Publications by authors named "Gerd Hasenfuß"

395 Publications

MicroRNA miR-29b regulates diabetic aortic remodeling and stiffening.

Mol Ther Nucleic Acids 2021 Jun 24;24:188-199. Epub 2021 Feb 24.

Department of Cardiology and Pneumology, Heart Center at the University Medical Center Göttingen, Göttingen, Germany.

Patients with type 2 diabetes (T2D) are threatened by excessive cardiovascular morbidity and mortality. While accelerated arterial stiffening may represent a critical mechanistic factor driving cardiovascular risk in T2D, specific therapies to contain the underlying diabetic arterial remodeling have been elusive. The present translational study investigates the role of microRNA-29b (miR-29b) as a driver and therapeutic target of diabetic aortic remodeling and stiffening. Using a murine model (db/db mice), as well as human aortic tissue samples, we find that diabetic aortic remodeling and stiffening is associated with medial fibrosis, as well as fragmentation of aortic elastic layers. miR-29b is significantly downregulated in T2D and miR-29b repression is sufficient to induce both aortic medial fibrosis and elastin breakdown through upregulation of its direct target genes and thereby increasing aortic stiffness. Moreover, antioxidant treatment restores aortic miR-29b levels and counteracts diabetic aortic remodeling. Concluding, we identify miR-29b as a comprehensive-and therefore powerful-regulator of aortic remodeling and stiffening in T2D that moreover qualifies as a (redox-sensitive) target for therapeutic intervention.
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http://dx.doi.org/10.1016/j.omtn.2021.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957025PMC
June 2021

Comparing the diagnostic value of Echocardiography In Stroke (CEIS) - results of a prospective observatory cohort study.

BMC Neurol 2021 Mar 17;21(1):118. Epub 2021 Mar 17.

Department for Neurology, University Medical Center Göttingen, Robert-Koch Straße 40, 37075, Göttingen, Germany.

Background: Echocardiography is one of the main diagnostic tools for the diagnostic workup of stroke and is already well integrated into the clinical workup. However, the value of transthoracic vs. transesophageal echocardiography (TTE/TEE) in stroke patients is still a matter of debate. Aim of this study was to characterize relevant findings of TTE and TEE in the management of stroke patients and to correlate them with subsequent clinical decisions and therapies.

Methods: We evaluated n = 107 patients admitted with an ischemic stroke or transient ischemic attack to our stroke unit of our university medical center. They underwent TTE and TEE examination by different blinded investigators.

Results: Major cardiac risk factors were found in 8 of 98 (8.2%) patients and minor cardiac risk factors for stroke were found in 108 cases. We found a change in therapeutic regime after TTE or TEE in 22 (22.5%) cases, in 5 (5%) cases TEE leads to the change of therapeutic regime, in 4 (4%) TTE and in 13 cases (13.3%) TTE and TEE lead to the same change in therapeutic regime. The major therapy change was the indication to close a patent foramen ovale (PFO) in 9 (9.2%) patients with TTE and in 10 (10.2%) patients with TEE (p = 1.000).

Conclusion: Major finding with clinical impact on therapy change is the detection of PFO. But for the detection of PFO, TTE is non inferior to TEE, implicating that TTE serves as a good screening tool for detection of PFO, especially in young age patients.

Trial Registration: The trial was registered and approved prior to inclusion by our local ethics committee (1/3/17).
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http://dx.doi.org/10.1186/s12883-021-02136-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968180PMC
March 2021

Prognostic impact of acute pulmonary triggers in patients with takotsubo syndrome: new insights from the International Takotsubo Registry.

Authors:
Ken Kato Victoria L Cammann L Christian Napp Konrad A Szawan Jozef Micek Sara Dreiding Rena A Levinson Vanya Petkova Michael Würdinger Alexandru Patrascu Rafael Sumalinog Sebastiano Gili Christian F Clarenbach Malcolm Kohler Manfred Wischnewsky Rodolfo Citro Carmine Vecchione Eduardo Bossone Michael Neuhaus Jennifer Franke Benjamin Meder Milosz Jaguszewski Michel Noutsias Maike Knorr Susanne Heiner Fabrizio D'Ascenzo Wolfgang Dichtl Christof Burgdorf Behrouz Kherad Carsten Tschöpe Annahita Sarcon Jerold Shinbane Lawrence Rajan Guido Michels Roman Pfister Alessandro Cuneo Claudius Jacobshagen Mahir Karakas Wolfgang Koenig Alexander Pott Philippe Meyer Marco Roffi Adrian Banning Mathias Wolfrum Florim Cuculi Richard Kobza Thomas A Fischer Tuija Vasankari K E Juhani Airaksinen Monika Budnik Rafal Dworakowski Philip MacCarthy Christoph Kaiser Stefan Osswald Leonarda Galiuto Christina Chan Paul Bridgman Daniel Beug Clément Delmas Olivier Lairez Ekaterina Gilyarova Alexandra Shilova Mikhail Gilyarov Ibrahim El-Battrawy Ibrahim Akin Martin Kozel Petr Tousek David E Winchester Jan Galuszka Christian Ukena Gregor Poglajen Pedro Carrilho-Ferreira Christian Hauck Carla Paolini Claudio Bilato Masanori Sano Iwao Ishibashi Masayuki Takahara Toshiharu Himi Yoshio Kobayashi Abhiram Prasad Charanjit S Rihal Kan Liu P Christian Schulze Matteo Bianco Lucas Jörg Hans Rickli Gonçalo Pestana Thanh H Nguyen Michael Böhm Lars S Maier Fausto J Pinto Petr Widimský Stephan B Felix Grzegorz Opolski Ruediger C Braun-Dullaeus Wolfgang Rottbauer Gerd Hasenfuß Burkert M Pieske Heribert Schunkert Martin Borggrefe Holger Thiele Johann Bauersachs Hugo A Katus John D Horowitz Carlo Di Mario Thomas Münzel Filippo Crea Jeroen J Bax Thomas F Lüscher Frank Ruschitzka Jelena R Ghadri Christian Templin

ESC Heart Fail 2021 Mar 13. Epub 2021 Mar 13.

Department of Cardiology, University Heart Center, University Hospital of Zurich, Raemistrasse 100, Zurich, 8091, Switzerland.

Aims: Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes.

Methods And Results: Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33-3.38; P = 0.002).

Conclusions: The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome.
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http://dx.doi.org/10.1002/ehf2.13165DOI Listing
March 2021

Determinants and consequences of heart rate and stroke volume response to exercise in patients with heart failure and preserved ejection fraction.

Eur J Heart Fail 2021 Mar 8. Epub 2021 Mar 8.

Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.

Aims: A hallmark of heart failure with preserved ejection fraction (HFpEF) is impaired exercise capacity of varying severity. The main determinant of exercise capacity is cardiac output (CO), however little information is available about the relation between the constituents of CO - heart rate and stroke volume - and exercise capacity in HFpEF. We sought to determine if a heterogeneity in heart rate and stroke volume response to exercise exists in patients with HFpEF and describe possible clinical phenotypes associated with differences in these responses.

