Incidence of atrial and ventricular arrhythmias in obese patients with heart failure with reduced ejection fraction treated with sacubitril/valsartan.

AIM: To compare clinical outcomes among patients with heart failure and reduced ejection fraction (HFrEF) according to body mass index (BMI) after initiating treatment with an angiotensin-receptor neprilysin inhibitor (ARNI). METHODS: We gathered data from 2016 to 2020 at the University Medical Center Mannheim; 208 consecutive patients were divided into two groups according to BMI (< 30 kg/m2 ; n = 116, ≥ 30 kg/m2 ; n = 92). Clinical outcomes, including mortality rate, all-cause hospitalizations and congestion, were systematically analysed. RESULTS: At the 12-month follow-up, the mortality rate was similar in both groups (7.9% in BMI < 30 kg/m2 vs. 5.6% in BMI ≥ 30 kg/m2 ; P = .76). All-cause hospitalization before ARNI treatment was comparable in both groups (63.8% in BMI < 30 kg/m2 vs. 57.6% in BMI ≥ 30 kg/m2 ; P = .69). After ARNI treatment, the hospitalization rate was also comparable in both groups at the 12-month follow-up (52.2% in BMI < 30 kg/m2 vs. 53.7% in BMI ≥ 30 kg/m2 ; P = .73). Obese patients experienced more congestion compared with non-obese patients at follow-up, without statistical significance (6.8% in BMI < 30 kg/m2 vs. 15.5% in BMI ≥ 30 kg/m2 ; P = .11). Median left ventricular ejection fraction (LVEF) improved in both groups, but significantly more in non-obese compared with obese patients at the 12-month follow-up (from 26% [3%-45%] [min.-max.] vs. 29% [10%-45%] [min.-max.] [P = .56] to 35.5% [15%-59%] [min.-max.] vs. 30% [13%-50%] [min.-max.] [P = .03], respectively). The incidence of atrial fibrillation (AF), non-sustained (ns) and sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) was less in non-obese than in obese patients after initiation of sacubitril/valsartan at the 12-month follow-up (AF: 43.5% vs. 53.7%; P = .20; nsVT: 9.8% vs. 28.4%; P = .01; VT: 14.1% vs. 17.9%; P = .52; VF: 7.6% vs. 13.4%; P = .23). CONCLUSIONS: The incidence of congestion in obese patients was higher compared with non-obese patients. LVEF improved significantly more in non-obese compared with obese HFrEF patients. Furthermore, AF and the ventricular tachyarrhythmia rate were revealed more in obesity compared with those without obesity at the 12-month follow-up.

A Preclinical Study on Brugada Syndrome with a CACNB2 Variant Using Human Cardiomyocytes from Induced Pluripotent Stem Cells.

Aims: Some gene variants in the sodium channels, as well as calcium channels, have been associated with Brugada syndrome (BrS). However, the investigation of the human cellular phenotype and the use of drugs for BrS in presence of variant in the calcium channel subunit is still lacking. Objectives: The objective of this study was to establish a cellular model of BrS in the presence of a CACNB2 variant of uncertain significance (c.425C > T/p.S142F) using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and test drug effects using this model. Methods and results: This study recruited cells from a patient with Brugada syndrome (BrS) and recurrent ventricular fibrillation carrying a missense variant in CACNB2 as well as from three healthy independent persons. These cells (hiPSC-CMs) generated from skin biopsies of healthy persons and the BrS patient (BrS-hiPSC-CMs) as well as CRISPR/Cas9 corrected cells (isogenic control, site-variant corrected) were used for this study. The hiPSC-CMs from the BrS patient showed a significantly reduced L-type calcium channel current (ICa-L) compared with the healthy control hiPSC-CMs. The inactivation curve was shifted to a more positive potential and the recovery from inactivation was accelerated. The protein expression of CACNB2 of the hiPSC-CMs from the BrS-patient was significantly decreased compared with healthy hiPSC-CMs. Moreover, the correction of the CACNB2 site-variant rescued the changes seen in the hiPSC-CMs of the BrS patient to the normal state. These data indicate that the CACNB2 gene variant led to loss-of-function of L-type calcium channels in hiPSC-CMs from the BrS patient. Strikingly, arrhythmia events were more frequently detected in BrS-hiPSC-CMs. Bisoprolol (beta-blockers) at low concentration and quinidine decreased arrhythmic events. Conclusions: The CACNB2 variant (c.425C > T/p.S142F) causes a loss-of-function of L-type calcium channels and is pathogenic for this type of BrS. Bisoprolol and quinidine may be effective for treating BrS with this variant.

