Publications by authors named "Daniel Sinnecker"

46 Publications

Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome.

Circulation 2021 Oct 25;144(17):1409-1428. Epub 2021 Oct 25.

Department of Pediatric Cardiology, Leiden University Medical Center, The Netherlands (M.E.R.).

Background: Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role.

Methods: To identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS parent-offspring trios, nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, single cell RNA sequencing, and 3D modeling in induced pluripotent stem cells from 3 patients with HLHS and 3 controls.

Results: Gene set enrichment and protein network analyses of damaging de novo mutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell cycle and cardiomyocyte maturation. Single-cell and 3D modeling with induced pluripotent stem cells demonstrated intrinsic defects in the cell cycle/unfolded protein response/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte subtype differentiation/maturation in HLHS. Premature cell cycle exit of ventricular cardiomyocytes from patients with HLHS prevented normal tissue responses to developmental signals for growth, leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues.

Conclusions: Our results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting novel therapeutic approaches.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542085PMC
October 2021

Nocturnal respiratory rate predicts ICD benefit: A prospective, controlled, multicentre cohort study.

EClinicalMedicine 2021 Jan 21;31:100695. Epub 2020 Dec 21.

Klinikum rechts der Isar, Medizinische Klinik und Poliklinik I, Technical University of Munich, Munich, Germany.

Background: Implantable cardioverter defibrillators (ICDs) prevent sudden cardiac death. ICD implantation decisions are currently based on reduced left ventricular ejection fraction (LVEF≤35%). However, in some patients, the non-arrhythmic death risk predominates thus diminishing ICD-therapy benefits. Based on previous observations, we tested the hypothesis that compared to the others, patients with nocturnal respiratory rate (NRR) ≥18 breaths per minute (brpm) benefit less from prophylactic ICD implantations.

Methods: This prospective cohort study was a pre-defined sub-study of EU-CERT-ICD trial conducted at 44 centers in 15 EU countries between May 12, 2014, and September 6, 2018. Patients with ischaemic or non-ischaemic cardiomyopathy were included if meeting primary prophylactic ICD implantation criteria. The primary endpoint was all-cause mortality. NRR was assessed blindly from pre-implantation 24-hour Holters. Multivariable models and propensity stratification evaluated the interaction between NRR and the ICD mortality effect. This study is registered with ClinicalTrials.gov (NCT0206419).

Findings: Of the 2,247 EU-CERT-ICD patients, this sub-study included 1,971 with complete records. In 1,363 patients (61.7 (12) years; 244 women) an ICD was implanted; 608 patients (63.2 (12) years; 108 women) were treated conservatively. During a median 2.5-year follow-up, 202 (14.8%) and 95 (15.6%) patients died in the ICD and control groups, respectively. NRR statistically significantly interacted with the ICD mortality effect ( = 0.0070). While the 1,316 patients with NRR<18 brpm showed a marked ICD benefit on mortality (adjusted HR 0.529 (95% CI 0.376-0.746);  = 0.0003), no treatment effect was demonstrated in 655 patients with NRR≥18 brpm (adjusted HR 0.981 (95% CI 0.669-1.438);  = 0.9202).

Interpretation: In the EU-CERT-ICD trial, patients with NRR≥18 brpm showed limited benefit from primary prophylactic ICD implantation. Those with NRR<18 brpm benefitted substantially.

Funding: European Community's 7th Framework Programme FP7/2007-2013 (602299).
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http://dx.doi.org/10.1016/j.eclinm.2020.100695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846675PMC
January 2021

A deep neural network trained to interpret results from electrocardiograms: better than physicians?

Authors:
Daniel Sinnecker

Lancet Digit Health 2020 07 4;2(7):e332-e333. Epub 2020 Jun 4.

Department of Cardiology, University Hospital Klinikum Rechts der Isar, Technical University of Munich, Munich 81675, Germany. Electronic address:

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http://dx.doi.org/10.1016/S2589-7500(20)30136-9DOI Listing
July 2020

Polyscore of autonomic parameters for risk stratification of the elderly general population: the Polyscore study.

Europace 2021 05;23(5):789-796

Klinik für Innere Medizin I, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.

Aims: Present society is constantly ageing and elderly frequently suffer from conditions that are difficult and/or costly to treat if detected late. Effective screening of the elderly is therefore needed so that those requiring detailed clinical work-up are identified early. We present a prospective validation of a screening strategy based on a Polyscore of seven predominantly autonomic, non-invasive risk markers.

Methods And Results: Within a population-based survey in Germany (INVADE study), participants aged ≥60 years were enrolled between August 2013 and February 2015. Seven prospectively defined Polyscore components were obtained during 30-min continuous recordings of electrocardiogram, blood pressure, and respiration. Out of 1956 subjects, 168 were excluded due to atrial fibrillation, implanted pacemaker, or unsuitable recordings. All-cause mortality over a median 4-year follow-up was prospectively defined as the primary endpoint. The Polyscore divided the investigated population (n = 1788, median age: 72 years, females: 58%) into three predefined groups with low (n = 1405, 78.6%), intermediate (n = 326, 18.2%), and high risk (n = 57, 3.2%). During the follow-up, 82 (4.6%) participants died. Mortality in the Polyscore-defined risk groups was 3.4%, 7.4%, and 17.5%, respectively (P < 0.0001). The Polyscore-based mortality prediction was independent of Framingham score, diabetes, chronic kidney disease, and major stroke and/or myocardial infarction history. It was particularly effective in those aged <75 years (n = 1145).