Methods And Results: Data from two prospective trials of HFpEF (n = 108) and a study of healthy participants (n = 42) with invasive haemodynamic measurements during exercise were utilized. Differences in central haemodynamic responses were analysed with regression models. Chronotropic incompetence was present in 39-56% of patients with HFpEF and 3-56% of healthy participants depending on the definition used, but some (n = 47, 44%) had an increase in heart rate similar to that of healthy controls. Patients with HFpEF had a smaller increase in their stroke volume index (SVI) (HFpEF: +4 ± 10 mL/m , healthy participants: +24 ± 12 mL/m , P < 0.0001), indeed, SVI fell in 28% of patients at peak exercise. Higher body mass index and lower SVI at rest were associated with smaller increases in heart rate during exercise, whereas higher resting heart rate, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use were associated with a greater increase in SVI in patients with HFpEF.

Conclusion: The haemodynamic response to exercise was very heterogeneous among patients with HFpEF, with chronotropic incompetence observed in up to 56%, and 28% had impaired increase in SVI. This suggests that haemodynamic exercise testing may be useful to identify which HFpEF patients may benefit from interventions targeting stroke volume and chronotropic response.
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http://dx.doi.org/10.1002/ejhf.2146DOI Listing
March 2021

Generation and cardiac differentiation of an induced pluripotent stem cell line from a patient with arrhythmia-induced cardiomyopathy.

Stem Cell Res 2021 Feb 20;53:102263. Epub 2021 Feb 20.

Clinic for Cardiology & Pneumology, University Medical Center Goettingen, and DZHK (German Centre for Cardiovascular Research), partner site Goettingen, Germany. Electronic address:

Arrhythmia-induced cardiomyopathy (AIC) is characterized by left-ventricular systolic dysfunction caused by persistent arrhythmia. To date, genetic or pathological drivers causing AIC remain unknown. Here, we generated induced pluripotent stem cells (iPSCs) from an AIC patient. The AIC-iPSCs exhibited full pluripotency and differentiation characteristics and maintained a normal karyotype after reprogramming. The AIC-iPSCs differentiated into functional beating AIC-iPSC-cardiomyocytes (CMs), which represents the cell-type of interest to study molecular, genetic and functional aspects of AIC.
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http://dx.doi.org/10.1016/j.scr.2021.102263DOI Listing
February 2021

The diagnostic and prognostic value of galectin-3 in patients at risk for heart failure with preserved ejection fraction: results from the DIAST-CHF study.

ESC Heart Fail 2021 Apr 10;8(2):829-841. Epub 2021 Feb 10.

Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, Berlin, 13353, Germany.

Aims: Galectin-3 (Gal-3) predicts long-term outcome among patients with heart failure (HF) with preserved ejection fraction (HFpEF). The ability of Gal-3 to diagnose and predict incident HFpEF in a cohort at risk for HFpEF is of particular interest. We aimed to determine the association between Gal-3 and clinical manifestations of HFpEF, the relationship between Gal-3 and all-cause mortality, or the composite of cardiovascular hospitalization and death.

Methods And Results: The observational Diast-CHF study included patients aged 50 to 85 years with ≥1 risk factor for HF (e.g. hypertension, diabetes mellitus, and atherosclerotic disease) or previously suspected HF. Patients were followed for 10 years. The association between Gal-3, evidence of diastolic dysfunction, and Framingham criteria for HF was examined. All deaths and hospitalizations were adjudicated as cardiovascular or non-cardiovascular. The analysis population was composed of 1386 subjects (67 years old, 50.9% female). The area under the receiver operating characteristic curve to diagnose HFpEF was 0.71. At a cut-off value of 13.57 ng/mL, sensitivity was 0.61 and specificity was 0.73 for Gal-3, and the diagnostic power to detect HFpEF was superior to N-terminal pro-brain natriuretic peptide (area under the receiver operating characteristic curve 0.59, P > 0.001). Baseline Gal-3 was associated with risk factors for HF (P < 0.001). Higher levels of Gal-3 predicted incident HFpEF (P < 0.05), adjusted all-cause mortality (P < 0.001), and the adjusted composite of cardiovascular hospitalization and death (P < 0.001), both independent from N-terminal pro-brain natriuretic peptide.

Conclusions: Gal-3 differentiated patients with HFpEF from an overall cohort of well-characterized patients with risk factors for HFpEF. Independent of other factors, baseline Gal-3 levels were associated with a higher risk for incident HFpEF, mortality, or the composite of cardiovascular hospitalization and death over 10 year follow-up. In conjunction with clinical parameters, Gal-3 adds a statistically significant value for the diagnosis of HFpEF within this study, yet the clinical relevance remains debatable.
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http://dx.doi.org/10.1002/ehf2.13174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006663PMC
April 2021

Venous lactate improves the prediction of in-hospital adverse outcomes in normotensive pulmonary embolism.

Eur J Intern Med 2021 Feb 5. Epub 2021 Feb 5.

German Center for Cardiovascular Research (DZHK), Partner site Berlin, Germany; Clinic of Cardiology and Pneumology, University Medical Center Göttingen, Germany; Department of Internal Medicine and Cardiology, Campus Virchow Klinikum (CVK), Charité - University Medicine Berlin, Germany; Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Germany. Electronic address:

Background: Arterial lactate is an established risk marker in patients with pulmonary embolism (PE). However, its clinical applicability is limited by the need of an arterial puncture. In contrast, venous lactate can easily be measured from blood samples obtained via routine peripheral venepuncture.

Methods: We investigated the prognostic value of venous lactate with regard to in-hospital adverse outcomes and mortality in 419 consecutive PE patients enrolled in a single-center registry between 09/2008 and 09/2017.

Results: An optimised venous lactate cut-off value of 3.3 mmol/l predicted both, in-hospital adverse outcome (OR 11.0 [95% CI 4.6-26.3]) and all-cause mortality (OR 3.8 [95%CI 1.3-11.3]). The established cut-off value for arterial lactate (2.0 mmol/l) and the upper limit of normal for venous lactate (2.3 mmol/l) had lower prognostic value for adverse outcomes (OR 3.6 [95% CI 1.5-8.7] and 5.7 [95% CI 2.4-13.6], respectively) and did not predict mortality. If added to the 2019 European Society of Cardiology (ESC) algorithm, venous lactate <2.3 mmol/l was associated with a high negative predictive value (0.99 [95% CI 0.97-1.00]) for adverse outcomes in intermediate-low-risk patients, whereas levels ≥3.3 mmol/l predicted adverse outcomes in the intermediate-high-risk group (OR 5.2 [95% CI 1.8-15.0]).

Conclusion: Venous lactate above the upper limit of normal was associated with increased risk for adverse outcomes and an optimised cut-off value of 3.3 mmol/l predicted adverse outcome and mortality. Adding venous lactate to the 2019 ESC algorithm may improve risk stratification. Importantly, the established cut-off value for arterial lactate has limited specificity in venous samples and should not be used.
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http://dx.doi.org/10.1016/j.ejim.2021.01.021DOI Listing
February 2021

Integrated Ca flux and AFM force analysis in human iPSC-derived cardiomyocytes.

Biol Chem 2020 11 27;402(1):113-121. Epub 2020 Oct 27.

Heart Center, Department of Cardiology and Pneumology, University Medical Center, Göttingen University, Robert-Koch-Strasse 40, D-37075, Göttingen, Germany.

