Publications by authors named "Boris Rudic"

54 Publications

Prediction of cardiac events with non-contrast magnetic resonance feature tracking in patients with ischaemic cardiomyopathy.

ESC Heart Fail 2021 Nov 24. Epub 2021 Nov 24.

1st Department of Medicine, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, Heidelberg, D-68167, Germany.

Aims: The aim of this study was to evaluate the prognostic value of feature tracking (FT) derived cardiac magnetic resonance (CMR) strain parameters of the left ventricle (LV)/right ventricle (RV) in ischaemic cardiomyopathy (ICM) patients treated with an implantable cardioverter-defibrillator (ICD). Current guidelines suggest a LV-ejection fraction ≤35% as major criterion for ICD implantation in ICM, but this is a poor predictor for arrhythmic events. Supplementary parameters are missing.

Methods And Results: Ischaemic cardiomyopathy patients (n = 242), who underwent CMR imaging prior to primary and secondary implantation of ICD, were classified depending on EF ≤ 35% (n = 188) or >35% (n = 54). FT parameters were derived from steady-state free precession cine views using dedicated software. The primary endpoint was a composite of cardiovascular mortality (CVM) and/or appropriate ICD therapy. There were no significant differences in FT-function or LV-/RV-function parameters in patients with an EF ≤ 35% correlating to the primary endpoint. In patients with EF > 35%, standard CMR functional parameters, such as LV-EF, did not reveal significant differences. However, significant differences in most FT parameters correlating to the primary endpoint were observed in this subgroup. LV-GLS (left ventricular-global longitudinal strain) and RV-GRS (right ventricular-global radial strain) revealed the best diagnostic performance in ROC curve analysis. The combination of LV-GLS and RV-GRS showed a sensitivity of 85% and a specificity of 76% for the prediction of future events.

Conclusions: The impact of FT derived measurements in the risk stratification of patients with ICM depends on LV function. The combination of LV-GLS/RV-GRS seems to be a predictor of cardiovascular mortality and/or appropriate ICD therapy in patients with EF > 35%.
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http://dx.doi.org/10.1002/ehf2.13712DOI Listing
November 2021

Implantation of cardiac electronic devices in active COVID-19 patients: Results from an international survey.

Heart Rhythm 2021 Oct 26. Epub 2021 Oct 26.

UCLA Cardiac Arrhythmia Center, Los Angeles, California.

Background: Cardiac implantable electronic device (CIED) implantation rates as well as the clinical and procedural characteristics and outcomes in patients with known active coronavirus disease 2019 (COVID-19) are unknown.

Objective: The purpose of this study was to gather information regarding CIED procedures during active COVID-19, performed with personal protective equipment, based on an international survey.

Methods: Fifty-three centers from 13 countries across 4 continents provided information on 166 patients with known active COVID-19 who underwent a CIED procedure.

Results: The CIED procedure rate in 133,655 hospitalized COVID-19 patients ranged from 0 to 16.2 per 1000 patients (P <.001). Most devices were implanted due to high-degree/complete atrioventricular block (112 [67.5%]) or sick sinus syndrome (31 [18.7%]). Of the 166 patients in the study survey, the 30-day complication rate was 13.9% and the 180-day mortality rate was 9.6%. One patient had a fatal outcome as a direct result of the procedure. Differences in patient and procedural characteristics and outcomes were found between Europe and North America. An older population (76.6 vs 66 years; P <.001) with a nonsignificant higher complication rate (16.5% vs 7.7%; P = .2) was observed in Europe vs North America, whereas higher rates of critically ill patients (33.3% vs 3.3%; P <.001) and mortality (26.9% vs 5%; P = .002) were observed in North America vs Europe.

Conclusion: CIED procedure rates during known active COVID-19 disease varied greatly, from 0 to 16.2 per 1000 hospitalized COVID-19 patients worldwide. Patients with active COVID-19 infection who underwent CIED implantation had high complication and mortality rates. Operators should take these risks into consideration before proceeding with CIED implantation in active COVID-19 patients.
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http://dx.doi.org/10.1016/j.hrthm.2021.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547796PMC
October 2021

[24-year-old man with successful resuscitation due to ventricular fibrillation without evident cause].

Herzschrittmacherther Elektrophysiol 2021 Dec 14;32(4):479-483. Epub 2021 Oct 14.

I. Medizinische Klinik, Universitätsmedizin Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Deutschland.

A 24-year-old man was resuscitated successfully after ventricular fibrillation. Structural heart disease and a primary channelopathy could not be identified despite extensive work-up, including molecular genetic testing. Three years after the initial event, ventricular fibrillation recurred and recording of the induction mechanism opened additional therapeutic options.
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http://dx.doi.org/10.1007/s00399-021-00811-1DOI Listing
December 2021

Recommendations regarding cardiac stereotactic body radiotherapy for treatment refractory ventricular tachycardia.

Heart Rhythm 2021 Dec 8;18(12):2137-2145. Epub 2021 Aug 8.

Department of Internal Medicine III, Section for Electrophysiology und Rhythmology, University Hospital Schleswig-Holstein, Kiel, Germany.

Background: Ventricular tachycardia (VT) is a potentially lethal complication of structural heart disease. Despite optimal management, a subgroup of patients continue to suffer from recurrent VT. Recently, cardiac stereotactic body radiotherapy (CSBRT) has been introduced as a treatment option in patients with VT refractory to antiarrhythmic drugs and catheter ablation.

Objective: The purpose of this study was to establish an expert consensus regarding the conduct and use of CSBRT for refractory VT.

Methods: We conducted a modified Delphi process. Thirteen experts from institutions from Germany and Switzerland participated in the modified Delphi process. Statements regarding the following topics were generated: treatment setting, institutional expertise and technical requirements, patient selection, target volume definition, and monitoring during and after CSBRT. Agreement was rated on a 5-point Likert scale. The strength of agreement was classified as strong agreement (≥80%), moderate agreement (≥66%) or no agreement (<66%).

