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Aims: Short QT syndrome type 1 (SQT1) is a genetic channelopathy caused by gain-of-function variants in human-ether-a-go-go (HERG) underlying the rapid delayed-rectifier K+ current (IKr), leading to QT-shortening, ventricular arrhythmias, and sudden cardiac death. Data on efficient pharmacotherapy for SQT1 are scarce. In patients with primary carnitine-deficiency, acquired-short QT syndrome (SQTS) has been observed and rescued by carnitine supplementation. Here, we assessed whether carnitine exerts direct beneficial (prolonging) effects on cardiac repolarization in genetic SQTS., Methods and Results: Adult wild-type (WT) and transgenic SQT1 rabbits (HERG-N588K, gain of IKr) were used. In vivo electrocardiograms (ECGs), ex vivo monophasic action potentials (APs) in Langendorff-perfused hearts, and cellular ventricular APs and ion currents were assessed at baseline and during L-Carnitine/C16-Carnitine-perfusion. Two-dimensional computer simulations were performed to assess re-entry-based ventricular tachycardia-inducibility. L-Carnitine/C16-Carnitine prolonged QT-intervals in WT and SQT1, leading to QT-normalization in SQT1. Similarly, monophasic and cellular AP duration (APD) was prolonged by L-Carnitine/C16-Carnitine in WT and SQT1. As underlying mechanisms, we identified acute effects on the main repolarizing ion currents: IKr-steady, which is pathologically increased in SQT1, was reduced by L-Carnitine/C16-Carnitine and deactivation kinetics were accelerated. Moreover, L-Carnitine/C16-Carnitine decreased IKs-steady and IK1. In silico modelling identified IKr changes as the main factor for L-Carnitine/C16-Carnitine-induced APD-prolongation. 2D simulations revealed increased sustained re-entry-based arrhythmia formation in SQT1 compared to WT, which was decreased to the WT-level when adding carnitine-induced ion current changes., Conclusion: L-Carnitine/C16-Carnitine prolong/normalize QT and whole-heart/cellular APD in SQT1 rabbits. These beneficial effects are mediated by acute effects on IKr. L-Carnitine may serve as a potential future QT-normalizing, anti-arrhythmic therapy in SQT1., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Literature on percutaneous coronary intervention (PCI) stated an inverse relationship between hospital volume and mortality, but the effects on other characteristics are unclear., Methods: Using German national records, all coronary angiographies with coronary artery disease in 2017 were identified. We applied risk-adjustment to account for differences in population characteristics., Results: Of overall 528,188 patients, 55.22% received at least one stent, with on average 1.01 stents implanted in all patients. Based on those patients who received at least one stent, this corresponds to an average number of 1.82 stents. In-hospital mortality across all patients was 2.93%, length of hospital stay was 6.46 days, and mean reimbursement was €5,531. There were comparatively more emergency admissions in low volume centers and more complex cases (3-vessel disease, left main stenosis, and in-stent stenosis) in high volume centers. In multivariable regression analysis, volume and likelihood of stent implantation ( p =0.003) as well as number of stents ( p =0.020) were positively correlated. No relationship was seen for in-hospital mortality ( p =0.105), length of stay ( p =0.201), and reimbursement ( p =0.108). Nonlinear influence of volume suggests a ceiling effect: In hospitals with ≤100 interventions, likelihood and number of implanted stents are lowest (∼34% and 0.6). After that, both rise steadily until a volume of 500 interventions. Finally, both remain stable in the categories of over 500 interventions (∼60% and 1.1)., Conclusion: In PCI, lower volume centers contribute to emergency care. Higher volume centers treat more complex cases and show a higher likelihood of stent implantations, with a stable safety., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Vera Oettinger et al.)

