Publications by authors named "Martin Borggrefe"

619 Publications

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

Hellenic J Cardiol 2021 May 31. Epub 2021 May 31.

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.

Background: 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 regarding 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 to 6.9), p=0.02) and RVOT/BSA (OR 3.1 (95%CI 1.0 to 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 a sECG. Moreover, RV circumferential strain and RVOT size provided additional prognostic information on the occurrence of MAE during follow-up, reflecting electrical vulnerability.
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http://dx.doi.org/10.1016/j.hjc.2021.05.003DOI Listing
May 2021

Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy.

Cardiovasc Res 2021 May 24. Epub 2021 May 24.

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

Aims: TASK-1 (K2P3.1) two-pore domain potassium channels are atrial-specific and significantly upregulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening. Doxapram was identified as a potent inhibitor of the TASK-1 channel. In the present study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF.

Methods And Results: Doxapram successfully cardioverted pigs with artificially induced episodes of AF. We established a porcine model of persistent AF in domestic pigs via intermittent atrial burst stimulation using implanted pacemakers. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 d of doxapram treatment. Pigs in the treatment group received intravenous administration of doxapram once per day. In doxapram-treated AF pigs, the AF burden was significantly reduced. After 14 d of treatment with doxapram, TASK-1 currents were still similar to values of sinus rhythm animals. Doxapram significantly suppressed AF episodes and normalized cellular electrophysiology by inhibition of the TASK-1 channel. Patch-clamp experiments on human atrial cardiomyocytes, isolated from patients with and without AF could reproduce the TASK-1 inhibitory effect of doxapram.

Conclusions: Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients.

Translational Perspective: Pharmacological suppression of atrial TASK 1 potassium currents prolongs atrial refractoriness with no effects on ventricular repolarization, resulting in atrial-specific class III antiarrhythmic effects. In our preclinical pilot study the respiratory stimulant doxapram was successfully administered for cardioversion of acute AF as well as rhythm control of persistent AF in a clinically relevant porcine animal model.
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http://dx.doi.org/10.1093/cvr/cvab177DOI Listing
May 2021

Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1.

Front Pharmacol 2021 7;12:675003. Epub 2021 May 7.

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

The short QT syndrome type 1 (SQT1) is linked to hERG channel mutations (e.g., N588K). Drug effects on hERG channel gating kinetics in SQT1-cells have not been investigated. This study used hiPSC-CMs of a healthy donor and a SQT1-patient carrying the N588K mutation and patch clamp to examine the drug effects on hERG channel gating kinetics. Ajmaline, amiodarone, ivabradine, flecainide, quinidine, mexiletine and ranolazine inhibited the hERG channel current (I) less strongly in hiPSC-CMs from the SQTS1-patient (SQT1-hiPSC-CMs) comparing with cells from the healthy donor (donor-hiPSC-CMs). Quinidine and mexiletine reduced, but ajmaline, amiodarone, ivabradine and ranolazine increased the time to peak of I similarly in SQT1-hiPSC-CMs and donor-hiPSC-CMs. Although regarding the shift of activation and inactivation curves, tested drugs showed differential effects in donor- and SQT1-hiPSC-CMs, quinidine, ajmaline, ivabradine and mexiletine but not amiodarone, flecainide and ranolazine reduced the window current in SQT1-hiPSC-CMs. Quinidine, ajmaline, ivabradine and mexiletine differentially changed the time constant of recovery from inactivation, but all of them increased the time constant of deactivation in SQT1-hiPSC-CMs. The window current-reducing and deactivation-slowing effects may be important for the antiarrhythmic effect of ajmaline, ivabradine, quinidine and mexiletine in SQT1-cells. This information may be helpful for selecting drugs for treating SQT1-patients with hERG channel mutation.
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http://dx.doi.org/10.3389/fphar.2021.675003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138577PMC
May 2021

Ethnic comparison in takotsubo syndrome: novel insights from the International Takotsubo Registry.

Clin Res Cardiol 2021 May 19. Epub 2021 May 19.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Background: Ethnic disparities have been reported in cardiovascular disease. However, ethnic disparities in takotsubo syndrome (TTS) remain elusive. This study assessed differences in clinical characteristics between Japanese and European TTS patients and determined the impact of ethnicity on in-hospital outcomes.

Methods: TTS patients in Japan were enrolled from 10 hospitals and TTS patients in Europe were enrolled from 32 hospitals participating in the International Takotsubo Registry. Clinical characteristics and in-hospital outcomes were compared between Japanese and European patients.

Results: A total of 503 Japanese and 1670 European patients were included. Japanese patients were older (72.6 ± 11.4 years vs. 68.0 ± 12.0 years; p < 0.001) and more likely to be male (18.5 vs. 8.4%; p < 0.001) than European TTS patients. Physical triggering factors were more common (45.5 vs. 32.0%; p < 0.001), and emotional triggers less common (17.5 vs. 31.5%; p < 0.001), in Japanese patients than in European patients. Japanese patients were more likely to experience cardiogenic shock during the acute phase (15.5 vs. 9.0%; p < 0.001) and had a higher in-hospital mortality (8.2 vs. 3.2%; p < 0.001). However, ethnicity itself did not appear to have an impact on in-hospital mortality. Machine learning approach revealed that the presence of physical stressors was the most important prognostic factor in both Japanese and European TTS patients.

Conclusion: Differences in clinical characteristics and in-hospital outcomes between Japanese and European TTS patients exist. Ethnicity does not impact the outcome in TTS patients. The worse in-hospital outcome in Japanese patients, is mainly driven by the higher prevalence of physical triggers.