Results: There was strong agreement regarding the experimental status of the procedure and the preference for treatment in clinical trials. CSBRT should be conducted at specialized centers with a strong expertise in the management of patients with ventricular arrhythmias and in stereotactic body radiotherapy for moving targets. CSBRT should be restricted to patients with refractory VT with optimal antiarrhythmic medication who underwent prior catheter ablation or have contraindications. Target volume delineation for CSBRT is complex. Therefore, interdisciplinary processes that should include cardiology/electrophysiology and radiation oncology as well as medical physics, radiology, and nuclear medicine are needed. Optimal follow-up is required.

Conclusion: Prospective trials and pooled registries are needed to gain further insight into this promising treatment option for patients with refractory VT.
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http://dx.doi.org/10.1016/j.hrthm.2021.08.004DOI Listing
December 2021

Cardiac Contractility Modulation in Patients with Ischemic versus Non-ischemic Cardiomyopathy: Results from the MAINTAINED Observational Study.

Int J Cardiol 2021 Nov 27;342:49-55. Epub 2021 Jul 27.

First Department of Medicine, University Medical Centre Mannheim (UMM), Faculty of Medicine Mannheim, University of Heidelberg, European Center for AngioScience (ECAS), and DZHK (German Center for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Mannheim, Germany. Electronic address:

Background: Cardiac contractility modulation (CCM) is an FDA-approved device-based therapy for patients with systolic heart failure and normal QRS width who are symptomatic despite optimal drug therapy. The purpose of this study was to compare the long-term therapeutic effects of CCM therapy in patients with ischemic (ICM) versus non-ischemic cardiomyopathy (NICM).

Methods: Changes in NYHA class, KDIGO CKD stage, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE), and NT-proBNP levels were compared as functional parameters. Moreover, observed mortality rates at 1 and 3 years were compared to those predicted by the MAGGIC heart failure risk score, and observed mortality rates were compared between groups for the entire follow-up period.

Results: One hundred and seventy-four consecutive patients with chronic heart failure and CCM device implantation between 2002 and 2019 were included in this retrospective analysis. LVEF was significantly higher in NICM patients after 3 years of CCM therapy (35 ± 9 vs. 30 ± 9%; p = 0.0211), and after 5 years, also TAPSE of NICM patients was significantly higher (21 ± 5 vs. 18 ± 5%; p = 0.0437). There were no differences in other effectiveness parameters. Over the entire follow-up period, 35% of all patients died (p = 0.81); only in ICM patients, mortality was lower than predicted at 3 years (35 vs. 43%, p = 0.0395).

Conclusions: Regarding improvement of biventricular systolic function, patients with NICM appear to benefit particularly from CCM therapy.
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http://dx.doi.org/10.1016/j.ijcard.2021.07.048DOI Listing
November 2021

Risk stratification of patients with Brugada syndrome: the impact of myocardial strain analysis using cardiac magnetic resonance feature tracking.

Hellenic J Cardiol 2021 Sep-Oct;62(5):329-338. Epub 2021 Jun 1.

First Department of Medicine, University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research) partner site Mannheim, Germany.

Objective: This study evaluated the prognostic significance of cardiac magnetic resonance myocardial feature tracking (CMR-FT) in patients with Brugada syndrome (BrS) to detect subclinical alterations and predict major adverse events (MAE).

Methods: CMR was performed in 106 patients with BrS and 25 healthy controls. Biventricular global strain analysis was assessed using CMR-FT. Patients were followed over a median of 11.6 [8.8 ± 13.8] years.

Results: The study cohort was subdivided according to the presence of a spontaneous type 1 ECG (sECG) into sBrS (BrS with sECG, n = 34 (32.1%)) and diBrS (BrS with drug-induced type 1 ECG, n = 72 (67.9%)). CMR-FT revealed morphological differences between sBrS and diBrS patients with regard to right ventricular (RV) strain (circumferential (%) (sBrS -7.9 ± 2.9 vs diBrS - 9.5 ± 3.1, p = 0.02) and radial (%) (sBrS 12.0 ± 4.3 vs diBrS 15.4 ± 5.4, p = 0.004)). During follow-up, MAE occurred in 11 patients (10.4%). Multivariable analysis was performed to identify independent predictors for the occurrence of events during follow-up. The strongest predictive value was found for RV circumferential strain (OR 3.2 (95% CI 1.4 - 6.9), p = 0.02) and RVOT/BSA (OR 3.1 (95% CI 1.0 - 7.0), p = 0.03).

Conclusions: Myocardial strain analysis detected early subclinical alterations, prior to apparent changes in myocardial function, in patients with BrS. While usual functional parameters were within the normal range, CMR-FT revealed pathological results in patients with an sECG. Moreover, RV circumferential strain and RVOT size provided additional prognostic information on the occurrence of MAE during follow-up, which reflects electrical vulnerability.
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http://dx.doi.org/10.1016/j.hjc.2021.05.003DOI Listing
November 2021

Extent of peri-infarct scar on late gadolinium enhancement cardiac magnetic resonance imaging and outcome in patients with ischemic cardiomyopathy.

Heart Rhythm 2021 06 28;18(6):954-961. Epub 2021 Jan 28.

Department of Medicine, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany; DZHK (German Centre for Cardiovascular Research) partner site, Mannheim, Germany.

Background: Only a minority of patients who receive an implantable cardioverter-defibrillator (ICD) on the basis of left ventricular ejection fraction receive appropriate ICD therapy. Peri-infarct scar zone assessed by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) is a possible substrate for ventricular tachyarrhytmias (VTAs).

Objective: The aim of our prospective study was to determine whether LGE-CMR parameters can predict the occurrence of VTA in patients with ischemic cardiomyopathy (ICM).

Methods: Two hundred sixteen patients with ICM underwent CMR imaging before primary or secondary ICD implantation and were prospectively followed. We assessed CMR indices and CMR scar characteristics (infarct core and peri-infarct zone) to predict outcome and VTAs.

