mir-29a, mir-29b, mir-101, mir-122, mir-133a) were measured at baseline in 198 patients in the biomarker substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Associations between baseline microRNA levels and changes in both PIIINP and PICP from baseline to month 9 were studied using multivariable analysis of covariance, adjusting for age, sex, history of hypertension and diabetes mellitus, prescription of ACE-inhibitors or angiotensin receptor blockers, baseline PIIINP or PICP, and eplerenone treatment. Furthermore, a treatment-by-microRNA interaction was studied.

Results: From the selected microRNAs, only mir-133a was associated with a PICP decrease (ß-6.43, 95%CI-12.71 to -0.15,p = 0.045). None of the microRNAs was associated with a PIIINP change. The microRNAs did not predict an effect of eplerenone on PICP and PIIINP changes.

Conclusion: Although serum mir-133a was associated with PICP change, none of the microRNAs previously linked to cardiac fibrosis predicted an antifibrotic response to eplerenone. Further study is needed to identify other suitable targets for a personalized treatment approach.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.088DOI Listing
June 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Role of endothelial microRNA 155 on capillary leakage in systemic inflammation.

Crit Care 2021 02 22;25(1):76. Epub 2021 Feb 22.

Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.

Background: Capillary leakage is a key contributor to the pathological host response to infections. The underlying mechanisms remain incompletely understood, and the role of microRNAs (MIR) has not been investigated in detail. We hypothesized that specific MIRs might be regulated directly in the endothelium thereby contributing to vascular leakage.

Methods: SmallRNA sequencing of endotoxemic murine pulmonary endothelial cells (ECs) was done to detect regulated vascular MIRs. In vivo models: transgenic zebrafish (flk1:mCherry/l-fabp:eGFP-DPB), knockout/wildtype mouse (B6.Cg-Mir155tm1.1Rsky/J); disease models: LPS 17.5 mg/kgBW and cecal ligation and puncture (CLP); in vitro models: stimulated human umbilical vein EC (HUVECs), transendothelial electrical resistance.

Results: Endothelial MIR155 was identified as a promising candidate in endotoxemic murine pulmonary ECs (25 × upregulation). Experimental overexpression in a transgenic zebrafish line and in HUVECs was sufficient to induce spontaneous vascular leakage. To the contrary, genetic MIR155 reduction protects against permeability both in vitro and in endotoxemia in vivo in MIR155 heterozygote knockout mice thereby improving survival by 40%. A tight junction protein, Claudin-1, was down-regulated both in endotoxemia and by experimental MIR155 overexpression. Translationally, MIR155 was detectable at high levels in bronchoalveolar fluid of patients with ARDS compared to healthy human subjects.

Conclusions: We found that MIR155 is upregulated in the endothelium in mouse and men as part of a systemic inflammatory response and might contribute to the pathophysiology of vascular leakage in a Claudin-1-dependent manner. Future studies have to clarify whether MIR155 could be a potential therapeutic target.
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http://dx.doi.org/10.1186/s13054-021-03500-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901081PMC
February 2021

Risk stratification and management of women with cardiomyopathy/heart failure planning pregnancy or presenting during/after pregnancy: a position statement from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy.

Eur J Heart Fail 2021 04 17;23(4):527-540. Epub 2021 Mar 17.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

This position paper focusses on the pathophysiology, diagnosis and management of women diagnosed with a cardiomyopathy, or at risk of heart failure (HF), who are planning to conceive or present with (de novo or previously unknown) HF during or after pregnancy. This includes the heterogeneous group of heart muscle diseases such as hypertrophic, dilated, arrhythmogenic right ventricular and non-classified cardiomyopathies, left ventricular non-compaction, peripartum cardiomyopathy, Takotsubo syndrome, adult congenital heart disease with HF, and patients with right HF. Also, patients with a history of chemo-/radiotherapy for cancer or haematological malignancies need specific pre-, during and post-pregnancy assessment and counselling. We summarize the current knowledge about pathophysiological mechanisms, including gene mutations, clinical presentation, diagnosis, and medical and device management, as well as risk stratification. Women with a known diagnosis of a cardiomyopathy will often require continuation of drug therapy, which has the potential to exert negative effects on the foetus. This position paper assists in balancing benefits and detrimental effects.
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http://dx.doi.org/10.1002/ejhf.2133DOI Listing
April 2021

Diagnostic value of circulating microRNAs compared to high-sensitivity troponin T for the detection of non-ST-segment elevation myocardial infarction.

