Publications by authors named "Erol Tülümen"

56 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

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

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

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

Effectivity and applicability of the German DEGRO/DGK-guideline for radiotherapy in CIED-bearing patients.

Radiother Oncol 2020 11 7;152:208-215. Epub 2020 Feb 7.

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: No evidence has been presented until now whether recommendations given in recently issued guidelines concerning CIED-bearing patients significantly decrease RT-related complications.

Materials And Methods: 160 RT-cases were prospectively treated with 3D-CRT, IMRT, SBRT using exclusively 6 MV photons (n = 146) and electrons (n = 14) according to the 2015 issued German DEGRO/DGK-guideline for CIED-bearing patients and compared to 40 RT-cases (3D-CRT, 10-23 MV photons (n = 39) and electrons (n = 1)) of CIED-bearing patients which were treated in concordance to the 1994 issued AAPM-guideline.

Results: With AAPM-recommendations, complications occurred in 7/39 (17.95%) photon-RT cases, one patient experienced inadequate defibrillation therapy. For all patients treated with photon energies between 6 and 23 MV, a relative risk for CIED failure if treated with > 6 MV was calculated to be 9.03 (95% CI 5.24-15.55). After implementation of the DEGRO/DGK guideline, no complications were noted in 147 cases treated with photons, even though CIED-doses were as high as 5.37 Gy. In 13 cases treated with electrons, one PM lost patient-related data in a patient receiving antiproliferative RT to mammary glands.

Conclusions: Implementation of the German DEGRO/DGK-guideline effectively prevented radiation-associated CIED failures in patients treated with photons. Limitation of photon energy to 6 MV, suspension of defibrillation therapy in ICDs, surveillance of patients according to risk stratification and avoidance of direct irradiation of CIEDs should become standard of care.
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http://dx.doi.org/10.1016/j.radonc.2020.01.006DOI Listing
November 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

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

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

Clinical outcomes associated with catecholamine use in patients diagnosed with Takotsubo cardiomyopathy.

BMC Cardiovasc Disord 2018 03 20;18(1):54. Epub 2018 Mar 20.

First Department of Medicine, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.

Background: Recent hypotheses have suggested the pathophysiological role of catecholamines in the evolution of the Takotsubo syndrome (TTS). The extent of cardiac and circulatory compromise dictates the use of some form of supportive therapy. This study was designed to investigate the clinical outcomes associated with catecholamine use in TTS patients.

Methods: Our institutional database constituted a collective of 114 patients diagnosed with TTS between 2003 and 2015. The study-patients were subsequently classified into two groups based on the need for catecholamine support during hospital stay (catecholamine group n = 93; 81%, non-catecholamine group = 21; 19%). The primary end-point of our study was all-cause mortality.

Results: Patients receiving catecholamine support showed higher grades of circulatory and cardiac compromise (left ventricular ejection fraction (LVEF) 39.6% vs. 32.7%, p-value < 0.01) and the course of disease was often complicated by the occurrence of different TTS-associated complications. The in-hospital mortality (3.2% vs. 28.5%, p < 0.01), 30-day mortality (17.2% vs. 51.4%, p < 0.01) as well as long-term mortality (38.7% vs. 80.9%, p < 0.01) was significantly higher in the group of patients receiving catecholamine support. A multivariate Cox regression analysis attributed EF ≤ 35% (HR 3.6, 95% CI 1.6-8.1; p < 0.01) and use of positive inotropic agents (HR 2.2, 95% CI 1.0-4.8; p 0.04) as independent predictors of the adverse outcome.

Conclusion: Rates of in-hospital events and short- as well as long-term mortality were significantly higher in TTS patients receiving catecholamine support as compared to the other study-patients. These results need further evaluation in pre-clinical and clinical trials to determine if external catecholamines contribute to an adverse clinical outcome already compromised by the initial insult.
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http://dx.doi.org/10.1186/s12872-018-0784-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859783PMC
March 2018

Therapy optimization in patients with heart failure: the role of the wearable cardioverter-defibrillator in a real-world setting.

BMC Cardiovasc Disord 2018 03 15;18(1):52. Epub 2018 Mar 15.

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

Background: The wearable cardioverter-defibrillator (WCD) has emerged as a valuable tool to temporarily protect patients at risk for sudden cardiac death (SCD). The aim of this study was to determine the value of the WCD for therapy optimization of heart failure patients.