Results: Patients were followed up for 1497 days (interquartile range 697-2237 days). Forty-seven patients (21%) received appropriate therapy during follow-up. Patients with appropriate ICD therapy had smaller core scar (31.5% ± 8.5% vs 36.8% ± 8.9%; P = .0004) but larger peri-infarct scar (12.4% ± 2.6% vs 10.5% ± 2.9%; P = .0001) than did patients without appropriate therapy. In multivariate Cox regression analysis, peri-infarct scar (hazard ratio 1.15; 95% confidence interval 1.07-1.24; P = .0001) was independently and significantly associated with VTAs whereas left ventricular ejection fraction, right ventricular ejection fraction, core scar, and left atrial ejection fraction were not.

Conclusion: Scar extent of peri-infarct border zone was significantly associated with appropriate ICD therapy. Thus, LGE-CMR parameters can identify a subgroup of patients with ICM and an increased risk of life-threatening VTAs.
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http://dx.doi.org/10.1016/j.hrthm.2021.01.023DOI Listing
June 2021

Interdisciplinary Clinical Target Volume Generation for Cardiac Radioablation: Multicenter Benchmarking for the RAdiosurgery for VENtricular TAchycardia (RAVENTA) Trial.

Int J Radiat Oncol Biol Phys 2021 07 27;110(3):745-756. Epub 2021 Jan 27.

I. Medizinische Klinik, Universitätsklinikum Mannheim and German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Mannheim, Germany.

Purpose: Cardiac radioablation is a novel treatment option for therapy-refractory ventricular tachycardia (VT) ineligible for catheter ablation. Three-dimensional clinical target volume (CTV) definition is a key step, and this complex interdisciplinary procedure includes VT-substrate identification based on electroanatomical mapping (EAM) and its transfer to the planning computed tomography (PCT). Benchmarking of this process is necessary for multicenter clinical studies such as the RAVENTA trial.

Methods And Materials: For benchmarking of the RAVENTA trial, patient data (epicrisis, electrocardiogram, high-resolution EAM, contrast-enhanced cardiac computed tomography, PCT) of 3 cases were sent to 5 university centers for independent CTV generation, subsequent structure analysis, and consensus finding. VT substrates were first defined on multiple EAM screenshots/videos and manually transferred to the PCT. The generated structure characteristics were then independently analyzed (volume, localization, surface distance and conformity). After subsequent discussion, consensus structures were defined.

Results: VT substrate on the EAM showed visible variability in extent and localization for cases 1 and 2 and only minor variability for case 3. CTVs ranged from 6.7 to 22.9 cm, 5.9 to 79.9 cm, and 9.4 to 34.3 cm; surface area varied from 1087 to 3285 mm, 1077 to 9500 mm, and 1620 to 4179 mm, with a Hausdorff-distance of 15.7 to 39.5 mm, 23.1 to 43.5 mm, and 15.9 to 43.9 mm for cases 1 to 3, respectively. The absolute 3-dimensional center-of-mass difference was 5.8 to 28.0 mm, 8.4 to 26 mm, and 3.8 to 35.1 mm for cases 1 to 3, respectively. The entire process resulted in CTV structures with a conformity index of 0.2 to 0.83, 0.02 to 0.85, and 0.02 to 0.88 (ideal 1) with the consensus CTV as reference.

Conclusions: Multicenter efficacy endpoint assessment of cardiac radioablation for therapy-refractory VT requires consistent CTV transfer methods from the EAM to the PCT. VT substrate definition and CTVs were comparable with current clinical practice. Remarkable differences regarding the degree of agreement of the CTV definition on the EAM and the PCT were noted, indicating a loss of agreement during the transfer process between EAM and PCT. Cardiac radioablation should be performed under well-defined protocols and in clinical trials with benchmarking and consensus forming.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.028DOI Listing
July 2021

Corrigendum to "Interaction between CIEDs and modern radiotherapy techniques: Flattening filter free-VMAT, dose-rate effects, scatter radiation, and neutron-generating energies" [Radiother Oncol 152 (2020) 196-202].

Radiother Oncol 2021 Jan 18;154:291. Epub 2021 Jan 18.

First Department of Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany; DZHK (German Centre for Cardiovascular Research) partner site, Mannheim, Germany.

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http://dx.doi.org/10.1016/j.radonc.2020.12.023DOI Listing
January 2021

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Genet Med 2021 01 7;23(1):47-58. Epub 2020 Sep 7.

Member of the European Reference Network for rare, low prevalence and/or complex diseases of the heart: ERN GUARD-Heart, Amsterdam, Netherlands.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.

Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.

Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

Comparison of transvenous vs subcutaneous defibrillator therapy in patients with cardiac arrhythmia syndromes and genetic cardiomyopathies.

Int J Cardiol 2021 01 29;323:100-105. Epub 2020 Aug 29.

1st Department of Medicine - Cardiology, University Medical Centre Mannheim, Germany; Partner Site Heidelberg/Mannheim, German Center for Cardiovascular Research (DZHK), Mannheim, Germany. Electronic address:

Background: Inherited arrhythmia syndromes and genetic cardiomyopathies attribute in a significant proportion to sudden cardiac death. Implantable cardioverter defibrillators (ICDs) are the cornerstone in the prevention of sudden death in high-risk patients. However, ICD therapy is also associated with high rates of inappropriate shocks and/or device-related complications especially in young patients.

Objective: To determine the outcome of high-risk patients with inherited arrhythmia syndromes and genetic cardiomyopathies comparing two defibrillator technologies.

Method: Between 2010 and 2018, 183 consecutive patients from two large German tertiary care centers were enrolled in the study. The majority of patients (83%) had either cardiac channelopathies or idiopathic ventricular fibrillation without cardiac structural abnormalities, while the remaining 17% had a genetic cardiomyopathy (HCM/ARVC). Eighty-six patients (47%) received a transvenous ICD (TV-ICD), while a subcutaneous ICD (S-ICD) was implanted in another 97 patients (53%).