Eur Heart J Acute Cardiovasc Care 2021 Jan 4. Epub 2021 Jan 4.

Zentrum für Innere Medizin, Klinik für Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Heidelberg, Germany.

Aims: To assess the diagnostic value of microRNAs (miRNAs) for the detection of non-ST-segment elevation myocardial infarction (NSTEMI).

Methods And Results: A total of 1042 patients presenting between August 2014 and April 2017 to the emergency department with the suspected acute coronary syndrome were included. Non-ST-segment elevation myocardial infarction was diagnosed per criteria of the fourth Universal definition of myocardial infarction (UDMI) using high-sensitivity troponin T (hs-cTnT). Expression levels of eleven microRNAs (miR-21, miR-22, miR-29a, miR-92a, miR-122, miR-126, miR-132, miR-133, miR-134, miR-191, and miR-423) were determined using RT-qPCR. Discrimination of NSTEMI was assessed for individual and a panel of miRNAs compared to the hs-cTnT reference using C-statistics and reclassification analysis. NSTEMI was diagnosed in 137 (13.1%) patients. The area under the curve (AUC) of the hs-cTnT based reference was 0.937. In a multivariate model, three miRNAs (miR-122, miR-133, and miR-134) were found to be associated with NSTEMI with AUCs between 0.506 and 0.656. A panel consisting of these miRNAs revealed an AUC of 0.662 for the diagnosis of NSTEMI. The AUC of the combination of the miRNA panel and troponin reference was significantly lower than the reference standard (AUC: 0.897 vs. 0.937, P = 0.006). Despite a significant improvement of NSTEMI reclassification measured by IDI and NRI, miRNAs did not improve the specificity of hs-cTnT kinetic changes for the diagnosis of NSTEMI (ΔAUC: 0.04).

Conclusion: Although single miRNAs are significantly associated with the diagnosis of NSTEMI a miRNA panel does not add diagnostic accuracy to the hs-cTnT reference considering baseline values and kinetic changes as recommended by the fourth version of UDMI.

Clinical Trials Identifier: NCT02116153.
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http://dx.doi.org/10.1093/ehjacc/zuaa034DOI Listing
January 2021

Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length.

Geroscience 2021 04 31;43(2):673-690. Epub 2021 Jan 31.

Cellular Neurophysiology, Hanover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.

Ageing provokes a plethora of molecular, cellular and physiological deteriorations, including heart failure, neurodegeneration, metabolic maladaptation, telomere attrition and hair loss. Interestingly, on the molecular level, the capacity to induce autophagy, a cellular recycling and cleaning process, declines with age across a large spectrum of model organisms and is thought to be responsible for a subset of age-induced changes. Here, we show that a 6-month administration of the natural autophagy inducer spermidine in the drinking water to aged mice is sufficient to significantly attenuate distinct age-associated phenotypes. These include modulation of brain glucose metabolism, suppression of distinct cardiac inflammation parameters, decreased number of pathological sights in kidney and liver and decrease of age-induced hair loss. Interestingly, spermidine-mediated age protection was associated with decreased telomere attrition, arguing in favour of a novel cellular mechanism behind the anti-ageing effects of spermidine administration.
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http://dx.doi.org/10.1007/s11357-020-00310-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110654PMC
April 2021

Reciprocal organ interactions during heart failure-a position paper from the ESC working group on myocardial function.

Cardiovasc Res 2021 Jan 22. Epub 2021 Jan 22.

Department of Medicine, Surgery and Dentistry, University of Salerno, Italy.