Aims: Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2., Methods and Results: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM., Conclusion: A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: In pure aortic regurgitation, transcatheter aortic valve replacement (TAVR) is not yet used on a regular base. Due to constant development of TAVR, it is necessary to analyze current data., Methods: By use of health records, we analyzed all isolated TAVR or surgical aortic valve replacements (SAVR) for pure aortic regurgitation between 2018 and 2020 in Germany., Results: 4,861 procedures-4,025 SAVR and 836 TAVR-for aortic regurgitation were identified. Patients treated with TAVR were older, showed a higher logistic EuroSCORE, and had more pre-existing diseases. While results indicate a slightly higher unadjusted in-hospital mortality for transapical TAVR (6.00%) vs. SAVR (5.71%), transfemoral TAVR showed better outcomes, with self-expanding compared to balloon-expandable transfemoral TAVR having significantly lower in-hospital mortality (2.41% vs. 5.17%; p  = 0.039). After risk adjustment, balloon-expandable as well as self-expanding transfemoral TAVR were associated with a significantly lower mortality vs. SAVR (balloon-expandable: risk adjusted OR = 0.50 [95% CI 0.27; 0.94], p  = 0.031; self-expanding: OR = 0.20 [0.10; 0.41], p  < 0.001). Furthermore, the observed in-hospital outcomes of stroke, major bleeding, delirium, and mechanical ventilation >48 h were significantly in favor of TAVR. In addition, TAVR showed a significantly shorter length of hospital stay compared to SAVR (transapical: risk adjusted Coefficient = -4.75d [-7.05d; -2.46d], p  < 0.001; balloon-expandable: Coefficient = -6.88d [-9.06d; -4.69d], p  < 0.001; self-expanding: Coefficient = -7.22 [-8.95; -5.49], p  < 0.001)., Conclusions: TAVR is a viable alternative to SAVR in the treatment of pure aortic regurgitation for selected patients, showing overall low in-hospital mortality and complication rates, especially with regard to self-expanding transfemoral TAVR., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Oettinger, Hilgendorf, Wolf, Stachon, Heidenreich, Zehender, Westermann, Kaier and von zur Mühlen.)

Background: COVID-19 has caused the deferral of millions of elective procedures, likely resulting in a backlog of cases. We estimate the number of postponed surgical aortic valve replacement (sAVR) and transcatheter aortic valve replacement (TAVR) procedures during the first two waves of the COVID-19 pandemic in Germany., Methods: Using German national records, all isolated TAVR and sAVR procedures between 2007 and 2020 were identified. Using weekly TAVR and sAVR procedures between 2017 and 2019, we created a forecast for 2020 and compared it with the observed number of procedures in 2020., Results: In Germany, a total of 225,398 isolated sAVR and 159,638 isolated TAVR procedures were conducted between 2007 and 2020 that were included in our analysis. The reduction in all AVR procedures (sAVR and TAVR) for the entire year 2020 was 19.07% (95%CI: 15.19-22.95%). During the first wave of the pandemic (week 12-21), the mean weekly reduction was 32.06% (23.44-40.68%) and during the second wave of the pandemic (week 41-52), the mean weekly reduction was 25.58% (14.19-36.97%). The number of sAVR procedures decreased more than the number of TAVR procedures (24.63% vs. 16.42% for the entire year 2020)., Conclusion: The first year of the COVID-19 pandemic saw a substantial postponing of AVR procedures in Germany. Postponing was higher for sAVR than for TAVR procedures and less pronounced during the second wave of the COVID-19 pandemic., (© 2023. The Author(s).)

Background: Severe aortic valve stenosis inhibits renal perfusion, thereby potentially worsening renal function, in particular in elderly patients most often assigned to transcatheter aortic valve implantation (TAVI). Pre-TAVI diagnostics and the procedure itself may adversely impact renal function, however renal perfusion and function may also improve post-procedure. This study aimed to clarify the impact of TAVI planning and procedure on kidney function METHODS: In this retrospective study, kidney function of patients who underwent transfemoral TAVI at a tertiary university hospital between 2016 and 2019 was analyzed. The present study investigated kidney function at baseline, after computed tomography (CT) was performed for evaluation of TAVI, after TAVI, at discharge and at follow-up., Results: Among 366 patients, the prevalence of acute kidney injury (AKI) was 14.5% after TAVI. Independent predictors of AKI were arterial hypertension, baseline creatinine, AKI post CT and coronary intervention during pre-procedural diagnostics. At discharge and follow-up, 2.1% and 3.4%, respectively had sustained relevant impairment of kidney function (defined as creatinine/baseline creatinine > 1.5 or renal replacement therapy). Patients with known chronic kidney disease showed no higher rates of short- and long-term impairment, but higher rates of improvement of renal function after TAVI., Conclusions: In most cases TAVI does not worsen renal function. A sustained impairment after TAVI was found in only a few cases. This was independent of reduced baseline kidney function. Transfemoral TAVI can thus be planned and performed even in patients with higher stages of chronic kidney disease.

