Electrophysiological Profile of Different Antiviral Therapies in a Rabbit Whole-Heart Model.

Antiviral therapies for treatment of COVID-19 may be associated with significant proarrhythmic potential. In the present study, the potential cardiotoxic side effects of these therapies were evaluated using a Langendorff model of the isolated rabbit heart. 51 hearts of female rabbits were retrogradely perfused, employing a Langendorff-setup. Eight catheters were placed endo- and epicardially to perform an electrophysiology study, thus obtaining cycle length-dependent action potential duration at 90% of repolarization (APD90), QT intervals and dispersion of repolarization. After generating baseline data, the hearts were assigned to four groups: In group 1 (HXC), hearts were treated with 1 µM hydroxychloroquine. Thereafter, 3 µM hydroxychloroquine were infused additionally. Group 2 (HXC + AZI) was perfused with 3 µM hydroxychloroquine followed by 150 µM azithromycin. In group 3 (LOP) the hearts were perfused with 3 µM lopinavir followed by 5 µM and 10 µM lopinavir. Group 4 (REM) was perfused with 1 µM remdesivir followed by 5 µM and 10 µM remdesivir. Hydroxychloroquine- and azithromycin-based therapies have a significant proarrhythmic potential mediated by action potential prolongation and an increase in dispersion. Lopinavir and remdesivir showed overall significantly less pronounced changes in electrophysiology. In accordance with the reported bradycardic events under remdesivir, it significantly reduced the rate of the ventricular escape rhythm.

Thromboembolic risk and oral anticoagulation in subclinical atrial fibrillation.

Availability of devices capable of continuous rhythm monitoring such as smartwatches, implantable loop recorders, or pacemakers/defibrillators is continuously increasing. Importantly, device detected "subclinical" atrial fibrillation seems to convey a significantly lower risk of thromboembolism than "clinical" atrial fibrillation verified by a conventional ECG recording. While current guidelines indicate a possible role of oral anticoagulation in selected high-risk patients with subclinical AF, recent trials show an ambiguous risk/benefit relationship of anticoagulation in this setting. The present review therefore summarizes current data on the role of oral anticoagulation in subclinical AF, aims at aiding in the decision process of anticoagulation, and illustrates current gaps in evidence regarding subclinical AF.

Divergent electrophysiologic action of dapagliflozin and empagliflozin on ventricular and atrial tachyarrhythmias in isolated rabbit hearts.

Background: The use of SGLT-2 inhibitors has revolutionized heart failure therapy. Evidence suggests a reduced incidence of ventricular and atrial arrhythmias in patients with dapagliflozin or empagliflozin treatment. It is unclear to what extent the reduced arrhythmia burden is due to direct effects of the SGLT2 inhibitors or is solely a marker of improved cardiac function. Methods: One hundred five rabbit hearts were allocated to eight groups and retrogradely perfused, employing a Langendorff setup. Action potential duration at 90% of repolarization (APD90), QT intervals, effective refractory periods, conduction velocity, and dispersion of repolarization were obtained with monophasic action potential catheters. A model for tachyarrhythmias was established with the IKr blocker erythromycin for QT prolongation associated proarrhythmia as well as the potassium channel opener pinacidil for a short-QT model. An atrial fibrillation (AF) model was created with isoproterenol and acetylcholine. With increasing concentrations of both SGLT2 inhibitors, reductions in QT intervals and APD90 were observed, accompanied by a slight increase in ventricular arrhythmia episodes. During drug-induced proarrhythmia, empagliflozin succeeded in decreasing QT intervals, APD90, and VT burden whereas dapagliflozin demonstrated no significant effects. In the presence of pinacidil induced arrhythmogenicity, neither SGLT2 inhibitor had a significant impact on cardiac electrophysiology. In the AF setting, perfusion with dapagliflozin showed significant suppression of AF in the course of restitution of electrophysiological parameters whereas empagliflozin showed no significant effect on atrial fibrillation incidence. Conclusion: In this model, empagliflozin and dapagliflozin demonstrated opposite antiarrhythmic properties. Empagliflozin reduced ventricular tachyarrhythmias whereas dapagliflozin showed effective suppression of atrial arrhythmias.

Cardiac Sarcoidosis-Diagnostic and Therapeutic Challenges.