Heart failure-either with reduced or preserved ejection fraction (HFrEF/HFpEF)-is a clinical syndrome of multifactorial and gender-dependent aetiology, indicating the insufficiency of the heart to pump blood adequately to maintain blood flow to meet the body's needs. Typical symptoms commonly include shortness of breath, excessive fatigue with impaired exercise capacity, and peripheral oedema, thereby alluding to the fact that heart failure is a syndrome that affects multiple organ systems. Patients suffering from progressed heart failure have a very limited life expectancy, lower than that of numerous cancer types. In this position paper, we provide an overview regarding interactions between the heart and other organ systems, the clinical evidence, underlying mechanisms, potential available or yet-to-establish animal models to study such interactions and finally discuss potential new drug interventions to be developed in the future. Our working group suggests that more experimental research is required to understand the individual molecular mechanisms underlying heart failure and reinforces the urgency for tailored therapeutic interventions that target not only the heart but also other related affected organ systems to effectively treat heart failure as a clinical syndrome that affects and involves multiple organs.
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http://dx.doi.org/10.1093/cvr/cvab009DOI Listing
January 2021

Renal AAV2-Mediated Overexpression of Long Non-Coding RNA Attenuates Ischemic Acute Kidney Injury Through Sponging of microRNA-30a-5p.

J Am Soc Nephrol 2021 Feb 21;32(2):323-341. Epub 2021 Jan 21.

Department of Nephrology, University Hospital Zürich, Zurich, Switzerland

Background: Renal ischemia-reperfusion (I/R) injury is a major cause of AKI. Noncoding RNAs are intricately involved in the pathophysiology of this form of AKI. Transcription of hypoxia-induced, long noncoding RNA , which shows high embryonic expression and is silenced in adults, is upregulated in renal I/R injury.

Methods: Lentivirus-mediated overexpression, as well as antisense oligonucleotide-based silencing, modulated . analyses used constitutive knockout mice. In addition, renal vein injection of adeno-associated virus 2 (AAV2) carrying caused overexpression in the kidney. Expression of in kidney transplant patients with I/R injury was investigated.

Results: is upregulated in kidney biopsies of patients with AKI, in murine ischemic kidney tissue, and in cultured and sorted hypoxic endothelial cells (ECs) and tubular epithelial cells (TECs). Transcription factors hypoxia-inducible factor 1-, LHX8, and SPI1 activate in ECs and TECs. overexpression promotes angiogenesis and , transient AAV2-mediated overexpression significantly improved kidney function, reduced apoptosis, and reduced inflammation, as well as preserving capillary density and tubular epithelial integrity. Sponging of miR-30a-5p mediated the effects, which, in turn, led to target regulation of Dll4, ATG5, and Snai1.

Conclusions: overexpression confers protection against renal injury by stimulating proangiogenic signaling. overexpression may be a promising future therapeutic option in the treatment of patients with ischemic AKI.
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http://dx.doi.org/10.1681/ASN.2020060775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054899PMC
February 2021

Blood-based protein profiling identifies serum protein c-KIT as a novel biomarker for hypertrophic cardiomyopathy.

Sci Rep 2021 Jan 19;11(1):1755. Epub 2021 Jan 19.

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.

Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary heart diseases and can be classified into an obstructive (HOCM) and non-obstructive (HNCM) form. Major characteristics for HCM are the hypertrophy of cardiomyocytes and development of cardiac fibrosis. Patients with HCM have a higher risk for sudden cardiac death compared to a healthy population. In the present study, we investigated the abundancy of selected proteins as potential biomarkers in patients with HCM. We included 60 patients with HCM and 28 healthy controls and quantitatively measured the rate of a set of 92 proteins already known to be associated with cardiometabolic processes via protein screening using the proximity extension assay technology in a subgroup of these patients (20 HCM and 10 healthy controls). After validation of four hits in the whole cohort of patients consisting of 88 individuals (60 HCM patients, 28 healthy controls) we found only one candidate, c-KIT, which was regulated significantly different between HCM patients and healthy controls and thus was chosen for further analyses. c-KIT is a tyrosine-protein kinase acting as receptor for the stem cell factor and activating several pathways essential for cell proliferation and survival, hematopoiesis, gametogenesis and melanogenesis. Serum protein levels of c-KIT were significantly lower in patients with HCM than in healthy controls, even after adjusting for confounding factors age and sex. In addition, c-KIT levels in human cardiac tissue of patients with HOCM were significant higher compared to controls indicating high levels of c-KIT in fibrotic myocardium. Furthermore, c-KIT concentration in serum significantly correlated with left ventricular end-diastolic diameter in HOCM, but not HCM patients. The present data suggest c-KIT as a novel biomarker differentiating between patients with HCM and healthy population and might provide further functional insights into fibrosis-related processes of HOCM.
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http://dx.doi.org/10.1038/s41598-020-80868-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815737PMC
January 2021