Abstract: Presentation and mortality of coronary artery disease (CAD) substantially differs in both sexes. Most of the existing data analyzing sex differences is older than 10 years and mostly was retrieved in clinical trials, which are potentially structured with a bias against the inclusion of women, leading to a potential selection-bias. Meanwhile, with better diagnostic and therapeutic options, actual data analyzing sex differences in emergency CAD patients is rare.Data on all emergency case numbers with CAD diagnosis in Germany 2017 was retrieved from the German Institute for Medical Documentation and Information. DRG, OPS, and ICD codes were used to determine comorbidities, in-hospital course, and outcome. Competing risk regression analysis for in-hospital mortality was performed analyzing age, European System for Cardiac Operative Risk Evaluation (EuroSCORE), severity of CAD, clinical presentation type and sex.264,742 patients were included. Female patients were older and had more comorbidities. Three-vessel CAD was significantly less present in female patients (36.5% vs 47.5%; P < .001). After adjusting for age, EuroSCORE and severity of CAD, female sex was an independent predictor of lower in-hospital mortality (subdistribution hazard ratio [sHR] 0.94, 95% CI: 0.90-0.98, P = .002) in the whole cohort and in non-ST-segment elevation myocardial infarction (NSTEMI) patients (sHR 0.85, 95% CI: 0.79-0.92, P < .001), whereas in ST-segment elevation myocardial infarction (STEMI) patients, female sex was associated with a higher in-hospital mortality (sHR 1.07, 95% CI: 1.01-1.14, P = .029).In all patients admitted as emergency with CAD diagnosis and in all NSTEMI patients, female sex is protective, whereas in STEMI patients, females show a higher in-hospital mortality risk., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

The literature has shown an inverse volume-outcome relationship for transcatheter aortic valve implantation (TAVI). However, little is known about emergency admissions in Germany. Using German national electronic health records, we identified all isolated balloon-expandable and self-expanding transfemoral TAVI in 2018. The focus was on those patients with emergency admission. 17,295 patients were treated with TAVI, including 1682 emergency cases. 49.2% of the emergency admissions were female, the mean age was 81.2 years and the logistic EuroSCORE was 23.3%. The percentage of emergency cases was higher in lower volume than in higher volume centers (p < 0.001): In detail, centers performing < 50 TAVI showed an emergency admission rate of ~ 15%, those with > 200 TAVI a rate of ~ 11%. After propensity score adjustment, analyzing the outcomes for an increase in volume per 10 emergency admissions, higher volume centers showed significantly better outcomes regarding in-hospital mortality (OR = 0.872, p = 0.043), major bleeding (OR = 0.772, p = 0.001), stroke (OR = 0.816, p = 0.044), mechanical ventilation > 48 h (OR = 0.749, p = 0.001), length of hospital stay (risk adjusted difference in days of hospitalization per 10 emergency admissions: - 1.01 days, p < 0.001), and reimbursement (risk adjusted difference in reimbursement per 10 emergency admissions: -€314.89, p < 0.001). Results were not significant for acute kidney injury (OR = 0.951, p = 0.104), postoperative delirium (OR = 0.975, p = 0.480), and permanent pacemaker implantation (OR = 1.010, p = 0.732). In conclusion, regarding transfemoral TAVI, the percentage of emergency cases was higher in lower volume centers in Germany. However, higher volume centers show significantly better outcomes for in-hospital mortality and complication rates as well as resource utilization parameters., (© 2022. The Author(s).)

