Publications by authors named "Hugo A Katus"

1,085 Publications

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Critical appraisal of the 2020 ESC guideline recommendations on diagnosis and risk assessment in patients with suspected non-ST-segment elevation acute coronary syndrome.

Clin Res Cardiol 2021 Feb 26. Epub 2021 Feb 26.

3rd Department of Internal Medicine, Cardiology and Intensive Care Medicine, Wilhelminenhospital, Vienna, Austria.

Multiple new recommendations have been introduced in the 2020 ESC guidelines for the management of acute coronary syndromes with a focus on diagnosis, prognosis, and management of patients presenting without persistent ST-segment elevation. Most recommendations are supported by high-quality scientific evidence. The guidelines provide solutions to overcome obstacles presumed to complicate a convenient interpretation of troponin results such as age-, or sex-specific cutoffs, and to give practical advice to overcome delays of laboratory reporting. However, in some areas, scientific support is less well documented or even missing, and other areas are covered rather by expert opinion or subjective recommendations. We aim to provide a critical appraisal on several recommendations, mainly related to the diagnostic and prognostic assessment, highlighting the discrepancies between Guideline recommendations and the existing scientific evidence.
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http://dx.doi.org/10.1007/s00392-021-01821-2DOI Listing
February 2021

Epigenetic regulation of cardiac electrophysiology in atrial fibrillation: HDAC2 determines action potential duration and suppresses NRSF in cardiomyocytes.

Basic Res Cardiol 2021 Feb 25;116(1):13. Epub 2021 Feb 25.

Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

Atrial fibrillation (AF) is associated with electrical remodeling, leading to cellular electrophysiological dysfunction and arrhythmia perpetuation. Emerging evidence suggests a key role for epigenetic mechanisms in the regulation of ion channel expression. Histone deacetylases (HDACs) control gene expression through deacetylation of histone proteins. We hypothesized that class I HDACs in complex with neuron-restrictive silencer factor (NRSF) determine atrial K channel expression. AF was characterized by reduced atrial HDAC2 mRNA levels and upregulation of NRSF in humans and in a pig model, with regional differences between right and left atrium. In vitro studies revealed inverse regulation of Hdac2 and Nrsf in HL-1 atrial myocytes. A direct association of HDAC2 with active regulatory elements of cardiac K channels was revealed by chromatin immunoprecipitation. Specific knock-down of Hdac2 and Nrsf induced alterations of K channel expression. Hdac2 knock-down resulted in prolongation of action potential duration (APD) in neonatal rat cardiomyocytes, whereas inactivation of Nrsf induced APD shortening. Potential AF-related triggers were recapitulated by experimental tachypacing and mechanical stretch, respectively, and exerted differential effects on the expression of class I HDACs and K channels in cardiomyocytes. In conclusion, HDAC2 and NRSF contribute to AF-associated remodeling of APD and K channel expression in cardiomyocytes via direct interaction with regulatory chromatin regions. Specific modulation of these factors may provide a starting point for the development of more individualized treatment options for atrial fibrillation.
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http://dx.doi.org/10.1007/s00395-021-00855-xDOI Listing
February 2021

Diagnostic performance of D-dimer in predicting venous thromboembolism and acute aortic dissection.

Eur Heart J Acute Cardiovasc Care 2020 Mar 18. Epub 2020 Mar 18.

Background: D-dimer is elevated in a variety of conditions. The purpose of this study was to assess the positive predictive value of D-dimer to rule in patients with confirmed pulmonary embolism, deep vein thrombosis, acute aortic dissection or thrombosis of the upper extremity in comparison to patients with elevated D-dimer for other reasons.

Methods And Results: We studied 1334 patients presenting to the emergency department with pulmonary embolism (n=193), deep vein thrombosis (n=73), acute aortic dissection (n=22), thrombosis of the upper extremity (n=8) and 1038 controls. The positive predictive value was increased with higher D-dimer concentrations improving the ability to identify diseases with high thrombus burden. Patients with venous thromboembolism, acute aortic dissection and thrombosis of the upper extremity showed a maximum positive predictive value of 85.2% at a D-dimer level of 7.8 mg/L (95% confidence interval (CI) 78.1 to 90.4). The maximum positive predictive value was lower in cancer patients with venous thromboembolism, acute aortic dissection and thrombosis of the upper extremity, reaching 68.9% at a D-dimer level of 7.5 mg/L (95% CI 57.4 to 78.4). The positive likelihood ratio was very consistent with the positive predictive value. Using a cut-off level of 0.5 mg/L, D-dimer showed a high sensitivity of at least 93%, but a very low specificity of nearly 0%. Conversely, an optimised cut-off value of 4.6 mg/L increased specificity to 95% for the detection of life-threatening venous thromboembolism, acute aortic dissection or thrombosis of the upper extremity at the costs of moderate sensitivities (58% for pulmonary embolism, 41% for deep vein thrombosis, 65% for pulmonary embolism with co-existent deep vein thrombosis, 50% for acute aortic dissection and 13% for thrombosis of the upper extremity). Using the same cut-off in cancer patients, higher values were observed for sensitivity at a specificity level of more than 95%. The area under the curve for the discrimination of venous thromboembolism/acute aortic dissection/thrombosis of the upper extremity from controls was significantly higher in cancer versus non-cancer patients (area under the curve 0.905 in cancer patients, 95% CI 0.89 to 0.92, vs. area under the curve 0.857 in non-cancer patients, 95% CI 0.84 to 0.88; P=0.0349).

Conclusion: D-dimers are useful not only to rule out but also to rule in venous thromboembolism and acute aortic dissection with an at least moderate discriminatory ability, both in patients with and without cancer.
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http://dx.doi.org/10.1177/2048872620907322DOI Listing
March 2020

Validation of two severity scores as predictors for outcome in Coronavirus Disease 2019 (COVID-19).

PLoS One 2021 19;16(2):e0247488. Epub 2021 Feb 19.

Department of Internal Medicine III, Cardiology, University of Heidelberg, Heidelberg, Germany.

Background: An established objective and standardized reporting of clinical severity and disease progression in COVID-19 is still not established. We validated and compared the usefulness of two classification systems reported earlier-a severity grading proposed by Siddiqi and a system from the National Australian COVID-19 guideline. Both had not been validated externally and were now tested for their ability to predict complications.

Methods: In this retrospective, single-centre observational study, patients hospitalized with confirmed COVID-19 across all severity stages were enrolled. The clinical severity was graded at admission and during hospitalization. Multivariate Cox regression was used to identify independent risk factors for mortality, a composite primary (mortality, incident acute respiratory distress syndrome, incident mechanical ventilation), a secondary endpoint (mortality, incident acute myocardial injury, incident venous thrombosis, pulmonary embolism or stroke) and progression of severity grades.