DGK and DZHK position paper on genome editing: basic science applications and future perspective.

Basic Res Cardiol 2021 01 15;116(1). Epub 2021 Jan 15.

Institute of Developmental Genetics, Helmholtz Zentrum München Germany, Technische Universität München-Weihenstephan, Neuherberg, Munich, Germany.

For a long time, gene editing had been a scientific concept, which was limited to a few applications. With recent developments, following the discovery of TALEN zinc-finger endonucleases and in particular the CRISPR/Cas system, gene editing has become a technique applicable in most laboratories. The current gain- and loss-of function models in basic science are revolutionary as they allow unbiased screens of unprecedented depth and complexity and rapid development of transgenic animals. Modifications of CRISPR/Cas have been developed to precisely interrogate epigenetic regulation or to visualize DNA complexes. Moreover, gene editing as a clinical treatment option is rapidly developing with first trials on the way. This article reviews the most recent progress in the field, covering expert opinions gathered during joint conferences on genome editing of the German Cardiac Society (DGK) and the German Center for Cardiovascular Research (DZHK). Particularly focusing on the translational aspect and the combination of cellular and animal applications, the authors aim to provide direction for the development of the field and the most frequent applications with their problems.
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http://dx.doi.org/10.1007/s00395-020-00839-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810637PMC
January 2021

Circulating cardiovascular microRNAs in critically ill COVID-19 patients.

Eur J Heart Fail 2021 03 5;23(3):468-475. Epub 2021 Mar 5.

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.

Aims: Coronavirus disease 2019 (COVID-19) is a still growing pandemic, causing many deaths and socio-economic damage. Elevated expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry receptor angiotensin-converting enzyme 2 on cardiac cells of patients with heart diseases may be related to cardiovascular burden. We have thus analysed cardiovascular and inflammatory microRNAs (miRs), sensitive markers of cardiovascular damage, in critically ill, ventilated patients with COVID-19 or influenza-associated acute respiratory distress syndrome (Influenza-ARDS) admitted to the intensive care unit and healthy controls.

Methods And Results: Circulating miRs (miR-21, miR-126, miR-155, miR-208a, and miR-499) were analysed in a discovery cohort consisting of patients with mechanically-ventilated COVID-19 (n = 18) and healthy controls (n = 15). A validation study was performed in an independent cohort of mechanically-ventilated COVID-19 patients (n = 20), Influenza-ARDS patients (n = 13) and healthy controls (n = 32). In both cohorts, RNA was isolated from serum and cardiovascular disease/inflammatory-relevant miR concentrations were measured by miR-specific TaqMan PCR analyses. In both the discovery and the validation cohort, serum concentration of miR-21, miR-155, miR-208a and miR-499 were significantly increased in COVID-19 patients compared to healthy controls. Calculating the area under the curve using receiver operating characteristic analysis miR-155, miR-208a and miR-499 showed a clear distinction between COVID-19 and Influenza-ARDS patients.

Conclusion: In this exploratory study, inflammation and cardiac myocyte-specific miRs were upregulated in critically ill COVID-19 patients. Importantly, miR profiles were able to differentiate between severely ill, mechanically-ventilated Influenza-ARDS and COVID-19 patients, indicating a rather specific response and cardiac involvement of COVID-19.
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http://dx.doi.org/10.1002/ejhf.2096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014268PMC
March 2021

Telomerase therapy attenuates cardiotoxic effects of doxorubicin.