Background: Oxytocin is used therapeutically in psychiatric patients. Many of these also receive anti-depressant or anti-psychotic drugs causing acquired long-QT-syndrome (LQTS) by blocking HERG/I Kr . We previously identified an oxytocin-induced QT-prolongation in LQT2 rabbits, indicating potential harmful effects of combined therapy. We thus aimed to analyze the effects of dual therapy with oxytocin and fluoxetine/risperidone on cardiac repolarization., Methods: Effects of risperidone, fluoxetine and oxytocin on QT/QTc, short-term variability (STV) of QT, and APD were assessed in rabbits using in vivo ECG and ex vivo monophasic AP recordings in Langendorff-perfused hearts. Underlying mechanisms were assessed using patch clamp in isolated cardiomyocytes., Results: Oxytocin, fluoxetine and risperidone prolonged QTc and APD in whole hearts. The combination of fluoxetine + oxytocin resulted in further QTc- and APD-prolongation, risperidone + oxytocin tended to increase QTc and APD compared to monotherapy. Temporal QT instability, STV QTc was increased by oxytocin, fluoxetine / fluoxetine + oxytocin and risperidone / risperidone + oxytocin. Similar APD-prolonging effects were confirmed in isolated cardiomyocytes due to differential effects of the compounds on repolarizing ion currents: Oxytocin reduced I Ks , fluoxetine and risperidone reduced I Kr , resulting in additive effects on I Ktotal -tail. In addition, oxytocin reduced I K1 , further reducing the repolarization reserve., Conclusion: Oxytocin, risperidone and fluoxetine prolong QTc / APD. Combined treatment further prolongs QTc/APD due to differential effects on I Ks and I K1 (block by oxytocin) and I Kr (block by risperidone and fluoxetine), leading to pronounced impairment of repolarization reserve. Oxytocin should be used with caution in patients in the context of acquired LQTS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Aim: Long QT syndrome (LQTS) is a cardiac channelopathy predisposing to ventricular arrhythmias and sudden cardiac death. Since current therapies often fail to prevent arrhythmic events in certain LQTS subtypes, new therapeutic strategies are needed. Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid, which enhances the repolarizing IKs current., Methods and Results: We investigated the effects of DHA in wild type (WT) and transgenic long QT Type 1 (LQT1; loss of IKs), LQT2 (loss of IKr), LQT5 (reduction of IKs), and LQT2-5 (loss of IKr and reduction of IKs) rabbits. In vivo ECGs were recorded at baseline and after 10 µM/kg DHA to assess changes in heart-rate corrected QT (QTc) and short-term variability of QT (STVQT). Ex vivo monophasic action potentials were recorded in Langendorff-perfused rabbit hearts, and action potential duration (APD75) and triangulation were assessed. Docosahexaenoic acid significantly shortened QTc in vivo only in WT and LQT2 rabbits, in which both α- and β-subunits of IKs-conducting channels are functionally intact. In LQT2, this led to a normalization of QTc and of its short-term variability. Docosahexaenoic acid had no effect on QTc in LQT1, LQT5, and LQT2-5. Similarly, ex vivo, DHA shortened APD75 in WT and normalized it in LQT2, and additionally decreased AP triangulation in LQT2., Conclusions: Docosahexaenoic acid exerts a genotype-specific beneficial shortening/normalizing effect on QTc and APD75 and reduces pro-arrhythmia markers STVQT and AP triangulation through activation of IKs in LQT2 rabbits but has no effects if either α- or β-subunits to IKs are functionally impaired. Docosahexaenoic acid could represent a new genotype-specific therapy in LQT2., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Objectives: To evaluate in-hospital outcomes of concomitant mitral valve replacement (MVR) in patients undergoing conventional aortic valve replacement due to aortic stenosis in a nationwide cohort., Methods: Administrative data from all patients with aortic stenosis undergoing conventional aortic and concomitant MVR (reason for MVR not specified) between 2017 and 2018 in Germany were analysed., Results: A total of 2597 patients with a preoperative logistic EuroScore of 9.81 (standard deviation: 8.56) were identified. In-hospital mortality was 6.8%. An in-hospital stroke occurred in 3.4%, acute kidney injury in 16.3%, prolonged mechanical ventilation of more than 48 h in 16.3%, postoperative delirium in 15.8% and postoperative pacemaker implantation in 7.6% of the patients. Mean hospital stay was 16.5 (standard deviation: 12.1) days. Age [odds ratio (OR): 1.03; P = 0.019], New York Heart Association class III or IV (OR: 1.63; P = 0.012), previous cardiac surgery (OR: 2.85, P = 0.002), peripheral vascular disease (OR: 2.01, P = 0.031), pulmonary hypertension (OR: 1.63, P = 0.042) and impaired renal function (glomerular filtration rate <15, OR: 3.58, P = 0.001; glomerular