Results: Of 109 patients 17 died, 31 and 48 developed the primary and secondary endpoint, respectively. Worsening of the severity grade by at least one stage occurred in 27 and 28 patients, respectively. Siddiqi and Australian classification were identified as independent predictors for the primary endpoint (adjusted hazard ratio (aHR) 2.30, p<0.001 and aHR 2.08, p<0.001), for the secondary endpoint (aHR 2.12, p<0.001 and aHR 1.79, p<0.001) and mortality (aHR 2.30, p = 0.071 and aHR 1.98, p = 0.017). Both classification systems showed very good agreement regarding initial grading and good agreement regarding progression of severity stages.

Conclusions: Standardized and objective severity grading is useful to unequivocally stratify patients presenting with COVID-19 for their individual risk of complications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247488PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895342PMC
March 2021

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

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

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

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

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

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

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

Age- and gender-related reference values of cardiac morphology and function in cardiovascular magnetic resonance.

Int J Cardiovasc Imaging 2021 Jan 22. Epub 2021 Jan 22.

Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

Cardiovascular magnetic resonance (CMR) is the reference standard for the quantitative assessment of cardiac morphology and function. The aim of the study was to determine age- and gender-related reference values for cardiac morphology and function according to current recommendations. 454 healthy volunteers (235 men, median age 52.0 (44.0-59.0) years) underwent a standard CMR scan and were divided into six groups of nearly equal size with regard to sex (male, female) and age (21-47 years, 48-57 years, 58-84 years). Left ventricular end-diastolic (LV-EDV) and end-systolic (LV-ESV) volumes and LV mass (LV-M) were measured at end-diastole and end-systole in steady-state free precession series with including papillary muscles and trabecular tissue in the LV-M. Absolute and indexed volumetric parameters were significantly different between gender groups with higher values in men compared to women (all p < 0.001). Furthermore, a significant age-dependent decline could be observed for left ventricular and right ventricular volumes (all p < 0.001), while LV-M did not show differences between the different age-groups. Parameters of longitudinal function for the left and right ventricle were higher in female compared to male subjects with a significant age-dependent decline. We provided normal values for cardiac volumes, function, and mass derived in accordance with current guidelines from a large population of healthy subjects, which can be implemented in clinical routine as a standard of reference.
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http://dx.doi.org/10.1007/s10554-021-02160-zDOI Listing
January 2021

Impaired in vitro growth response of plasma-treated cardiomyocytes predicts poor outcome in patients with transthyretin amyloidosis.

Clin Res Cardiol 2021 Jan 22. Epub 2021 Jan 22.

Department of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, INF 410, 69120, Heidelberg, Germany.

Objectives: Direct toxic effects of transthyretin amyloid in patient plasma upon cardiomyocytes are discussed. However, no data regarding the relevance of this putative effect for clinical outcome are available. In this monocentric prospective study, we analyzed cellular hypertrophy after phenylephrine stimulation in vitro in the presence of patient plasma and correlated the cellular growth response with phenotype and prognosis.

Methods And Results: Progress in automated microscopy and image analysis allows high-throughput analysis of cell morphology. Using the InCell microscopy system, changes in cardiomyocyte's size after treatment with patient plasma from 89 patients suffering from transthyretin amyloidosis and 16 controls were quantified. For this purpose, we propose a novel metric that we named Hypertrophic Index, defined as difference in cell size after phenylephrine stimulation normalized to the unstimulated cell size. Its prognostic value was assessed for multiple endpoints (HTX: death/heart transplantation; DMP: cardiac decompensation; MACE: combined) using Cox proportional hazard models. Cells treated with plasma from healthy controls and hereditary transthyretin amyloidosis with polyneuropathy showed an increase in Hypertrophic Index after phenylephrine stimulation, whereas stimulation after treatment with hereditary cardiac amyloidosis or wild-type transthyretin patient plasma showed a significantly attenuated response. Hypertrophic Index was associated in univariate analyses with HTX (hazard ratio (HR) high vs low: 0.12 [0.02-0.58], p = 0.004), DMP: (HR 0.26 [0.11-0.62], p = 0.003) and MACE (HR 0.24 [0.11-0.55], p < 0.001). Its prognostic value was independent of established risk factors, cardiac TroponinT or N-terminal prohormone brain natriuretic peptide (NTproBNP).

Conclusions: Attenuated cardiomyocyte growth response after stimulation with patient plasma in vitro is an independent risk factor for adverse cardiac events in ATTR patients.
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http://dx.doi.org/10.1007/s00392-020-01801-yDOI Listing
January 2021

Fast Strain-Encoded Cardiac Magnetic Resonance for Diagnostic Classification and Risk Stratification of Heart Failure Patients.

JACC Cardiovasc Imaging 2021 Jan 4. Epub 2021 Jan 4.

Department of Cardiology, Marien Hospital Hamburg, Hamburg, Germany.

Objectives: The purpose of this study was to compare the ability of fast-strain encoded magnetic resonance (fast-SENC) cardiac magnetic resonance (CMR) to classify and risk stratify all-comer patients with different stages of chronic heart failure (Stages of heart failure A to D) based on American College of Cardiology/American Heart Association guidelines with standard clinical and CMR imaging data.

Background: Heart failure is a major cause of morbidity and mortality, resulting in millions of deaths and hospitalizations annually.

Methods: The study population consisted of 1,169 consecutive patients between September 2017 and February 2019 who underwent CMR for clinical reasons, and 61 healthy volunteers. In addition, clinical follow-up was performed in Stages A and B patients after 1.9 ± 0.4 years. Wall motion score and late gadolinium enhancement score indexes, left ventricular (LV) ejection fraction, and global circumferential and longitudinal strain based on fast-SENC acquisitions, were calculated in all subjects. The percentage of myocardial segments with strain ≤-17% (% normal myocardium) was determined in all subjects.

Results: LV ejection fraction, global circumferential and longitudinal strain, and % normal myocardium significantly decreased with increasing heart failure stages (p < 0.001 for all by analysis of variance). By multivariable analysis, % normal myocardium remained an independent predictor of heart failure stages, exhibiting closer association than LV ejection fraction (r = 0.76 vs. r = 0.30; p < 0.001). Importantly, 149 of 399 (37%) with Stage A were reclassified to Stage B, that is, as having subclinical LV dysfunction based on % normal myocardium <80%. Such patients exhibited significantly higher rates of all-cause mortality and hospital stay due to heart failure during follow-up, compared with patients with % normal myocardium ≥80% (χ = 6.9; p = 0.03).