Results: During a mean follow-up of 4.3 years, 30 patients had an appropriate ICD therapy (annual rate 3.8%). Fifteen patients experienced an inappropriate shock (annual rate 1.9%). Lead failure occurred in 17 (9%) patients and was less frequent in the S-ICD group (OR 0.48, 95%CI 0.38-0.62). Adverse defibrillator events, defined as a composite of inappropriate shocks and lead failure requiring surgical revision were significantly lower in the S-ICD group as compared to the TV-ICD group (OR 0.55, 95%CI 0.41-0.72). There was a non-significant trend towards lower appropriate shocks in the S-ICD group, that in combination with all-cause shocks yielded in a significantly higher freedom of any shock in the S-ICD group (RR 39%, p = 0.003). No deaths occurred during follow-up.

Conclusion: The present data favor the use of the subcutaneous ICD for patients with inherited arrhythmia syndromes and genetic cardiomyopathies who do not need anti-bradycardia pacing.
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http://dx.doi.org/10.1016/j.ijcard.2020.08.089DOI Listing
January 2021

Risk stratification in families with history of idiopathic ventricular fibrillation.

HeartRhythm Case Rep 2020 Jul 29;6(7):386-389. Epub 2020 Mar 29.

First Department of Medicine-Cardiology, University Medical Centre Mannheim, Mannheim, Germany, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Mannheim, Germany.

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http://dx.doi.org/10.1016/j.hrcr.2020.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360980PMC
July 2020

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Circulation 2020 07 20;142(4):324-338. Epub 2020 May 20.

Masonic Medical Research Institute, Utica, NY (R.P.).

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.

Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.

Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (<5×10) near , , and , and 1 missense variant in (p.Asp85Asn) at the suggestive threshold (<10). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r=0.40; =3.2×10). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (<0.005).

Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382531PMC
July 2020

Radiosurgery for ventricular tachycardia: preclinical and clinical evidence and study design for a German multi-center multi-platform feasibility trial (RAVENTA).

Clin Res Cardiol 2020 Nov 18;109(11):1319-1332. Epub 2020 Apr 18.

Klinik für Innere Medizin III, Abteilung für Elektrophysiologie und Rhythmologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Background: Single-session high-dose stereotactic radiotherapy (radiosurgery) is a new treatment option for otherwise untreatable patients suffering from refractory ventricular tachycardia (VT). In the initial single-center case studies and feasibility trials, cardiac radiosurgery has led to significant reductions of VT burden with limited toxicities. However, the full safety profile remains largely unknown.

Methods/design: In this multi-center, multi-platform clinical feasibility trial which we plan is to assess the initial safety profile of radiosurgery for ventricular tachycardia (RAVENTA). High-precision image-guided single-session radiosurgery with 25 Gy will be delivered to the VT substrate determined by high-definition endocardial electrophysiological mapping. The primary endpoint is safety in terms of successful dose delivery without severe treatment-related side effects in the first 30 days after radiosurgery. Secondary endpoints are the assessment of VT burden, reduction of implantable cardioverter defibrillator (ICD) interventions [shock, anti-tachycardia pacing (ATP)], mid-term side effects and quality-of-life (QoL) in the first year after radiosurgery. The planned sample size is 20 patients with the goal of demonstrating safety and feasibility of cardiac radiosurgery in ≥ 70% of the patients. Quality assurance is provided by initial contouring and planning benchmark studies, joint multi-center treatment decisions, sequential patient safety evaluations, interim analyses, independent monitoring, and a dedicated data and safety monitoring board.

Discussion: RAVENTA will be the first study to provide the initial robust multi-center multi-platform prospective data on the therapeutic value of cardiac radiosurgery for ventricular tachycardia.

Trial Registration Number: NCT03867747 (clinicaltrials.gov). Registered March 8, 2019. The study was initiated on November 18th, 2019, and is currently recruiting patients.
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http://dx.doi.org/10.1007/s00392-020-01650-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588361PMC
November 2020

Extent of Late Gadolinium Enhancement Predicts Thromboembolic Events in Patients With Hypertrophic Cardiomyopathy.

Circ J 2020 04 1;84(5):754-762. Epub 2020 Apr 1.

1st Department of Medicine Cardiology, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg.

Background: Thromboembolic complications such as ischemic stroke or peripheral arterial thromboembolism are known complications in hypertrophic cardiomyopathy (HCM). We sought to assess the clinical and cardiovascular magnetic resonance (CMR) characteristics of patients with HCM suffering from thromboembolic events and analyzed the predictors of these unfavorable outcomes.Methods and Results:The 115 HCM patients underwent late gadolinium enhanced (LGE) CMR and were included in the study. Follow-up was 5.6±3.6 years. The primary endpoint was the occurrence of thromboembolic events (ischemic stroke or peripheral arterial thromboembolism). It occurred in 17 (14.8%) patients (event group, EG), of whom 64.7% (11) were men. During follow-up, 10 (8.7%) patients died. Patients in the EG showed more comorbidities, such as heart failure (EG 41.2% vs. NEG (non-event group) 14.3%, P<0.01) and atrial fibrillation (AF: EG 70.6% vs. NEG 36.7%, P<0.01). Left atrial end-diastolic volume was significantly higher in the EG (EG 73±24 vs. NEG 50±33 mL/m, P<0.01). Both the presence and extent of LGE were enhanced in the EG (extent% EG 23±15% vs. NEG 8±9%, P<0.0001). No patient without LGE experienced a thromboembolic event. Multivariate analysis revealed AF and LGE extent as independent predictors.

Conclusions: LGE extent (>14.4%) is an independent predictor for thromboembolic complications in patients with HCM and might therefore be considered as an important risk marker. The risk for thromboembolic events is significantly elevated if accompanied by AF.
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http://dx.doi.org/10.1253/circj.CJ-19-0936DOI Listing
April 2020

Incidence, mechanisms, and clinical impact of inappropriate shocks in patients with a subcutaneous defibrillator.