Methods: One hundred five consecutive patients that received WCD between 4/2012 and 9/2016 were included in the study. All patients were followed for clinical outcome and echocardiographic parameters during WCD therapy and had continued follow-up after WCD therapy, irrespective of subsequent implantable cardioverter-defibrillator (ICD) implantation.

Results: The most common indication for WCD were newly diagnosed ischemic (ICM) or non-ischemic cardiomyopathy (NICM) with left ventricular ejection fraction (LVEF) ≤35%. Mean WCD wear time was 68.8 ± 50.4 days with a mean daily use of 21.5 ± 3.5 h. Five patients (4.8%) received a total of five appropriate WCD shocks. During WCD wear, patients with ICM and NICM showed significant improvement in LVEF, reducing the proportion of patients with a need for primary preventive ICD implantation to 54.8% (ICM) and 48.8% (NICM). An ICD was finally implanted in 51.4% of the study patients (24 trans-venous ICDs, 30 subcutaneous ICDs). After discontinuation of WCD therapy, all patients were followed for a mean of 18.6 ± 12.3 months. 5.6% of patients with implanted ICDs received appropriate therapies. No patient with subcutaneous ICD needed change to a trans-venous device. None of the patients without an implanted ICD suffered from ventricular tachyarrhythmias and no patient died suddenly. In patients with NICM a significant LVEF improvement was observed during long-term follow-up (from 34.8 ± 11.1% to 41.0 ± 10.2%).

Conclusions: WCD therapy successfully bridged all patients to either LVEF recovery or ICD implantation. Following WCD, ICD implantation could be avoided in almost half of the patients. In selected patients, prolongation of WCD therapy beyond 3 months might further prevent unnecessary ICD implantation. The WCD as an external monitoring system contributed important information to optimize device selection in patients that needed ICD implantation.
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http://dx.doi.org/10.1186/s12872-018-0790-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856002PMC
March 2018

Incidence and Prognostic Relevance of Cardiopulmonary Failure in Takotsubo Cardiomyopathy.

Sci Rep 2017 11 7;7(1):14673. Epub 2017 Nov 7.

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

Recent studies have indicated that patients with takotsubo cardiomyopathy (TTC) have a higher mortality rate than the general population. There is a distinct possibility that TTC could be associated with adverse life-threatening complications like cardiopulmonary failure. Our institutional database constituted a collective of 114 patients diagnosed with TTC. The frequency, determinants and predictors of cardiopulmonary failure were assessed. The patients were subsequently classified into two groups based on the presence (n = 44, 38.6%) or absence (n = 70, 61.4%) of cardiopulmonary failure. Multivariable logistic-regression analysis identified impaired left ventricular function defined as ≤35% at presentation and life-threatening arrhythmia as a positive significant independent predictor of cardiopulmonary failure. A majority of the patients with cardiopulmonary failure were treated with either non-invasive or invasive ventilator support (88%), while 48% of the patients required treatment with catecholamine. The in-hospital mortality rate was greater in the cardiopulmonary failure group. Cardiopulmonary failure patients were at ongoing increased risk of death with a higher mortality at 30-day, 1-year and at 5 years of follow-up. Cardiopulmonary failure is a frequent complication in TTC with an increased short- and long-term mortality. Patient susceptible to this condition could be identified by a reduced ejection fraction and life-threatening arrhythmia.
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http://dx.doi.org/10.1038/s41598-017-15327-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676737PMC
November 2017

Low Prevalence of Inappropriate Shocks in Patients With Inherited Arrhythmia Syndromes With the Subcutaneous Implantable Defibrillator Single Center Experience and Long-Term Follow-Up.

J Am Heart Assoc 2017 Oct 17;6(10). Epub 2017 Oct 17.

Department of Medicine, University Medical Center Mannheim, Mannheim, Germany.

Background: Up to 40% of patients with transvenous implantable cardioverter-defibrillator (ICD) experience lead-associated complications and may suffer from high complication rates when lead extraction is indicated. Subcutaneous ICD may represent a feasible alternative; however, the efficacy of the subcutaneous ICD in the detection and treatment of ventricular arrhythmias in patients with hereditary arrhythmia syndromes has not been fully evaluated.