Conclusions: % normal myocardium, determined by fast-SENC, enables improved identification of asymptomatic patients with subclinical LV dysfunction compared with LV ejection fraction and risk stratification of patients with so far asymptomatic heart failure. The identification of such presumably healthy patients at high risk for heart failure-related outcomes may bear important medical implications.
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http://dx.doi.org/10.1016/j.jcmg.2020.10.024DOI Listing
January 2021

Case series of high-risk percutaneous coronary intervention with rotational atherectomy under short-term mechanical circulatory support with TandemHeart in the setting of acute myocardial infarction.

Eur Heart J Case Rep 2020 Aug 16;4(4):1-6. Epub 2020 Sep 16.

Department of Internal Medicine III, Cardiology, Angiology and Pulmonology University Hospital of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.

Background : TandemHeart is a percutaneous Ventricular Assist Device, most commonly used to provide mechanical circulatory support during high-risk percutaneous coronary intervention and postcardiotomy cardiac failure. However, TandemHeart has not been applied in patients with severe heart failure due to myocardial infarction during high-risk percutaneous coronary intervention with the need for rotational artherectomy (RA) before, so we present a first-in-man case series.

Case Summary : Three patients with severe HF[Please spell out HF, LA and MI (if necessary).] due to acute myocardial infarction revealed severely calcified lesions of the unprotected left main artery. We successfully used the TandemHeart as percutaneous Ventricular Assist Device during high-risk percutaneous coronary intervention with RA.

Discussion : We here report our experience and show that RA under TandemHeart mechanical circulatory support is feasible and safe in case of acute MI.
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http://dx.doi.org/10.1093/ehjcr/ytaa219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780489PMC
August 2020

Predictors and Prognostic Implications of Cardiac Arrhythmias in Patients Hospitalized for COVID-19.

J Clin Med 2021 Jan 2;10(1). Epub 2021 Jan 2.

Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.

Background: Cardiac manifestation of COVID-19 has been reported during the COVID pandemic. The role of cardiac arrhythmias in COVID-19 is insufficiently understood. This study assesses the incidence of cardiac arrhythmias and their prognostic implications in hospitalized COVID-19-patients.

Methods: A total of 166 patients from eight centers who were hospitalized for COVID-19 from 03/2020-06/2020 were included. Medical records were systematically analyzed for baseline characteristics, biomarkers, cardiac arrhythmias and clinical outcome parameters related to the index hospitalization. Predisposing risk factors for arrhythmias were identified. Furthermore, the influence of arrhythmia on the course of disease and related outcomes was assessed using univariate and multiple regression analyses.

Results: Arrhythmias were detected in 20.5% of patients. Atrial fibrillation was the most common arrhythmia. Age and cardiovascular disease were predictors for new-onset arrhythmia. Arrhythmia was associated with a pronounced increase in cardiac biomarkers, prolonged hospitalization, and admission to intensive- or intermediate-care-units, mechanical ventilation and in-hospital mortality. In multiple regression analyses, incident arrhythmia was strongly associated with duration of hospitalization and mechanical ventilation. Cardiovascular disease was associated with increased mortality.

Conclusions: Arrhythmia was the most common cardiac event in association with hospitalization for COVID-19. Older age and cardiovascular disease predisposed for arrhythmia during hospitalization. Whereas in-hospital mortality is affected by underlying cardiovascular conditions, arrhythmia during hospitalization for COVID-19 is independently associated with prolonged hospitalization and mechanical ventilation. Thus, incident arrhythmia may indicate a patient subgroup at risk for a severe course of disease.
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http://dx.doi.org/10.3390/jcm10010133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796041PMC
January 2021

Broken Heartstrings-Post-Traumatic Stress Disorder and Psychological Burden after Acute Mitral Regurgitation Due to Chordae Tendineae Rupture.

J Clin Med 2020 Dec 15;9(12). Epub 2020 Dec 15.

Center for Psychosocial Medicine, Department of General Internal Medicine and Psychosomatics, University Hospital of Heidelberg, University of Heidelberg, 69115 Heidelberg, Germany.

Chordae tendineae rupture (CTR) is a potentially life-threatening cardiac event often resulting in Acute mitral regurgitation (AMR). We assessed Post-traumatic stress disorder (PTSD), depression, and anxiety symptoms in n=21 CTR patients with AMR (age 82.3 ± 4.2 years; 66.7% men) and compared them to n=23 CTR patients with Chronic mitral regurgitation (CMR) and n=35 Myocardial infraction (MI) patients. Regression analyses revealed that PTSD scores were significantly higher in CTR patients with AMR than in CTR patients with CMR or MI patients. CTR patients with CMR had the lowest levels of PTSD-symptoms. Depression and anxiety scores were elevated across all three groups. Our results suggest that psychosocial factors need to be considered in CTR patients' care.
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http://dx.doi.org/10.3390/jcm9124048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765219PMC
December 2020

Initial experience with percutaneous mitral valve repair in patients with cardiac amyloidosis.

Eur J Clin Invest 2020 Dec 16:e13473. Epub 2020 Dec 16.

Division of Cardiology, Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany.

Background: Percutaneous mitral valve repair (PMVR) is a therapeutic option for severe mitral regurgitation (MR) in patients with heart failure due to differential aetiologies. However, only little is known about the safety and efficacy of this procedure in patients with amyloid cardiomyopathy.

Methods: Five patients with cardiac amyloidosis and moderate to severe or severe MR undergoing PMVR were analysed retrospectively and compared to seven patients with cardiac amyloidosis and severe MR without intervention. Clinical and functional data, renal function and cardiac biomarkers as well as established risk scores for cardiac amyloidosis were assessed. Primary endpoint was the reduction in MR one year after PMVR. Secondary endpoints were safety, overall mortality after 12 months compared with the control group, as well as changes in clinical and functional parameters.

Results: Amyloidosis risk assessment documented amyloid cardiomyopathy at an advanced stage in all patients. Procedural, technical and device success of PMVR were all 100% and residual MR remained mild to moderate at 12 months follow-up (P = .038 vs before PMVR). Differences in survival compared with the control (no PMVR) group pointed to a possible survival benefit in the PMVR group (P = .02).

Conclusion: PMVR is a feasible and safe procedure in patients with cardiac amyloidosis and might carry a possible survival benefit in this patient group.
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http://dx.doi.org/10.1111/eci.13473DOI Listing
December 2020

HDAC2-dependent remodeling of K2.2 (KCNN2) and K2.3 (KCNN3) K channels in atrial fibrillation with concomitant heart failure.

Life Sci 2021 Feb 10;266:118892. Epub 2020 Dec 10.

Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; HCR (Heidelberg Center for Heart Rhythm Disorders), University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.