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

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.

Galectin-3 reflects the echocardiographic quantification of right ventricular failure.

Objectives. Galectin-3 (gal-3) is a mediator of extracellular matrix metabolism and reflects an ongoing cardiac fibrotic process. The aim of this study was to determine the potential use of gal-3 in evaluating the structural and functional parameters of the right ventricle as determined by echocardiography. Design. Ninety-one patients undergoing routine echocardiography were prospectively enrolled in this monocentric study. Serum samples for gal-3 and aminoterminal pro-brain natriuretic peptide (NT-proBNP) were collected within 24 h of echocardiographic examination. Patients were arbitrarily divided into subgroups based on right ventricular function as measured by tricuspid annular plane systolic excursion (TAPSE) and these included TAPSE >24 mm (n = 23); TAPSE 18-24 mm (n = 55); TAPSE ≤17 mm (n = 13); permitting the detailed statistical analysis of derived data. Results. Serum levels of gal-3 in all patients correlated with age (r = 0.36. p < .001), creatinine (r = 0.60, p < .001), NT-proBNP (r = 0.53, p < .001), RA area (r = 0.38, p < .001) and TAPSE (r = -0.3. p < .01). The distribution of echocardiographic indices according to TAPSE subgroups revealed an association between gal-3 and its ability to identify patients with right ventricular failure (RVF) as diagnosed by a TAPSE ≤17 mm (r = 0.04, p < .001). The multivariable logistic regression model with adjusted odds ratio showed the ability of gal-3 to identify RVF when adjusted to age and gender (adjusted odds ratio 3.60, 95% CI 1.055-12.282, p < .05). Conclusion. Gal-3 correlated with echocardiographic indices of RVF and could effectively diagnose these patients. The supplementary use of NT-proBNP strengthened the diagnostic capability of each biomarker. Trial Registration: The 'Cardiovascular Imaging and Biomarker Analyses' (CIBER Study), clinicaltrials.gov identifier: NCT03074253. Registered 3/8/2017. https://www.clinicaltrials.gov/ct2/show/NCT03074253.

Arrhythmic events in Brugada syndrome patients induced by fever.

INTRODUCTION: The Brugada syndrome is associated with arrhythmic events, which may even lead to sudden cardiac death (SCD) as it causes arrhythmic events. A typical Brugada syndrome ECG type I can be triggered at fever situations. The aim of this pooled meta-analysis is to further explore the baseline characteristics and the association of fever to BrS-related arrhythmic events. METHODS: We compiled data from a search of databases (PubMed, Web of Science, Cochrane Library, and Google Scholar). We included 17 studies including 14 case reports and a total of 53 patients. RESULTS: Our population including 53 patients showed a male predominance of 92% with a mean age of 40.6 ± 17.7 years. 58% of patients had a family history of SCD or BrS. Genetic screening was performed in 14 patients (26%) and revealed a SCN5A mutation in 21% of the patients. ICD implantation was initiated in six patients. 75% (n = 39) of patients did not have symptoms before the fever event. Symptoms at fever included life-threatening arrhythmia such as ventricular fibrillation (VF) or ventricular tachycardia (VT; 17%), syncope (13%), and cardiac arrest or aborted SCD (13%). One patient developed electrical storm which led to not aborted SCD. CONCLUSION: Fever is a great risk factor for arrhythmia events in BrS patients. Patients with known fever triggered Brugada syndrome should be surveilled closely during fever and be started on antipyretic therapy as soon as possible.

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

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.

Impact of T-inversion on the outcome of Takotsubo syndrome as compared to acute coronary syndrome.