Trial Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01947621.
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http://dx.doi.org/10.1007/s00392-021-01857-4DOI Listing
May 2021

Atrial fibrillation increases the risk of recurrent ventricular tachyarrhythmias in implantable cardioverter defibrillator recipients.

Arch Cardiovasc Dis 2021 May 6. Epub 2021 May 6.

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

Background: Data regarding recurrences of ventricular tachyarrhythmias in implantable cardioverter defibrillator (ICD) recipients according to atrial fibrillation is limited.

Objective: To assess the prognostic impact of atrial fibrillation on recurrences of ventricular tachyarrhythmias in implantable cardioverter defibrillator recipients.

Methods: A large retrospective registry was used, including all ICD recipients with episodes of ventricular tachycardia or fibrillation from 2002 to 2016. Patients with atrial fibrillation were compared to those without atrial fibrillation. The primary endpoint was first recurrence of ventricular tachyarrhythmias at 5 years. Secondary endpoints comprised recurrences of ICD-related therapies, first cardiac rehospitalization and all-cause mortality at 5 years. Cox regression, Kaplan-Meier and propensity score-matching analyses were applied.

Results: A total of 592 consecutive ICD recipients were included (33% with atrial fibrillation). Atrial fibrillation was associated with reduced freedom from recurrent ventricular tachyarrhythmias (42% vs. 50%, log-rank P=0.004; hazard ratio 1.445, 95% confidence interval 1.124-1.858), mainly attributable to recurrent ventricular fibrillation in secondary-preventive ICD recipients. Accordingly, atrial fibrillation was associated with reduced freedom from first appropriate ICD therapies (31% vs. 42%, log-rank P=0.001; hazard ratio 1.598, 95% confidence interval 1.206-2.118). Notably, the primary endpoint of freedom from first episode of recurrent ventricular tachyarrhythmias was still reduced in those with atrial fibrillation compared to those without atrial fibrillation after propensity score matching. Regarding secondary endpoints, patients with atrial fibrillation still showed a trend towards reduced freedom from appropriate ICD therapies.

Conclusions: Atrial fibrillation was associated with increased rates of recurrent ventricular tachyarrhythmias and appropriate device therapies in ICD recipients with ventricular tachyarrhythmias.
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http://dx.doi.org/10.1016/j.acvd.2020.12.010DOI Listing
May 2021

Determinants of arterial stiffness in patients with atrial fibrillation.

Arch Cardiovasc Dis 2021 Apr 23. Epub 2021 Apr 23.

First department of medicine (cardiology), University Medical Centre Mannheim, Medical Faculty Mannheim, University of Heidelberg, European Centre for AngioScience (ECAS), 68167 Mannheim, Germany; DZHK (German centre for cardiovascular research) Partner Site Heidelberg/Mannheim, 68167 Mannheim, Germany. Electronic address:

Background: Arterial stiffness has emerged as a strong predictor of cardiovascular disease, end-organ damage and all-cause mortality. Although increased arterial stiffness has been described as a predictor of atrial fibrillation, the relationship between arterial stiffness and atrial fibrillation is uncertain.

Aim: We assessed arterial stiffness in patients with atrial fibrillation compared with that in a control group.

Methods: We enrolled 151 patients with atrial fibrillation who underwent pulmonary vein isolation (mean age 71.1±9.8 years) and 54 control patients with similar cardiovascular risk profiles and sinus rhythm, matched for age (mean age 68.6±15.7 years) and sex. Aortic distensibility as a measure of arterial stiffness was assessed by transoesophageal echocardiography. Patients with atrial fibrillation were followed over a median of 21 (15 to 31) months.

Results: Compared with control patients, patients with atrial fibrillation had significantly lower aortic distensibility (1.8±1.1 vs. 2.1±1.1 10mmHg; P=0.02). Age (hazard ratio 0.67, 95% confidence interval 0.003 to 0.03; P=0.02) and pulse pressure (hazard ratio -1.35, 95% confidence interval -0.07 to -0.03; P<0.0001) were the strongest predictors of decreased aortic distensibility in the study cohort. This effect was independent of the type of atrial fibrillation (paroxysmal/persistent). During follow-up, decreased aortic distensibility was a predictor of cardiovascular and all-cause hospitalizations, as well as recurrences of atrial fibrillation, with a higher incidence rate of events in patients in the lowest aortic distensibility quartile (P=0.001).

Conclusions: Aortic distensibility was significantly reduced in patients with atrial fibrillation, with age and pulse pressure showing the strongest correlation, independent of the type of atrial fibrillation. Additionally, decreased aortic distensibility was associated with cardiovascular and all-cause hospitalizations, as well as recurrences of atrial fibrillation, which showed a quartile-dependent occurrence.
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http://dx.doi.org/10.1016/j.acvd.2020.12.009DOI Listing
April 2021

Electrical storm reveals worse prognosis compared to myocardial infarction complicated by ventricular tachyarrhythmias in ICD recipients.

Heart Vessels 2021 Apr 26. Epub 2021 Apr 26.