Aims: Atrial fibrillation (AF) with concomitant heart failure (HF) is associated with prolonged atrial refractoriness. Small-conductance, calcium-activated K (K, KCNN) channels promote action potential (AP) repolarization. KCNN2 and KCNN3 variants are associated with AF risk. In addition, histone deacetylase (HDAC)-related epigenetic mechanisms have been implicated in AP regulation. We hypothesized that HDAC2-dependent remodeling of KCNN2 and KCNN3 expression contributes to atrial arrhythmogenesis in AF complicated by HF. The objectives were to assess HDAC2 and KCNN2/3 transcript levels in AF/HF patients and in a pig model, and to investigate cellular epigenetic effects of HDAC2 inactivation on KCNN expression.

Materials And Methods: HDAC2 and KCNN2/3 transcript levels were quantified in patients with AF and HF, and in a porcine model of atrial tachypacing-induced AF and reduced left ventricular function. Tachypacing and anti-Hdac2 siRNA treatment were employed in HL-1 atrial myocytes to study effects on KCNN2/3 mRNA and K protein abundance.

Key Findings: Atrial KCNN2 and KCNN3 expression was reduced in AF/HF patients and in a corresponding pig model. HDAC2 displayed significant downregulation in humans and a tendency towards reduced expression in right atrial tissue of pigs. Tachypacing recapitulated downregulation of Kcnn2/K2.2, Kcnn3/K2.3 and Hdac2/HDAC2, indicating that high atrial rates trigger epigenetic remodeling mechanisms. Finally, knock-down of Hdac2 in vitro reduced Kcnn3/K2.3 expression.

Significance: KCNN2/3 and HDAC2 expression is suppressed in AF complicated by HF. Hdac2 directly regulates Kcnn3 mRNA levels in atrial cells. The mechanistic and therapeutic significance of epigenetic electrophysiological effects in AF requires further validation.
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http://dx.doi.org/10.1016/j.lfs.2020.118892DOI Listing
February 2021

A Multi-Network Comparative Analysis of Transcriptome and Translatome Identifies Novel Hub Genes in Cardiac Remodeling.

Front Genet 2020 16;11:583124. Epub 2020 Nov 16.

Section of Bioinformatics and Systems Cardiology, Klaus Tschira Institute for Integrative Computational Cardiology, Heidelberg, Germany.

Our understanding of the transition from physiological to pathological cardiac hypertrophy remains elusive and largely based on reductionist hypotheses. Here, we profiled the translatomes of 15 mouse hearts to provide a molecular blueprint of altered gene networks in early cardiac remodeling. Using co-expression analysis, we showed how sub-networks are orchestrated into functional modules associated with pathological phenotypes. We discovered unappreciated hub genes, many undocumented for their role in cardiac hypertrophy, and genes in the transcriptional network that were rewired in the translational network, and associated with semantically different subsets of enriched functional terms, such as , a novel musculoskeletal modulator, or , implicated in protein quality control. Using their correlation structure, we found that transcriptome networks are only partially reproducible at the translatome level, providing further evidence of post-transcriptional control at the level of translation. Our results provide novel insights into the complexity of the organization of cardiac regulatory networks.
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http://dx.doi.org/10.3389/fgene.2020.583124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701244PMC
November 2020

Prognostic value of texture analysis from cardiac magnetic resonance imaging in patients with Takotsubo syndrome: a machine learning based proof-of-principle approach.

Sci Rep 2020 11 25;10(1):20537. Epub 2020 Nov 25.

Acute Cardiac Care, Andreas Grüntzig Heart Catheterization Laboratories, Department of Cardiology, University Heart Center, University Hospital Zurich, University of Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.

Cardiac magnetic resonance (CMR) imaging has become an important technique for non-invasive diagnosis of takotsubo syndrome (TTS). The long-term prognostic value of CMR imaging in TTS has not been fully elucidated yet. This study sought to evaluate the prognostic value of texture analysis (TA) based on CMR images in patients with TTS using machine learning. In this multicenter study (InterTAK Registry), we investigated CMR imaging data of 58 patients (56 women, mean age 68 ± 12 years) with TTS. CMR imaging was performed in the acute to subacute phase (median time after symptom onset 4 days) of TTS. TA of the left ventricle was performed using free-hand regions-of-interest in short axis late gadolinium-enhanced and on T2-weighted (T2w) images. A total of 608 TA features adding the parameters age, gender, and body mass index were included. Dimension reduction was performed removing TA features with poor intra-class correlation coefficients (ICC ≤ 0.6) and those being redundant (correlation matrix with Pearson correlation coefficient r > 0.8). Five common machine-learning classifiers (artificial neural network Multilayer Perceptron, decision tree J48, NaïveBayes, RandomForest, and Sequential Minimal Optimization) with tenfold cross-validation were applied to assess 5-year outcome including major adverse cardiac and cerebrovascular events (MACCE). Dimension reduction yielded 10 TA features carrying prognostic information, which were all based on T2w images. The NaïveBayes machine learning classifier showed overall best performance with a sensitivity of 82.9% (confidence interval (CI) 80-86.2), specificity of 83.7% (CI 75.7-92), and an area-under-the receiver operating characteristics curve of 0.88 (CI 0.83-0.92). This proof-of-principle study is the first to identify unique T2w-derived TA features that predict long-term outcome in patients with TTS. These features might serve as imaging prognostic biomarkers in TTS patients.
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http://dx.doi.org/10.1038/s41598-020-76432-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689426PMC
November 2020

CaM Kinase II-δ Is Required for Diabetic Hyperglycemia and Retinopathy but Not Nephropathy.

Diabetes 2021 Feb 25;70(2):616-626. Epub 2020 Nov 25.

Institute of Experimental Cardiology, Heidelberg University, Heidelberg, Germany

Type 2 diabetes has become a pandemic and leads to late diabetic complications of organs, including kidney and eye. Lowering hyperglycemia is the typical therapeutic goal in clinical medicine. However, hyperglycemia may only be a symptom of diabetes but not the sole cause of late diabetic complications; instead, other diabetes-related alterations could be causative. Here, we studied the role of CaM kinase II-δ (CaMKIIδ), which is known to be activated through diabetic metabolism. CaMKIIδ is expressed ubiquitously and might therefore affect several different organ systems. We crossed diabetic leptin receptor-mutant mice to mice lacking CaMKIIδ globally. Remarkably, CaMKIIδ-deficient diabetic mice did not develop hyperglycemia. As potential underlying mechanisms, we provide evidence for improved insulin sensing with increased glucose transport into skeletal muscle and also reduced hepatic glucose production. Despite normoglycemia, CaMKIIδ-deficient diabetic mice developed the full picture of diabetic nephropathy, but diabetic retinopathy was prevented. We also unmasked a retina-specific gene expression signature that might contribute to CaMKII-dependent retinal diabetic complications. These data challenge the clinical concept of normalizing hyperglycemia in diabetes as a causative treatment strategy for late diabetic complications and call for a more detailed analysis of intracellular metabolic signals in different diabetic organs.
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http://dx.doi.org/10.2337/db19-0659DOI Listing
February 2021

Prospective multicentric validation of a novel prediction model for paroxysmal atrial fibrillation.