Conclusion: The Polyscore-based mortality risk assessment from short-term non-invasive recordings is effective in the elderly general population, especially those aged 60-74 years. Implementation of a comprehensive Polyscore screening of this age group is proposed to advance preventive medical care.
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http://dx.doi.org/10.1093/europace/euaa359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139819PMC
May 2021

Risk Prediction After Myocardial Infarction by Cyclic Variation of Heart Rate, a Surrogate of Sleep-Disordered Breathing Assessed From Holter ECGs.

Front Physiol 2019 15;10:1570. Epub 2020 Jan 15.

Klinik und Poliklinik für Innere Medizin I, University Hospital Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.

Aims: Sleep-disordered breathing (SDB) is common among cardiac patients, but its role as an independent risk predictor after myocardial infarction (MI) is unclear. SDB causes cyclic variation of heart rate (CVHR). The aim of this study was to score Holter ECGs of a large cohort of MI survivors for SDB-related CVHR to investigate its value for mortality prediction.

Methods: A total of 1590 survivors of acute MI in sinus rhythm were prospectively enrolled and followed for 5-year all-cause mortality. Heart rate (HR) tachograms were generated from nocturnal (00:00-06.00 am) segments of Holter ECGs, and the minutes with CVHR were quantified by a previously developed algorithm. According to a pre-specified cutpoint, SDB was assumed if CVHR was present during ≥72 min.

Results: Seventy-seven patients (4.8%) had flat HR tachograms which prohibited analysis for SDB. Of the remaining 1513 patients, 584 (38.6%) were classified as having SDB. Mortality rates in groups stratified according to ECG-derived SDB did not differ significantly. Taken as a continuous variable, low CVHR duration was associated with increased mortality.The mortality of patients with flat HR tachograms was significantly increased, even after adjustment for age, sex, LVEF, GRACE score and diabetes mellitus. Mortality prediction by a flat HR tachogram was also independent of heart rate variability (HRV), heart rate turbulence (HRT), and deceleration capacity (DC).

Conclusion: In Holter ECG recordings of survivors of acute MI, signs suggestive of SDB were frequently present, but not associated with mortality. A flat nocturnal HR tachogram was a strong, independent predictor of 5-year all-cause mortality.
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http://dx.doi.org/10.3389/fphys.2019.01570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974555PMC
January 2020

Placebo and Nocebo Effects in Patients With Takotsubo Cardiomyopathy and Heart-Healthy Controls.

Front Psychiatry 2019 2;10:549. Epub 2019 Aug 2.

Department of Psychosomatic Medicine and Psychotherapy, Klinikum rechts der Isar, Technische Universitaet Munich, Munich, Germany.

The etiology of takotsubo cardiomyopathy (TTC)-a rare, reversible, and acquired form of cardiac diseases-is not yet fully explained. An exaggerated activation of the sympathetic-nervous-system (SNS) following stressful psychosocial life events is discussed to be of key importance. In this experimental study, we tested whether TTC patients, compared to heart-healthy controls, respond more strongly to supporting placebo interventions and stressful nocebo interventions targeting cardiac function. In a single experimental session, 20 female TTC patients and 20 age matched (mean age 61.5 years, ± 12.89) catheter-confirmed heart-healthy women were examined. Saline solution was administered three times i.v. to all participants, with the verbal suggestion they receive an inert substance with no effects on the heart (neutral condition), a drug that would support cardiac functions (positive condition), and a drug that would burden the heart (negative condition). Systolic and diastolic blood pressure (DBP/SBP), heart rate (HR), endocrine markers cortisol (µg/dl), copeptin (pmol/l), and subjective stress ratings (SUD) were assessed to examine alterations of the SNS and the hypothalamic-pituitary-adrenal axis (HPA). Before and after each intervention SUD was rated. One pre and three post serum cortisol and copeptin samples were assessed, and a long-term electrocardiogram as well as non-invasive, continuous blood pressure was recorded. The study design elucidated a significant increase of SUD levels as a response to the nocebo intervention, while perceived stress remained unaffected during the preceding neutral and positive interventions. Increasing SUD levels were accompanied by higher SBP and an anticipatory increase of HR shortly prior to the nocebo intervention. SBP increased also as a response to positive verbal suggestions (Bonferroni-corrected p-values > .05). Alterations of cortisol and copeptin due to the interventions and significant placebo effects failed to appear. Interestingly no differences between TCC patients and controls could be found.These findings do not support the assumption of an exaggerated activation of the SNS as a discriminatory factor for TTC. Since especially the nocebo intervention revealed negative subjective and objective effects, our results underscore the urgent need to consider carefully the impact of verbal suggestions in the interaction with cardiac patients in daily clinical routine. This study is registered at the Deutsches Register Klinischer Studien (DRKS00009296).
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http://dx.doi.org/10.3389/fpsyt.2019.00549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688659PMC
August 2019

Monocyte-platelet aggregates affect local inflammation in patients with acute myocardial infarction.

Int J Cardiol 2019 07 8;287:7-12. Epub 2019 Apr 8.