filtration rate <30, OR: 2.51, P = 0.037) were identified as independent predictors for in-hospital mortality., Conclusions: In this nationwide analysis, concomitant aortic and MVR was associated with acceptable in-hospital mortality, morbidity and length of in-hospital stay. The regression analyses may help to identify high-risk patients and further optimize treatment strategies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: This study aimed to evaluate the acute treatment of patients with severe aortic valve stenosis in Germany., Methods and Results: Three treatment strategies in 11,027 patients acutely admitted due to aortic valve stenosis were compared from 2014 until 2018 using German nationwide records: The annual number of transcatheter aortic valve replacement (TAVR) procedures (1,294 to 1,827) and balloon valvuloplasty (BV only) procedures (170 to 233) in patients acutely admitted increased, but surgical aortic valve replacement (SAVR) procedures decreased (426 to 316). In comparison to BV only patients (mean age 81.3; EuroSCORE 23.2) SAVR patients were younger and at lower logistic EuroSCORE (mean age 66.9; EuroSCORE 9.4). Patients treated with TAVR were at comparable age and operative risk (mean age 81.3; EuroSCORE 24.4) as those patients treated with BV only. Primary outcome was in-hospital mortality. Reimbursement was considered secondary outcome. After risk adjustment using multivariable logistic and linear regression analyses, SAVR (OR 0.26 [96%CI 0.16;0.45], p < 0.001) and TAVR (OR 0.38 [0.29;0.49], p < 0.001) were associated with lower risk for mortality compared to BV only. Compared to BV only, hospitalization costs of patients undergoing SAVR were reduced by €5,578 ([95%CI €8,023; €3,133], p < 0.001). TAVR procedures were associated with higher hospitalization costs than BV only (risk-adjusted difference €4,143 [€2,330; €5,926], p < 0.001)., Conclusions: BV only was associated with a substantially increased risk of in-hospital mortality in acute patients. We conclude that a definitive aortic valve replacement should be preferred as primary treatment in patients with severe aortic valve stenosis causing an acute admission., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2021 The Author(s).)

Background: If the transfemoral access is not feasible, a transapical access or surgical aortic valve replacement (SAVR) are alternatives for patients with aortic valve stenosis., Objectives: To identify patient groups who benefit from SAVR or transapical transcatheter aortic valve replacement (TA-TAVR), we compared in-hospital outcomes of patients in a nationwide dataset., Methods: We identified 19,016 isolated SAVR and 6432 TA-TAVR performed in Germany from 2014 to 2016. We adjusted for risk factors using a covariate- and propensity-adjusted analysis., Results: Patients undergoing TA-TAVR were older, had more comorbidities, and accordingly greater estimated operative risk (logistic European System for Cardiac Operative Risk Evaluation 5.3 vs 17.0, P < .001). However, adjusted risk for in-hospital complications such as stroke, acute kidney injury, relevant bleeding, and prolonged mechanical ventilation >48 hours was lower in patients undergoing TA-TAVR (all P < .001). When we compared in-hospital mortality of all patients undergoing either TA-TAVR or SAVR, neither treatment strategy had a clear advantage (covariate-adjusted odds ratio [caOR], 1.13, P = .251; propensity-adjusted OR [paOR], 1.12, P = .309). Two patient subgroups seem to benefit more from SAVR than TA-TAVR: patients <75 years (caOR, 1.29, P = .237; paOR, 2.12, P = .001) and those with European System for Cardiac Operative Risk Evaluation 4-9 (caOR, 1.32, P = .114; paOR, 1.43, P = .041). Female patients had a tendency toward lower risk for in-hospital mortality when undergoing SAVR (caOR, 1.42, P = .030). In patients with chronic renal failure, TA-TAVR was superior (caOR, 0.56, P = .039, P = .040)., Conclusions: Patients <75 years and those at low operative risk who underwent SAVR had lower in-hospital mortality than those undergoing TA-TAVR. Patients with chronic renal failure who underwent TA-TAVR had lower in hospital mortality than those that underwent SAVR., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Aims: The early repolarization syndrome (ERS) can cause ventricular fibrillation (VF) and sudden death in young, otherwise healthy individuals. There are limited data suggesting that ERS might be heritable. The aim of this study was to characterize the clinical phenotype and to identify a causal variant in an affected family using an exome-sequencing approach., Methods and Results: Early repolarization syndrome was diagnosed according to the recently proposed Shanghai ERS Score. After sequencing of known ERS candidate genes, whole-exome sequencing (WES) was performed. The index patient (23 years, female) showed