We developed a new approach for combined analysis of calcium (Ca) handling and beating forces in contractile cardiomyocytes. We employed human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from dilated cardiomyopathy (DCM) patients carrying an inherited mutation in the sarcomeric protein troponin T (TnT), and isogenic TnT-KO iPSC-CMs generated via CRISPR/Cas9 gene editing. In these cells, Ca handling as well as beating forces and -rates using single-cell atomic force microscopy (AFM) were assessed. We report impaired Ca handling and reduced contractile force in DCM iPSC-CMs compared to healthy WT controls. TnT-KO iPSC-CMs display no contractile force or Ca transients but generate Ca sparks. We apply our analysis strategy to Ca traces and AFM deflection recordings to reveal maximum rising rate, decay time, and duration of contraction with a multi-step background correction. Our method provides adaptive computing of signal peaks for different Ca flux or force levels in iPSC-CMs, as well as analysis of Ca sparks. Moreover, we report long-term measurements of contractile force dynamics on human iPSC-CMs. This approach enables deeper and more accurate profiling of disease-specific differences in cardiomyocyte contraction profiles using patient-derived iPSC-CMs.
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http://dx.doi.org/10.1515/hsz-2020-0212DOI Listing
November 2020

Caveolin3 Stabilizes McT1-Mediated Lactate/Proton Transport in Cardiomyocytes.

Circ Res 2021 Mar 25;128(6):e102-e120. Epub 2021 Jan 25.

Cellular Biophysics and Translational Cardiology Section, Heart Research Center Göttingen (J.P., D.K.-D., G.W., S.B., T.K., G.H., J.W., S.E.L.), University Medical Center Göttingen.

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316547DOI Listing
March 2021

[Symptom control in heart failure patients - how to handle GFR decrease and hyperkalaemia].

Dtsch Med Wochenschr 2021 Mar 22;146(6):e47-e55. Epub 2021 Jan 22.

Klinik für Nephrologie, Blutreinigung und Rheumatologie, Klinikum Braunschweig.

For heart failure patients with reduced ejection fraction, optimised medication improves symptom control and reduces mortality. Substances influencing the renin-angiotensin-aldosteron-system, so-called RAAS-inhibitors, are the cornerstone of heart failure treatment. This article summarises a consensus between experts in cardiology and in nephrology on a pragmatic approach to manage a drop in glomerular filtration rate and incident hyperkalaemia - the two most common reasons for reducing or discontinuing heart failure medication.
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http://dx.doi.org/10.1055/a-1307-8652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972821PMC
March 2021

Exercise Stress Real-Time Cardiac Magnetic Resonance Imaging for Noninvasive Characterization of Heart Failure With Preserved Ejection Fraction: The HFpEF-Stress Trial.

Circulation 2021 Apr 21;143(15):1484-1498. Epub 2021 Jan 21.

From the Department of Cardiology and Pneumology, Georg-August University (S.J.B., T.L., E.F.G., K.H., M.B., R.W., U.R., G.H., T.S., A.S.), University Medical Center Göttingen, Germany.

Background: Right heart catheterization using exercise stress is the reference standard for the diagnosis of heart failure with preserved ejection fraction (HFpEF) but carries the risk of the invasive procedure. We hypothesized that real-time cardiac magnetic resonance (RT-CMR) exercise imaging with pathophysiologic data at excellent temporal and spatial resolution may represent a contemporary noninvasive alternative for diagnosing HFpEF.

Methods: The HFpEF-Stress trial (CMR Exercise Stress Testing in HFpEF; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03260621. URL: https://dzhk.de/; Unique identifier: DZHK-17) prospectively recruited 75 patients with echocardiographic signs of diastolic dysfunction and dyspnea on exertion (E/e'>8, New York Heart Association class ≥II) to undergo echocardiography, right heart catheterization, and RT-CMR at rest and during exercise stress. HFpEF was defined according to pulmonary capillary wedge pressure (≥15 mm Hg at rest or ≥25 mm Hg during exercise stress). RT-CMR functional assessments included time-volume curves for total and early (1/3) diastolic left ventricular filling, left atrial (LA) emptying, and left ventricular/LA long axis strain.

Results: Patients with HFpEF (n=34; median pulmonary capillary wedge pressure at rest, 13 mm Hg; at stress, 27 mm Hg) had higher E/e' (12.5 versus 9.15), NT-proBNP (N-terminal pro-B-type natriuretic peptide; 255 versus 75 ng/L), and LA volume index (43.8 versus 36.2 mL/m) compared with patients with noncardiac dyspnea (n=34; rest, 8 mm Hg; stress, 18 mm Hg; ≤0.001 for all). Seven patients were excluded because of the presence of non-HFpEF cardiac disease causing dyspnea on imaging. There were no differences in RT-CMR left ventricular total and early diastolic filling at rest and during exercise stress (≥0.164) between patients with HFpEF and noncardiac dyspnea. RT-CMR revealed significantly impaired LA total and early (<0.001) diastolic emptying in patients with HFpEF during exercise stress. RT-CMR exercise stress LA long axis strain was independently associated with HFpEF (adjusted odds ratio, 0.657 [95% CI, 0.516-0.838]; =0.001) after adjustment for clinical and imaging measures and emerged as the best predictor for HFpEF (area under the curve at rest 0.82 versus exercise stress 0.93; =0.029).

Conclusions: RT-CMR allows highly accurate identification of HFpEF during physiologic exercise and qualifies as a suitable noninvasive diagnostic alternative. These results will need to be confirmed in multicenter prospective research studies to establish widespread routine clinical use. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03260621. URL: https://dzhk.de/; Unique identifier: DZHK-17.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051542DOI Listing
April 2021

High-sensitivity troponin I for risk stratification in normotensive pulmonary embolism.

ERJ Open Res 2020 Oct 21;6(4). Epub 2020 Dec 21.

German Center for Cardiovascular Research (DZHK), partner site Berlin, Germany.

While numerous studies have confirmed the prognostic role of high-sensitivity troponin T (hsTnT) in pulmonary embolism (PE), high-sensitivity troponin I (hsTnI) is inappropriately studied. This study aimed to investigate the prognostic relevance of hsTnI in normotensive PE, establish the optimal cut-off value for risk stratification and to compare the prognostic performances of hsTnI and hsTnT. Based on data from 459 consecutive PE patients enrolled in a single-centre registry, receiver operating characteristic analysis was used to identify an optimal hsTnI cut-off value for prediction of in-hospital adverse outcomes (PE-related death, cardiopulmonary resuscitation or vasopressor treatment) and all-cause mortality. Patients who suffered an in-hospital adverse outcome (4.8%) had higher hsTnI concentrations compared with those with a favourable clinical course (57 (interquartile range (IQR) 22-197) 15 (IQR 10-86) pg·mL, p=0.03). A hsTnI cut-off value of 16 ng·mL provided optimal prognostic performance and predicted in-hospital adverse outcomes (OR 6.5, 95% CI 1.9-22.4) and all-cause mortality (OR 3.7, 95% CI 1.0-13.3). Between female and male patients, no relevant differences in hsTnI concentrations (17 (IQR 10-97) 17 (IQR 10-92) pg·mL, p=0.79) or optimised cut-off values were observed. Risk stratification according to the 2019 European Society of Cardiology algorithm revealed no differences if calculated based on either hsTnI or hsTnT (p=0.68). Our findings confirm the prognostic role of hsTnI in normotensive PE. HsTnI concentrations >16 pg·mL predicted in-hospital adverse outcome and all-cause mortality; sex-specific cut-off values do not seem necessary. Importantly, our results suggest that hsTnI and hsTnT can be used interchangeably for risk stratification.
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http://dx.doi.org/10.1183/23120541.00625-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792860PMC
October 2020

Disease Phenotypes and Mechanisms of iPSC-Derived Cardiomyocytes From Brugada Syndrome Patients With a Loss-of-Function SCN5A Mutation.