First Department of Medicine, Faculty of Medicine Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Both acute myocardial infarction complicated by ventricular tachyarrhythmias (AMI-VTA) and electrical storm (ES) represent life-threatening clinical conditions. However, a direct comparison of both sub-groups regarding prognostic endpoints has never been investigated. All consecutive implantable cardioverter-defibrillator (ICD) recipients were included retrospectively from 2002 to 2016. Patients with ES apart from AMI (ES) were compared to patients with AMI accompanied by ventricular tachyarrhythmias (AMI-VTA). The primary endpoint was all-cause mortality at 3 years, secondary endpoints were in-hospital mortality, rehospitalization rates and major adverse cardiac event (MACE) at 3 years. A total of 198 consecutive ICD recipients were included (AMI-VTA: 56%; ST-segment elevation myocardial infarction (STEMI): 22%; non-ST-segment myocardial infarction (NSTEMI) 78%; ES: 44%). ES patients were older and had higher rates of severely reduced left ventricular ejection fraction (LVEF) < 35%. ES was associated with increased all-cause mortality at 3 years (37% vs. 19%; p = 0.001; hazard ratio [HR] = 2.242; 95% CI 2.291-3.894; p = 0.004) and with increased risk of first cardiac rehospitalization (44% vs. 12%; p = 0.001; HR = 4.694; 95% CI 2.498-8.823; p = 0.001). This worse prognosis of ES compared to AMI-VTA was still evident after multivariable adjustment (long-term all-cause mortality: HR = 2.504; 95% CI 1.093-5.739; p = 0.030; first cardiac rehospitalization: HR = 2.887; 95% CI 1.240-6.720; p = 0.014). In contrast, the rates of MACE (40% vs. 32%; p = 0.326) were comparable in both groups. At long-term follow-up of 3 years, ES was associated with higher rates of all-cause mortality and rehospitalization compared to patients with AMI-VTA.
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http://dx.doi.org/10.1007/s00380-021-01844-9DOI Listing
April 2021

Comparison of the prognosis and outcome of heart failure with reduced ejection fraction patients treated with sacubitril/valsartan according to age.

Future Cardiol 2021 Mar 18. Epub 2021 Mar 18.

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

The treatment with sacubitril/valsartan in patients suffering from chronic heart failure with reduced ejection fraction increases left ventricular ejection fraction and decreases the risk of sudden cardiac death. We conducted a retrospective analysis regarding the impact of age differences on the treatment outcome of sacubitril/valsartan in patients with chronic heart failure with reduced ejection fraction. Patients were defined as adults if ≤65 years (n = 51) and older if >65 years of age (n = 76). The incidence of ventricular arrhythmias at 1-year follow-up was comparable in both groups (30.8 vs 26.5%; p = 0.71). The mortality rate in adult patients is significantly lower as compared with older patients (2 vs 14.5%; log-rank = 0.04). Older patients may suffer remarkably more side effects than adult patients (21.1 vs 11.8%; p = 0.03).
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http://dx.doi.org/10.2217/fca-2020-0213DOI Listing
March 2021

The current evidence of Takotsubo syndrome.

Future Cardiol 2021 Mar 17. Epub 2021 Mar 17.

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

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http://dx.doi.org/10.2217/fca-2020-0224DOI Listing
March 2021

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

ESC Heart Fail 2021 Jun 13;8(3):1924-1932. Epub 2021 Mar 13.

Department of Cardiology, Charité, Campus Rudolf Virchow, Berlin, Germany.

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

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

Conclusions: The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome.
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http://dx.doi.org/10.1002/ehf2.13165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120351PMC
June 2021

Incomplete neo-endothelialization of left atrial appendage closure devices is frequent after 6 months: a pilot imaging study.

Int J Cardiovasc Imaging 2021 Mar 5. Epub 2021 Mar 5.

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

Purpose: To bridge neo-endothelialization (NE) of implanted left atrial appendage closure (LAA/LAAC) devices, dual antiplatelet therapy is prescribed. Cardiac computed tomography angiography (cCTA) has been proposed for the evaluation of interventional LAAC. This prospective longitudinal observational study applied a standardized imaging protocol to detect progression of NE of LAAC devices 6 months after implantation.

Methods: Consecutive cCTA datasets of patients six months after LAAC were acquired and the standardized multi-planar reconstruction LAA occluder view for post-implantation evaluation (LOVE) algorithm was used. Residual flow of contrast agent inside the LAA without a peri-device leak (PDL) was defined as incomplete neo-endothelialization. Absence of residual flow was defined as complete neo-endothelialization. Since PDL allows residual flow in the LAA, irrespective of neoendothelialization, PDL were excluded from this study. Diabetes mellitus, liver disease, body-mass-index, age, device sizes and type will be assessed as predictors for incomplete NE.

Results: 53 consecutive patients were recruited for cCTA imaging. 36 (68%) showed no PDL and were included in the study (median age 77 years, 19% female). At median follow-up of 6 months (median 180 days, IQR 178-180), 44% of patients showed complete NE compared to 56% with NE still incomplete. Age, BMI, device type and size as well as prevalence of diabetes mellitus and liver disease did not show significant correlation with the completeness of NE.

Conclusion: This pilot study showed that neo-endothelialization is still incomplete in a majority of patients at mid-term follow-up of 6 months after successful LAAC therapy. Further investigation on the consequences of incomplete endothelialization is needed to guide antiplatelet therapy schedules.
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http://dx.doi.org/10.1007/s10554-021-02192-5DOI Listing
March 2021

The dawn of radiofrequency catheter ablation for cardiac arrhythmias.

Heart Rhythm 2021 Mar;18(3):485-486

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.

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http://dx.doi.org/10.1016/j.hrthm.2020.11.030DOI Listing
March 2021

[Acute ischemic stroke and elevated troponin: Diagnostic work-up and therapeutic consequences].

Dtsch Med Wochenschr 2021 Apr 26;146(8):534-541. Epub 2021 Feb 26.

I. Medizinische Klinik, Universitätsmedizin Mannheim (UMM), Medizinische Fakultät Mannheim, Ruprecht-Karls-Universität Heidelberg, European Center for AngioScience (ECAS) und Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) Standort Heidelberg/Mannheim, Mannheim, Deutschland.