BACKGROUND: Previous studies revealed that patients with Takotsubo syndrome (TTS) have a higher mortality rate than the general population and a comparable mortality to acute coronary syndrome (ACS). Repolarisation abnormalities, namely T-wave amplitude, may provide incremental prognostic information, in addition to traditional risk factors in ACS. This study was performed to determine the short- and long-term prognostic impact of inverted T-waves in TTS patients, as compared to ACS patients. METHODS AND RESULTS: Our institutional database constituted a collective of 138 patients diagnosed with TTS from 2003 to 2017, as well as 532 patients suffering from ACS. Patients with TTS or with ACS (n = 138 per group) were matched for age and sex and assessed retrospectively and prospectively and divided into two groups, TTS with inverted T-waves (n = 123) and ACS with inverted T-waves (n = 80). In-hospital complications such as respiratory failure with the need of respiratory support (60.2% vs 6.3%; P < 0.01), thromboembolic events (13.8% vs 2.5%; P < 0.01) and cardiogenic shock (18.9% vs 8.8%; P = 0.05) were significantly more presented in TTS as compared to ACS patients. Among cardiovascular risk factors diabetes mellitus (23.6% vs 45.0%; P < 0.01) and arterial hypertension (57.7% vs 78.8%; P < 0.01) were more presented in ACS patients as compared to TTS patients. Short-term mortality was similar, however the long-term mortality of 5 years was significantly higher in the TTS group (25.2% vs 7.5%; P < 0.01). In univariate analysis were male gender, EF < 35%, GFR < 60 mL/min, cardiogenic shock, inotropic drugs and history of cancer predictors of 5-year mortality. The multivariate analysis showed only male gender (HR 2.7, 95% CI 1.1-6.5; P = 0.02), GFR < 60 mL/min (HR 2.8, 95% CI 1.2-6.0; P = 0.01) and history of cancer (HR 3.6, 95% CI 1.4-9.3; P < 0.01) as independent predictors of 5-year mortality. CONCLUSION: Rates of long-term mortality were significantly higher in TTS patients showing inverted T-waves compared with patients diagnosed with ACS with inverted T-waves. However, T-inversion was not an independent predictor of 5-year mortality in the multivariate analysis.

Prognostic Impact of Angiotensin-Converting Enzyme Inhibitors and Receptor Blockers on Recurrent Ventricular Tachyarrhythmias and Implantable Cardioverter-Defibrillator Therapies.

This study sought to assess the prognostic impact of treatment with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) on recurrences of ventricular tachyarrhythmias in recipients of implantable cardioverter-defibrillators (ICD). Using a large retrospective registry including consecutive ICD recipients with documented episodes of ventricular tachycardia (VT) or fibrillation (VF) from 2002 to 2016, those patients treated with ACEi/ARB were compared with patients without. The primary prognostic endpoint was the first recurrence of ventricular tachyarrhythmias and related ICD therapies at 5 years. Multivariable Cox regression analyses were applied within the entire cohort, and thereafter, Kaplan-Meier analyses were performed in propensity-matched subgroups. A total of 592 consecutive ICD recipients were included (81% treated with ACEi/ARB and 19% without). Although ACEi/ARB was associated with no differences in overall recurrence of ventricular tachyarrhythmias, ACEi/ARB was associated with improved freedom from appropriate ICD therapy within multivariable Cox regressions (hazard ratio = 0.666; P = 0.043), especially in patients with index episodes of VF, left ventricular ejection fraction <35%, coronary artery disease, secondary preventive ICD, and glomerular filtration rate <45 mL/min/1.73 m. In the propensity-matched subgroup, ACEi/ARB still prolonged freedom from appropriate ICD therapies (hazard ratio = 0.380; 95% confidence interval 0.193-0.747; P = 0.005). In conclusion, ACEi/ARB therapy was associated with improved freedom from appropriate ICD therapies.