Sarcoidosis is a multisystem disorder of unknown etiology. The leading hypothesis involves an antigen-triggered dysregulated T-cell-driven immunologic response leading to non-necrotic granulomas. In cardiac sarcoidosis (CS), the inflammatory response can lead to fibrosis, culminating in clinical manifestations such as atrioventricular block and ventricular arrhythmias. Cardiac manifestations frequently present as first and isolated signs or may appear in conjunction with extracardiac manifestations. The incidence of sudden cardiac death (SCD) is high. Diagnosis remains a challenge. For a definite diagnosis, endomyocardial biopsy (EMB) is suggested. In clinical practice, compatible findings in advanced imaging using cardiovascular magnetic resonance (CMR) and/or positron emission tomography (PET) in combination with extracardiac histological proof is considered sufficient. Management revolves around the control of myocardial inflammation by employing immunosuppression. However, data regarding efficacy are merely based on observational evidence. Prevention of SCD is of particular importance and several guidelines provide recommendations regarding device therapy. In patients with manifest CS, outcome data indicate a 5-year survival of around 90% and a 10-year survival in the range of 80%. Data for patients with silent CS are conflicting; some studies suggest an overall benign course of disease while others reported contrasting observations. Future research challenges involve better understanding of the immunologic pathogenesis of the disease for a targeted therapy, improving imaging to aid early diagnosis, assessing the need for screening of asymptomatic patients and randomized trials.

Use of direct oral anticoagulants in patients on chronic hemodialysis: Contemporary appraisal on the role for patients with atrial fibrillation.

Atrial fibrillation (AF) is common in patients with chronic kidney disease (CKD) undergoing hemodialysis and in this patient population, management in terms of oral anticoagulation (OAC) presents unique challenges due to the increased risk of both thromboembolic events and bleeding complications. The attributable risk of AF for stroke may differ from patients without CKD, raising the question if OAC is indicated at all. Historically, vitamin K antagonists (VKA) have been the standard treatment for anticoagulation in AF; however, direct oral anticoagulants (DOACs) have emerged as an alternative therapeutic option, whereby data from prospective randomised trials with hemodialysis patients is limited resulting in great variability of practice and guideline recommendations. This review summarizes existing data sources regarding the use and benefit of oral anticoagulation with VKA and DOAC in hemodialysis patients.

Predictors for major in-hospital complications after catheter ablation of ventricular arrhythmias: validation and modification of the Risk in Ventricular Ablation (RIVA) Score.

OBJECTIVE AND BACKGROUND: Catheter-based treatment of patients with ventricular arrhythmias (VA) reduces VA and mortality in selected patients. With regard to potential risks of catheter ablation, a benefit-risk assessment should be carried out. This can be performed with risk scores such as the recently published "Risk in Ventricular Ablation (RIVA) Score". We sought to validate this score and to test for possible additional predictors in a large database of VT ablations. METHODS AND RESULTS: We analyzed 1964 catheter ablations for VA in patients with (1069; 54.4%) and without (893, 45.6%) structural heart disease (SHD) and observed an overall major adverse event rate of 4.0% with an in-hospital mortality of 1.3% with significantly less complications occurring in patients without structural heart disease (6.5% vs. 1.1%; p ≤ 0.01). The RIVA Score demonstrated to be a valid predictive tool for major in-hospital complications (OR 1.18; 95% CI 1.12, 1.25; p ≤ 0.001). NYHA Class ≥ III (OR 2.5; 95% CI 1.5, 4.2; p < 0.001) and age (OR 1.04; 95% CI 1.02, 1.07; p ≤ 0.001) proved to be additional predictive parameters. Hence, a modified RIVA Score (mRIVA) model was analyzed with a subset of established predictors (SHD, eGFR, epicardial puncture) as well as new predictive parameters (age, NYHA Class ≥ III), that achieved a higher predictive value for major complications compared with the model based on all RIVA variables. CONCLUSION: Adding age and functional heart failure status (NYHA class) as simple clinical parameters to the recently published RIVA Score increases the predictive value for ablation-associated complications in a large VT ablations registry.

Usefulness of the MADIT-ICD Benefit Score in a Large Mixed Patient Cohort of Primary Prevention of Sudden Cardiac Death.