Front Cell Dev Biol 2020 22;8:592893. Epub 2020 Oct 22.

Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany.

Brugada syndrome (BrS) is one of the major causes of sudden cardiac death in young people, while the underlying mechanisms are not completely understood. Here, we investigated the pathophysiological phenotypes and mechanisms using induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) from two BrS patients (BrS-CMs) carrying a heterozygous mutation p.S1812X. Compared to CMs derived from healthy controls (Ctrl-CMs), BrS-CMs displayed a 50% reduction of density, a 69.5% reduction of Na1.5 expression, and the impaired localization of Na1.5 and connexin 43 (Cx43) at the cell surface. BrS-CMs exhibited reduced action potential (AP) upstroke velocity and conduction slowing. The in BrS-CMs was significantly augmented, and the window current probability was increased. Our data indicate that the electrophysiological mechanisms underlying arrhythmia in BrS-CMs may involve both depolarization and repolarization disorders. Cilostazol and milrinone showed dramatic inhibitions of in BrS-CMs and alleviated the arrhythmic activity, suggesting their therapeutic potential for BrS patients.
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http://dx.doi.org/10.3389/fcell.2020.592893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642519PMC
October 2020

Cardiotoxicity and Cardiovascular Biomarkers in Patients With Breast Cancer: Data From the GeparOcto-GBG 84 Trial.

J Am Heart Assoc 2020 12 16;9(23):e018143. Epub 2020 Nov 16.

Department of Cardiology and Pneumology University of Göttingen Medical Center Göttingen Germany.

Background Patients with breast cancer can be affected by cardiotoxic reactions through cancer therapies. Cardiac biomarkers, like NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin T, might have predictive value. Methods and Results Echocardiography, ECG, hemodynamic parameters, NT-proBNP and high-sensitivity cardiac troponin T were assessed in 853 patients with early-stage breast cancer randomized in the German Breast Group GeparOcto-GBG 84 phase III trial. Patients received neo-adjuvant dose-dense, dose-intensified epirubicin, paclitaxel, and cyclophosphamide (iddEPC group, n=424) or paclitaxel, non-pegylated doxorubicin, and in triple negative breast cancer, (paclitaxel, non-pegylated doxorubicin, carboplatin group, n=429) treatment for 18 weeks. Patients positive for human epidermal growth receptor 2 (n=354, 41.5%) received monoclonal antibodies on top of allocated therapy; 119 (12.9%) of all patients showed a cardiotoxic reaction during therapy (15 [1.8%] using a more strict definition). Presence of cardiotoxic reactions was irrespective of treatment allocation (=0.31). Small but significant increases in NT-proBNP developed early in patients with a cardiotoxic reaction as compared with those without in whom NT-proBNP rose only towards the end of therapy (=0.04). High-sensitivity cardiac troponin T rose early in both groups. Logistic regression showed that NT-proBNP (odds ratio [OR], 1.03; 95% CI, 1.008-1.055; =0.01) and hemoglobin (OR, 1.31; 95% CI, 1.05-1.63; =0.02) measured at 6 weeks after treatment initiation were significantly associated with cardiotoxic reactions. Conclusions NT-proBNP and hemoglobin are significantly associated with cardiotoxic reactions in patients with early-stage breast cancer undergoing dose-dense and dose-intensified chemotherapy, but high-sensitivity cardiac troponin T is not. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT02125344.
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http://dx.doi.org/10.1161/JAHA.120.018143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763783PMC
December 2020

Functional and prognostic implications of cardiac magnetic resonance feature tracking-derived remote myocardial strain analyses in patients following acute myocardial infarction.

Clin Res Cardiol 2021 02 20;110(2):270-280. Epub 2020 Oct 20.

Department of Cardiology and Pneumology, Göttingen Germany and German Centre for Cardiovascular Research (DZHK), Partner Site Göttingen, University Medical Center Göttingen, Georg-August University, Robert-Koch-Straße 40, Göttingen, Germany.

Background: Cardiac magnetic resonance myocardial feature tracking (CMR-FT)-derived global strain assessments provide incremental prognostic information in patients following acute myocardial infarction (AMI). Functional analyses of the remote myocardium (RM) are scarce and whether they provide an additional prognostic value in these patients is unknown.

Methods: 1034 patients following acute myocardial infarction were included. CMR imaging and strain analyses as well as infarct size quantification were performed after reperfusion by primary percutaneous coronary intervention. The occurrence of major adverse cardiac events (MACE) within 12 months after the index event was defined as primary clinical endpoint.

Results: Patients with MACE had significantly lower RM circumferential strain (CS) compared to those without MACE. A cutoff value for RM CS of - 25.8% best identified high-risk patients (p < 0.001 on log-rank testing) and impaired RM CS was a strong predictor of MACE (HR 1.05, 95% CI 1.07-1.14, p = 0.003). RM CS provided further risk stratification among patients considered at risk according to established CMR parameters for (1) patients with reduced left ventricular ejection fraction (LVEF) ≤ 35% (p = 0.038 on log-rank testing), (2) patients with reduced global circumferential strain (GCS) > -  18.3% (p = 0.015 on log-rank testing), and (3) patients with large microvascular obstruction ≥ 1.46% (p = 0.002 on log-rank testing).

Conclusion: CMR-FT-derived RM CS is a useful parameter to characterize the response of the remote myocardium and allows improved stratification following AMI beyond commonly used parameters, especially of high-risk patients.

Trial Registration: ClinicalTrials.gov, NCT00712101 and NCT01612312 Defining remote segments (R) in the presence of infarct areas (I) for the analysis of remote circumferential strain (CS). Remote CS was significantly lower in patients who suffered major adverse cardiac events (MACE) and a cutoff value for remote CS of - 25.8% best identified high-risk patients. In addition, impaired remote CS ≥ - 25.8 % (Remote -) and preserved remote CS < - 25.8 % (Remote +) enabled further risk stratification when added to established parameters like left ventricular ejection fraction (LVEF), global circumferential strain (GCS) or microvascular obstruction (MVO).
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http://dx.doi.org/10.1007/s00392-020-01747-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862195PMC
February 2021

Long-term effects of empagliflozin on excitation-contraction-coupling in human induced pluripotent stem cell cardiomyocytes.

J Mol Med (Berl) 2020 12 9;98(12):1689-1700. Epub 2020 Oct 9.

Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.