Mol Ther 2021 04 1;29(4):1395-1410. Epub 2021 Jan 1.

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover 30625, Germany; REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School, Hannover 30625, Germany. Electronic address:

Doxorubicin is one of the most potent chemotherapeutic agents. However, its clinical use is restricted due to the severe risk of cardiotoxicity, partially attributed to elevated production of reactive oxygen species (ROS). Telomerase canonically maintains telomeres during cell division but is silenced in adult hearts. In non-dividing cells such as cardiomyocytes, telomerase confers pro-survival traits, likely owing to the detoxification of ROS. Therefore, we hypothesized that pharmacological overexpression of telomerase may be used as a therapeutic strategy for the prevention of doxorubicin-induced cardiotoxicity. We used adeno-associated virus (AAV)-mediated gene therapy for long-term expression of telomerase in in vitro and in vivo models of doxorubicin-induced cardiotoxicity. Overexpression of telomerase protected the heart from doxorubicin-mediated apoptosis and rescued cardiac function, which was accompanied by preserved cardiomyocyte size. At the mechanistic level, we observed altered mitochondrial morphology and dynamics in response to telomerase expression. Complementary in vitro experiments confirmed the anti-apoptotic effects of telomerase overexpression in human induced pluripotent stem cell-derived cardiomyocytes after doxorubicin treatment. Strikingly, elevated levels of telomerase translocated to the mitochondria upon doxorubicin treatment, which helped to maintain mitochondrial function. Thus, telomerase gene therapy could be a novel preventive strategy for cardiotoxicity by chemotherapy agents such as the anthracyclines.
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http://dx.doi.org/10.1016/j.ymthe.2020.12.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058493PMC
April 2021

Novel antisense therapy targeting microRNA-132 in patients with heart failure: results of a first-in-human Phase 1b randomized, double-blind, placebo-controlled study.

Eur Heart J 2021 01;42(2):178-188

Cardior Pharmaceuticals GmbH, Hannover Medical School Campus, Feodor-Lynen-Straße 15, Hannover 30625, Germany.

Aims: Cardiac microRNA-132-3p (miR-132) levels are increased in patients with heart failure (HF) and mechanistically drive cardiac remodelling processes. CDR132L, a specific antisense oligonucleotide, is a first-in-class miR-132 inhibitor that attenuates and even reverses HF in preclinical models. The aim of the current clinical Phase 1b study was to assess safety, pharmacokinetics, target engagement, and exploratory pharmacodynamic effects of CDR132L in patients on standard-of-care therapy for chronic ischaemic HF in a randomized, placebo-controlled, double-blind, dose-escalation study (NCT04045405).

Methods And Results: Patients had left ventricular ejection fraction between ≥30% and <50% or amino terminal fragment of pro-brain natriuretic peptide (NT-proBNP) >125 ng/L at screening. Twenty-eight patients were randomized to receive CDR132L (0.32, 1, 3, and 10 mg/kg body weight) or placebo (0.9% saline) in two intravenous infusions, 4 weeks apart in four cohorts of seven (five verum and two placebo) patients each. CDR132L was safe and well tolerated, without apparent dose-limiting toxicity. A pharmacokinetic/pharmacodynamic dose modelling approach suggested an effective dose level at ≥1 mg/kg CDR132L. CDR132L treatment resulted in a dose-dependent, sustained miR-132 reduction in plasma. Patients given CDR132L ≥1 mg/kg displayed a median 23.3% NT-proBNP reduction, vs. a 0.9% median increase in the control group. CDR132L treatment induced significant QRS narrowing and encouraging positive trends for relevant cardiac fibrosis biomarkers.

Conclusion: This study is the first clinical trial of an antisense drug in HF patients. CDR132L was safe and well tolerated, confirmed linear plasma pharmacokinetics with no signs of accumulation, and suggests cardiac functional improvements. Although this study is limited by the small patient numbers, the indicative efficacy of this drug is very encouraging justifying additional clinical studies to confirm the beneficial CDR132L pharmacodynamic effects for the treatment of HF.
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http://dx.doi.org/10.1093/eurheartj/ehaa898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954267PMC
January 2021

Pharmacokinetics and Proceedings in Clinical Application of Nucleic Acid Therapeutics.