a dynamic inferolateral early repolarization (ER) pattern and electrical storm with intractable VF. Isoproterenol enabled successful termination of electrical storm with no recurrence on hydroquinidine therapy during 33 months of follow-up. The index patient's brother (25 years) had a persistent inferior ER pattern with malignant features and a history of syncope. Both parents were asymptomatic and showed no ER pattern. While there was no pathogenic variant in candidate genes, WES detected a novel missense variant affecting a highly conserved residue (p. H2245R) in the ANK3 gene encoding Ankyrin-G in the two siblings and the father., Conclusion: We identified two siblings with a malignant ERS phenotype sharing a novel ANK3 variant. A potentially pathogenic role of the novel ANK3 variant is suggested by the direct interaction of Ankyrin-G with the cardiac sodium channel, however, more patients with ANK3 variants and ERS would be required to establish ANK3 as novel ERS susceptibility gene. Our study provides additional evidence that ERS might be a heritable condition., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: This study hypothesized that cerebral protection prevents strokes in patients undergoing transfemoral transcatheter aortic valve replacement (TAVR) in clinical practice., Background: Preventing strokes is an important aim in TAVR procedures. Embolic protection devices may protect against cardiac embolism during TAVR, but their use and outcomes in clinical practice remain controversial., Methods: Isolated transfemoral TAVR procedures performed in Germany with or without cerebral protection devices were extracted from a comprehensive nationwide billing dataset., Results: A total of 41,654 TAVR procedures performed between 2015 and 2017 were analyzed. The overall share of procedures incorporating cerebral protection devices was 3.8%. Patients receiving cerebral protection devices were at increased operative risk (European System for Cardiac Operative Risk Evaluation score 13.8 vs. 14.7; p < 0.001) but of lower age (81.1 vs. 80.6 years; p = 0.001). To compare outcomes that may be related to the use of cerebral protection devices, a propensity score comparison was performed. The use of a cerebral protection device did not reduce the risk for stroke (adjusted risk difference [aRD]: +0.88%; 95% confidence interval [CI]: -0.07% to 1.83%; p = 0.069) or the risk for developing delirium (aRD: +1.31%; 95% CI: -0.28% to 2.89%; p = 0.106) as a sign of acute brain failure. Although brain damage could not be prevented, in-hospital mortality was lower in the group receiving a cerebral protection device (aRD: -0.76%; 95% CI: -1.46% to -0.06%; p = 0.034)., Conclusions: In this large national database, cerebral embolic protection devices were infrequently used during TAVR procedures. Device use was associated with lower mortality but not a reduction in stroke or delirium. Future studies are needed to confirm these findings., Competing Interests: Author Disclosures This study was supported by internal funding from the University Heart Center Freiburg. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Reliable prediction of pro-arrhythmic side effects of novel drug candidates is still a major challenge. Although drug-induced pro-arrhythmia occurs primarily in patients with pre-existing repolarisation disturbances, healthy animals are employed for pro-arrhythmia testing. To improve current safety screening, transgenic long QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss-of-function mutations of human HERG (HERG-G628S, loss of I Kr ; LQT2), KCNE1 (KCNE1-G52R, decreased I Ks ; LQT5), or both transgenes (LQT2-5) in the heart., Experimental Approach: Effects of K + channel blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild-type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff-perfused hearts., Key Results: LQTS models reflect patients with clinically "silent" (LQT5) or "manifest" (LQT2 and LQT2-5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting I Kr -blocking (LQT5) or I K1 /I Ks -blocking (LQT2 and LQT2-5) properties of drugs compared to healthy WT animals. Impaired QT-shortening capacity at fast heart rates was observed due to disturbed I Ks function in LQT5 and LQT2-5. Importantly, LQTS models exhibited higher incidence, longer duration, and more malignant types of ex vivo arrhythmias than WT., Conclusion and Implications: LQTS models represent patients with reduced repolarisation reserve due to different pathomechanisms. As they demonstrate increased sensitivity to different specific ion channel blockers (I Kr blockade in LQT5 and I K1 and I Ks blockade in LQT2 and LQT2-5), their combined use could provide more reliable and more thorough prediction of (multichannel-based) pro-arrhythmic potential of novel drug candidates., (© 2020 The British Pharmacological Society.)