Elevated troponin values are frequently detected in patients with acute ischemic stroke, requiring adequate diagnostic work-up due to the high cardiac mortality after stroke. Since dual platelet inhibition can cause secondary intracerebral hemorrhage careful consideration of invasive coronary intervention is mandatory. Based on three case reports, this review article presents a diagnostic algorithm taking into account latest findings from the literature.
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http://dx.doi.org/10.1055/a-1308-7490DOI Listing
April 2021

Blood Cholesterol and Outcome of Patients with Cancer under Regular Cardiological Surveillance.

Curr Oncol 2021 Feb 12;28(1):863-872. Epub 2021 Feb 12.

University Medical Centre Mannheim, First Department of Medicine (Cardiology), Medical Faculty Mannheim, Heidelberg University, European Centre for AngioScience (ECAS), 68167 Mannheim, Germany.

Cardiovascular (CV) diseases and cancer share several similarities, including common risk factors. In the present investigation we assessed the relationship between cholesterol levels and mortality in a cardiooncological collective. In total, 551 patients receiving anticancer treatment were followed over a median of 41 (95% CI 40, 43) months and underwent regular cardiological surveillance. A total of 140 patients (25.4%) died during this period. Concomitant cardiac diseases were more common in patients who deceased (53 (37.9%) vs. 67 (16.3%), < 0.0001), as well as prior stroke. There were no differences in the distribution of classical CV risk factors, such as hypertension, diabetes or nicotine consumption. While total cholesterol (mg/dL) was significantly lower in patients who deceased (157 ± 59 vs. 188 ± 53, < 0.0001), both HDL and LDL cholesterol were not differing. In addition, cholesterol levels varied between different tumour entities; lowest levels were found in patients with tumours of the hepatopancreaticobiliary system (median 121 mg/dL), while patients with melanoma, cerebral tumours and breast cancer had rather high cholesterol levels (median > 190 mg/dL). Cholesterol levels were significantly lower in patients who died of cancer; lowest cholesterol levels were observed in patients who died of tumours with higher mitotic rate (mesenchymal tumours, cerebral tumours, breast cancer). Cox regression analysis revealed a significant mortality risk for patients with stem cell transplantation (HR 4.31) and metastasised tumour stages (HR 3.31), while cardiac risk factors were also associated with a worse outcome (known cardiac disease HR 1.58, prior stroke/TIA HR 1.73, total cholesterol HR 1.70), with the best discriminative performance found for total cholesterol ( = 0.002).
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http://dx.doi.org/10.3390/curroncol28010085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985794PMC
February 2021

Alpha 1-adrenoceptor signalling contributes to toxic effects of catecholamine on electrical properties in cardiomyocytes.

Europace 2021 Feb 19. Epub 2021 Feb 19.

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

Aims: This study aimed to investigate possible roles and underlying mechanisms of alpha-adrenoceptor coupled signalling for the pathogenesis of Takotsubo syndrome (TTS).

Methods And Results: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with a toxic concentration of epinephrine (Epi, 0.5 mM for 1 h) to mimic the setting of TTS. Patch-clamp technique, polymerase chain reaction (PCR) and Fluorescence-activated cell sorting (FACS) were employed for the study. High concentration Epi suppressed the depolarization velocity, prolonged duration of action potentials and induced arrhythmic events in hiPSC-CMs. The Epi effects were attenuated by an alpha-adrenoceptor blocker (phentolamine), suggesting involvement of alpha-adrenoceptor signalling in arrhythmogenesis related to QT interval prolongation in the setting of TTS. An alpha 1-adrenoceptor agonist (phenylephrine) but not an alpha 2-adrenoceptor agonist (clonidine) mimicked Epi effects. Epi enhanced ROS production, which could be attenuated by the alpha- adrenoceptor blocker. Treatment of cells with H2O2 (100 µM) mimicked the effects of Epi on action potentials and a reactive oxygen species (ROS)-blocker (N-acetyl-I-cysteine, 1 mM) prevented the Epi effects, indicating that the ROS signalling is involved in the alpha-adrenoceptor actions. Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidases were involved in alpha 1-adrenoceptor signalling. A protein kinase C (PKC) blocker suppressed the effects of Epi, phenylephrine and ROS as well, implying that PKC participated in alpha 1-adrenoceptor signalling and acted as a downstream factor of ROS. The abnormal action potentials resulted from alpha 1-adrenoceptor activation-induced dysfunctions of ion channels including the voltage-dependent Na+ and L-type Ca2+ channels.

Conclusions: Alpha 1-adrenoceptor signalling plays important roles for arrhythmogenesis of TTS. Alpha-adrenoceptor blockers might be clinically helpful for treating arrhythmias in patients with TTS.
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http://dx.doi.org/10.1093/europace/euab008DOI Listing
February 2021

Multiple breath washout (MBW) testing using sulfur hexafluoride: reference values and influence of anthropometric parameters.

Thorax 2021 Feb 16. Epub 2021 Feb 16.

Department of Biomedical Informatics, Centre for Preventive Medicine & Digital Health Baden-Württemberg, University Medical Centre Mannheim, Mannheim, Germany.

Background: Multiple breath washout (MBW) using sulfur hexafluoride (SF) has the potential to reveal ventilation heterogeneity which is frequent in patients with obstructive lung disease and associated small airway dysfunction. However, reference data are scarce for this technique and mostly restricted to younger cohorts. We therefore set out to evaluate the influence of anthropometric parameters on SF-MBW reference values in pulmonary healthy adults.

Methods: We evaluated cross-sectional data from 100 pulmonary healthy never-smokers and smokers (mean 51 (SD 20), range 20-88 years). Lung clearance index (LCI), acinar (S) and conductive (S) ventilation heterogeneity were derived from triplicate SF-MBW measurements. Global ventilation heterogeneity was calculated for the 2.5% (LCI) and 5% (LCI) stopping points. Upper limit of normal (ULN) was defined as the 95th percentile.