The SGLT2 inhibitor empagliflozin improved cardiovascular outcomes in patients with diabetes. As the cardiac mechanisms remain elusive, we investigated the long-term effects (up to 2 months) of empagliflozin on excitation-contraction (EC)-coupling in human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CM) in a blinded manner. IPSC from 3 donors, differentiated into pure iPSC-CM (4 differentiations), were treated with a clinically relevant concentration of empagliflozin (0.5 μmol/l) or vehicle control. Treatment, data acquisition, and analysis were conducted externally blinded. Epifluorescence microscopy measurements in iPSC-CM showed that empagliflozin has neutral effects on Ca transient amplitude, diastolic Ca levels, Ca transient kinetics, or sarcoplasmic Ca load after 2 weeks or 8 weeks of treatment. Confocal microscopy determining possible effects on proarrhythmogenic diastolic Ca release events showed that in iPSC-CM, Ca spark frequency and leak was not altered after chronic treatment with empagliflozin. Finally, in patch-clamp experiments, empagliflozin did not change action potential duration, amplitude, or resting membrane potential compared with vehicle control after long-term treatment. Next-generation RNA sequencing (NGS) and mapped transcriptome profiles of iPSC-CMs untreated and treated with empagliflozin for 8 weeks showed no differentially expressed EC-coupling genes. In line with NGS data, Western blots indicate that empagliflozin has negligible effects on key EC-coupling proteins. In this blinded study, direct treatment of iPSC-CM with empagliflozin for a clinically relevant duration of 2 months did not influence cardiomyocyte EC-coupling and electrophysiology. Therefore, it is likely that other mechanisms independent of cardiomyocyte EC-coupling are responsible for the beneficial treatment effect of empagliflozin. KEY MESSAGES: This blinded study investigated the clinically relevant long-term effects (up to 2 months) of empagliflozin on cardiomyocyte excitation-contraction (EC)-coupling. Human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CM) were used to study a human model including a high repetition number of experiments. Empagliflozin has neutral effects on cardiomyocyte Ca transients, sarcoplasmic Ca load, and diastolic sarcoplasmic Ca leak. In patch-clamp experiments, empagliflozin did not change the action potential. Next-generation RNA sequencing, mapped transcriptome profiles, and Western blots of iPSC-CM untreated and treated with empagliflozin showed no differentially expressed EC-coupling candidates.
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http://dx.doi.org/10.1007/s00109-020-01989-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679329PMC
December 2020

Cachexia, muscle wasting, and frailty in cardiovascular disease.

Eur J Heart Fail 2020 12 14;22(12):2314-2326. Epub 2020 Oct 14.

Department of Cardiology and Pneumology, University of Göttingen Medical Center, Göttingen, Germany.

The last several years have seen increasing interest in understanding cachexia, muscle wasting, and physical frailty across the broad spectrum of patients with cardiovascular illnesses. This interest originally started in the field of heart failure, but has recently been extended to other areas such as atrial fibrillation, coronary artery disease, peripheral artery disease as well as to patients after cardiac surgery or transcatheter aortic valve implantation. Tissue wasting and frailty are prevalent among many of the affected patients. The ageing process itself and concomitant cardiovascular illness decrease lean mass while fat mass is relatively preserved, making elderly patients particularly prone to develop wasting syndromes and frailty. The aim of this review is to provide an overview of the available knowledge of body wasting and physical frailty in patients with cardiovascular illness, particularly focussing on patients with heart failure in whom most of the available data have been gathered. In addition, mechanisms of wasting and possible therapeutic targets are discussed.
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http://dx.doi.org/10.1002/ejhf.2011DOI Listing
December 2020

Frequency and prognostic impact of right ventricular involvement in acute myocardial infarction.

Heart 2020 Sep 2. Epub 2020 Sep 2.

Department of Cardiology and Pneumology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany.

Objective: Right ventricular (RV) involvement complicating myocardial infarction (MI) is thought to impact prognosis, but potent RV markers for risk stratification are lacking. Therefore, the aim of this trial was to assess the frequency and prognostic implications of concomitant structural and functional RV injury in MI.

Methods: Cardiac magnetic resonance (CMR) was performed in 1235 patients with MI (ST-elevation myocardial infarction: n=795; non-STEMI: n=440) 3 days after reperfusion by primary percutaneous coronary intervention. Central core laboratory-masked analyses included structural (oedema representing reversible ischaemia, irreversible infarction, microvascular obstruction (MVO)) and functional (ejection fraction, global longitudinal strain (GLS)) RV alterations. The clinical end point was the 12-month rate of major adverse cardiac events (MACE).

Results: RV ischaemia and infarction were observed in 19.6% and 12.1% of patients, respectively, suggesting complete myocardial salvage in one-third of patients. RV ischaemia was associated with a significantly increased risk of MACE (10.1% vs 6.2%; p=0.035), while patients with RV infarction showed only numerically increased event rates (p=0.075). RV MVO was observed in 2.4% and not linked to outcome (p=0.894). Stratification according to median RV GLS (10.2% vs 3.8%; p<0.001) but not RV ejection fraction (p=0.175) resulted in elevated MACE rates. Multivariable analysis including clinical and left ventricular MI characteristics identified RV GLS as an independent predictor of outcome (HR 1.05, 95% CI 1.00 to 1.09; p=0.034) in addition to age (p=0.001), Killip class (p=0.020) and left ventricular GLS (p=0.001), while RV ischaemia was not independently associated with outcome.

Conclusions: RV GLS is a predictor of postinfarction adverse events over and above established risk factors, while structural RV involvement was not independently associated with outcome.
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http://dx.doi.org/10.1136/heartjnl-2020-317184DOI Listing
September 2020

Is myosin activation a new treatment for heart failure?

Authors:
Gerd Hasenfuss

Eur J Heart Fail 2020 09;22(9):1659-1661

Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.

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http://dx.doi.org/10.1002/ejhf.1983DOI Listing
September 2020

Fully Automated Cardiac Assessment for Diagnostic and Prognostic Stratification Following Myocardial Infarction.

J Am Heart Assoc 2020 09 2;9(18):e016612. Epub 2020 Sep 2.

Medical Clinic II (Cardiology/Angiology/Intensive Care Medicine) University Heart Center LübeckUniversity Hospital Schleswig-Holstein Lübeck Germany.

Background Cardiovascular magnetic resonance imaging is considered the reference methodology for cardiac morphology and function but requires manual postprocessing. Whether novel artificial intelligence-based automated analyses deliver similar information for risk stratification is unknown. Therefore, this study aimed to investigate feasibility and prognostic implications of artificial intelligence-based, commercially available software analyses. Methods and Results Cardiovascular magnetic resonance data (n=1017 patients) from 2 myocardial infarction multicenter trials were included. Analyses of biventricular parameters including ejection fraction (EF) were manually and automatically assessed using conventional and artificial intelligence-based software. Obtained parameters entered regression analyses for prediction of major adverse cardiac events, defined as death, reinfarction, or congestive heart failure, within 1 year after the acute event. Both manual and uncorrected automated volumetric assessments showed similar impact on outcome in univariate analyses (left ventricular EF, manual: hazard ratio [HR], 0.93 [95% CI 0.91-0.95]; <0.001; automated: HR, 0.94 [95% CI, 0.92-0.96]; <0.001) and multivariable analyses (left ventricular EF, manual: HR, 0.95 [95% CI, 0.92-0.98]; =0.001; automated: HR, 0.95 [95% CI, 0.92-0.98]; =0.001). Manual correction of the automated contours did not lead to improved risk prediction (left ventricular EF, area under the curve: 0.67 automated versus 0.68 automated corrected; =0.49). There was acceptable agreement (left ventricular EF: bias, 2.6%; 95% limits of agreement, -9.1% to 14.2%; intraclass correlation coefficient, 0.88 [95% CI, 0.77-0.93]) of manual and automated volumetric assessments. Conclusions User-independent volumetric analyses performed by fully automated software are feasible, and results are equally predictive of major adverse cardiac events compared with conventional analyses in patients following myocardial infarction. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00712101 and NCT01612312.
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http://dx.doi.org/10.1161/JAHA.120.016612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726968PMC
September 2020

Head-to-head comparison of cardiovascular MR feature tracking cine versus acquisition-based deformation strain imaging using myocardial tagging and strain encoding.

Magn Reson Med 2021 01 27;85(1):357-368. Epub 2020 Aug 27.

Department of Cardiology and Pneumology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany.