Background: Prone positioning (PP) has shown to improve survival in patients with severe acute respiratory distress syndrome (ARDS). To this point, it is unclear if PP is also beneficial for ARDS patients treated with veno-venous extracorporeal membrane oxygenation (VV ECMO) support., Methods: We report retrospective data of a single-centre registry of patients with severe ARDS requiring VV ECMO support between October 2010 and May 2018. Patients were allocated to the PP group if PP was performed during VV ECMO treatment or the supine positioning group. VV ECMO weaning success and hospital survival were analysed before and after propensity score matching., Results: A total of 158 patients could be analysed, and 38 patients (24.1%) received PP. There were no significant differences in VV ECMO weaning rate (47.4% vs. 46.7%, p = 0.94) and hospital survival (36.8% vs. 36.7%, p = 0.98) between the prone and supine groups, respectively. The analysis of 38 propensity score matched pairs also showed no difference in hospital survival (36.8% vs. 36.8%, p = 1.0) or VV ECMO weaning rate (47.4% vs. 44.7%, p = 0.82). Hospital survival was superior in the subgroup of patients treated with early PP (cutoff < 17 h via Youden's Index) as compared to late or no PP (81.8% vs. 33.3%, p = 0.02)., Conclusion: In this propensity score matched cohort of severe ARDS patients requiring VV ECMO support, prone positioning at any time was not associated with improved weaning or survival. However, early initiation of prone positioning was linked to a significant reduction of hospital mortality.

Aims: Patients with postoperative delirium (POD) after transcatheter aortic valve replacement (TAVR) are ventilated and hospitalized longer and suffer increased in-hospital mortality. This study hypothesized that a minimalistic approach with conscious sedation during transfemoral aortic valve replacement (TF-AVR) protects against delirium, time of mechanical ventilation, and increased length of stay in intensive care unit (ICU) compared to intubation anaesthesia., Methods and Results: 308 patients which underwent TF-AVR in our centre between 01/2013 and 08/2017 were retrospectively evaluated regarding postoperative delirium, time of mechanical ventilation, and days in ICU. TF-AVR was performed with intubation anaesthesia in 245 patients and with conscious sedation in 63. The operative risk estimated by the logEUROScore was similar in both groups (intubation: 13.28 +/-9.06%, conscious sedation: 12.24 +/-6.77%, p = 0.395). In the conscious sedation group procedure duration was shorter (0.61 +/-0.91h vs. 1.75 +/-0.96h, p<0.001). The risk for intraprocedural complications was not influenced by the anaesthesia method (OR conscious sedation instead of intubation 1.66, p = 0.117), but days on ICU (-2.21 days, p<0.0001) and minutes of mechanical ventilation (-531.2 min, p < 0.0001) were reduced. Furthermore, the risk of POD was decreased when TF-AVR was performed under conscious sedation (6.35% vs. 18.18%, OR 0.29, p = 0.021)., Conclusions: Time of mechanical ventilation, risk of POD, and days on ICU were substantially reduced in patients who underwent TF-AVR under conscious sedation. Our data suggest that TF-AVR with conscious sedation is safe with a beneficial postoperative course in clinical practice, and should be considered the favoured approach., Competing Interests: The authors have declared that no competing interests exist.