Results: Age was the only meaningful parameter influencing SF-MBW parameters, explaining 47% (CI 33% to 59%) of the variance in LCI, 32% (CI 18% to 47%) in S and 10% (CI 2% to 22%) in S. Mean LCI increases from 6.3 (ULN 7.4) to 8.8 (ULN 9.9) in subjects between 20 and 90 years. Smoking accounted for 2% (CI 0% to 8%) of the variability in LCI, 4% (CI 0% to 13%) in S and 3% (CI 0% to 13%) in S.

Conclusion: SF-MBW outcome parameters showed an age-dependent increase from early adulthood to old age. The effect was most pronounced for global and acinar ventilation heterogeneity and smaller for conductive ventilation heterogeneity. No influence of height, weight and sex was seen. Reference values can now be provided for all important SF-MBW outcome parameters over the whole age range.

Trial Registration Number: NCT04099225.
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http://dx.doi.org/10.1136/thoraxjnl-2020-214717DOI Listing
February 2021

The Experimental TASK-1 Potassium Channel Inhibitor A293 Can Be Employed for Rhythm Control of Persistent Atrial Fibrillation in a Translational Large Animal Model.

Front Physiol 2020 21;11:629421. Epub 2021 Jan 21.

Department of Cardiology, Heidelberg University, Heidelberg, Germany.

Background: Upregulation of the two-pore-domain potassium channel TASK-1 (hK 3.1) was recently described in patients suffering from atrial fibrillation (AF) and resulted in shortening of the atrial action potential. In the human heart, TASK-1 channels facilitate repolarization and are specifically expressed in the atria. In the present study, we tested the antiarrhythmic effects of the experimental ion channel inhibitor A293 that is highly affine for TASK-1 in a porcine large animal model of persistent AF.

Methods: Persistent AF was induced in German landrace pigs by right atrial burst stimulation via implanted pacemakers using a biofeedback algorithm over 14 days. Electrophysiological and echocardiographic investigations were performed before and after the pharmacological treatment period. A293 was intravenously administered once per day. After a treatment period of 14 days, atrial cardiomyocytes were isolated for patch clamp measurements of currents and atrial action potentials. Hemodynamic consequences of TASK-1 inhibition were measured upon acute A293 treatment.

Results: In animals with persistent AF, the A293 treatment significantly reduced the AF burden (6.5% vs. 95%; < 0.001). Intracardiac electrophysiological investigations showed that the atrial effective refractory period was prolonged in A293 treated study animals, whereas, the QRS width, QT interval, and ventricular effective refractory periods remained unchanged. A293 treatment reduced the upregulation of the TASK-1 current as well as the shortening of the action potential duration caused by AF. No central nervous side effects were observed. A mild but significant increase in pulmonary artery pressure was observed upon acute TASK-1 inhibition.

Conclusion: Pharmacological inhibition of atrial TASK-1 currents exerts antiarrhythmic effects that can be employed for rhythm control in a porcine model of persistent AF. Care has to be taken as TASK-1 inhibition may increase pulmonary artery pressure levels.
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http://dx.doi.org/10.3389/fphys.2020.629421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858671PMC
January 2021

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

Heart Rhythm 2021 Jun 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

Chronic kidney disease impairs prognosis in electrical storm.

J Interv Card Electrophysiol 2021 Jan 23. Epub 2021 Jan 23.

First Department of Medicine, University Medical Centre Mannheim, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, 68167, Deutschland.

Background: The study sought to assess the prognostic impact of chronic kidney disease (CKD) in patients with electrical storm (ES). ES represents a life-threatening heart rhythm disorder. In particular, CKD patients are at risk of suffering from ES. However, data regarding the prognostic impact of CKD on long-term mortality in ES patients is limited.

Methods: All consecutive ES patients with an implantable cardioverter-defibrillator (ICD) were included retrospectively from 2002 to 2016. Patients with CKD (MDRD-GFR < 60 ml/min/1.73 m) were compared to patients without CKD. The primary endpoint was all-cause mortality at 3 years. Secondary endpoints were in-hospital mortality, cardiac rehospitalization, recurrences of electrical storm (ES-R), and major adverse cardiac events (MACE) at 3 years.

Results: A total of 70 consecutive ES patients were included. CKD was present in 43% of ES patients with a median glomerular filtration rate (GFR) of 43.3 ml/min/1.73 m. CKD was associated with increased all-cause mortality at 3 years (63% vs. 20%; p = 0.001; HR = 4.293; 95% CI 1.874-9.836; p = 0.001) and MACE (57% vs. 30%; p = 0.025; HR = 3.597; 95% CI 1.679-7.708; p = 0.001). In contrast, first cardiac rehospitalization (43% vs. 45%; log-rank p = 0.889) and ES-R (30% vs. 20%; log-rank p = 0.334) were not affected by CKD. Even after multivariable adjustment, CKD was still associated with increased long-term mortality (HR = 2.397; 95% CI 1.012-5.697; p = 0.047), as well as with the secondary endpoint MACE (HR = 2.520; 95% CI 1.109-5.727; p = 0.027).

Conclusions: In patients with ES, the presence of CKD was associated with increased long-term mortality and MACE.
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http://dx.doi.org/10.1007/s10840-020-00924-6DOI Listing
January 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

Copeptin reliably reflects longitudinal right ventricular function.

Ann Clin Biochem 2021 Feb 11:4563221989364. Epub 2021 Feb 11.

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

Background: Data is limited evaluating novel biomarkers in right ventricular dysfunction. Normal right heart function improves the prognosis of patients with heart failure. Therefore, this study investigates the association between the novel biomarker copeptin and right heart function compared to NT-proBNP.