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

AIMS: Brugada syndrome (BrS) is associated with a pronounced risk to develop sudden cardiac death (SCD). Up to 21% of patients are related to mutations in SCN5A. Studies identified SCN10A as a contributor of BrS. However, the investigation of the human cellular phenotype of BrS in the presence of SCN10A mutations remains lacking. The objective of this study was to establish a cellular model of BrS in presence of SCN10A mutations using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). METHODS AND RESULTS: Dermal fibroblasts obtained from a BrS patient suffering from SCD harbouring the SCN10A double variants (c.3803G>A and c.3749G>A) and three independent healthy control subjects were reprogrammed to hiPSCs. Human-induced pluripotent stem cells were differentiated into cardiomyocytes (hiPSC-CMs).The hiPSC-CMs from the BrS patient showed a significantly reduced peak sodium channel current (INa) and a significantly reduced ATX II (sea anemone toxin, an enhancer of late INa) sensitive as well as A-887826 (a blocker of SCN10A channel) sensitive late sodium channel current (INa) when compared with the healthy control hiPSC-CMs, indicating loss-of-function of sodium channels. Consistent with reduced INa the action potential amplitude and upstroke velocity (Vmax) were significantly reduced, which may contribute to arrhythmogenesis of BrS. Moreover, Ajmaline effects on action potentials were stronger in BrS-hiPSC-CMs than in healthy control cells. This is in agreement with the higher susceptibility of patients to sodium channel blocking drugs in unmasking BrS. CONCLUSION: Patient-specific hiPSC-CMs are able to recapitulate single-cell phenotype features of BrS with SCN10A mutations and may provide novel opportunities to further elucidate the cellular disease mechanism.

Statin therapy is associated with improved survival in patients with ventricular tachyarrhythmias.

OBJECTIVES: The study sought to assess the impact of statin therapy on survival in patients presenting with ventricular tachyarrhythmias. BACKGROUND: Data regarding the outcome of patients with statin therapy presenting with ventricular tachyarrhythmias is limited. METHODS: A large retrospective registry was used including all consecutive patients presenting with ventricular tachycardia (VT) or fibrillation (VF) from 2002 to 2016. Patients with statin were compared to patients without statin therapy (non-statin). The primary prognostic endpoint was long-term all-cause death at 3 years. Uni- and multivariable Cox regression analyses were applied in propensity-score matched cohorts. RESULTS: A total of 424 matched patients was included. The rates of VT and VF were similar in both groups (VT: statin 71% vs. non-statin 68%; VF: statin 29% vs. 32%; p = 0.460). Statin therapy was associated with lower all-cause mortality at long-term follow-up (mortality rates 16% versus 33%; log rank, p = 0.001; HR = 0.438; 95% CI 0.290-0.663; p = 0.001), irrespective of the underlying type of ventricular tachyarrhythmia (VT/VF), left ventricular ejection fraction (LVEF) > 35%, presence of an activated implantable cardioverter defibrillator (ICD), cardiogenic shock or cardiopulmonary resuscitation (CPR). CONCLUSION: Statin therapy is independently associated with lower long-term mortality in patients presenting with ventricular tachyarrhythmias on admission. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02982473 , 11/29/2016, Retrospectively registered.

Protective effect of acquired long QT syndrome in Takotsubo syndrome.

BACKGROUND: Clinical variables that predict long-term mortality and recurrence of Takotsubo syndrome (TTS) are not completely understood as the role of acquired corrected QT interval (QTc) prolongation. AIM: To detect the prevalence of QTc interval prolongation in patients with TTS and to evaluate its long-term prognostic impact. METHODS: QTc intervals were analysed in 105 patients presenting with symptoms of TTS. These patients were included in an ongoing retrospective cohort database. The cohort was subsequently subdivided into two groups based on the presence (long QT (LQT) group, n = 73, 69.52%) or absence (non-long QT (non-LQT) group, n = 32, 30.43%) of QTc interval prolongation. Patients were followed up over a mean period of 4.2 years. The rate of life-threatening arrhythmia during the first 30 days in the LQT group was comparable with the non-LQT group (10.9 vs 12.5%), whereas in-hospital mortality and 30-day mortality occurred less frequently in the LQT group (2.7 vs 18.75%, P < 0.01). RESULTS: During this time span, 17 (23.3%) patients with acquired LQT syndrome died, whereas 14 (43.7%) patients with non-LQT duration died. Kaplan-Meier survival rates were significantly higher in the LQT group than those in the non-LQT group (Log-rank-test, P = 0.02). On multivariate analysis, the QTc interval was an independent negative predictor of all-cause mortality (P = 0.02). CONCLUSION: The QTc interval at admission is an independent negative predictor of long-term adverse outcome in patients with TTS.