Aims: Women with long QT syndrome 2 (LQT2) have a particularly high postpartal risk for lethal arrhythmias. We aimed at investigating whether oxytocin and prolactin contribute to this risk by affecting repolarization., Methods and Results: In female transgenic LQT2 rabbits (HERG-G628S, loss of IKr), hormone effects on QT/action potential duration (APD) were assessed (0.2-200 ng/L). Hormone effects (200 ng/L) on ion currents and cellular APD were determined in transfected cells and LQT2 cardiomyocytes. Hormone effects on ion channels were assessed with qPCR and western blot. Experimental data were incorporated into in silico models to determine the pro-arrhythmic potential. Oxytocin prolonged QTc and steepened QT/RR-slope in vivo and prolonged ex vivo APD75 in LQT2 hearts. Prolactin prolonged APD75 at high concentrations. As underlying mechanisms, we identified an oxytocin- and prolactin-induced acute reduction of IKs-tail and IKs-steady (-25.5%, oxytocin; -13.3%, prolactin, P < 0.05) in CHO-cells and LQT2-cardiomyocytes. IKr currents were not altered. This oxytocin-/prolactin-induced IKs reduction caused APD90 prolongation (+11.9%/+13%, P < 0.05) in the context of reduced/absent IKr in LQT2 cardiomyocytes. Hormones had no effect on IK1 and ICa,L in cardiomyocytes. Protein and mRNA levels of CACNA1C/Cav1.2 and RyR2 were enhanced by oxytocin and prolactin. Incorporating these hormone effects into computational models resulted in reduced repolarization reserve and increased propensity to pro-arrhythmic permanent depolarization, lack of capture and early afterdepolarizations formation., Conclusions: Postpartum hormones oxytocin and prolactin prolong QT/APD in LQT2 by reducing IKs and by increasing Cav1.2 and RyR2 expression/transcription, thereby contributing to the increased postpartal arrhythmic risk in LQT2., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

X-ray fluoroscopy is the gold standard for coronary diagnostics and intervention. Magnetic resonance imaging is a radiation-free alternative to x-ray with excellent soft tissue contrast in arbitrary slice orientation. Here, we assessed real-time MRI-guided coronary interventions from femoral access using newly designed MRI technologies. Six Goettingen minipigs were used to investigate coronary intervention using real-time MRI. Catheters were custom-designed and equipped with an active receive tip-coil to improve visibility and navigation capabilities. Using modified standard clinical 5 F catheters, intubation of the left coronary ostium was successful in all animals. For the purpose of MR-guided coronary interventions, a custom-designed 8 F catheter was used. In spite of the large catheter size, and therefore limited steerability, intubation of the left coronary ostium was successful in 3 of 6 animals within seconds. Thereafter, real-time guided implantation of a non-metallic vascular scaffold into coronary arteries was possible. This study demonstrates that real-time MRI-guided coronary catheterization and intervention via femoral access is possible without the use of any contrast agents or radiation, including placement of non-metallic vascular scaffolds into coronary arteries. Further development, especially in catheter and guidewire technology, will be required to drive forward routine MR-guided coronary interventions as an alternative to x-ray fluoroscopy.

Background Transfemoral transcatheter aortic valve replacement (TF-TAVR) is recommended for patients suffering from aortic valve stenosis at increased operative risk. Beyond that, patients with different comorbidities could benefit from TF-TAVR. The present study compares real-world in-hospital outcomes of surgical aortic valve replacement and TF-TAVR. Methods and Results For all 33 789 isolated TF-TAVR and surgical aortic valve replacement procedures performed in Germany in 2014 and 2015, comorbidities and in-hospital outcomes were identified by International Classification of Diseases (ICD)- and OPS (Operation and procedure key)-codes. Patients undergoing TF-TAVR were older and at increased estimated risk. Outcomes were risk-adjusted to allow comparison. TF-TAVR was associated with a lower risk for acute kidney injuries (odds ratio [OR] 0.62, P<0.001), for bleeding (OR 0.17, P<0.001), and for prolonged mechanical ventilation (>48 hours, OR 0.21, P<0.001). Risk for stroke was similar (OR 1.07, P=0.558). As expected, the risk for pacemaker implantations was higher after TF-TAVR (OR 4.61, P<0.001). In all patients, none of the treatment strategies had a clear advantage on the risk for in-hospital mortality (OR 0.83, P=0.068). However, in patients aged >80 years and at high operative risk undergoing TF-TAVR in-hospital mortality was lower (TF-TAVR versus surgical aortic valve replacement 80-84, OR 0.55; P=0.002; ≥85 years, OR 0.42, P=0.006; EuroSCORE (European System for Cardiac Operative Risk Evaluation) >9: OR 0.62, P=0.001). TF-TAVR was superior in patients with renal failure and in NYHA (New York Heart Association)-Class III/IV. Other risk groups were not found to be factors favoring a treatment strategy. Conclusions The present study indicates a superiority of TF-TAVR in clinical practice for patients at increased operative risk, aged >80 years, in NYHA-Class III/IV, and with renal failure.