Methods: Patients undergoing routine echocardiography were enrolled prospectively. Right ventricular function was assessed by tricuspid annular plane systolic excursion (TAPSE) and further right ventricular and atrial parameters. Exclusion criteria were age under 18 years, left ventricular ejection fraction < 50% and moderate to severe valvular heart disease. Blood samples were taken for biomarker measurements within 72 h of echocardiography.

Results: Ninety-one patients were included. Median values of copeptin increased significantly according to decreasing values of TAPSE ( = 0.001; right heart function grade I: tricuspid annular plane systolic excursion; TAPSE > 24 mm: 5.20 pmol/L; grade II: TAPSE 18-24 mm: 8.10 pmol/L; grade III: TAPSE < 18 mm: 26.50 pmol/L). Copeptin concentrations were able to discriminate patients with decreased right heart function defined as TAPSE < 18 mm (area under the curves [AUC]: copeptin: 0.793;  = 0.001; NT-proBNP: 0.805;  = 0.0001). Within a multivariable linear regression model, copeptin was independently associated with TAPSE (copeptin: T: -4.43;  = 0.0001; NT-proBNP: T: -1.21;  = 0.23). Finally, copeptin concentrations were significantly associated with severely reduced right heart function (TAPSE < 18 mm) within a multivariate logistic regression model (copeptin: odds ratio: 0.94; 95% confidence interval: 0.911-0.975;  = 0.001).

Conclusions: This study demonstrates that the novel biomarker copeptin reflects longitudinal right heart function assessed by standardized transthoracic echocardiography compared with NT-proBNP.
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http://dx.doi.org/10.1177/0004563221989364DOI Listing
February 2021

Prognostic Impact of Pretherapeutic Hemoglobin Levels on All-cause Mortality in Cardiooncology.

Anticancer Res 2021 Jan;41(1):369-378

First Department of Medicine (Cardiology), University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, European Centre for AngioScience (ECAS), Mannheim, Germany.

Background/aim: We investigated the prognostic impact of hemoglobin (Hb) levels in tumour patients receiving routine cardiological surveillance during anticancer treatment. The aim of the study was to identify independent predictors of all-cause mortality in a cardio-oncological collective.

Patients And Methods: A total of 551 patients (273 males, 278 females) were enrolled in the Mannheim Registry for Cardiooncology and were included in the present analysis. Median follow-up was 41 months (95% CI=40-43).

Results: Patients were grouped according to a pretherapeutic Hb-threshold (determined by ROC analysis) into cohorts with Hb<11.4 g/dl (n=232, 42.1%) and Hb >11.4 g/dl (n=319, 57.9%). Patients with lower Hb levels were older at the time of first diagnosis (63.8±14.4 vs. 59.9±15.4 years, p=0.003) and were more likely to have advanced tumour stages (92 (39.7%) vs. 83 (26.0%), p=0.0007). There were no differences regarding cardiovascular comorbidities such as hypertension or diabetes, while chronic kidney disease was more common in patients with lower Hb. Anticoagulants were used more often in patients with lower Hb (88 (37.9%) vs. 84 (26.3%), p=0.01). Left ventricular ejection fraction (LVEF) was lower in patients with Hb <11.4 g/dl (51.9±11.0% vs. 55.1±9.7%, p=0.003). Correlation analysis revealed a significant correlation of Hb levels and LVEF (R=0.07, p<0.0001). During follow-up, a total of 140 patients (25.4%) were deceased, with significantly more deaths occurring in the group of patients with low Hb values [108 (46.6%) vs. 32 (10.0%), p<0.0001]. In multivariable analysis, Hb was identified as independent predictor for mortality (OR=5.3, CI=0.41-0.89, p<0.0001).

Conclusion: Low Hb levels were identified as an independent predictor of mortality in patients with cancer. There was a significant correlation of Hb and LVEF, suggesting that low Hb values are not solely due to anaemia, but rather reflect the severity of cancer.
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http://dx.doi.org/10.21873/anticanres.14785DOI Listing
January 2021

No impact of mineralocorticoid receptor antagonists on long-term recurrences of ventricular tachyarrhythmias.

Pacing Clin Electrophysiol 2021 Feb 5;44(2):213-224. Epub 2021 Jan 5.

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

Objective: The study sought to assess the prognostic impact of treatment with mineralocorticoid receptor antagonists (MRA) on recurrences of ventricular tachyarrhythmias in implantable cardioverter-defibrillator (ICD) recipients with systolic heart failure (HF).

Background: Data regarding the outcome of patients with ventricular tachyarrhythmias treated with MRA is limited.

Methods: A large retrospective registry was used including consecutive ICD recipients with systolic HF (i.e., left ventricular ejection fraction < 45%) and index episodes of ventricular tachyarrhythmias from 2002 to 2016. Patients treated with MRA were compared to patients without (non-MRA). Kaplan-Meier and multivariable Cox regression analyses were applied for the evaluation of the primary endpoint defined as first recurrence of ventricular tachyarrhythmias at five years. Secondary endpoints were appropriate ICD therapies, first cardiac rehospitalization, and all-cause mortality.

Results: 366 ICD recipients with systolic HF were included, 20% treated with MRA (spironolactone: 65%; eplerenone: 35%) and 80% without. At five years, treatment with MRA was not associated with the primary endpoint of first recurrence of ventricular tachyarrhythmias [47% vs. 48%, log-rank p = 0.732; hazard ratio (HR) = 1.067; 95% confidence interval (CI) 0.736-1.546; p = 0.732]. Accordingly, risk of first appropriate ICD therapies, first cardiac rehospitalization, and all-cause mortality were not affected by the presence of MRA therapy. Finally, patients with spironolactone and eplerenone had comparable risk of first recurrences of ventricular tachyarrhythmias (50% vs. 45%; p = 0.255; HR = 2.263; 95% CI 0.495-10.341; p = 0.292).