Male sex increases mortality in ventricular tachyarrhythmias.

BACKGROUND: Ventricular tachyarrhythmias are still associated with poor clinical outcomes. Therefore, it is important to stratify high-risk patients presenting with ventricular tachyarrhythmias for their individual risk of future outcomes. AIM: To assess the impact of male sex on survival in patients presenting with ventricular tachyarrhythmias. METHODS: All consecutive patients surviving ventricular tachycardia (VT) and fibrillation (VF) on admission from 2002 to 2016 were included and stratified according to sex differences by propensity score matching. The primary prognostic end-point was all-cause mortality at 30 months. Secondary end-points were all-cause mortality at 30 days, at index hospitalisation, after discharge, the composite of recurrent ventricular tachyarrhythmias and appropriate implantable cardioverter defibrillator (ICD) therapies, and finally rehospitalisation related to ventricular tachyarrhythmias. RESULTS: A total of 784 (392 males and 392 females) matched patients was included. The rate of VT and VF was similar in both groups (VT: male 65% vs female 62%; VF: male 35% vs female 38%). Male sex was independently associated with the primary end-point of all-cause mortality at 30 months (31% vs 23%; hazard ratio (HR) = 1.432; 95% confidence interval (CI) 1.089-1.883; P = 0.010) as well as with the secondary end-point of all-cause mortality at index hospitalisation (mortality rate 31% vs 23%; log-rank P = 0.010; HR = 1.432; 95% CI 1.089-1.883; P = 0.010; mortality rate 10% vs 15%; HR = 1.685; 95% CI 1.117-2.542; P = 0.013). No differences in further secondary end-points were found. Sex differences of the primary end-point were predominantly observed in patients with VT at index (mortality rate 28% versus 20%; HR = 1.512; 95% CI 1.040-2.189; P = 0.028), without an ICD and with left ventricular ejection fraction ≥35% (log-rank values, P < 0.05). CONCLUSION: Males presenting with ventricular tachyarrhythmias on admission were associated with higher all-cause mortality at 30 months and all-cause mortality at index hospitalisation.

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

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.

Electrical dysfunctions in human-induced pluripotent stem cell-derived cardiomyocytes from a patient with an arrhythmogenic right ventricular cardiomyopathy.

Aims: Our aim is to investigate the arrhythmogenic mechanism in arrhythmogenic right ventricular cardiomyopathy (ARVC)-patients by using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods and results: Human-induced pluripotent stem cell-derived cardiomyocytes were generated from human skin fibroblasts of two healthy donors and an ARVC-patient with a desmoglein-2 (DSG2) mutation. Patch clamp, quantitative polymerase chain reaction, and calcium imaging techniques were employed for the study. The amplitude and maximal upstroke velocity (Vmax) of action potential (AP) in ARVC-cells were smaller than that in healthy donor cells, whereas the resting potential and AP duration (APD) was not changed. The reduced Vmax resulted from decreased peak sodium current. The reason for undetected changes in APD may be the counter-action of reduced transient outward, small conductance Ca2+-activated, adenosine triphosphate-sensitive, Na/Ca exchanger (INCX) currents, and enhanced rapidly delayed rectifier currents. Isoprenaline (Iso) reduced INCX and shortened APD in both donor and ARVC-hiPSC-CMs. However, the effects of Iso in ARVC-cells are significantly larger than that in donor cells. In addition, ARVC-hiPSC-CMs showed more frequently than donor cells arrhythmogenic events induced by adrenergic stimulation. Conclusion: Cardiomyocytes derived from the ARVC patient with a DSG2 mutation displayed multiple ion channel dysfunctions and abnormal cellular electrophysiology as well as enhanced sensitivity to adrenergic stimulation. These may underlie the arrhythmogenesis in ARVC patients.

Beta-Blockers and ACE Inhibitors Are Associated with Improved Survival Secondary to Ventricular Tachyarrhythmia.