Europace 2020 05;22(5):761-768

1st Department of Medicine - Cardiology, University Medical Centre Mannheim, D-68167 Mannheim, Germany.

Aims: Inappropriate shocks (IAS) remain a challenge for patients and physicians after implantation of the subcutaneous implantable cardioverter-defibrillator (S-ICD). The aims were to assess and characterize different patterns of IAS.

Methods And Results: Two hundred and thirty-nine patients were implanted with an S-ICD between 2010 and 2018 for primary and secondary prevention. Follow-up data of at least 6 months were analysed. During a mean follow-up of 34.9 ± 16.0 months, a total of 73 shocks occurred in 38 patients (6%). Forty-three (59%) shocks were considered appropriate due to ventricular tachycardia/ventricular fibrillation, while 30 (41%) were inappropriate and occurred in 19 patients (8%). Myopotentials/noise was the most frequent cause of inappropriate shocks (n = 8), followed by T-wave oversensing (n = 6) and undersensing of the QRS, resulting in adaptation of the automatic gain control and inappropriate shock (n = 5). Seventy-four percent of all IAS occurred on the primary vector, while no IAS occurred on the alternate vector. In seven of eight patients (88%), IAS related to myopotentials have occurred on the primary sensing vector. Multivariate analysis identified taller patients, primary sensing vector and first-generation S-ICD device as predictors for IAS. SMART pass effectively reduced the occurrence of IAS in the second-generation S-ICD system.

Conclusion: Inappropriate therapies are less frequently observed on the alternate vector. The primary vector seems to be unfavourable with regard to oversensing caused by myopotentials. Inappropriate shocks were associated with an increased rate of rehospitalization but not mortality. These observations have implications for the prevention of inappropriate S-ICD shocks.
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http://dx.doi.org/10.1093/europace/euaa026DOI Listing
May 2020

Interaction between CIEDs and modern radiotherapy techniques: Flattening filter free-VMAT, dose-rate effects, scatter radiation, and neutron-generating energies.

Radiother Oncol 2020 11 20;152:196-202. Epub 2020 Jan 20.

First Department of Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany; DZHK (German Centre for Cardiovascular Research) partner site, Mannheim, Germany.

Background And Purpose: Providing evidence for radiotherapy (RT)-induced effects on cardiac implantable electric devices (CIEDs) with focus on flattening filter free-volumetric modulated arc therapy (FFF-VMAT) at 6 and 10 MV as well as 3D-conformal radiotherapy (3D-CRT) at 18 MV.

Materials And Methods: 68 CIEDs (64 implantable cardioverter-defibrillators (ICDs) and 4 cardiac pacemakers (PMs)) were located on the left chest position on a slab phantom and irradiated under telemetrical surveillance either directly, or distant to 3D-CRT or FFF-VMAT, dose-rate 2500 cGy/min, and target dose of 150 Gy. Devices were placed within, close by (2.5 cm and 5 cm), and distant (35 cm) to the radiation field. Scatter radiation (SR) and photon neutrons (PN) were recorded. CIEDs were investigated in following groups: 1a) 18 MV 3D-CRT - 4 ICDs/4 PMs out of radiation field, 1b) 18 MV open field - 4 ICDs/4 PMs within radiation field, 2) 6 MV FFF-VMAT, 15 ICDs in 35 cm distance to VMAT, 3) 10 MV-FFF VMAT, 15 ICDs in 35 cm distance to VMAT, 4) 6 MV FFF-VMAT, 15 ICDs in 2.5 cm distance to VMAT, 5) 10 MV FFF-VMAT, 15 ICDs in 2.5 cm distance to VMAT.

Results: No incidents occurred at 6 MV FFF. 10 MV FFF-VMAT and 18 MV 3D-CRT resulted in data loss, reset, and erroneous sensing with inhibition of pacing (leading to inadequate defibrillation) in 8/34 ICDs and 2/4 PMs which were not located within radiation. Direct radiation triggered instantaneous defibrillation in 3/4 ICDs.

Conclusions: 6 MV FFF-VMAT is safe even at high dose-rates of 2500 cGy/min, regardless whether CIEDs are located close (2.5 cm) or distant (35 cm) to the radiation beam. CIEDs should never be placed within radiation and energy should always be limited to 6 MV. At 6 MV, VMAT at high dose-rates can be used to treat tumors, which are located close to CIEDs.
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http://dx.doi.org/10.1016/j.radonc.2019.12.007DOI Listing
November 2020

Ventricular conduction delay as marker of risk in Brugada Syndrome. Results from the analysis of clinical and electrocardiographic features of a large cohort of patients.

Int J Cardiol 2020 03 18;302:171-177. Epub 2019 Nov 18.

Division of Cardiology, University of Torino, Department of Medical Sciences, "Città della Salute e della Scienza" Hospital, Torino, Italy.

Background: Brugada Syndrome is a genetic arrhythmogenic disease with a variable clinical spectrum. The role of clinical and ECG parameters in the risk stratification is still uncertain.

Aims: In a large cohort of Brugada patients we analysed clinical and ECG features to determine the variables with prognostic value for the occurrence of a first documented arrhythmic event and for recurrences.

Methods: We enrolled 614 patients, subdivided into 3 groups according to their clinical presentation: 531 (88%) asymptomatic, 69 (10%) with previous unexplained syncope and 14 (2%) with aborted sudden death. We also compared the ECG characteristics of patients with a single documented arrhythmic event (either at presentation or at follow-up, 17 patients), with those of patients with arrhythmic recurrences (13 patients).

Results: The event rate was 1.3% in the asymptomatic patients and 15% among patients with unexplained syncope (median follow-up 6 years), p < 0.0001. In both groups a QRS duration ≥110 ms in lead II and/or V6 and/or S wave duration ≥40 ms in lead I and/or II were significant risk factors for the occurrence and timing of events at follow-up. The same ECG risk factors were also significantly associated with arrhythmic recurrences.