Purpose: Myocardial feature-tracking (FT) deformation imaging is superior for risk stratification compared with volumetric approaches. Because there is no clear recommendation regarding FT postprocessing, we compared different FT-strain analyses with reference standard techniques, including tagging and strain-encoded (SENC) MRI.

Methods: Feature-tracking software from four different vendors (TomTec, Medis, Circle [CVI], and Neosoft), tagging (Segment), and fastSENC (MyoStrain) were used to determine left ventricular global circumferential strains (GCS) and longitudinal strains (GLS) in 12 healthy volunteers and 12 patients with heart failure. Variability and agreements were assessed using intraclass correlation coefficients for absolute agreement (ICCa) and consistency (ICCc) as well as Pearson correlation coefficients.

Results: For FT-GCS, consistency was excellent comparing different FT vendors (ICCc = 0.84-0.97, r = 0.86-0.95) and in comparison to fast SENC (ICCc = 0.78-0.89, r = 0.73-0.81). FT-GCS consistency was excellent compared with tagging (ICCc = 0.79-0.85, r = 0.74-0.77) except for TomTec (ICCc = 0.68, r = 0.72). Absolute FT-GCS agreements among FT vendors were highest for CVI and Medis (ICCa = 0.96) and lowest for TomTec and Neosoft (ICCa = 0.32). Similarly, absolute FT-GCS agreements were excellent for CVI and Medis compared with both tagging and fast SENC (ICCa = 0.84-0.88), good to excellent for Neosoft (ICCa = 0.77 and 0.64), and lowest for TomTec (ICCa = 0.41 and 0.47). For FT-GLS, consistency was excellent (ICCc ≥ 0.86, r ≥ 0.76). Absolute agreements among FT vendors were excellent (ICCa = 0.91-0.93) or good to excellent for TomTec (ICCa = 0.69-0.85). Absolute agreements (ICCa) were good (CVI 0.70, Medis 0.60) and fair (TomTec 0.41, Neosoft 0.59) compared with tagging, but excellent compared with fast SENC (ICCa = 0.77-0.90).

Conclusion: Although absolute agreements differ depending on deformation assessment approaches, consistency and correlation are consistently high regardless of the method chosen, thus indicating reliable strain assessment. Further standardisation and introduction of uniform references is warranted for routine clinical implementation.
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http://dx.doi.org/10.1002/mrm.28437DOI Listing
January 2021

Definition of tachycardia for risk stratification of pulmonary embolism.

Eur J Intern Med 2020 12 23;82:76-82. Epub 2020 Aug 23.

Center for Thrombosis and Hemostasis (CTH), University Medical Centre of the Johannes Gutenberg University Mainz, Germany; Clinic of Cardiology and Pneumology, University Medical Centre Göttingen, Germany; Department of Internal Medicine and Cardiology, Campus Virchow Klinikum (CVK), Charité - University Medicine Berlin, Germany. Electronic address:

Background: Tachycardia is a reliable predictor of adverse outcomes in normotensive patients with acute pulmonary embolism (PE). However, different prognostic relevant heart rate thresholds have been proposed. The aim of the study was to investigate the prognostic performance of different thresholds used for defining tachycardia in normotensive PE patients.

Methods: We performed a post-hoc analysis of normotensive patients with confirmed PE consecutively included in a single-centre and a multi-centre registry. An adverse outcome was defined as PE-related death, need for mechanical ventilation, cardiopulmonary resuscitation or administration of catecholamines.

Results: Of 1567 patients (median age: 72 [IQR, 59-79] years; females: 46.1%) included in the analysis, 78 patients (5.0%) had an in-hospital adverse outcome. The rate of an adverse outcome was higher in patients with a heart rate ≥100 bpm (7.6%) and ≥110 bpm (8.3%) compared to patients with a heart rate <100 bpm (3.0%). A heart rate ≥100 bpm and ≥110 bpm was associated with a 2.7 (95% CI 1.7-4.3) and 2.4-fold (95% CI 1.5-3.7) increased risk for an adverse outcome, respectively. Receiver operating characteristics analysis revealed a similar area under the curve with regard to an adverse outcome for all scores and algorithm (ESC 2019 algorithm, modified FAST and Bova score) if calculated with a heart rate threshold of ≥100 bpm or of ≥110 bpm.

Conclusions: Defining tachycardia by a heart rate ≥100 bpm is sufficient for risk stratification of normotensive patients with acute PE. The use of different heart rate thresholds for calculation of scores and algorithm does not appear necessary.
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http://dx.doi.org/10.1016/j.ejim.2020.08.009DOI Listing
December 2020

Impact of Interatrial Shunts on Invasive Hemodynamics and Exercise Tolerance in Patients With Heart Failure.

J Am Heart Assoc 2020 09 15;9(17):e016760. Epub 2020 Aug 15.

Cardiovascular Research Foundation New York NY USA.

Approximately 50% of patients with heart failure have preserved ejection fraction. Although a wide variety of conditions cause or contribute to heart failure with preserved ejection fraction, elevated left ventricular filling pressures, particularly during exercise, are common to all causes. Acute elevation in left-sided filling pressures promotes lung congestion and symptoms of dyspnea, while chronic elevations often lead to pulmonary vascular remodeling, right heart failure, and increased risk of mortality. Pharmacologic therapies, including neurohormonal modulation and drugs that modify the nitric oxide/cyclic GMP-protein kinase G pathway have thus far been limited in reducing symptoms or improving outcomes in patients with heart failure with preserved ejection fraction. Hence, alternative means of reducing the detrimental rise in left-sided heart pressures are being explored. One proposed method of achieving this is to create an interatrial shunt, thus unloading the left heart at rest and during exercise. Currently available studies have shown 3- to 5-mm Hg decreases of pulmonary capillary wedge pressure during exercise despite increased workload. The mechanisms underlying the hemodynamic changes are just starting to be understood. In this review we summarize results of recent studies aimed at elucidating the potential mechanisms of improved hemodynamics during exercise tolerance following interatrial shunt implantation and the current interatrial shunt devices under investigation.
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http://dx.doi.org/10.1161/JAHA.120.016760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660772PMC
September 2020

Muscle wasting as an independent predictor of survival in patients with chronic heart failure.

J Cachexia Sarcopenia Muscle 2020 10 6;11(5):1242-1249. Epub 2020 Aug 6.

Division of Cardiology and Metabolism, Department of Cardiology and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Charité-Universitätsmedizin Berlin (CVK), Berlin, Germany.

Background: Skeletal muscle wasting is an extremely common feature in patients with heart failure, affecting approximately 20% of ambulatory patients with even higher values during acute decompensation. Its occurrence is associated with reduced exercise capacity, muscle strength, and quality of life. We sought to investigate if the presence of muscle wasting carries prognostic information.

Methods: Two hundred sixty-eight ambulatory patients with heart failure (age 67.1 ± 10.9 years, New York Heart Association class 2.3 ± 0.6, left ventricular ejection fraction 39 ± 13.3%, and 21% female) were prospectively enrolled as part of the Studies Investigating Co-morbidities Aggravating Heart Failure. Muscle wasting as assessed using dual-energy X-ray absorptiometry was present in 47 patients (17.5%).

Results: During a mean follow-up of 67.2 ± 28.02 months, 95 patients (35.4%) died from any cause. After adjusting for age, New York Heart Association class, left ventricular ejection fraction, creatinine, N-terminal pro-B-type natriuretic peptide, and iron deficiency, muscle wasting remained an independent predictor of death (hazard ratio 1.80, 95% confidence interval 1.01-3.19, P = 0.04). This effect was more pronounced in patients with heart failure with reduced than in heart failure with preserved ejection fraction.