Conclusion: Treatment with MRA was not associated with recurrences of ventricular tachyarrhythmias and ICD therapies at five years.
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http://dx.doi.org/10.1111/pace.14137DOI Listing
February 2021

Comparable risk of recurrent ventricular tachyarrhythmias in implantable cardioverter-defibrillator recipients treated with single beta-blocker or combined amiodarone.

Basic Clin Pharmacol Toxicol 2021 Mar 27;128(3):493-502. Epub 2020 Nov 27.

First Department of Medicine, Faculty of Medicine Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, DZHK (German Center for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Mannheim, Germany.

This study sought to assess the prognostic impact of treatment with single beta-blocker (BB) compared to combined therapy with BB plus amiodarone (BB-AMIO) on recurrences of ventricular tachyarrhythmias in implantable cardioverter-defibrillator (ICD) recipients. A large retrospective registry was used including consecutive ICD recipients with index episodes of ventricular tachyarrhythmias from 2002 to 2016. Patients treated with BB were compared to patients treated with BB-AMIO. Kaplan-Meier and Cox regression analyses were applied for the evaluation of the primary end-point defined as first recurrences of ventricular tachyarrhythmias at five years. Secondary end-points comprised first appropriate ICD therapies, first cardiac rehospitalization and all-cause mortality at five years. Among 512 ICD recipients, 81% were treated with BB and 19% with BB-AMIO. BB and BB-AMIO were associated with comparable risk of first recurrences of ventricular tachyarrhythmias (46% vs. 43%; log rank P = .941; HR = 1.013; 95% CI 0.725-1.415; P = .941) and appropriate ICD therapies (35% vs. 37%; log rank P = .389; HR = 0.852; 95% CI 0.591-1.228; P = .390). BB was associated with decreased long-term all-cause mortality within an univariable analysis only (20% vs. 28%; log rank p = 0.023). In conclusion, BB and BB-AMIO were associated with comparable risks regarding recurrences of ventricular tachyarrhythmias at five years.
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http://dx.doi.org/10.1111/bcpt.13532DOI Listing
March 2021

Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in Families.

Circ Genom Precis Med 2020 12 9;13(6):e002911. Epub 2020 Nov 9.

National Cerebral and Cardiovascular Center, Osaka, Japan (S.O., T.I., W.S., N.M., T.A.).

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- is the most common mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and mutation type on BrS phenotype in BrS families with mutations.

Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles).

Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; =0.0078). Among -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; =0.0846). In -negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; =0.0146). Among E1784K- positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; =0.0011).

Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a mutation and severity of loss of function.
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http://dx.doi.org/10.1161/CIRCGEN.120.002911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748043PMC
December 2020

Ionic Mechanisms of Disopyramide Prolonging Action Potential Duration in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1.

Front Pharmacol 2020 12;11:554422. Epub 2020 Oct 12.

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

Short QT syndrome (SQTS) is associated with tachyarrhythmias and sudden cardiac death. So far, only quinidine has been demonstrated to be effective in patients with SQTS type 1(SQTS1). The aim of this study was to investigate the mechanisms of disopyramide underlying its antiarrhythmic effects in SQTS1 with the N588K mutation in HERG channel. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with SQTS1 and a healthy donor, patch clamp, and calcium imaging measurements were employed to assess the drug effects. Disopyramide prolonged the action potential duration (APD) in hiPSC-CMs from a SQTS1-patient (SQTS1-hiPSC-CMs). In spontaneously beating SQTS1-hiPSC-CMs challenged by carbachol plus epinephrine, disopyramide reduced the arrhythmic events. Disopyramide enhanced the inward L-type calcium channel current (I), the late sodium channel current (late I) and the Na/Ca exchanger current (I), but it reduced the outward small-conductance calcium-activated potassium channel current (I), leading to APD-prolongation. Disopyramide displayed no effects on the rapidly and slowly activating delayed rectifier and ATP-sensitive potassium channel currents. In hiPSC-CMs from the healthy donor, disopyramide reduced peak I, I, I, and I but enhanced late I and I. The results demonstrated that disopyramide may be effective for preventing tachyarrhythmias in SQTS1-patients carrying the N588K mutation in HERG channel by APD-prolongation enhancing I, late I, I, and reducing I.
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http://dx.doi.org/10.3389/fphar.2020.554422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586889PMC
October 2020

Prognostic impact of coronary chronic total occlusion on recurrences of ventricular tachyarrhythmias and ICD therapies.

Clin Res Cardiol 2021 Feb 4;110(2):281-291. Epub 2020 Nov 4.

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

Background: Despite a few studies evaluating the prognostic impact of coronary chronic total occlusion (CTO) in implantable cardioverter defibrillator (ICD) recipients, the impact of CTO on different types of recurrences of ventricular tachyarrhythmias, as well as their predictors has not yet been investigated in CTO patients.

Methods: A large retrospective registry was used including all consecutive patients with ventricular tachyarrhythmias undergoing coronary angiography at index from 2002 to 2016. Only ICD recipients with CTO were compared to patients without (non-CTO). Kaplan-Meier and Cox regression analyses were applied for the primary end point of first recurrence of ventricular tachyarrhythmias at 5 years. Secondary end points comprised of the different types of recurrences, first appropriate ICD therapy and all-cause mortality at 5 years.