Conclusions: The arrhythmic risk of Brugada patients is related not only to the symptoms at presentation, but also to the presence of a ventricular conduction delay (QRS duration ≥ 110 ms and/or S wave duration ≥ 40 ms). The ECG conduction parameters also affect the timing of events and recurrences.
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http://dx.doi.org/10.1016/j.ijcard.2019.11.121DOI Listing
March 2020

Clinical Profile and Long-Term Follow-Up of Children with Brugada Syndrome.

Pediatr Cardiol 2020 Feb 20;41(2):290-296. Epub 2019 Nov 20.

First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Brugada syndrome (BrS) is a rare channelopathy associated with sudden cardiac death (SCD). Although outcome data of adult cohorts are well known, information on children are lacking. The aim of the present study was to analyze the clinical profile, treatment approach and long-term outcome of children affected with BrS. After a systematic review of the literature compiled from a thorough database search (PubMed, Web of Science, Cochrane Libary, Cinahl), data from a total of 4 studies which included 262 BrS patients were identified. The mean age of patients was 12.1 ± 5.5, 53.8% males and 19.8% spontaneous BrS type I. 80.2% of patients presented BrS ECG I after receiving sodium channel blockers. 76% of these patients were asymptomatic while only 17.9% suffered from recurrent syncope. Around 1.5% of the patients were admitted due to aborted SCD, and 3% suffered from atrial arrhythmias. Electrophysiological work-up was performed in 132 patients. Induction of ventricular tachycardia/ventricular fibrillation using programmed ventricular stimulation was inducible in 16 patients. 56 children received an ICD. 11 patients received quinidine. An electrical storm was documented in 1 patient. Appropriate shocks occured in 16% of the patients over a median follow-up period of 62.2 (54-64). ICD-related complications were observed in 11 patients (19.6%) with a predominance of inappropriate shocks and lead failure and/or fracture. Although BrS in the childhood is rare, diagnosis and management continues to be challenging. ICD therapy is an effective therapy in high-risk children with BrS, however, with relevant ICD-related complications.
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http://dx.doi.org/10.1007/s00246-019-02254-5DOI Listing
February 2020

Defibrillation failure in patients undergoing replacement of subcutaneous defibrillator pulse generator.

Heart Rhythm 2020 03 25;17(3):455-459. Epub 2019 Oct 25.

1(st) Department of Medicine-Cardiology, University Medical Centre Mannheim, Mannheim, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, Mannheim, Germany.

Background: Defibrillation threshold (DFT) testing is commonly performed in patients undergoing subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation. Growing evidence indicates that successful DFT testing correlates with the technique used for implantation of the defibrillation lead and pulse generator. However, evidence on whether DFT testing should be performed in patients undergoing S-ICD pulse generator replacement is lacking.

Objective: The purpose of this study was to determine the outcome of DFT testing in patients undergoing replacement of an S-ICD pulse generator.

Methods: A total of 357 S-ICD implantations were performed between November 2010 and July 2019. Twenty-five consecutive patients underwent S-ICD replacement between 2015 and 2019. Clinical data, perioperative medication, technical measurements, and PRAETORIAN score were assessed and grouped according to the outcome of DFT testing.

Results: In 5 of 25 patients (20%), induced ventricular fibrillation was not successfully terminated after the first or second 65-J shock after pulse generator replacement with need for external defibrillation. Repositioning of the pulse generator and/or capsulectomy at the pocket site were necessary to achieve effective DFT with 65 J in all cases. Shock impedance increased in all patients at the time of pulse generator replacement compared to first implantation and was significantly higher in patients with ineffective DFT (119 ± 17 Ω vs 93 ± 26 Ω; P = .03). Otherwise, no differences in clinical characteristics, comorbidities, body mass index, intraoperative medication, or PRAETORIAN score were predictive of defibrillation failure.

Conclusion: The high proportion of patients with DFT failure after S-ICD pulse generator replacement indicates that DFT testing is mandatory to ensure safe function of the S-ICD.
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http://dx.doi.org/10.1016/j.hrthm.2019.10.024DOI Listing
March 2020

Implantable cardioverter-defibrillators in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia resuscitated from sudden cardiac arrest.

Eur Heart J 2019 09;40(35):2953-2961

Department of Cardiology, Centre for Cardiological Innovation, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, Oslo, Norway.

Aims: In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), implantable cardioverter-defibrillator (ICD) shocks are sometimes ineffective and may even trigger fatal electrical storms. We assessed the efficacy and complications of ICDs placed in patients with CPVT who presented with a sentinel event of sudden cardiac arrest (SCA) while undiagnosed and therefore untreated.

Methods And Results: We analysed 136 patients who presented with SCA and in whom CPVT was diagnosed subsequently, leading to the initiation of guideline-directed therapy, including β-blockers, flecainide, and/or left cardiac sympathetic denervation. An ICD was implanted in 79 patients (58.1%). The primary outcome of the study was sudden cardiac death (SCD). The secondary outcomes were composite outcomes of SCD, SCA, appropriate ICD shocks, and syncope. After a median follow-up of 4.8 years, SCD had occurred in three patients (3.8%) with an ICD and none of the patients without an ICD (P = 0.1). SCD, SCA, or appropriate ICD shocks occurred in 37 patients (46.8%) with an ICD and 9 patients (15.8%) without an ICD (P < 0.0001). Inappropriate ICD shocks occurred in 19 patients (24.7%) and other device-related complications in 22 patients (28.9%).