Clin Res Cardiol 2020 Nov 19. Epub 2020 Nov 19.

Digital Health Center, Berlin Institute of Health (BIH) and Charité, Anna-Louisa-Karsch-Straße 2, 10178, Berlin, Germany.

Background: The early recognition of paroxysmal atrial fibrillation (pAF) is a major clinical challenge for preventing thromboembolic events. In this prospective and multicentric study we evaluated prediction scores for the presence of pAF, calculated from non-invasive medical history and echocardiographic parameters, in patients with unknown AF status.

Methods: The 12-parameter score with parameters age, LA diameter, aortic root diameter, LV,ESD, TDI A', heart frequency, sleep apnea, hyperlipidemia, type II diabetes, smoker, ß-blocker, catheter ablation, and the 4-parameter score with parameters age, LA diameter, aortic root diameter and TDI A' were tested. Presence of pAF was verified by continuous electrocardiogram (ECG) monitoring for up to 21 days in 305 patients.

Results: The 12-parameter score correctly predicted pAF in all 34 patients, in which pAF was newly detected by ECG monitoring. The 12- and 4-parameter scores showed sensitivities of 100% and 82% (95%-CI 65%, 93%), specificities of 75% (95%-CI 70%, 80%) and 67% (95%-CI 61%, 73%), and areas under the receiver operating characteristic (ROC) curves of 0.84 (95%-CI 0.80, 0.88) and 0.81 (95%-CI 0.74, 0.87). Furthermore, properties of AF episodes and durations of ECG monitoring necessary to detect pAF were analysed.

Conclusions: The prediction scores adequately detected pAF using variables readily available during routine cardiac assessment and echocardiography. The model scores, denoted as ECHO-AF scores, represent simple, highly sensitive and non-invasive tools for detecting pAF that can be easily implemented in the clinical practice and might serve as screening test to initiate further diagnostic investigations for validating the presence of pAF. Prospective validation of a novel prediction model for paroxysmal atrial fibrillation based on echocardiography and medical history parameters by long-term Holter ECG.
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http://dx.doi.org/10.1007/s00392-020-01773-zDOI Listing
November 2020

Feasibility of CardioSecur®, a Mobile 4-Electrode/22-Lead ECG Device, in the Prehospital Emergency Setting.

Front Cardiovasc Med 2020 9;7:551796. Epub 2020 Oct 9.

Department of Cardiology, Angiology, and Pneumology, University Hospital Heidelberg, Heidelberg, Germany.

This study explores the application of CardioSecur® (CS-ECG), a hand-held 4-electrode/22-lead ECG-device, in comparison with conventional 12-lead electrocardiogram (c12L-ECG) in patients with acute chest pain in the prehospital emergency setting. CS-ECG systems were provided for two physician-staffed emergency ambulances and parallel recordings of c12L-ECG and CS-ECG were obtained from all patients with acute chest pain. Treating emergency physicians were asked to evaluate the CS-ECG system with a standardized questionnaire. Following study completion, acquired ECGs were analyzed separately by two independent cardiologists blinded to all other medical records. Over a period of 20 months a total of 203 patients were included in our study. According to a standardized questionnaire, 79% of emergency medical professionals preferred application of CS-ECG, with 87% of teams judging CS-ECG to be beneficial for patients. Morover, 79% of physicians reported a reduction in time to definitive diagnosis with implementation of CS-ECG. The majority of professional users attested user-friendliness and feasibility of CS-ECG in terms of easy general handling (94%), application (93%), and placement of electrodes (98%). During prehospital triage, both c12L-ECG and CS-ECG correctly identified 31 (91%) patients with ST-elevation myocardial infarction (STEMI). In this first pilot study, implementation of the CardioSecur®-ECG system in the prehospital emergency setting demonstrated feasibility and user-friendliness so that emergency teams generally preferred CS-ECG to c12L-ECG. Diagnostic yield of CS-ECG was similar to c12L-ECG recordings.
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http://dx.doi.org/10.3389/fcvm.2020.551796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581708PMC
October 2020

Prognostic Value of Elevated Copeptin and High-Sensitivity Cardiac Troponin T in Patients with and without Acute Coronary Syndrome: The ConTrACS Study.

J Clin Med 2020 Nov 11;9(11). Epub 2020 Nov 11.

Department of Internal Medicine III, Heidelberg University Hospital, 69120 Heidelberg, Germany.

Aims: We aimed to assess the prognostic role of copeptin in patients presenting to the emergency department with acute symptoms and increased high-sensitivity cardiac troponin T.

Methods: A total of 3890 patients presenting with acute symptoms to the emergency department of Heidelberg University Hospital were assessed for increased hs-cTnT (>14 ng/L) from three cohorts: the Heidelberg Acute Coronary Syndrome (ACS) Registry ( = 2477), the BIOPS Registry ( = 320), and the ACS OMICS Registry ( = 1093). In a pooled analysis, 1956 patients remained, comprising of 1600 patients with ACS and 356 patients with non-ACS.

Results: Median follow-up was 1468 days in the ACS cohort and 709 days in the non-ACS cohort. Elevated copeptin levels (>10 pmol/L) were found in 1174 patients (60.0%) in the entire cohort (58.1% in ACS and 68.5% in non-ACS, respectively) and mortality rates were significantly higher than in patients with normal copeptin levels (29.0% vs. 10.7%, < 0.001). In a multivariate Cox regression, elevated copeptin was independently associated with all-cause death in the ACS (HR = 1.7, 1.3-2.3, = 0.002) and non-ACS cohort (HR = 2.7, 1.4-5.0, = 0.0018).

Conclusion: Copeptin may aid in identifying patients at risk for adverse outcomes in patients with increased levels of hs-cTnT in ACS patients and in non-ACS conditions.
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http://dx.doi.org/10.3390/jcm9113627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696893PMC
November 2020

cardiac pacemaker function of differentiated human mesenchymal stem cells from adipose tissue transplanted into porcine hearts.

World J Stem Cells 2020 Oct;12(10):1133-1151

Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg D-69120, Germany.

Background: Mesenchymal stem cells (MSC) modified by gene transfer to express cardiac pacemaker channels such as HCN2 or HCN4 were shown to elicit pacemaker function after intracardiac transplantation in experimental animal models. Human MSC derived from adipose tissue (haMSC) differentiate into cells with pacemaker properties , but little is known about their behavior after intracardiac transplantation.