Methods And Results: Patients with primary hereditary arrhythmia syndromes who fulfilled indication for defibrillator placement were eligible for enrollment. Between 2010 and 2016, 62 consecutive patients with primary hereditary arrhythmia syndromes, without indication for antibradycardia therapy, were enrolled in the study. Mean follow-up was 31.0±14.2 months. The study cohort comprised of 24 patients with Brugada syndrome, 17 with idiopathic ventricular fibrillation, 6 with long-QT syndrome, 1 with short-QT syndrome, 3 with catecholaminergic polymorphic ventricular tachycardia, 8 with hypertrophic cardiomyopathy, and 3 with arrhythmogenic right ventricular cardiomyopathy. Thirty-nine patients were implanted for secondary prevention. Twenty-two patients had a previous transvenous ICD implanted, but required revision because of infection or lead defects. A total of 20 spontaneous ventricular tachyarrhythmias requiring shock intervention occurred in 10 patients during follow-up. All episodes were terminated within the first ICD shock delivery with 80 J. Two patients had inappropriate therapies caused by oversensing following an uneventful implantation. No pocket-site infections and no premature revisions have occurred during follow-up.

Conclusions: Our study supports the use of the subcutaneous ICD for both secondary and primary prevention of sudden cardiac death as a reliable alternative to the conventional transvenous ICD.
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http://dx.doi.org/10.1161/JAHA.117.006265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721842PMC
October 2017

Incremental benefit of late gadolinium cardiac magnetic resonance imaging for risk stratification in patients with hypertrophic cardiomyopathy.

Sci Rep 2017 07 24;7(1):6336. Epub 2017 Jul 24.

1st Department of Medicine, University Medical Centre Mannheim, Mannheim, Germany.

Hypertrophic cardiomyopathy (HCM) has a low risk for sudden cardiac death (SCD). The ESC clinical risk prediction model estimates the risk of SCD using clinical and echocardiographical parameters without taking into account cardiac magnetic resonance (CMR) parameters. Therefore, we compared the CMR characteristics of 149 patients with low, intermediate and high ESC risk scores. In these patients left and right ventricular ejection fraction and volumes were comparable. Patients with a high ESC risk score revealed a significantly higher extent of late gadolinium enhancement (LGE) compared to patients with intermediate or a low risk scores. During follow-up of 4 years an extent of LGE ≥20% identified patients at a higher risk for major adverse cardiac arrhythmic events in the low and intermediate ESC risk group whereas an extent of LGE <20% was associated with a low risk of major adverse cardiac arrhythmic events despite a high ESC risk score ≥6%. Hence, we hypothesize that the extent of fibrosis might be an additional risk marker.
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http://dx.doi.org/10.1038/s41598-017-06533-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524944PMC
July 2017

Impact and management of left ventricular function on the prognosis of Takotsubo syndrome.

Eur J Clin Invest 2017 Jul 20;47(7):477-485. Epub 2017 Jun 20.

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

Background: Early research has proposed that patients with Takotsubo syndrome (TTS) could have a higher mortality rate than the general population. Our study was conducted to determine the short- and long-term outcome of TTS patients associated with a significantly compromised left ventricular function on hospital admission.

Materials And Methods: Our institutional database constituted a collective of 112 patients diagnosed with TTS between 2003 and 2015. The patients were classified into two groups based on the left ventricular ejection fraction (LVEF), with those presenting with a LVEF > 35% on admission categorized into one group (n = 65, 58%) and those presenting with LVEF ≤ 35% (n=47, 42%) categorized into another group. The endpoint was the all-cause of mortality over a mean follow-up of 1529 ± 1121 days.

Results: Preliminary results indicated that patients with an EF ≤ 35% had a significantly greater risk of developing life-threatening arrhythmias, and were much more likely to suffer from cardiogenic shock. Patients often required varying forms of mechanical respiratory support. The in-hospital mortality, 30-day mortality, 1-year mortality and ongoing long-term mortality was significantly higher in TTS patients with an EF ≤ 35%. In a multivariate Cox regression analysis, an EF ≤ 35% (HR 3·3, 95% CI: 1·2-9·2, P < 0·05) was identified as a strong independent predictor of the primary endpoint.

Conclusions: In-hospital events as well as short- and long-term mortality rates among TTS patients diagnosed with a significantly reduced LVEF on admission were significantly higher. There is an urgent need for randomized trials, which could help define uniform clinical management strategies for high risk TTS patients.
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http://dx.doi.org/10.1111/eci.12768DOI Listing
July 2017

Prevalence of malignant arrhythmia and sudden cardiac death in takotsubo syndrome and its management.

Europace 2018 05;20(5):843-850

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

Aims: Recent studies have highlighted that takotsubo syndrome (TTS) is associated with a poor clinical outcome. Our study was conducted to determine the short- and long-term prevalence, recurrence rate and impact of life-threatening arrhythmias (LTA) on the clinical outcome of TTS.