OBJECTIVE: The study sought to assess the impact of treatment with beta-blocker (BB) or ACE inhibitor/angiotensin receptor blocker (ACEi/ARB) on secondary survival in patients presenting with ventricular tachyarrhythmia. BACKGROUND: Data regarding outcome of patients presenting with ventricular tachyarrhythmia treated with BB and ACEi/ARB is limited. METHODS: A large retrospective registry was used including consecutive patients presenting with ventricular tachycardia and fibrillation from 2002 to 2016 on admission. Applying propensity-score matching for harmonization, the impact of "BB" and "ACEi/ARB" was comparatively evaluated. The primary prognostic outcome was long-term all-cause death at 3 years. RESULTS: A total of 972 matched patients were included. Both patients with BB (long-term mortality rate 18 versus 27%; log rank p = 0.041; HR = 0.661; 95% CI = 0.443-0.986; p = 0.043) and with ACEi/ARB (long-term mortality rate 13 versus 23%; log rank p = 0.004; HR = 0.544; 95% CI = 0.359-0.824; p = 0.004) revealed better secondary survival compared to patients without after presenting with ventricular tachyarrhythmia on admission. The prognostic benefit of BB was comparable to ACEi/ARB (long-term mortality rate 21 versus 26%; log rank p = 0.539). CONCLUSION: BB and ACEi/ARB were associated with improved secondary survival in patients surviving ventricular tachyarrhythmia on admission. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02982473.

Real-world experience comparing two common left atrial appendage closure devices.

BACKGROUND: The interventional left atrial appendage closure (LAAC) is a guideline-conform alternative to oral anticoagulation (OAC) in non-valvular atrial fibrillation patients with OAC ineligibility. It was aimed to directly compare two contemporary devices in a real-world patient population. METHODS: LAAC was conducted in two centres between 2010 and 2014 as well as between 2014 and 2017, respectively, in a standard fashion based on the specific manufacturer's recommendations. Baseline characteristics, procedural data and event rates during intra-hospital and 6 months follow-up were registered in a retrospective approach, and analysed in device-related groups. RESULTS: A total of 189 patients presented for LAAC device implantation. Baseline characteristics were mostly evenly distributed. In 148 patients, a Watchman™ device (Boston Scientific, Natick, MA, USA) was successfully implanted, an Amplatzer™ Amulet™ (St. Jude Medical, St. Paul, MN, USA) in 34 patients (96.1 and 97.1%, respectively; p = 1.00). Major access site bleedings were more frequent in the Amplatzer™ Amulet™ group (8.9 versus 1.4%; p = 0.046). No intra-hospital thromboembolic event was present. During 6 months follow-up, peri-device leaks > 5 mm and thromboembolic events were uncommon (each p = n.s.). CONCLUSIONS: While procedural success was equally high with both contemporary devices, complications during follow-up were rare, and evenly distributed.

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

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.

Pentraxin-3 Predicts Short- and Mid-term Mortality in Patients with Sepsis and Septic Shock During Intensive Care Treatment.

BACKGROUND: The prognostic value of the acute phase protein Pentraxin 3 (PTX-3) is not well evaluated in patients with septic shock, which reveal an unacceptably high short- and long-term mortality. New Sepsis-3 definitions are not yet implemented in most biomarker studies. Therefore, this study assesses the prognostic value of PTX-3 for short- and mid-term mortality in patients with sepsis or septic shock, as defined by the latest definitions, treated at a medical intensive care unit (ICU). METHODS: The study includes 213 ICU patients with clinical criteria of sepsis and septic shock. Plasma levels of PTX-3, procalcitonin (PCT) and interleukin-6 were measured on day 1, 3, and 8. All-cause mortality was followed up to 30 days and at 6 months. RESULTS: On all three days, PTX-3 levels were able to discriminate non-survivors from survivors at 30 days and 6 months (AUC range: 0.59 - 0.70; 95% CI: 0.52 - 0.79; p ≤ 0.02). Highest PTX-3 levels within the fourth quartiles during the first week of ICU treatment were associated with an increased mortality rate at 30 days (OR = 7; 95% CI: 2.0 - 23.5; p ≤ 0.002) and at 6 months (OR = 5; 95% CI: 2.1 - 11.4; p ≤ 0.006). Additionally, the prognostic value of PTX-3 was proven for all patients as well as in subcohorts of patients with sepsis and septic shock, according to Sepsis-3 criteria, both in univariate and multivariate analyses for 30-day and 6-months all-cause mortality, especially predicting all-cause mortality in septic shock (HRs range: 1.0 - 2.9; 95% CI: 0.3 - 5.1; p ≤ 0.03). CONCLUSIONS: PTX-3 offers prognostic value for the prediction of short- and mid-term all-cause mortality in patients suffering from sepsis and septic shock according to the latest Sepsis-3 criteria.