Klinik und Poliklinik für Innere Medizin I, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. Electronic address:

The local inflammatory response following acute myocardial infarction (AMI) is increasingly being recognized as a central factor determining infarct healing. Myocardial inflammation can be visualized in patients using fasting F-FDG PET/MRI. Although this novel biosignal correlates with long-term functional outcome, the corresponding cellular substrate is not well understood. Here we present a retrospective analysis of 29 patients with AMI who underwent revascularization, suggesting a connection between post infarction myocardial fasting F-FDG uptake, monocyte platelet aggregates (MPA), and P2Y inhibition. In detail, patients with high MPA percentages of CD14CD16 and CD14CD16 monocytes had significantly higher local F-FDG uptake (SUV) in the infarcted myocardium than patients with low MPA (p < 0.05). Furthermore, there was an association of high MPA percentage in all monocyte subpopulations with deteriorating ΔLV-EF after 6 months (p < 0.01), which was confirmed in an extended analysis with additional 29 patients without PET/MRI data available. In this analysis, administration of Ticagrelor was associated with lower MPA percentage of CD14 monocyte subpopulations than Clopidogrel (p < 0.01) or Prasugrel (p < 0.05). Taken together, the findings from this analysis suggest that platelet aggregability may affect monocyte extravasation into the infarcted myocardium and influence long-term functional outcome. P2Y inhibition may intervene in this pathophysiologic process. Prospective studies are needed to further examine this important relationship.
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http://dx.doi.org/10.1016/j.ijcard.2019.04.009DOI Listing
July 2019

Effects of smoking status, history and intensity on heart rate variability in the general population: The CHRIS study.

PLoS One 2019 9;14(4):e0215053. Epub 2019 Apr 9.

Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy.

Background: Heart rate variability (HRV) reflects the autonomous nervous system modulation on heart rate and is associated with several pathologies, including cardiac mortality. While mechanistic studies show that smoking is associated with lower HRV, population-based studies present conflicting results.

Methods: We assessed the mutual effects of active smoking status, cumulative smoking history, and current smoking intensity, on HRV among 4751 adults from the Cooperative Health Research In South Tyrol (CHRIS) study. The HRV metrics standard deviation of normal-to-normal (NN) inter-beat intervals (SDNN), square root of the mean squared differences of consecutive NN intervals (RMSSD), total power (TP), low (LF) and high frequency (HF) power, and their ratio (LF/HF), were derived from 20-minute electrocardiograms. Smoking status, pack-years (PY), and tobacco grams/day from standardized questionnaires were the main exposures. We fitted linear mixed models to account for relatedness, non-linearity, and moderating effects, and including fractional polynomials.

Results: Past smokers had higher HRV levels than never smokers, independently of PY. The association of HRV with current smoking became apparent when accounting for the interaction between smoking status and PY. In current smokers, but not in past smokers, we observed HRV reductions between 2.0% (SDNN) and 4.9% (TP) every 5 PY increase. Furthermore, current smokers were characterized by dose-response reductions of 9.8% (SDNN), 8.9% (RMSSD), 20.1% (TP), 17.7% (LF), and 19.1% (HF), respectively, every 10 grams/day of smoked tobacco, independently of common cardiometabolic conditions and HRV-modifying drugs. The LF/HF ratio was not associated with smoking status, history, or intensity.

Conclusions: Smoking cessation was associated with higher HRV levels. In current smokers, heavier smoking intensity appears gradually detrimental on HRV, corroborating previous evidence. By affecting both the sympathetic and parasympathetic nervous system indexes, but not the LF/HF balance, smoking intensity seems to exert a systemic dysautonomic effect.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215053PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456196PMC
December 2019

Polyscore of Non-invasive Cardiac Risk Factors.

Front Physiol 2019 4;10:49. Epub 2019 Feb 4.

Klinik für Innere Medizin I, Technische Universität München, Munich, Germany.

Non-invasive risk stratification of cardiac patients has been the subject of numerous studies. Most of these investigations either researched unique risk predictors or compared the predictive power of different predictors. Fewer studies suggested a combination of a small number of non-invasive indices to increase the accuracy of high-risk group selection. To advance non-invasive risk assessment of cardiac patients, we propose a combination score (termed the Polyscore) of seven different cardiac risk stratifiers that predominantly quantify autonomic cardiovascular control and regulation, namely the slope of heart rate turbulence, deceleration capacity of heart rate, non-invasively assessed baroreflex sensitivity, resting respiration frequency, expiration triggered sinus arrhythmia, post-ectopic potentiation of systolic blood pressure, and frequency of supraventricular and ventricular ectopic beats. These risk stratification tests have previously been researched and their dichotomies defining abnormal results have been derived from previous reports. The Polyscore combination was defined as the number of positive tests among these seven risk predictors, giving a numerical scale which ranges from 0 (all tests normal) to 7 (all tests abnormal). The Polyscore was tested in a population of 941 contemporarily treated survivors of acute myocardial infarction (median age 61 years, 182 females) of whom 72 (7.65%) died during a 5-year follow-up. In these patients, all the risk predictors combined in the Polyscore were assessed during in-hospital 30-min simultaneous non-invasive recordings of high-frequency orthogonal electrocardiogram, continuous blood pressure and respiration. Compared to Polyscore 0 stratum, the hazard ratios of mortality during follow-up increased almost exponentially in strata 1 through 7 (vs. stratus 0, the hazard ratios were 1.37, 1.96, 7.03, 15.0, 35.7, 48.2, and 114, in strata 1 to 7, respectively; < 0.0001). This allowed selecting low-risk (Polyscore ≤ 2), intermediate risk (Polyscore 3 or 4) and high-risk (Polyscore ≥ 5) sub-groups of the population that differed greatly in the Kaplan-Meier probabilities of mortality during follow-up. Since the Polyscore was derived from recordings of only 30-min duration, it can be reasonably applied in different clinical situations including population-wide screening. We can therefore conclude that the Polyscore is a reasonable method for cardiac risk stratification that is ready for prospective validation in future independent studies.
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http://dx.doi.org/10.3389/fphys.2019.00049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369149PMC
February 2019

Subtype-specific Optical Action Potential Recordings in Human Induced Pluripotent Stem Cell-derived Ventricular Cardiomyocytes.