Aim: To investigate whether haMSC elicit biological pacemaker function after transplantation into pig hearts.

Methods: haMSC under native conditions (nhaMSC) or after pre-conditioning by medium differentiation (dhaMSC) ( = 6 pigs each, 5 × 10 cells/animal) were injected into the porcine left ventricular free wall. Animals receiving PBS injection served as controls ( = 6). Four weeks later, total atrioventricular (AV)-block was induced by radiofrequency catheter ablation, and electronic pacemaker devices were implanted for backup stimulation and heart rate monitoring. Ventricular rate and rhythm of pigs were evaluated during a follow-up of 15 d post ablation by 12-lead-ECG with heart rate assessment, 24-h continuous rate monitoring recorded by electronic pacemaker, assessment of escape recovery time, and pharmacological challenge to address catecholaminergic rate response. Finally, hearts were analyzed by histological and immunohistochemical investigations.

Results: transplantation of dhaMSC into the left ventricular free wall of pigs elicited spontaneous and regular rhythms that were pace-mapped to ventricular injection sites (mean heart rate 72.2 ± 3.6 bpm; 6) after experimental total AV block. Ventricular rhythms were stably detected over a 15-d period and were sensitive to catecholaminergic stimulation (mean maximum heart rate 131.0 ± 6.2 bpm; 6; 0.001). Pigs, which received nhaMSC or PBS presented significantly lower ventricular rates (mean heart rates 47.2 ± 2.5 bpm and 37.4 ± 3.2 bpm, respectively; 6 each; < 0.001) and exhibited little sensitivity towards catecholaminergic stimulation (mean maximum heart rates 76.4 ± 3.1 bpm and 60.5 ± 3.1 bpm, respectively; 6 each; < 0.05). Histological and immunohistochemical evaluation of hearts treated with dhaMSC revealed local clusters of transplanted cells at the injection sites that lacked macrophage or lymphocyte infiltrations or tumor formation. Intense fluorescence signals at these sites indicated membrane expression of HCN4 and other pacemaker-specific proteins involved in cardiac automaticity and impulse propagation.

Conclusion: dhaMSC transplanted into pig left ventricles sustainably induced rate-responsive ventricular pacemaker activity after engraftment for four weeks. The data suggest that pre-conditioned MSC may further differentiate along a pacemaker-related lineage after myocardial integration and may establish superior pacemaker properties .
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http://dx.doi.org/10.4252/wjsc.v12.i10.1133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596441PMC
October 2020

MitraClip implantation followed by insertion of a left ventricular assist device in patients with advanced heart failure.

ESC Heart Fail 2020 Oct 26. Epub 2020 Oct 26.

Division of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg, 69120, Germany.

Aims: Mitral valve regurgitation (MR) is common in patients with advanced heart failure (HF). Percutaneous mitral valve repair (PMVR) via MitraClip (MC) has emerged as a feasible treatment strategy for these high-risk patients. However, as HF often further progresses, there is a frequent need for left ventricular assist device (LVAD) implantation in these patients. We aimed to investigate whether prior MC implantation affects the subsequent LVAD implantation and outcome.

Methods And Results: Thirty-seven patients with advanced HF and significant MR who underwent LVAD implantation were retrospectively analysed. Follow-up data were collected at 1 year after LVAD implantation. Primary endpoint was all-cause mortality. Secondary endpoint included peri-operative parameters and clinical development depicted as New York Heart Association (NYHA) class and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level. Seventeen patients initially received a MC device (MC group), resulting in a significant reduction in MR grade. After MC, NYHA class and INTERMACS level further worsened, leading to subsequent LVAD implantation after a median time of 475 days in the MC group. At LVAD implantation, overall characteristics were comparable with those of the patients undergoing LVAD implantation without prior MC placement (no-MC group). Procedural data revealed a higher incidence of right ventricular (RV) failure needing mechanical RV assistance and a longer need for nitric oxide ventilation in the MC group after LVAD implantation. One-year survival was slightly better in the no-MC group compared with the MC group [41% (n = 7/17) vs. 65% (n = 13/20); P = 0.15], albeit event-free survival was comparable between both groups, MC and no-MC.

Conclusions: LVAD implantation after MC is feasible and safe. However, in patients with advanced HF and severe MR, PMVR may only delay a needed LVAD implantation and thereby lead to poorer peri-operative RV function and impaired outcome. Arguably, these patients might benefit from the timely management of advanced HF by the means of early LVAD implantation or heart transplantation.
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http://dx.doi.org/10.1002/ehf2.12982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754960PMC
October 2020

The arrhythmogenic face of COVID-19: Brugada ECG pattern during acute infection.

Eur Heart J Case Rep 2020 Oct 30;4(FI1):1-2. Epub 2020 Jul 30.

Department of Cardiology, University of Heidelberg, Heidelberg, Germany.

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http://dx.doi.org/10.1093/ehjcr/ytaa230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454489PMC
October 2020

Effects of crowding in the emergency department on the diagnosis and management of suspected acute coronary syndrome using rapid algorithms: an observational study.

BMJ Open 2020 10 8;10(10):e041757. Epub 2020 Oct 8.

Department of Cardiology, Angiology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany

Objectives: Fast diagnostic algorithms using high-sensitivity troponin (hsTn) in suspected acute coronary syndrome (ACS) are regarded as beneficial to expedite diagnosis and safe discharge of patients in crowded emergency departments (ED). This study investigates the effects of crowding on process times related to the diagnostic protocol itself or other time delays, and outcomes.

Design: Prospective single-centre observational study.

Setting: ED (Germany).

Participants: Final study population of 2525 consecutive patients with suspected ACS within 12 months, after exclusion of patients with ST-elevation myocardial infarction, missing blood samples, referral from other hospitals or repeated visits.

Interventions: Use of fast algorithms as per 2015 European Society of Cardiology guidelines.

Main Outcome Measures: Crowding was defined as mismatch between patient numbers and monitoring capacities, or mean physician time per case, categorised as normal, high and very high crowding. Outcome measures were length of ED stay, direct discharge from ED, laboratory turn around times (TAT), utilisation of fast algorithms, absolute and relative non-laboratory time, as well as mortality.

Results: Crowding was associated with increased length of ED stay (3.75-4.89 hours, p<0.001). While median TAT of the first hsTnT increased (53-57 min, p<0.001), total TAT of serial hsTnT did not increase significantly with higher crowding (p=0.170). Lower utilisation of fast algorithms (p=0.009) and increase of additional hsTnT measurements after diagnosis (p=0.001) were observed in higher crowding. Most importantly, crowding was significantly associated with prolonged absolute (p<0.001), and particularly relative non-laboratory time (63.3%-71.3%, p<0.001). However, there was no significant effect of crowding on mortality, even after adjustment for relevant clinical variables.