Inverse remodelling of K2P3.1 K+ channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation: implications for patient-specific antiarrhythmic drug therapy.

AIMS: Atrial fibrillation (AF) prevalence increases with advanced stages of left ventricular (LV) dysfunction. Remote proarrhythmic effects of ventricular dysfunction on atrial electrophysiology remain incompletely understood. We hypothesized that repolarizing K2P3.1 K+ channels, previously implicated in AF pathophysiology, may contribute to shaping the atrial action potential (AP), forming a specific electrical substrate with LV dysfunction that might represent a target for personalized antiarrhythmic therapy. METHODS AND RESULTS: A total of 175 patients exhibiting different stages of LV dysfunction were included. Ion channel expression was quantified by real-time polymerase chain reaction and Western blot. Membrane currents and APs were recorded from atrial cardiomyocytes using the patch-clamp technique. Severely reduced LV function was associated with decreased atrial K2P3.1 expression in sinus rhythm patients. In contrast, chronic (c)AF resulted in increased K2P3.1 levels, but paroxysmal (p)AF was not linked to significant K2P3.1 remodelling. LV dysfunction-related suppression of K2P3.1 currents prolonged atrial AP duration (APD) compared with patients with preserved LV function. In individuals with concomitant LV dysfunction and cAF, APD was determined by LV dysfunction-associated prolongation and by cAF-dependent shortening, respectively, consistent with changes in K2P3.1 abundance. K2P3.1 inhibition attenuated APD shortening in cAF patients irrespective of LV function, whereas in pAF subjects with severely reduced LV function, K2P3.1 blockade resulted in disproportionately high APD prolongation. CONCLUSION: LV dysfunction is associated with reduction of atrial K2P3.1 channel expression, while cAF leads to increased K2P3.1 abundance. Differential remodelling of K2P3.1 and APD provides a basis for patient-tailored antiarrhythmic strategies.

Interventional Left Atrial Appendage Closure Affects the Metabolism of Acylcarnitines.

BACKGROUND: Left atrial appendage closure (LAAC) represents the interventional alternative to oral anticoagulation for stroke prevention in atrial fibrillation (AF). The metabolism of acylcarnitines was shown to affect cardiovascular diseases. This study evaluates the influence of successful LAAC on the metabolism of acylcarnitines. METHODS: Patients undergoing successful LAAC were enrolled prospectively. Peripheral blood samples for metabolomics measurements were collected immediately before (i.e., index) and six months after LAAC (i.e., mid-term). A targeted metabolomics analysis based on electrospray ionization-liquid chromatography-mass spectrometry (ESI-LC-MS/MS) and MS/MS measurements was performed. RESULTS: 44 patients with non-valvular AF (median CHA2DS2-VASc score 4, median HAS-BLED score 4) and successful LAAC were included. Significant changes in acylcarnitine levels were found in the total cohort, which were mainly attributed to patients with impaired left ventricular and renal function, elevated amino-terminal pro-brain natriuretic peptide (NT-proBNP) and diabetes mellitus. Adjusted multivariable regression models revealed significant changes of five metabolites over mid-term follow-up: C2, C14:1, C16, and C18:1 decreased significantly (each p < 0.05); short-chain C5 acylcarnitine plasma levels increased significantly (p < 0.05). CONCLUSION: This study demonstrates that successful LAAC affects the metabolism of acylcarnitines at mid-term follow-up. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02985463.