J Vis Exp 2018 09 27(139). Epub 2018 Sep 27.

Medical Department I, University Hospital Klinikum rechts der Isar, Technical University of Munich; German Centre for Cardiovascular Research (DZHK), Munich Heart Alliance;

Cardiomyocytes generated from human induced pluripotent stem cells (iPSC-CMs) are an emerging tool in cardiovascular research. Rather than being a homogenous population of cells, the iPSC-CMs generated by current differentiation protocols represent a mixture of cells with ventricular-, atrial-, and nodal-like phenotypes, which complicates phenotypic analyses. Here, a method to optically record action potentials specifically from ventricular-like iPSC-CMs is presented. This is achieved by lentiviral transduction with a construct in which a genetically-encoded voltage indicator is under the control of a ventricular-specific promoter element. When iPSC-CMs are transduced with this construct, the voltage sensor is expressed exclusively in ventricular-like cells, enabling subtype-specific optical membrane potential recordings using time-lapse fluorescence microscopy.
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http://dx.doi.org/10.3791/58134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235334PMC
September 2018

Change in Left Ventricular Ejection Fraction Following First Myocardial Infarction and Outcome.

JACC Clin Electrophysiol 2018 05 1;4(5):672-682. Epub 2018 Mar 1.

Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada. Electronic address:

Objectives: This study hypothesizes that a lack of left ventricular ejection fraction (LVEF) recovery after myocardial infarction (MI) would be associated with a poor outcome.

Background: A reduced LVEF early after MI identifies patients at risk of adverse outcomes. Whether the change in LVEF in the weeks to months following MI provides additional information on prognosis is less certain.

Methods: Change in LVEF between the early (2 to 7 days) and later (2 to 12 weeks) post-MI periods in patients with a first MI was assessed in 3 independent cohorts (REFINE [Risk Estimation Following Infarction Noninvasive Evaluation]; CARISMA [Cardiac Arrhythmia and Risk Stratification after Myocardial Infarction]; ISAR [Improved Stratification of Autonomy Regulation]). Patients were categorized as having no recovery (Δ ≤0%), a modest increase (Δ 1% to 9%), or a large increase (Δ ≥10%) in LVEF. The relationship between change in LVEF and risk of sudden cardiac arrest (SCA) and all-cause mortality were assessed in Cox multivariable models.

Results: In REFINE, patients with no LVEF recovery had a higher risk of sudden cardiac arrest (hazard ratio: 5.8; 95% confidence interval: 2.1 to 16.6; p = 0.001) and death (hazard ratio: 3.9; 95% confidence interval: 1.5 to 10.1; p < 0.001), independent of revascularization, baseline LVEF, and medical therapy compared with patients with recovery. Similar findings were observed in the other cohorts. LVEF reassessments beyond 6 weeks post-MI were more predictive of outcome than were earlier reassessments.

Conclusions: The degree of LVEF recovery after a first MI provides important prognostic information. Patients with no recovery in LVEF after MI are at high risk of sudden cardiac arrest events and death.
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http://dx.doi.org/10.1016/j.jacep.2017.12.015DOI Listing
May 2018

Interplay of cell-cell contacts and RhoA/MRTF-A signaling regulates cardiomyocyte identity.

EMBO J 2018 06 15;37(12). Epub 2018 May 15.

Klinik und Poliklinik Innere Medizin I, Klinikum rechts der Isar - Technical University of Munich, Munich, Germany

Cell-cell and cell-matrix interactions guide organ development and homeostasis by controlling lineage specification and maintenance, but the underlying molecular principles are largely unknown. Here, we show that in human developing cardiomyocytes cell-cell contacts at the intercalated disk connect to remodeling of the actin cytoskeleton by regulating the RhoA-ROCK signaling to maintain an active MRTF/SRF transcriptional program essential for cardiomyocyte identity. Genetic perturbation of this mechanosensory pathway activates an ectopic fat gene program during cardiomyocyte differentiation, which ultimately primes the cells to switch to the brown/beige adipocyte lineage in response to adipogenesis-inducing signals. We also demonstrate by fate mapping and clonal analysis of cardiac progenitors that cardiac fat and a subset of cardiac muscle arise from a common precursor expressing Isl1 and Wt1 during heart development, suggesting related mechanisms of determination between the two lineages.
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http://dx.doi.org/10.15252/embj.201798133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003642PMC
June 2018

Cardiac regeneration using HLA-matched induced pluripotent stem cells-no monkey business, but still a long and winding road ahead.

Authors:
Daniel Sinnecker

J Thorac Dis 2017 Mar;9(3):492-494

1st Medical Department, The University Hospital Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

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http://dx.doi.org/10.21037/jtd.2017.03.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394076PMC
March 2017

Perspectives and Challenges of Pluripotent Stem Cells in Cardiac Arrhythmia Research.

Curr Cardiol Rep 2017 03;19(3):23

Klinikum rechts der Isar, Technische Universität München, Klinik und Poliklinik Innere Medizin I - Kardiologie, Ismaningerstrasse 22, 81675, Munich, Germany.

Purpose Of Review: The promises of human-induced pluripotent stem cells (hiPSCs) for modeling arrhythmogenic disease, but also for drug discovery and toxicity tests, are straightforward and exciting. However, the full potential of this new technology has not been fully realized yet. The purpose of this review is to provide an overview of the state-of-the-art research in arrhythmogenic disease modeling and drug discovery and an outlook of what can be expected from the second decade of hiPSC-based arrhythmia research.