Conclusions: Process times, and particularly non-laboratory times, are prolonged in a crowded ED diminishing some positive effects of fast diagnostic algorithms in suspected ACS. Higher crowding levels were not significantly associated with higher all-cause mortality rates.

Trial Registration Number: NCT03111862.
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http://dx.doi.org/10.1136/bmjopen-2020-041757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545662PMC
October 2020

Dual Functional States of R406W-Desmin Assembly Complexes Cause Cardiomyopathy With Severe Intercalated Disc Derangement in Humans and in Knock-In Mice.

Circulation 2020 Dec 7;142(22):2155-2171. Epub 2020 Oct 7.

Institute of Neuropathology (H.H., D.S., M.S., R.S.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany.

Background: Mutations in the human desmin gene cause myopathies and cardiomyopathies. This study aimed to elucidate molecular mechanisms initiated by the heterozygous R406W-desmin mutation in the development of a severe and early-onset cardiac phenotype.

Methods: We report an adolescent patient who underwent cardiac transplantation as a result of restrictive cardiomyopathy caused by a heterozygous R406W-desmin mutation. Sections of the explanted heart were analyzed with antibodies specific to 406W-desmin and to intercalated disc proteins. Effects of the R406W mutation on the molecular properties of desmin were addressed by cell transfection and in vitro assembly experiments. To prove the genuine deleterious effect of the mutation on heart tissue, we further generated and analyzed R405W-desmin knock-in mice harboring the orthologous form of the human R406W-desmin.

Results: Microscopic analysis of the explanted heart revealed desmin aggregates and the absence of desmin filaments at intercalated discs. Structural changes within intercalated discs were revealed by the abnormal organization of desmoplakin, plectin, N-cadherin, and connexin-43. Next-generation sequencing confirmed the variant c.1216C>T (p.R406W) as the sole disease-causing mutation. Cell transfection studies disclosed a dual behavior of R406W-desmin with both its integration into the endogenous intermediate filament system and segregation into protein aggregates. In vitro, R406W-desmin formed unusually thick filaments that organized into complex filament aggregates and fibrillar sheets. In contrast, assembly of equimolar mixtures of mutant and wild-type desmin generated chimeric filaments of seemingly normal morphology but with occasional prominent irregularities. Heterozygous and homozygous R405W-desmin knock-in mice develop both a myopathy and a cardiomyopathy. In particular, the main histopathologic results from the patient are recapitulated in the hearts from R405W-desmin knock-in mice of both genotypes. Moreover, whereas heterozygous knock-in mice have a normal life span, homozygous animals die at 3 months of age because of a smooth muscle-related gastrointestinal phenotype.

Conclusions: We demonstrate that R406W-desmin provokes its severe cardiotoxic potential by a novel pathomechanism, where the concurrent dual functional states of mutant desmin assembly complexes underlie the uncoupling of desmin filaments from intercalated discs and their structural disorganization.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050218DOI Listing
December 2020

Transcatheter or surgical aortic valve implantation in chronic dialysis patients: a German Aortic Valve Registry analysis.

Clin Res Cardiol 2021 Mar 23;110(3):357-367. Epub 2020 Sep 23.

Department of Cardiology, University Hospital Frankfurt am Main, Frankfurt, Germany.

Objectives: The aim of this study was to compare outcomes of transcatheter and surgical aortic valve implantation in chronic dialysis patients with aortic valve stenosis (AS).

Background: Chronic dialysis patients undergoing heart valve surgery are at higher risk for morbidity and mortality. Whether interventional techniques can reduce this risk is unclear because dialysis patients have thus far been excluded from randomized trials.

Methods: Chronic dialysis patients with AS enrolled in the German Aortic Valve Registry (GARY) between 2012 and 2015 were analyzed to compare transcatheter aortic valve implantation (TAVI n = 661) with surgical aortic valve replacement (SAVR n = 457). Propensity scores for inverse probability of treatment weighting (IPTW) were used to adjust the comparison of the two treatment groups for potential confounders.

Results: TAVI patients were older (78 ± 7.3 vs. 69 ± 10.2 years, p < 0.01, unadjusted) and had more comorbidities. Mortality at 1 year was the same (TAVI: 33.4% vs. SAVR 35.0%, p = 0.72, IPTW-adjusted) while it was lower with TAVI at 30 days (8.6% vs. 15.0%, p = 0.02, IPTW-adjusted). TAVI patients required more pacemaker implantation and showed more aortic regurgitation. SAVR patients required more blood transfusions and had longer hospital stay. Diabetes mellitus, atrial fibrillation, previous PCI, urgent procedure and EuroSCORE were associated with elevated 30-day mortality. Atrial fibrillation and older age were independent risk factor of 1-year mortality in both groups.

Conclusions: Chronic dialysis patients with AS undergoing TAVI or SAVR had the same 1-year mortality, although survival at 30 days was better with TAVI. These results suggest that TAVI may improve peri-procedural outcomes.
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http://dx.doi.org/10.1007/s00392-020-01717-7DOI Listing
March 2021

Reactive Oxidative Species-Modulated Ca Release Regulates β Integrin Activation on CD4 CD28 T Cells of Acute Coronary Syndrome Patients.

J Immunol 2020 Oct 16;205(8):2276-2286. Epub 2020 Sep 16.

Department of Cardiology, Heidelberg University Hospital, Ruprecht-Karls-University, D-69120 Heidelberg, Germany; and

The number and activity of T cell subsets in the atherosclerotic plaques are critical for the prognosis of patients with acute coronary syndrome. β Integrin activation is pivotal for T cell recruitment and correlates with future cardiac events. Despite this knowledge, differential regulation of adhesiveness in T cell subsets has not been explored yet. In this study, we show that in human T cells, SDF-1α-mediated β integrin activation is driven by a, so far, not-described reactive oxidative species (ROS)-regulated calcium influx. Furthermore, we show that CD4CD28 T cells represent a highly reactive subset showing 25-fold stronger β integrin activation upon SDF-1α stimulation compared with CD28 T cells. Interestingly, ROS-dependent Ca release was much more prevalent in the pathogenetically pivotal CD28 subset compared with the CD28 T cells, whereas the established mediators of the classical pathways for β integrin activation (PKC, PI3K, and PLC) were similarly activated in both T cell subsets. Thus, interference with the calcium flux attenuates spontaneous adhesion of CD28 T cells from acute coronary syndrome patients, and calcium ionophores abolished the observed differences in the adhesion properties between CD28 and CD28 T cells. Likewise, the adhesion of these T cell subsets was indistinguishable in the presence of exogenous ROS/HO Together, these data provide a molecular explanation of the role of ROS in pathogenesis of plaque destabilization.
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http://dx.doi.org/10.4049/jimmunol.2000327DOI Listing
October 2020

Relationship Between Cardiac Fibroblast Activation Protein Activity by Positron Emission Tomography and Cardiovascular Disease.