Methods And Results: Our institutional database constituted a collective of 114 patients diagnosed with TTS between 2003 and 2015. The patient groups, divided according to the presence (n = 13, 11.4%) or absence (n = 101, 88.6%) of LTAs, were followed-up over a period of 3 years so as to determine the clinical outcome. Our analyses suggest that patients comprising the LTA group suffered significantly more often from an acute cardiovascular event including cases of a newly diagnosed atrial fibrillation (38.4% vs. 2.9%), cardiogenic shock with use of inotropic agents (53.8% vs. 14.8%) and cardiopulmonary resuscitation (61.5% vs. 1%). The short-term recurrence rate of a LTA episode was 15.3%, while the long-term recurrence rate of any LTA was around 5%. Whereas, in-hospital mortality was significantly higher in TTS associated with LTAs, the overall survival rate over 3 years was similar. A multivariate Cox regression analysis suggested atrial fibrillation, EF ≤ 35%, cardiogenic shock, and glomerular filtration rate <60 mL/min. as independent predictors of adverse outcome.

Conclusion: The short- as well as the long-term prevalence and recurrence of LTAs in TTS patients is high. The long-term mortality rates were similar to the TTS patients presenting without any LTAs. LTAs in TTS could be triggered by a concomitant atrial fibrillation.
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http://dx.doi.org/10.1093/europace/eux073DOI Listing
May 2018

Simultaneous Non-Invasive Epicardial and Endocardial Mapping in Patients With Brugada Syndrome: New Insights Into Arrhythmia Mechanisms.

J Am Heart Assoc 2016 11 14;5(11). Epub 2016 Nov 14.

Department of Medicine, University Medical Center Mannheim, Mannheim, Germany.

Background: The underlying mechanisms of Brugada syndrome (BrS) are not completely understood. Recent studies provided evidence that the electrophysiological substrate, leading to electrocardiogram abnormalities and/or ventricular arrhythmias, is located in the right ventricular outflow tract (RVOT). The purpose of this study was to examine abnormalities of epicardial and endocardial local unipolar electrograms by simultaneous noninvasive mapping in patients with BrS.

Methods And Results: Local epicardial and endocardial unipolar electrograms were analyzed using a novel noninvasive epi- and endocardial electrophysiology system (NEEES) in 12 patients with BrS and 6 with right bundle branch block for comparison. Fifteen normal subjects composed the control group. Observed depolarization abnormalities included fragmented electrograms in the anatomical area of RVOT endocardially and epicardially, significantly prolonged activation time in the RVOT endocardium (65±20 vs 38±13 ms in controls; P=0.008), prolongation of the activation-recovery interval in the RVOT epicardium (281±34 vs 247±26 ms in controls; P=0.002). Repolarization abnormalities included a larger area of ST-segment elevation >2 mV and T-wave inversions. Negative voltage gradient (-2.5 to -6.0 mV) between epicardium and endocardium of the RVOT was observed in 8 of 12 BrS patients, not present in patients with right bundle branch block or in controls.

Conclusions: Abnormalities of epicardial and endocardial electrograms associated with depolarization and repolarization properties were found using NEEES exclusively in the RVOT of BrS patients. These findings support both, depolarization and repolarization abnormalities, being operative at the same time in patients with BrS.
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http://dx.doi.org/10.1161/JAHA.116.004095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210320PMC
November 2016

Systematic ajmaline challenge in patients with long QT 3 syndrome caused by the most common mutation: a multicentre study.

Europace 2017 Oct;19(10):1723-1729

Department of Cardiology and Angiology, Rhythmology and Electrophysiology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany.

Aims: Overlap syndromes of long QT 3 syndrome (LQT3) and the Brugada syndrome (BrS) have been reported. Identification of patients with an overlapping phenotype is crucial before initiation of Class I antiarrhythmic drugs for LQT3. Aim of the present study was to elucidate the yield of ajmaline challenge in unmasking the Brugada phenotype in patients with LQT3 caused by the most common mutation, SCN5A-E1784K.