Recent Findings: Remarkable advances in genomic discoveries, stem cell biology, and genome editing via sequence-specific nucleases have been made in recent years. Together, these breakthroughs have allowed us to progress from studying monogenetic diseases with a direct genotype-phenotype relationship to genetically more complex diseases such as arrhythmogenic right ventricular dysplasia and atrial fibrillation. In addition, newly developed tools for arrhythmia research such as optical action potential recordings have facilitated the use of hiPSCs for drug and toxicity screening and their eventual clinical use. These advances in in vitro assay development, genome editing, and stem cell biology will soon enable the implementation of hiPSC-based findings into clinical practice and provide us with unprecedented insights into mechanisms of complex arrhythmogenic diseases.
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http://dx.doi.org/10.1007/s11886-017-0828-zDOI Listing
March 2017

Elucidating arrhythmogenic mechanisms of long-QT syndrome CALM1-F142L mutation in patient-specific induced pluripotent stem cell-derived cardiomyocytes.

Cardiovasc Res 2017 Apr;113(5):531-541

Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan, Italy.

Aims: Calmodulin (CaM) is a small protein, encoded by three genes (CALM1-3), exerting multiple Ca2+-dependent modulatory roles. A mutation (F142L) affecting only one of the six CALM alleles is associated with long QT syndrome (LQTS) characterized by recurrent cardiac arrests. This phenotypic severity is unexpected from the predicted allelic balance. In this work, the effects of heterozygous CALM1-F142L have been investigated in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) obtained from a LQTS patient carrying the F142L mutation, i.e. in the context of native allelic ratio and potential gene modifiers.

Methods And Results: Skin fibroblasts of the mutation carrier and two unrelated healthy subjects (controls) were reprogrammed to hiPSC and differentiated into hiPSC-CMs. Scanty IK1 expression, an hiPSC-CMs feature potentially biasing repolarization, was corrected by addition of simulated IK1 (Dynamic-Clamp). Abnormalities in repolarization rate-dependency (in single cells and cell aggregates), membrane currents and intracellular Ca2+ dynamics were evaluated as putative arrhythmogenic factors. CALM1-F142L prolonged repolarization, altered its rate-dependency and its response to isoproterenol. This was associated with severe impairment of Ca2+-dependent inactivation (CDI) of ICaL, resulting in augmented inward current during the plateau phase. As a result, the repolarization of mutant cells failed to adapt to high pacing rates, a finding well reproduced by using a recent hiPSC-CM action potential model. The mutation failed to affect IKs and INaL and changed If only marginally. Intracellular Ca2+ dynamics and Ca2+ store stability were not significantly modified. Mutation-induced repolarization abnormalities were reversed by verapamil.

Conclusion: The main functional derangement in CALM1-F142L was prolonged repolarization with altered rate-dependency and sensitivity to β-adrenergic stimulation. Impaired CDI of ICaL underlined the electrical abnormality, which was sensitive to ICaL blockade. High mutation penetrance was confirmed in the presence of the native genotype, implying strong dominance of effects.
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http://dx.doi.org/10.1093/cvr/cvx006DOI Listing
April 2017

Post-extrasystolic Blood Pressure Potentiation as a Risk Predictor in Cardiac Patients.

Arrhythm Electrophysiol Rev 2016 May;5(1):27-30

1st Medical Clinic and Policlinic, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

For more than 100 years physicians have observed that heartbeats following extrasystolic beats are characterised by augmented myocardial contractility. This phenomenon was termed post-extrasystolic potentiation (PESP). In the 1970s it was first noted that PESP measured at the blood pressure level is typically pronounced in heart failure patients. Only recently, it was shown that PESP measured non-invasively as post-extrasystolic blood pressure potentiation was a strong and independent predictor of death in survivors of myocardial infarction and in patients with chronic heart failure. A similar parameter (PESPAfib) can be also assessed in patients with atrial fibrillation. PESP and PESPAfib can be understood as non-invasive parameters that indicate myocardial dysfunction. They have the potential to improve risk stratification strategies for cardiac patients.
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http://dx.doi.org/10.15420/aer.2016.14.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939308PMC
May 2016

Expiration-Triggered Sinus Arrhythmia Predicts Outcome in Survivors of Acute Myocardial Infarction.

J Am Coll Cardiol 2016 05;67(19):2213-2220

1. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. Electronic address:

Background: Respiratory sinus arrhythmia (RSA), a measure of cardiac vagal modulation, provides cardiac risk stratification information. RSA can be quantified from Holter recordings as the high-frequency component of heart rate variability or as the variability of RR intervals in individual respiratory cycles. However, as a risk predictor, RSA is neither exceptionally sensitive nor specific.

Objectives: This study aimed to improve RSA determination by quantifying the amount of sinus arrhythmia related to expiration (expiration-triggered sinus arrhythmia [ETA]) from short-term recordings of electrocardiogram and respiratory chest excursions, and investigated the predictive power of ETA in survivors of acute myocardial infarction.

Methods: Survivors of acute myocardial infarction (N = 941) underwent 30-min recordings of electrocardiogram and respiratory chest excursions. ETA was quantified as the RR interval change associated with expiration by phase-rectified signal averaging. Primary outcome was 5-year all-cause mortality. Univariable and multivariable Cox regression was used to investigate the association of ETA with mortality.