Conclusions: Muscle wasting is an independent predictor of death in ambulatory patients with heart failure. Clinical trials are needed to identify treatment approaches to this co-morbidity.
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http://dx.doi.org/10.1002/jcsm.12603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567155PMC
October 2020

Sacubitrilat reduces pro-arrhythmogenic sarcoplasmic reticulum Ca leak in human ventricular cardiomyocytes of patients with end-stage heart failure.

ESC Heart Fail 2020 10 25;7(5):2992-3002. Epub 2020 Jul 25.

Abt. Kardiologie und Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Göttingen, Germany.

Aims: Inhibition of neprilysin and angiotensin II receptor by sacubitril/valsartan (Val) (LCZ696) reduces mortality in heart failure (HF) patients compared with sole inhibition of renin-angiotensin system. Beneficial effects of increased natriuretic peptide levels upon neprilysin inhibition have been proposed, whereas direct effects of sacubitrilat (Sac) (LBQ657) on myocardial Ca cycling remain elusive.

Methods And Results: Confocal microscopy (Fluo-4 AM) was used to investigate pro-arrhythmogenic sarcoplasmic reticulum (SR) Ca leak in freshly isolated murine and human ventricular cardiomyocytes (CMs) upon Sac (40 μmol/L)/Val (13 μmol/L) treatment. The concentrations of Sac and Val equalled plasma concentrations of LCZ696 treatment used in PARADIGM-HF trial. Epifluorescence microscopy measurements (Fura-2 AM) were performed to investigate effects on systolic Ca release, SR Ca load, and Ca -transient kinetics in freshly isolated murine ventricular CMs. The impact of Sac on myocardial contractility was evaluated using in toto-isolated, isometrically twitching ventricular trabeculae from human hearts with end-stage HF. Under basal conditions, the combination of Sac/Val did not influence diastolic Ca -spark frequency (CaSpF) nor pro-arrhythmogenic SR Ca leak in isolated murine ventricular CMs (n CMs/hearts = 80/7 vs. 100/7, P = 0.91/0.99). In contrast, Sac/Val treatment reduced CaSpF by 35 ± 9% and SR Ca leak by 45 ± 9% in CMs put under catecholaminergic stress (isoproterenol 30 nmol/L, n = 81/7 vs. 62/7, P < 0.001 each). This could be attributed to Sac, as sole Sac treatment also reduced both parameters by similar degrees (reduction of CaSpF by 57 ± 7% and SR Ca leak by 76 ± 5%; n = 101/4 vs. 108/4, P < 0.01 each), whereas sole Val treatment did not. Systolic Ca release, SR Ca load, and Ca -transient kinetics including SERCA activity (k ) were not compromised by Sac in isolated murine CMs (n = 41/6 vs. 39/6). Importantly, the combination of Sac/Val and Sac alone also reduced diastolic CaSpF and SR Ca leak (reduction by 74 ± 7%) in human left ventricular CMs from patients with end-stage HF (n = 71/8 vs. 78/8, P < 0.05 each). Myocardial contractility of human ventricular trabeculae was not acutely affected by Sac treatment as the developed force remained unchanged over a time course of 30 min (n trabeculae/hearts = 3/3 vs. 4/3).

Conclusion: This study demonstrates that neprilysin inhibitor Sac directly improves Ca homeostasis in human end-stage HF by reducing pro-arrhythmogenic SR Ca leak without acutely affecting systolic Ca release and inotropy. These effects might contribute to the mortality benefits observed in the PARADIGM-HF trial.
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http://dx.doi.org/10.1002/ehf2.12918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586991PMC
October 2020

In vivo [U-C]glucose labeling to assess heart metabolism in murine models of pressure and volume overload.

Am J Physiol Heart Circ Physiol 2020 08 10;319(2):H422-H431. Epub 2020 Jul 10.

King's College London British Heart Foundation Centre of Excellence, School of Cardiovascular Medicine & Sciences, London, United Kingdom.

Alterations in the metabolism of substrates such as glucose are integrally linked to the structural and functional changes that occur in the remodeling heart. Assessment of such metabolic changes under in vivo conditions would provide important insights into this interrelationship. We aimed to investigate glucose carbon metabolism in pressure-overload and volume-overload cardiac hypertrophy by using an in vivo [U-C]glucose labeling strategy to enable analyses of the metabolic fates of glucose carbons in the mouse heart. Therefore, [U-C]glucose was administered in anesthetized mice by tail vein infusion, and the optimal duration of infusion was established. Hearts were then excised for C metabolite isotopomer analysis by NMR spectroscopy. [U-C]glucose infusions were performed in mice 2 wk following transverse aortic constriction (TAC) or aortocaval fistula (Shunt) surgery. At this time point, there were similar increases in left ventricular (LV) mass in both groups, but TAC resulted in concentric hypertrophy with impaired LV function, whereas Shunt caused eccentric hypertrophy with preserved LV function. TAC was accompanied by significant changes in glycolysis, mitochondrial oxidative metabolism, glucose metabolism to anaplerotic substrates, and de novo glutamine synthesis. In contrast to TAC, hardly any metabolic changes could be observed in the Shunt group. Taken together, in vivo [U-C]glucose labeling is a valuable method to investigate the fate of nutrients such as glucose in the remodeling heart. We find that concentric and eccentric cardiac remodeling are accompanied by distinct differences in glucose carbon metabolism. This study implemented a method for assessing the fate of glucose carbons in the heart in vivo and used this to demonstrate that pressure and volume overload are associated with distinct changes. In contrast to volume overload, pressure overload-induced changes affect the tricarboxylic acid cycle, glycolytic pathways, and glutamine synthesis. A better understanding of cardiac glucose metabolism under pathological conditions in vivo may provide new therapeutic strategies specific for different types of hemodynamic overload.
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http://dx.doi.org/10.1152/ajpheart.00219.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473922PMC
August 2020

Intronic CRISPR Repair in a Preclinical Model of Noonan Syndrome-Associated Cardiomyopathy.

Circulation 2020 Sep 6;142(11):1059-1076. Epub 2020 Jul 6.

Clinic for Cardiology and Pneumology (U.H., M.K., L.R., R.H., G.H., L.C.).

Background: Noonan syndrome (NS) is a multisystemic developmental disorder characterized by common, clinically variable symptoms, such as typical facial dysmorphisms, short stature, developmental delay, intellectual disability as well as cardiac hypertrophy. The underlying mechanism is a gain-of-function of the RAS-mitogen-activated protein kinase signaling pathway. However, our understanding of the pathophysiological alterations and mechanisms, especially of the associated cardiomyopathy, remains limited and effective therapeutic options are lacking.

Methods: Here, we present a family with two siblings displaying an autosomal recessive form of NS with massive hypertrophic cardiomyopathy as clinically the most prevalent symptom caused by biallelic mutations within the leucine zipper-like transcription regulator 1 (). We generated induced pluripotent stem cell-derived cardiomyocytes of the affected siblings and investigated the patient-specific cardiomyocytes on the molecular and functional level.