Methods And Results: Consecutive families in tertiary referral centres diagnosed with LQT3 caused by SCN5A-E1784K were included in the study. Besides routine clinical work-up, ajmaline challenge was performed after informed consent. A total of 23 subjects (11 female, mean age 27 ± 14 years) from 4 unrelated families with a family history of sudden cardiac death and familial diagnosis of the SCN5A-E1784K mutation underwent ajmaline challenge and genetic testing. Sixteen subjects (9 female) were found to be heterozygous carriers of SCN5A-E1784K. Ajmaline challenge was positive in 12 out of the 16 (75%) mutation carriers, but negative in all non-carriers. Following ajmaline, a significant shortening of the rate-corrected JT (JTc) interval was observed in mutation carriers. The baseline JTc interval was significantly longer in mutation carriers with a positive ajmaline challenge compared with those with a negative one.

Conclusion: Overlap of LQT3 and BrS in patients carrying the most common mutation is high. Therefore, ajmaline challenge represents an important step to rule out potential BrS overlap in these patients before starting sodium channel blockers for the beneficial effect of QT shortening in LQT3.
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http://dx.doi.org/10.1093/europace/euw214DOI Listing
October 2017

Hyperthermia Influences the Effects of Sodium Channel Blocking Drugs in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

PLoS One 2016 9;11(11):e0166143. Epub 2016 Nov 9.

First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Introduction: Fever can increase the susceptibility to supraventricular and ventricular arrhythmias, in which sodium channel dysfunction has been implicated. Whether fever influences the efficacy of sodium channel blocking drugs is unknown. The current study was designed to investigate the temperature dependent effects of distinct sodium channel blocking drugs on the sodium currents in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).

Methods And Results: hiPSC-CMs were generated from human skin fibroblasts of a healthy donor. The peak and late sodium currents (INa), steady-state activation, inactivation and recovery from inactivation of INa in hiPSC-CMs were analyzed using the whole-cell patch clamp technique. The effects of different concentrations of the antiarrhythmic drugs flecainide, lidocaine, ajmaline and the antianginal drug ranolazine on INa were tested at 36°C and 40°C. Increasing the temperature of the bath solution from 36°C to 40°C enhanced the inhibition of peak INa but reduced the inhibition of late INa by flecainide and lidocaine. By contrast, increasing the temperature reduced the effect of ajmaline and ranolazine on the peak INa but not late INa. None of the tested drugs showed temperature-dependent effects on the steady-state activation and inactivation as well as on the recovery from inactivation of INa in hiPSC-CMs.

Conclusions: Temperature variation from the physiological to the febrile range apparently influences the effects of sodium channel blockers on the sodium currents. This may influence their antiarrhythmic efficacy in patients suffering from fever.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166143PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102382PMC
June 2017

Expression of Inflammation-related Intercellular Adhesion Molecules in Cardiomyocytes In Vitro and Modulation by Pro-inflammatory Agents.

In Vivo 2016 May-Jun;30(3):213-7

First Department of Medicine, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany German Center for Cardiovascular Research, Partner Site, Heidelberg-Mannheim, Mannheim, Germany.

Background: Cell-surface adhesion molecules regulate multiple intercellular and intracellular processes and play important roles in inflammation by facilitating leukocyte endothelial transmigration. Whether cardiomyocytes express surface-adhesion molecules related to inflammation and the effect of pro-inflammatory mediators remain unknown.

Materials And Methods: In the present study, the expression of different cell-adhesion molecules (CD11a, CD11b, CD31, CD62P, CD162, F11 receptor and mucosal vascular addressin cell adhesion molecule 1 (MADCAM1)) and the effect of pro-inflammatory mediators were investigated in an in vitro model of human cardiomyocytes. Cells were supplied as a primary culture of cardiac alpha actin-positive cells from human heart tissue. The cells were incubated for 24 h with 1 U/ml thrombin or 700 ng/ml lipopolysaccharide (LPS) or with a combination of both. The expression of the cell adhesion molecules was measured by flow cytometry.

Results: In cultured human cardiomyocytes, 22.8% of cells expressed CD31, 7.1% MADCAM1 and 2.6% F11R. CD11a, CD11b, CD62P and CD162 were expressed by fewer than 2% of the cells at baseline. CD31 expression increased on incubation of cardiomyocytes with thrombin by 26% (p<0.05) and with LPS by 26% (p=0.06). The combination of thrombin and LPS did not result in increased levels of CD31 (p>0.10). The pro-inflammatory agents LPS and thrombin had no effect on the expression of MADCAM1 and F11R.

Conclusion: Inflammation-related cell-adhesion molecules CD31, MADCAM1 and F11R were shown to be expressed on the surface of human cardiomyocytes in an in vitro model. Incubation with LPS or thrombin resulted in increased expression of CD31, however, it did not modify the expression of the cell adhesion molecules MADCAM1 and F11R.
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March 2017

Early repolarization pattern: a marker of increased risk in patients with catecholaminergic polymorphic ventricular tachycardia.