Results: ETA was a strong predictor of mortality, both in univariable and multivariable analysis. In a multivariable model including respiratory rate, left ventricular ejection fraction, diabetes mellitus, and GRACE score, ETA ≤0.19 ms was associated with a hazard ratio of 3.41 (95% confidence interval: 1.10 to 5.89, p < 0.0001). In patient subgroups defined by abnormal left ventricular ejection fraction, increased respiratory rate, high GRACE score, or presence of diabetes mellitus, patients were classified as high or low risk on the basis of ETA.

Conclusions: Expiration-triggered sinus arrhythmia (ETA) is a potent and independent post-infarction risk marker.
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http://dx.doi.org/10.1016/j.jacc.2016.03.484DOI Listing
May 2016

Electrocardiographic and Cardiac Autonomic Indices - Implications of Sex-Specific Risk Stratification in Women After Acute Myocardial Infarction.

Curr Pharm Des 2016 ;22(25):3817-28

Medizinische Klinik und Poliklinik I, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, München 81675, Germany.

Background: The debate on whether sex-specific predictive models improve risk stratification after myocardial infarction is ongoing.

Methods: This review summarises the current clinical knowledge on sex-specific differences in post-infarction risk stratification parameters. Particular focus is given to electrocardiographic risk factors and indices of cardiac autonomic status.

Results: Differences in the underlying pathophysiology between men and women are known. However, clinical findings often lead to uncertain conclusions for a number of risk predictors including, among others, resting heart rate, heart rate variability, heart rate turbulence, QT interval duration, and QRS-T angle. The review links recent findings in prognostic parameters with successful approaches in sex-specific non-invasive risk stratification.

Conclusion: Disparities are described in the current clinical opinions on the relevance of investigated parameters in women and possible directions for further research in the field are given.
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http://dx.doi.org/10.2174/1381612822666160311115605DOI Listing
November 2017

Genetically Encoded Voltage Indicators in Circulation Research.

Int J Mol Sci 2015 Sep 8;16(9):21626-42. Epub 2015 Sep 8.

Research Centre for Molecular Imaging and Screening, Institute for Molecular Cell Biology, Saarland University, Homburg/Saar 66421, Germany.

Membrane potentials display the cellular status of non-excitable cells and mediate communication between excitable cells via action potentials. The use of genetically encoded biosensors employing fluorescent proteins allows a non-invasive biocompatible way to read out the membrane potential in cardiac myocytes and other cells of the circulation system. Although the approaches to design such biosensors date back to the time when the first fluorescent-protein based Förster Resonance Energy Transfer (FRET) sensors were constructed, it took 15 years before reliable sensors became readily available. Here, we review different developments of genetically encoded membrane potential sensors. Furthermore, it is shown how such sensors can be used in pharmacological screening applications as well as in circulation related basic biomedical research. Potentials and limitations will be discussed and perspectives of possible future developments will be provided.
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http://dx.doi.org/10.3390/ijms160921626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613271PMC
September 2015

Impact of sympathetic renal denervation: a randomized study in patients after renal transplantation (ISAR-denerve).

Nephrol Dial Transplant 2015 Nov 1;30(11):1928-36. Epub 2015 Sep 1.

Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.

Background: Sympathetic overactivity is frequently observed following renal transplantation (RTx), and post-transplant hypertension is a major contributing factor to graft failure and cardiovascular morbidity. This process is perpetuated by preservation of sympathetic afferent activity from the native non-functional kidneys, in the absence of efferent feedback to the renal transplant, which would otherwise modulate neurohumoral activity. We investigated the feasibility and efficacy of renal sympathetic denervation (RDN) in renal transplant recipients.

Methods: Patients (n = 18) with post-transplant hypertension were randomized 1:1 to receive RDN or medical treatment alone. The primary efficacy end point was change in office systolic blood pressure (SBP) and mean 24-h ambulatory blood pressure monitoring (ABPM) at 6 months. Safety end points were changes in renal function or renovascular complications.

Results: After 6 months, patients in the RDN group had a significant reduction in office SBP of 23.3 ± 14.5 mmHg (P = 0.001 for change difference between the groups). In ABPM, nocturnal blood pressure was reduced in the RDN group by -10.38 ± 12.8 mmHg (P = 0.06), whereas no change was measured during the day. In the RDN group, significantly more patients converted from non-dippers to dippers (P = 0.035). There were no adverse safety events in either group.

Conclusion: RDN is feasible and safe in renal transplant recipients. However, larger sham-controlled studies will be necessary to clarify the potential role of RDN in this population.

Clinical Trial Registration: NCT01899456.
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http://dx.doi.org/10.1093/ndt/gfv311DOI Listing
November 2015

Magnetic resonance imaging at 1.5-T in a patient with implantable leadless pacemaker.

Eur Heart J 2016 08 10;37(30):2441. Epub 2015 Aug 10.

Medizinische Klinik und Poliklinik I, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str.22, Munich 81675, Germany

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http://dx.doi.org/10.1093/eurheartj/ehv360DOI Listing
August 2016

[Fragmented QRS. Relevance in clinical practice].