Results: From a total of 422 consecutive ICD recipients with ventricular tachyarrhythmias at index, at least one CTO was present in 25%. CTO was associated with the primary end point of first recurrence of ventricular tachyarrhythmias at 5 years (55% vs. 39%; log rank p = 0.001; HR = 1.665; 95% CI 1.221-2.271; p = 0.001), as well as increased risk of first appropriate ICD therapy (40% vs. 31%; log rank p = 0.039; HR = 1.454; 95% CI 1.016-2.079; p = 0.041) and all-cause mortality at 5 years (26% vs. 16%; log rank p = 0.011; HR = 1.797; 95% CI 1.133-2.850; p = 0.013). Less developed collaterals (i.e., either ipsi- or contralateral compared to bilateral) and a J-CTO score ≥ 3 were strongest predictors of recurrences in CTO patients at 5 years.

Conclusion: A coronary CTO even in the presence of less developed collaterals and more complex CTO category is associated with increasing risk of recurrent ventricular tachyarrhythmias at 5 years in consecutive ICD recipients.
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http://dx.doi.org/10.1007/s00392-020-01758-yDOI Listing
February 2021

Association Between Mortality and Left Ventricular Ejection Fraction in Patients With Takotsubo Syndrome Acute Coronary Syndrome.

In Vivo 2020 Nov-Dec;34(6):3639-3648

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

Background/aim: The association between ejection fraction (EF) and mortality in TTS patients as compared to ACS is limited. This study aims to investigate the association between EF and clinical outcomes in patients with TTS as compared to ACS.

Patients And Methods: This study compared in-hospital, and long-term incidence of clinical outcomes for 5 years in patients with TTS and ACS. The study was composed of two groups EF≥35% and EF<35%.

Results: The long-term mortality of the EF≥35% for 5 years was significantly higher in TTS patients as compared to ACS (18.1% vs. 7.7%, log-Rank; p<0.01). Irrespective of EF, a non-cardiovascular death was significantly higher in TTS as compared to ACS patients with EF≥35 (6.4% vs. 2.1%; p=0.02) and with EF<35% (21.4% vs. 7.5%; p=0.03).

Conclusion: The long-term mortality is significantly higher in TTS as compared to ACS dominated by a non-cardiovascular cause of death at 5-years-follow-up.
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http://dx.doi.org/10.21873/invivo.12210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811595PMC
August 2020

Comparison of the Outcome of Patients Protected by the Wearable Cardioverter Defibrillator (WCD) for <90 Wear Days ≥90 Wear Days.

In Vivo 2020 Nov-Dec;34(6):3601-3610

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

Background/aim: The wearable cardioverter/defibrillator (WCD) is recommended to prevent sudden cardiac death (SCD). Guidelines suggest a 90 days' period, but prolongation of WCD wear time until increasing the ejection fraction (≥35%) might be suggested.

Patients And Methods: A cohort of 153 patients with prescribed WCD were divided into two groups: A <90 wear days' group (n=112) vs. ≥90 wear days' group (n=41) and followed.

Results: In the first group, WCD shock occurred in 3.6% of patients, 47.3% improved in left ventricular ejection fraction (LVEF) after 3 months, and 37.5% had a cardiac implantable electronic device (CIED) implantation with appropriate implantable cardioverter defibrillator (ICD) shock events occurring in 6 patients. Two of these patients already received WCD shock therapy due to ventricular fibrillation. A 20.5% improved in LVEF after 6-12 months, but 73% were already implanted with ICD. In the second group, 4.9% received WCD shock, 34.1% improved in LVEF after 3 months, 48.8% were implanted with ICD, and 2 had ICD shocks during follow up time. LVEF improvement after 6-12 months occurred in 26.8%. ICD implantation was prevented in 7.3% of patients due to LVEF recovery.

Conclusion: Prolonging wearing days of WCD may reduce the number of inappropriate ICD implantation.
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http://dx.doi.org/10.21873/invivo.12205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811610PMC
August 2020

Automated Noninvasive Central Blood Pressure Measurements by Oscillometric Radial Pulse Wave Analysis: Results of the MEASURE-cBP Validation Studies.

Am J Hypertens 2021 04;34(4):383-393

1st Department of Medicine (Cardiology, Angiology, Pulmonary and Intensive Care), University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background: Central blood pressure becomes increasingly accepted as an important diagnostic and therapeutic parameter. Accuracy of widespread applanation tonometry can be affected by calibration and operator training. To overcome this, we aimed to evaluate novel VascAssist 2 using automated oscillometric radial pulse wave analysis and a refined multi-compartment model of the arterial tree.

Methods: Two hundred and twenty-five patients were prospectively enrolled. Invasive aortic root measurements served as reference in MEASURE-cBP 1 (n = 106) whereas applanation tonometry (SphygmoCor) was used in MEASURE-cBP 2 (n = 119).

Results: In MEASURE-cBP 1, we found a mean overestimation for systolic values of 4 ± 12 mmHg (3 ± 10%) and 6 ± 10 mmHg (9 ± 14%) for diastolic values. Diabetes mellitus and low blood pressure were associated with larger variation. In MEASURE-cBP 2, mean overestimation of systolic values was 4 ± 4 mmHg (4 ± 4%) and 1 ± 4 mmHg (1 ± 7%) of diastolic values. Arrhythmia was significantly more frequent in invalid measurements (61 vs. 18%, P < 0.0001) which were most often due to a low quality index of SphygmoCor.

Conclusions: Central blood pressure estimates using VascAssist 2 can be considered at least as accurate as available techniques, even including diabetic patients. In direct comparison, automated measurement considerably facilitates application not requiring operator training and can be reliably applied even in patients with arrhythmias.
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http://dx.doi.org/10.1093/ajh/hpaa174DOI Listing
April 2021