Europace 2016 Oct 23;18(10):1587-1592. Epub 2015 Dec 23.

University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.

Aims: The early repolarization pattern (ERP) has been shown to be associated with arrhythmias in patients with short QT syndrome, Brugada syndrome, and ischaemic heart disease. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome and related to malignant ventricular tachyarrhythmias in a structurally normal heart. The aim of this study was to evaluate the prevalence of ERP and clinical events in patients with CPVT.

Methods And Results: Digitalized resting 12-lead ECGs of patients were analysed for ERP and for repolarization markers (QT and T-T interval). The ERP was diagnosed as 'notching' or 'slurring' at the terminal portion of QRS with ≥0.1 mV elevation in at least two consecutive inferior (II, III, aVF) and/or lateral leads (V4-V6, I, aVL). Among 51 CPVT patients (mean age 36 ± 15 years, 11 males), the ERP was present in 23 (45%): strictly in the inferior leads in 9 (18%) patients, in the lateral leads in 9 (18%) patients, and in infero-lateral leads in 5 (10%) patients. All patients with ERP were symptomatic at presentation (23 of 23 patients with ERP vs. 19 of 28 patients without ERP, P = 0.003). Syncope was also more frequent in patients with ERP (18 of 23 patients with ERP vs. 11 of 28 patients without ERP, P = 0.005).

Conclusion: A pathologic ERP is present in an unexpected large proportion (45%) of patients and is associated with an increased frequency of syncope. In patients with unexplained syncope and ERP at baseline, exercise testing should be performed to detect CPVT.
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http://dx.doi.org/10.1093/europace/euv357DOI Listing
October 2016

Mid-regional pro-adrenomedullin and N-terminal pro B-type natriuretic peptide predict the recurrence of atrial fibrillation after cryoballoon pulmonary vein isolation.

Int J Cardiol 2016 Jan 19;203:369-71. Epub 2015 Oct 19.

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

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http://dx.doi.org/10.1016/j.ijcard.2015.10.134DOI Listing
January 2016

Brugada syndrome: clinical presentation and genotype-correlation with magnetic resonance imaging parameters.

Europace 2016 Sep 28;18(9):1411-9. Epub 2015 Oct 28.

1st Department of Medicine, University Medical Centre Mannheim, Theodor-Kutzer-Ufer 1-3, Mannheim 68167, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Mannheim, Germany.

Aims: The purpose of the this study was to evaluate a possible genotype-phenotype correlation in BrS patients and to analyze possible associations with clinical events in affected patients. SCN5A gene encodes the alpha-subunit of the voltage-gated sodium channel NaV1.5. Its mutations are associated with a broad spectrum of hereditary arrhythmias such as long-QT syndrome, cardiac conduction diseases, and Brugada syndrome (BrS). Experimental studies have shown an interaction between SCN5A and cellular cytoskeleton, explaining its functional role in cellular integrity of heart cells.

Methods And Results: Cardiovascular magnetic resonance was performed on 81 consecutive genetically screened BrS patients and 30 healthy controls. Left ventricular (LV) and right ventricular (RV) volumes and dimensions were assessed and compared with respect to the genotype. Brugada syndrome patients with an SCN5A mutation (16 patients; 20%) revealed significantly larger RV volumes, along with lower RV ejection fraction, than patients without a mutation or controls, indicating a more severe phenotype in patients with a mutation. Furthermore, patients with an SCN5A mutation showed significantly more often a spontaneous type 1 BrS-electrocardiogram (ECG). In multivariate analysis, the presence of a spontaneous type 1 BrS-ECG showed the strongest association with cardiac events. Receiver-operating characteristic curve analysis indicated good predictive performance of RV end-diastolic volume, RV end-systolic, and LV cardiac output (area under the curve = 0.81, 0.81, and 0.2), with respect to the presence of an SCN5A mutation.

Conclusion: Brugada syndrome patients with an SCN5A mutation reveal distinct changes in RV volumes and function when compared with those without an SCN5A mutation. Furthermore, mutation-positive patients have a higher likelihood of a spontaneous type 1 BrS-ECG, which is associated with a higher incidence of clinical events. Cardiovascular magnetic resonance may provide additional insight to distinguish between SCN5A mutation-positive and -negative BrS patients.
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http://dx.doi.org/10.1093/europace/euv300DOI Listing
September 2016
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