Circ Cardiovasc Imaging 2020 Sep 11;13(9):e010628. Epub 2020 Sep 11.

Department of Cardiology, Angiology, and Pneumology (M.B.H., F.R., D.F., H.A.K., F.L., L.H.L.), Heidelberg University Hospital, Germany.

Background: FAP (fibroblast activation protein) plays an important role in cardiac wound healing and remodeling. Although initially developed as a theranostic ligand for metastasized cancer, FAPI (FAP inhibitor) tracers have recently been used to study cardiac remodeling following myocardial infarction in small-animal models. The aim of the study was to evaluate the activity of FAP via FAPI-positron emission tomography-computed tomography scans in human hearts.

Methods: FAPI-positron emission tomography-computed tomography scans of 229 patients of 2 consecutive cohorts (modeling cohort: n=185; confirmatory cohort: n=44) suffering from metastasized cancer were analyzed applying the American Heart Association 17-segment model of the left ventricle. Logistic regression models were created using data from the modeling cohort. Multivariate regression models were established using Akaike information criterion in a step-down approach.

Results: Fourteen percent of patients had preexisting coronary artery disease (n=31), 33% arterial hypertension (n=75), and 12% diabetes mellitus type II (n=28). Forty-three percent had been treated with platin derivatives (n=100), 14% with anthracyclines (n=32), and 10% had a history of prior radiation to the chest (n=23). High left ventricular FAPI signals correlated with the presence of cardiovascular risk factors (odds ratio [OR], 4.3, =0.0029), a focal myocardial signal pattern (OR, 3.9, =0.0068), diabetes mellitus type II (OR, 4.1, =0.046), and beta-blocker use (OR, 3.8, =0.049) in univariate regression models. In a multivariate analysis, increased signal intensity was significantly higher in patients with cardiovascular risk factors (overweight [OR, 2.6, =0.023], diabetes mellitus type II [OR, 2.9, =0.041], certain chemotherapies [platinum derivatives; OR, 3.0, =0.034], and a history of radiation to the chest [OR, 3.5, =0.024]). A focal enrichment pattern was more frequently observed in patients with known cardiovascular risk factors (<0.0001).

Conclusions: FAPI-positron emission tomography-computed tomography scans represent a new imaging modality to investigate cardiac FAP. High signal intensities correlate with cardiovascular risk factors and metabolic disease.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.010628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497888PMC
September 2020

A Minimal-Invasive Approach for Standardized Induction of Myocardial Infarction in Mice.

Circ Res 2020 Oct 28;127(9):1214-1216. Epub 2020 Aug 28.

Department of Internal Medicine III, University of Heidelberg, Germany (F.S., Y.Z., L.L., M.H.K., H.A.K., F.L.).

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739440PMC
October 2020

COVID-19 among heart transplant recipients in Germany: a multicenter survey.

Clin Res Cardiol 2020 Dec 11;109(12):1531-1539. Epub 2020 Aug 11.

Department of Cardiology, Angiology and Pneumology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

Aims: Heart transplantation may represent a particular risk factor for severe coronavirus infectious disease 2019 (COVID-19) due to chronic immunosuppression and frequent comorbidities. We conducted a nation-wide survey of all heart transplant centers in Germany presenting the clinical characteristics of heart transplant recipients with COVID-19 during the first months of the pandemic in Germany.

Methods And Results: A multicenter survey of all heart transplant centers in Germany evaluating the current status of COVID-19 among adult heart transplant recipients was performed. A total of 21 heart transplant patients with COVID-19 was reported to the transplant centers during the first months of the pandemic in Germany. Mean patient age was 58.6 ± 12.3 years and 81.0% were male. Comorbidities included arterial hypertension (71.4%), dyslipidemia (71.4%), diabetes mellitus (33.3%), chronic kidney failure requiring dialysis (28.6%) and chronic-obstructive lung disease/asthma (19.0%). Most patients received an immunosuppressive drug regimen consisting of a calcineurin inhibitor (71.4%), mycophenolate mofetil (85.7%) and steroids (71.4%). Eight of 21 patients (38.1%) displayed a severe course needing invasive mechanical ventilation. Those patients showed a high mortality (87.5%) which was associated with right ventricular dysfunction (62.5% vs. 7.7%; p = 0.014), arrhythmias (50.0% vs. none; p = 0.012), and thromboembolic events (50.0% vs. none; p = 0.012). Elevated high-sensitivity cardiac troponin T- and N-terminal prohormone of brain natriuretic peptide were significantly associated with the severe form of COVID-19 (p = 0.017 and p < 0.001, respectively).

Conclusion: Severe course of COVID-19 was frequent in heart transplanted patients. High mortality was associated with right ventricular dysfunction, arrhythmias, thromboembolic events, and markedly elevated cardiac biomarkers.
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http://dx.doi.org/10.1007/s00392-020-01722-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418884PMC
December 2020

Ablation of Atrial Fibrillation in Patients with Hypertension-An Analysis from the German Ablation Registry.

J Clin Med 2020 Jul 27;9(8). Epub 2020 Jul 27.

Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.

Background: Hypertension (HTN) constitutes a risk factor for the development of atrial fibrillation (AF), as well as for thromboembolic and bleeding events. We analysed the outcome after catheter ablation of AF in HTN in a cohort from the prospective multicenter German Ablation Registry.

Methods: Between 03/2008 and 01/2010, 626 patients undergoing AF-ablation were analysed. Patients diagnosed with HTN ( = 386) were compared with patients without HTN ( = 240) with respect to baseline, procedural and long-term outcome parameters.

Results: Patients with HTN were older and more often presented with persistent forms of AF and cardiac comorbidities. Major and moderate in-hospital complications were low. At long-term follow-up, major cardiovascular events were rare in both groups. Rates of AF-recurrence, freedom from antiarrhythmic medication and repeat ablation were not statistically different between groups. Most patients reported improvement of symptoms and satisfaction with the treatment. However, patients with HTN more frequently complained of dyspnea of New York Heart Association (NYHA) class ≥ II and angina. They were more often rehospitalized, particularly when persistent AF had been diagnosed.

Conclusion: Catheter ablation of AF is associated with low complication rates and favorable arrhythmia-related results in patients with HTN. Residual clinical symptoms may be due to cardiac comorbidities and require additional attention in this important subgroup of AF-patients.
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http://dx.doi.org/10.3390/jcm9082402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463680PMC
July 2020