Conclusion: In previously undiagnosed patients with CPVT who presented with SCA, an ICD was not associated with improved survival. Instead, the ICD was associated with both a high rate of appropriate ICD shocks and inappropriate ICD shocks along with other device-related complications. Strict adherence to guideline-directed therapy without an ICD may provide adequate protection in these patients without all the potential disadvantages of an ICD.
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http://dx.doi.org/10.1093/eurheartj/ehz309DOI Listing
September 2019

A cellular model of Brugada syndrome with SCN10A variants using human-induced pluripotent stem cell-derived cardiomyocytes.

Europace 2019 Sep;21(9):1410-1421

First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, Mannheim, Germany.

Aims: Brugada syndrome (BrS) is associated with a pronounced risk to develop sudden cardiac death (SCD). Up to 21% of patients are related to mutations in SCN5A. Studies identified SCN10A as a contributor of BrS. However, the investigation of the human cellular phenotype of BrS in the presence of SCN10A mutations remains lacking. The objective of this study was to establish a cellular model of BrS in presence of SCN10A mutations using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).

Methods And Results: Dermal fibroblasts obtained from a BrS patient suffering from SCD harbouring the SCN10A double variants (c.3803G>A and c.3749G>A) and three independent healthy control subjects were reprogrammed to hiPSCs. Human-induced pluripotent stem cells were differentiated into cardiomyocytes (hiPSC-CMs).The hiPSC-CMs from the BrS patient showed a significantly reduced peak sodium channel current (INa) and a significantly reduced ATX II (sea anemone toxin, an enhancer of late INa) sensitive as well as A-887826 (a blocker of SCN10A channel) sensitive late sodium channel current (INa) when compared with the healthy control hiPSC-CMs, indicating loss-of-function of sodium channels. Consistent with reduced INa the action potential amplitude and upstroke velocity (Vmax) were significantly reduced, which may contribute to arrhythmogenesis of BrS. Moreover, Ajmaline effects on action potentials were stronger in BrS-hiPSC-CMs than in healthy control cells. This is in agreement with the higher susceptibility of patients to sodium channel blocking drugs in unmasking BrS.

Conclusion: Patient-specific hiPSC-CMs are able to recapitulate single-cell phenotype features of BrS with SCN10A mutations and may provide novel opportunities to further elucidate the cellular disease mechanism.
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http://dx.doi.org/10.1093/europace/euz122DOI Listing
September 2019

Cardioprotective Effects of Dronedarone Mediated by the Influence on the Expression of Urokinase-Type Plasminogen Activator Receptor.

J Vasc Res 2019 10;56(2):92-96. Epub 2019 May 10.

First Department of Medicine, University Medical Centre Mannheim (UMM), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany,

Purpose: Dronedarone is a multichannel-blocking antiarrhythmic drug for the treatment of atrial fibrillation. Observational data hypothesized a cardioprotective effect. In an in vitro endothelial cell-platelet model, we evaluated the molecular atheroprotective effects of dronedarone.

Methods: Following a 24-h incubation of human umbilical vein endothelial cells (HUVECs) with dronedarone (concentration 50, 100, and 150 ng/mL), they were then stimulated for 1 h with lipopolysaccharide (LPS) and were subsequently incubated in direct contact with thrombin-activated platelets. After incubation, the expression of CD40L and CD62P on platelets, and the expression of ICAM-1, VCAM-1, urokinase-type plasminogen activator receptor (uPAR), and membrane type 1 matrix metalloproteinase (MT1-MMP) on endothelial cells were measured by flow cytometry.

Results: Preincubation with 150 ng/mL of dronedarone reduced the expression of uPAR on endothelial cells after proinflammatory stimulation with LPS and also by direct endothelial contact with activated platelets (p = 0.0038). In contrast, the expression of CD40L and CD62P on platelets after proinflammatory stimulation with thrombin was significantly increased through direct preincubation with 50/100/150 ng/mL of dronedarone. However, dronedarone had no effects on the expression of MT1-MMP and ICAM-1 in HUVECs.

Conclusion: In this in vitro analysis, dronedarone directly increased platelet activation but showed significant direct effects on endothelial cells and indirect effects on platelets on selected markers of atherosclerosis.
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http://dx.doi.org/10.1159/000499526DOI Listing
January 2020

Long-term follow-up of implantable cardioverter-defibrillators in Short QT syndrome.

Clin Res Cardiol 2019 Oct 16;108(10):1140-1146. Epub 2019 Mar 16.

First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Background: Short QT syndrome (SQTS) is associated with sudden cardiac death and implantable cardioverter-defibrillator (ICD) implantation is recommended in this rare disease. However, only a few SQTS families have been reported in literature with limited follow-up data.

Objectives: In the recent study, we describe the outcome data of 57 SQTS patients receiving ICD implantation. This includes seven SQTS families consecutively admitted to our hospital between 2002 and 2017 as well as patients reported in published literature.

Methods: Seven SQTS patients admitted to our hospital were followed up. Additionally, 7 studies out of a total of 626 researched articles were identified through systematic database search (PubMed, Web of Science, Cochrane Library, and Cinahl) and their data analyzed according to our model.

Results: Complications during a median follow-up time of 67.4 months (IQR 6-162 months) were documented in 31 (54%) patients. Inappropriate shocks were seen in 33% due to T wave oversensing (8.7%), supraventricular tachycardia (19%), lead failure and fracture (21%). Further complications were infection (10%), battery depletion (7%) and psychological distress (3.5%). Appropriate shocks were documented in 19%. Three patients (5%) were treated with s-ICD due to recurrent complications of transvenous ICD.

Conclusion: ICD therapy is an effective therapy in SQTS patients. However, it is also associated with significant risk of device-related complications.
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http://dx.doi.org/10.1007/s00392-019-01449-3DOI Listing
October 2019

Long-Term Follow-Up of Patients With Short QT Syndrome: Clinical Profile and Outcome.

J Am Heart Assoc 2018 12;7(23):e010073

1 First Department of Medicine Faculty of Medicine University Medical Centre Mannheim (UMM) University of Heidelberg Mannheim Germany.