Results: Patients' induced pluripotent stem cell-derived cardiomyocytes recapitulated the hypertrophic phenotype and uncovered a so-far-not-described causal link between LZTR1 dysfunction, RAS-mitogen-activated protein kinase signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. Calcium channel blockade and MEK inhibition could prevent some of the disease characteristics, providing a molecular underpinning for the clinical use of these drugs in patients with NS, but might not be a sustainable therapeutic option. In a proof-of-concept approach, we explored a clinically translatable intronic CRISPR (clustered regularly interspaced short palindromic repeats) repair and demonstrated a rescue of the hypertrophic phenotype.

Conclusions: Our study revealed the human cardiac pathogenesis in patient-specific induced pluripotent stem cell-derived cardiomyocytes from NS patients carrying biallelic variants in and identified a unique disease-specific proteome signature. In addition, we identified the intronic CRISPR repair as a personalized and in our view clinically translatable therapeutic strategy to treat NS-associated hypertrophic cardiomyopathy.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044794DOI Listing
September 2020

Real-time cardiovascular magnetic resonance T1 and extracellular volume fraction mapping for tissue characterisation in aortic stenosis.

J Cardiovasc Magn Reson 2020 06 22;22(1):46. Epub 2020 Jun 22.

University Medical Center Göttingen, Department of Cardiology and Pneumology, Georg-August University, Robert-Koch-Str. 40, 37099, Göttingen, Germany.

Background: Myocardial fibrosis is a major determinant of outcome in aortic stenosis (AS). Novel fast real-time (RT) cardiovascular magnetic resonance (CMR) mapping techniques allow comprehensive quantification of fibrosis but have not yet been compared against standard techniques and histology.

Methods: Patients with severe AS underwent CMR before (n = 110) and left ventricular (LV) endomyocardial biopsy (n = 46) at transcatheter aortic valve replacement (TAVR). Midventricular short axis (SAX) native, post-contrast T1 and extracellular volume fraction (ECV) maps were generated using commercially available modified Look-Locker Inversion recovery (MOLLI) (native: 5(3)3, post-contrast: 4(1)3(1)2) and RT single-shot inversion recovery Fast Low-Angle Shot (FLASH) with radial undersampling. Focal late gadolinium enhancement was excluded from T1 and ECV regions of interest. ECV and LV mass were used to calculate LV matrix volumes. Variability and agreements were assessed between RT, MOLLI and histology using intraclass correlation coefficients, coefficients of variation and Bland Altman analyses.

Results: RT and MOLLI derived ECV were similar for midventricular SAX slice coverage (26.2 vs. 26.5, p = 0.073) and septal region of interest (26.2 vs. 26.5, p = 0.216). MOLLI native T1 time was in median 20 ms longer compared to RT (p < 0.001). Agreement between RT and MOLLI was best for ECV (ICC > 0.91), excellent for post-contrast T1 times (ICC > 0.81) and good for native T1 times (ICC > 0.62). Diffuse collagen volume fraction by biopsies was in median 7.8%. ECV (RT r = 0.345, p = 0.039; MOLLI r = 0.40, p = 0.010) and LV matrix volumes (RT r = 0.45, p = 0.005; MOLLI r = 0.43, p = 0.007) were the only parameters associated with histology.

Conclusions: RT mapping offers fast and sufficient ECV and LV matrix volume calculation in AS patients. ECV and LV matrix volume represent robust and universally comparable parameters with associations to histologically assessed fibrosis and may emerge as potential targets for clinical decision making.
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http://dx.doi.org/10.1186/s12968-020-00632-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310147PMC
June 2020

Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.

Hum Genet 2020 Nov 8;139(11):1443-1454. Epub 2020 Jun 8.

Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany.

Dilated cardiomyopathy (DCM) belongs to the most frequent forms of cardiomyopathy mainly characterized by cardiac dilatation and reduced systolic function. Although most cases of DCM are classified as sporadic, 20-30% of cases show a heritable pattern. Familial forms of DCM are genetically heterogeneous, and mutations in several genes have been identified that most commonly play a role in cytoskeleton and sarcomere-associated processes. Still, a large number of familial cases remain unsolved. Here, we report five individuals from three independent families who presented with severe dilated cardiomyopathy during the neonatal period. Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals. The identified variants co-segregated with the disease in each of the three families and were absent or very rare in the human population, in line with an autosomal recessive inheritance pattern. They are located within the conserved RPL3 domain of the protein and were classified as deleterious by several in silico prediction software applications. RPL3L is one of the four non-canonical riboprotein genes and it encodes the 60S ribosomal protein L3-like protein that is highly expressed only in cardiac and skeletal muscle. Three-dimensional homology modeling and in silico analysis of the affected residues in RPL3L indicate that the identified changes specifically alter the interaction of RPL3L with the RNA components of the 60S ribosomal subunit and thus destabilize its binding to the 60S subunit. In conclusion, we report that bi-allelic pathogenic variants in RPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy, and we show for the first time that cytoplasmic ribosomal proteins are involved in the pathogenesis of non-syndromic cardiomyopathies.
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http://dx.doi.org/10.1007/s00439-020-02188-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519902PMC
November 2020

Coexistence and outcome of coronary artery disease in Takotsubo syndrome.

Authors:
L Christian Napp Victoria L Cammann Milosz Jaguszewski Konrad A Szawan Manfred Wischnewsky Sebastiano Gili Maike Knorr Susanne Heiner Rodolfo Citro Eduardo Bossone Fabrizio D'Ascenzo Michael Neuhaus Jennifer Franke Ioana Sorici-Barb Michel Noutsias Christof Burgdorf Wolfgang Koenig Behrouz Kherad Annahita Sarcon Lawrence Rajan Guido Michels Roman Pfister Alessandro Cuneo Claudius Jacobshagen Mahir Karakas Alexander Pott Philippe Meyer Jose D Arroja Adrian Banning Florim Cuculi Richard Kobza Thomas A Fischer Tuija Vasankari K E Juhani Airaksinen Christian Hauck Carla Paolini Claudio Bilato Yoichi Imori Ken Kato Yoshio Kobayashi Grzegorz Opolski Monika Budnik Rafal Dworakowski Philip MacCarthy Christoph Kaiser Stefan Osswald Leonarda Galiuto Wolfgang Dichtl Christina Chan Paul Bridgman Daniel Beug Clément Delmas Olivier Lairez Ibrahim El-Battrawy Ibrahim Akin Ekaterina Gilyarova Alexandra Shilova Mikhail Gilyarov John D Horowitz Karolina Polednikova Petr Tousek Petr Widimský David E Winchester Jan Galuszka Christian Ukena Gregor Poglajen Pedro Carrilho-Ferreira Carlo Di Mario Abhiram Prasad Charanjit S Rihal P Christian Schulze Matteo Bianco Filippo Crea Martin Borggrefe Lars S Maier Fausto J Pinto Ruediger C Braun-Dullaeus Wolfgang Rottbauer Hugo A Katus Gerd Hasenfuß Carsten Tschöpe Burkert M Pieske Holger Thiele Heribert Schunkert Michael Böhm Stephan B Felix Thomas Münzel Jeroen J Bax Johann Bauersachs Eugene Braunwald Thomas F Lüscher Frank Ruschitzka Jelena R Ghadri Christian Templin

Eur Heart J 2020 09;41(34):3255-3268

University Heart Center, Department of Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.

Aims: Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS.

Methods And Results: Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort.

Conclusions: Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome.

Trial Registration: ClinicalTrials.gov number: NCT01947621.
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http://dx.doi.org/10.1093/eurheartj/ehaa210DOI Listing
September 2020