Herzschrittmacherther Elektrophysiol 2015 Sep;26(3):235-41

I. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 22, 81675, München, Deutschland,

The QRS complex represents the electrical depolarization of ventricular myocardium. In the case of an undisturbed depolarization, the QRS complex has a normal configuration and duration, but abnormal electrical conduction leads to widening of the QRS complex. The block of one of the Tawara branches results in a typical bundle branch block pattern. A QRS complex that cannot be classified as bundle branch block due to an atypical configuration and contains notched R or S waves is called a fragmented QRS. The underlying pathophysiologies are manifold and include myocardial scars induced by ischemic heart disease, myocardial fibrosis due to other diseases, primary cardiac pathologies as well as systemic diseases with cardiac involvement. Pathologies on the cellular level, such as ion channel dysfunctions, also correlate with fragmented QRS. Besides the diagnostic relevance, fragmented QRS is known to have prognostic properties, for example in identifying high risk patients with coronary artery disease, cardiomyopathy, Brugada syndrome and acquired long QT syndrome; however, fragmented QRS may also be detected in ECGs of healthy individuals.
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http://dx.doi.org/10.1007/s00399-015-0390-6DOI Listing
September 2015

Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy.

EMBO Mol Med 2015 May;7(5):562-76

I. Medical Department - Cardiology, Klinikum rechts der Isar - Technische Universität München, Munich, Germany DZHK (German Centre for Cardiovascular Research) - partner site Munich Heart Alliance, Munich, Germany

Frameshift mutations in the TTN gene encoding titin are a major cause for inherited forms of dilated cardiomyopathy (DCM), a heart disease characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure. To date, there are no specific treatment options for DCM patients but heart transplantation. Here, we show the beneficial potential of reframing titin transcripts by antisense oligonucleotide (AON)-mediated exon skipping in human and murine models of DCM carrying a previously identified autosomal-dominant frameshift mutation in titin exon 326. Correction of TTN reading frame in patient-specific cardiomyocytes derived from induced pluripotent stem cells rescued defective myofibril assembly and stability and normalized the sarcomeric protein expression. AON treatment in Ttn knock-in mice improved sarcomere formation and contractile performance in homozygous embryos and prevented the development of the DCM phenotype in heterozygous animals. These results demonstrate that disruption of the titin reading frame due to a truncating DCM mutation can be restored by exon skipping in both patient cardiomyocytes in vitro and mouse heart in vivo, indicating RNA-based strategies as a potential treatment option for DCM.
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http://dx.doi.org/10.15252/emmm.201505047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492817PMC
May 2015

Functional comparison of induced pluripotent stem cell- and blood-derived GPIIbIIIa deficient platelets.

PLoS One 2015 21;10(1):e0115978. Epub 2015 Jan 21.

I. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany; DZHK (German Centre for Cardiovascular Research)-partner site Munich Heart Alliance, Munich, Germany.

Human induced pluripotent stem cells (hiPSCs) represent a versatile tool to model genetic diseases and are a potential source for cell transfusion therapies. However, it remains elusive to which extent patient-specific hiPSC-derived cells functionally resemble their native counterparts. Here, we generated a hiPSC model of the primary platelet disease Glanzmann thrombasthenia (GT), characterized by dysfunction of the integrin receptor GPIIbIIIa, and compared side-by-side healthy and diseased hiPSC-derived platelets with peripheral blood platelets. Both GT-hiPSC-derived platelets and their peripheral blood equivalents showed absence of membrane expression of GPIIbIIIa, a reduction of PAC-1 binding, surface spreading and adherence to fibrinogen. We demonstrated that GT-hiPSC-derived platelets recapitulate molecular and functional aspects of the disease and show comparable behavior to their native counterparts encouraging the further use of hiPSC-based disease models as well as the transition towards a clinical application.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0115978PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301811PMC
January 2016

Force-interval relationship predicts mortality in survivors of myocardial infarction with atrial fibrillation.

Int J Cardiol 2015 Mar 6;182:315-20. Epub 2015 Jan 6.

1. Medizinische Klinik und Deutsches Herzzentrum München der Technischen Universität München, Munich, Germany; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. Electronic address:

Background: RR interval variations lead to beat-to-beat blood pressure differences through the myocardial force-interval relationship (FIR). In sinus rhythm, an altered FIR leads to post-extrasystolic potentiation (PESP) of systolic blood pressure, which has been shown to predict adverse outcome in survivors of acute myocardial infarction (MI). The purpose of this study was (1) to develop a parameter to assess the FIR in patients with atrial fibrillation (AF) and (2) to investigate its association with mortality in MI survivors suffering from AF.

Methods And Results: Thirty-two patients with acute MI and AF underwent 30-min recordings of ECG and continuous blood pressure. Episodes of a short RR interval (<80% of mean interval, RRi) preceding a long interval (>140%, RRi+1) were identified. The systolic pressures of the pulse waves following RRi and RRi+1 were labeled Pi and Pi+1. PESPAfib was calculated as (Pi+1-Pi)/(RRi+1-RRi). During 5years of follow-up, 13 patients died. When PESPAfib was dichotomized at the median, mortality rates were 63% and 19% in patients with high and low PESPAfib. Hazard ratio for mortality was 4.88 for patients with high PESPAfib (1.33-17.84, p=0.004). The association of PESPAfib and mortality was independent from LVEF, age, diabetes mellitus or mean heart rate.

Conclusions: PESPAfib, a measure for the FIR in patients with AF, can be derived from simultaneous ECG and blood pressure recordings. The results of this pilot study indicate that PESPAfib may be useful to predict adverse outcome in survivors of myocardial infarction suffering from AF.
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http://dx.doi.org/10.1016/j.ijcard.2015.01.018DOI Listing
March 2015

Direct nkx2-5 transcriptional repression of isl1 controls cardiomyocyte subtype identity.

Stem Cells 2015 Apr;33(4):1113-29

I. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.