Background Short QT syndrome ( SQTS ) is a rare inheritable disease associated with sudden cardiac death. Data on long-term outcomes of families with SQTS are limited. Methods and Results Seventeen patients with SQTS in 7 independent families (48% men; median age, 42.4 years; corrected QT interval, 324.9±40.8 ms) were followed up for 13.5±2.5 years. A history of sudden cardiac death was documented in 71% of families. A large number of them showed sudden cardiac deaths at a younger age, with a predominance of men (67%). Five patients had syncope (29%) and 9 (53%) had atrial fibrillation or atrial flutter. An SQTS -related gene was found in 76% of the patients as follows: KCNH 2 ( SQTS 1) in 4, CACNA 1C ( SQTS 4) in 3, and CACN b2 ( SQTS 5) in 6. Five patients (29%) received an implantable cardioverter-defibrillator and 5 patients received long-term prophylaxis with hydroquinidine. During follow-up, 1 patient received an appropriate implantable cardioverter-defibrillator shock attributable to ventricular fibrillation. The patient received no further implantable cardioverter-defibrillator shocks after treatment with hydroquinidine. Conclusions The risk of sudden cardiac death in SQTS families is high. However, after appropriate risk assessment and individualized treatment options (hydroquinidine and/or implantable cardioverter-defibrillator), the long-term outcome is relatively benign when patients are seen at a reference center.
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http://dx.doi.org/10.1161/JAHA.118.010073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405569PMC
December 2018

A shocking experience: inappropriate subcutaneous implantable cardioverter-defibrillator shock at a public swimming pool.

Europace 2018 12;20(12):2020

1st Medical Department, I. Med Clinic - Cardiology, Angiology, Pulmonology and Intensive Care, University Medical Center Mannheim GmbH, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.

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http://dx.doi.org/10.1093/europace/euy209DOI Listing
December 2018

SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups.

Eur Heart J 2018 08;39(31):2879-2887

L'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France.

Aims: To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification.

Methods And Results: A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE.

Conclusion: In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function.
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http://dx.doi.org/10.1093/eurheartj/ehy412DOI Listing
August 2018

Cardiac impact of R-wave triggered irreversible electroporation therapy.

Heart Rhythm 2018 12 12;15(12):1872-1879. Epub 2018 Jul 12.

Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background: Irreversible electroporation (IRE) is a novel tumor ablative therapy technique, using electric fields to induce apoptosis in target tissues. Whether these electric pulses of high field strength can cause cardiac damage and/or ablation-induced arrhythmias is unclear.

Objective: The purpose of this study was to systematically evaluate the safety of electrocardiogram (ECG)-gated IRE with regard to cardiac side effects.

Methods: In all patients, 12-lead ECG and signal-averaged ECG (SAECG) recordings were performed before and after IRE and 24-hour Holter recording on the day of the IRE procedure. Venous blood samples (N-terminal pro-brain-type natriuretic peptide [NT-proBNP], high-sensitive troponin I [hsTnI]) were obtained before and 4 and 16 hours after the procedure. Patients with abnormal findings were reevaluated after 3 months.

Results: In total, 26 patients with an oncologic indication for IRE (11 females, mean age 62.9 years) were prospectively enrolled. Nine patients (34.6%) showed an increase in hsTnI and 21 patients (80.8%) an increase in NT-proBNP after ablation. Fifteen patients (57%) developed arrhythmias related to the procedure. One patient, in whom hsTnI and NT-proBNP had increased, developed multiple, nonsustained ventricular tachycardia events. In another patient, atrial fibrillation was triggered twice in 2 separate procedures. Twelve patients had clinically benign arrhythmias. SAECG was negative in all patients.

Conclusion: Subclinical myocardial injury and nonfatal cardiac arrhythmias can occur in the context of IRE treatment. Although no sustained cardiac injuries could be found at 3-month follow-up, we propose implementation of a cardiac safety algorithm consisting of cardiac biomarkers and ECG monitoring when IRE is conducted.
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http://dx.doi.org/10.1016/j.hrthm.2018.07.013DOI Listing
December 2018

Long-term results of combined cardiac contractility modulation and subcutaneous defibrillator therapy in patients with heart failure and reduced ejection fraction.

Clin Cardiol 2018 Apr 26;41(4):518-524. Epub 2018 Apr 26.

First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany.

Background: Cardiac contractility modulation (CCM) is an electrical-device therapy for patients with heart failure with reduced ejection fraction (HFrEF). Patients with left ventricular ejection fraction (LVEF) ≤35% also have indication for an implantable cardioverter-defibrillator (ICD), and in some cases subcutaneous ICD (S-ICD) is selected.

Hypothesis: CCM and S-ICD can be combined to work efficaciously and safely.

Methods: We report on 20 patients with HFrEF and LVEF ≤35% who received CCM and S-ICD. To exclude device interference, patients received intraoperative crosstalk testing, S-ICD testing, and bicycle exercise testing while CCM was activated. Clinical and QOL measures before CCM activation and at last follow-up were analyzed. S-ICD performance was evaluated while both CCM and S-ICD were active.

Results: Mean follow-up was 34.3 months. NYHA class improved from 2.9 ± 0.4 to 2.1 ± 0.7 (P < 0.0001), Minnesota Living With Heart Failure Questionnaire score improved from 50.2 ± 23.7 to 29.6 ± 22.8 points (P < 0.0001), and LVEF improved from 24.4% ± 8.1% to 30.9% ± 9.6% (P = 0.002). Mean follow-up time with both devices active was 22 months. Three patients experienced a total of 6 episodes of sustained ventricular tachycardia, all successfully treated with first ICD shock. One case received an inappropriate shock unrelated to the concomitant CCM. One patient received an LVAD, so CCM and S-ICD were discontinued.

Conclusions: CCM and S-ICD can be successfully combined in patients with HFrEF. S-ICD and CCM remain efficacious when used together, with no interference affecting their function.
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http://dx.doi.org/10.1002/clc.22919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947638PMC
April 2018
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