Mol Ther 2021 02 12;29(2):521-539. Epub 2020 Nov 12.

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School (MHH), Hannover, Germany; REBIRTH Center for Translational Regenerative Medicine, Hannover Medical School (MHH), Hannover, Germany; Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany. Electronic address:

Oligonucleotide therapeutics are a novel promising class of drugs designed to specifically target either coding or non-coding RNA molecules to revolutionize treatment of various diseases. During preclinical development, investigations of the pharmacokinetic characteristics of these oligonucleotide-based drug candidates are essential. Oligonucleotides possess a long history of chemical modifications to enhance their stability and binding affinity, as well as reducing toxicity. Phosphorothioate backbone modifications of oligonucleotides were a hallmark of this development process that greatly enhanced plasma stability and protein binding of these agents. Modifications such as 2'-O-methylation further improved stability, while other modifications of the ribose, such as locked nucleic acid (LNA) modification, significantly increased binding affinity, potency, and tissue half-life. These attributes render oligonucleotide therapeutics able to regulate protein expression in both directions depending on the target RNA. Thus, a growing interest has emerged using these oligonucleotides in the treatment of neurodegenerative and cardiac disorders as well as cancer, since the deregulation of certain coding and non-coding RNAs plays a key role in the development of these diseases. Cutting edge research is being performed in the field of non-coding RNAs, identifying potential therapeutic targets, and developing novel oligonucleotide-based agents that outperform classical drugs. Some of these agents are either in clinical trials showing promising results or are already US Food and Drug Administration (FDA) approved, with more oligonucleotides being developed for therapeutic purposes. This is the advent of mechanism-based next-generation therapeutics for a wide range of diseases.
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http://dx.doi.org/10.1016/j.ymthe.2020.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854291PMC
February 2021

Combined high-throughput library screening and next generation RNA sequencing uncover microRNAs controlling human cardiac fibroblast biology.

J Mol Cell Cardiol 2021 01 28;150:91-100. Epub 2020 Oct 28.

Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany; REBIRTH Excellence Cluster, Hannover Medical School, Hannover, Germany. Electronic address:

Background: Myocardial fibrosis is a hallmark of the failing heart, contributing to the most common causes of deaths worldwide. Several microRNAs (miRNAs, miRs) controlling cardiac fibrosis were identified in recent years; however, a more global approach to identify miRNAs involved in fibrosis is missing.

Methods And Results: Functional miRNA mimic library screens were applied in human cardiac fibroblasts (HCFs) to identify annotated miRNAs inducing proliferation. In parallel, miRNA deep sequencing was performed after subjecting HCFs to proliferating and resting stimuli, additionally enabling discovery of novel miRNAs. In-depth in vitro analysis confirmed the pro-fibrotic nature of selected, highly conserved miRNAs miR-20a-5p and miR-132-3p. To determine downstream cellular pathways and their role in the fibrotic response, targets of the annotated miRNA candidates were modulated by synthetic siRNA. We here provide evidence that repression of autophagy and detoxification of reactive oxygen species by miR-20a-5p and miR-132-3p explain some of their pro-fibrotic nature on a mechanistic level.

Conclusion: We here identified both miR-20a-5p and miR-132-3p as crucial regulators of fibrotic pathways in an in vitro model of human cardiac fibroblast biology.
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http://dx.doi.org/10.1016/j.yjmcc.2020.10.008DOI Listing
January 2021

Common mechanistic pathways in cancer and heart failure. A scientific roadmap on behalf of the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

Eur J Heart Fail 2020 12 12;22(12):2272-2289. Epub 2020 Nov 12.

Medical University of Graz, University Heart Center - Division of Cardiology, Graz, Austria.

The co-occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre-clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time.
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http://dx.doi.org/10.1002/ejhf.2029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894564PMC
December 2020