During cardiogenesis, most myocytes arise from cardiac progenitors expressing the transcription factors Isl1 and Nkx2-5. Here, we show that a direct repression of Isl1 by Nkx2-5 is necessary for proper development of the ventricular myocardial lineage. Overexpression of Nkx2-5 in mouse embryonic stem cells (ESCs) delayed specification of cardiac progenitors and inhibited expression of Isl1 and its downstream targets in Isl1(+) precursors. Embryos deficient for Nkx2-5 in the Isl1(+) lineage failed to downregulate Isl1 protein in cardiomyocytes of the heart tube. We demonstrated that Nkx2-5 directly binds to an Isl1 enhancer and represses Isl1 transcriptional activity. Furthermore, we showed that overexpression of Isl1 does not prevent cardiac differentiation of ESCs and in Xenopus laevis embryos. Instead, it leads to enhanced specification of cardiac progenitors, earlier cardiac differentiation, and increased cardiomyocyte number. Functional and molecular characterization of Isl1-overexpressing cardiomyocytes revealed higher beating frequencies in both ESC-derived contracting areas and Xenopus Isl1-gain-of-function hearts, which associated with upregulation of nodal-specific genes and downregulation of transcripts of working myocardium. Immunocytochemistry of cardiomyocyte lineage-specific markers demonstrated a reduction of ventricular cells and an increase of cells expressing the pacemaker channel Hcn4. Finally, optical action potential imaging of single cardiomyocytes combined with pharmacological approaches proved that Isl1 overexpression in ESCs resulted in normally electrophysiologically functional cells, highly enriched in the nodal subtype at the expense of the ventricular lineage. Our findings provide an Isl1/Nkx2-5-mediated mechanism that coordinately regulates the specification of cardiac progenitors toward the different myocardial lineages and ensures proper acquisition of myocyte subtype identity.
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http://dx.doi.org/10.1002/stem.1923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750130PMC
April 2015

In-silico assessment of the dynamic effects of amiodarone and dronedarone on human atrial patho-electrophysiology.

Europace 2014 Nov;16 Suppl 4:iv30-iv38

Institute of Biomedical Engineering, Karlsruhe Institute of Technology (KIT), Kaiserstr. 12, 76128 Karlsruhe, Germany.

Aims: The clinical efficacy in preventing the recurrence of atrial fibrillation (AF) is higher for amiodarone than for dronedarone. Moreover, pharmacotherapy with these drugs is less successful in patients with remodelled substrate induced by chronic AF (cAF) and patients suffering from familial AF. To date, the reasons for these phenomena are only incompletely understood. We analyse the effects of the drugs in a computational model of atrial electrophysiology.

Methods And Results: The Courtemanche-Ramirez-Nattel model was adapted to represent cAF remodelled tissue and hERG mutations N588K and L532P. The pharmacodynamics of amiodarone and dronedarone were investigated with respect to their dose and heart rate dependence by evaluating 10 descriptors of action potential morphology and conduction properties. An arrhythmia score was computed based on a subset of these biomarkers and analysed regarding circadian variation of drug concentration and heart rate. Action potential alternans at high frequencies was observed over the whole dronedarone concentration range at high frequencies, while amiodarone caused alternans only in a narrow range. The total score of dronedarone reached critical values in most of the investigated dynamic scenarios, while amiodarone caused only minor score oscillations. Compared with the other substrates, cAF showed significantly different characteristics resulting in a lower amiodarone but higher dronedarone concentration yielding the lowest score.

Conclusion: Significant differences exist in the frequency and concentration-dependent effects between amiodarone and dronedarone and between different atrial substrates. Our results provide possible explanations for the superior efficacy of amiodarone and may aid in the design of substrate-specific pharmacotherapy for AF.
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http://dx.doi.org/10.1093/europace/euu230DOI Listing
November 2014

Sex differences in the non-invasive risk stratification and prognosis after myocardial infarction.

J Electrocardiol 2014 Nov-Dec;47(6):874-80. Epub 2014 Aug 12.

Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; DZHK (German Centre for Cardiovascular Research, partner site Munich Heart Aliance), Berlin, Germany. Electronic address:

Background: Women have unfavorable prognosis after myocardial infarction (MI). This text describes sex differences in mortality and in the power of risk predictors in contemporarily-treated MI patients.

Methods: A population of 4141 MI patients (26.5% females) was followed up for 5years. Effects of sex and age on total mortality were investigated by multivariable Cox analysis. Mortality predictors were investigated by receiver-operator characteristics analysis. Stepwise multivariable Cox regression was used to create sex-specific predictive models.

Results: Thirty-day mortality was 1.5-fold higher in women. However, sex was not a significant mortality predictor in a model adjusted for age. Predictors for 5-year mortality performed differently in male and female patients. In women, a sex-specific model provided better risk stratification than a sex-neutral model.

Conclusion: The unfavorable prognosis of female MI patients can be explained by advanced age. Sex-specific predictive models might improve risk stratification in female survivors of acute MI.
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http://dx.doi.org/10.1016/j.jelectrocard.2014.08.010DOI Listing
October 2015

Extending human induced pluripotent stem cell technology to infectious diseases: new model for viral myocarditis.

Circ Res 2014 Aug;115(6):537-9

From the I. Medical Department, Cardiology, Klinikum rechts der Isar-Technische Universität München, Munich, Germany (D.S., K.-L.L., A.M.); and DZHK (German Centre for Cardiovascular Research)-Partner Site Munich Heart Alliance, Munich, Germany (K.-L.L., A.M.).

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http://dx.doi.org/10.1161/CIRCRESAHA.114.304786DOI Listing
August 2014
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