Background: Decision-making in primary prevention is not always trivial and many clinical scenarios are not reflected in current guidelines. To help evaluate a patient's individual risk, a new score to predict the benefit of an implantable defibrillator (ICD) for primary prevention, the MADIT-ICD benefit score, has recently been proposed. The score tries to predict occurrence of ventricular arrhythmias and non-arrhythmic death based on data from four previous MADIT trials. We aimed at examining its usefulness in a large single-center register of S-ICD patients with various underlying cardiomyopathies. Methods and results: All S-ICD patients with a primary preventive indication for ICD implantation from our large single-center database were included in the analysis (n = 173). During a follow-up of 1227 ± 978 days, 27 patients developed sustained ventricular arrhythmias, while 6 patients died for non-arrhythmic reasons. There was a significant correlation for patients with ischemic cardiomyopathy (ICM) (n = 29, p = 0.04) to the occurrence of ventricular arrhythmia. However, the occurrence of ventricular arrhythmias could not sufficiently be predicted by the MADIT-ICD VT/VF score (p = 0.3) in patients with (n = 142, p = 0.19) as well as patients without structural heart disease (n = 31, p = 0.88) and patients with LV-EF < 35%. Of the risk factors included in the risk score calculation, only non-sustained ventricular tachycardias were significantly associated with sustained ventricular arrhythmias (p = 0.02). Of note, non-arrhythmic death could effectively be predicted by the proposed non-arrhythmic mortality score as part of the benefit score (p = 0.001, r = 0.3) also mainly driven by ICM patients. Age, diabetes mellitus, and a BMI < 23 kg/m2 were key predictors of non-arrhythmic death implemented in the score. Conclusion: The MADIT-ICD benefit score adds a new option to evaluate expected benefit of ICD implantation for primary prevention. In a large S-ICD cohort of primary prevention, the value of the score was limited to patients with ischemic cardiomyopathy. Future research should evaluate the performance of the score in different subgroups and compare it to other risk scores to assess its value for daily clinical practice.

The Impact of Cardiac Devices on Patients' Quality of Life-A Systematic Review and Meta-Analysis.

The implantation of cardiac devices significantly reduces morbidity and mortality in patients with cardiac arrhythmias. Arrhythmias as well as therapy delivered by the device may impact quality of life of patients concerned considerably. Therefore we aimed at conducting a systematic search and meta-analysis of trials examining the impact of the implantation of cardiac devices, namely implantable cardioverter-defibrillators (ICD), pacemakers and left-ventricular assist devices (LVAD) on quality of life. After pre-registering the trial with the PROSPERO database, we searched Medline, PsycINFO, Web of Science and the Cochrane databases for relevant publications. Study quality was assessed by two independent reviewers using standardized protocols. A total of 37 trials met our inclusion criteria. Of these, 31 trials were cohort trials while 6 trials used a randomized controlled design. We found large pre-post effect sizes for positive associations between quality of life and all types of devices. The effect sizes for LVAD, pacemaker and ICD patients were g = 1.64, g = 1.32 and g = 0.64, respectively. There was a lack of trials examining the effect of implantation on quality of life relative to control conditions. Trials assessing quality of life in patients with cardiac devices are still scarce. Yet, the existing data suggest beneficial effects of cardiac devices on quality of life. We recommend that clinical trials on cardiac devices routinely assess quality of life or other parameters of psychological well-being as a decisive study endpoint. Furthermore, improvements in psychological well-being should influence decisions about implantations of cardiac devices and be part of patient education and may impact shared decision-making.

Detection of Patients with Congenital and Often Concealed Long-QT Syndrome by Novel Deep Learning Models.

INTRODUCTION: The long-QT syndrome (LQTS) is the most common ion channelopathy, typically presenting with a prolonged QT interval and clinical symptoms such as syncope or sudden cardiac death. Patients may present with a concealed phenotype making the diagnosis challenging. Correctly diagnosing at-risk patients is pivotal to starting early preventive treatment. OBJECTIVE: Identification of congenital and often concealed LQTS by utilizing novel deep learning network architectures, which are specifically designed for multichannel time series and therefore particularly suitable for ECG data. DESIGN AND RESULTS: A retrospective artificial intelligence (AI)-based analysis was performed using a 12-lead ECG of genetically confirmed LQTS (n = 124), including 41 patients with a concealed LQTS (33%), and validated against a control cohort (n = 161 of patients) without known LQTS or without QT-prolonging drug treatment but any other cardiovascular disease. The performance of a fully convolutional network (FCN) used in prior studies was compared with a different, novel convolutional neural network model (XceptionTime). We found that the XceptionTime model was able to achieve a higher balanced accuracy score (91.8%) than the associated FCN metric (83.6%), indicating improved prediction possibilities of novel AI architectures. The predictive accuracy prevailed independently of age and QTc parameters. CONCLUSIONS: In this study, the XceptionTime model outperformed the FCN model for LQTS patients with even better results than in prior studies. Even when a patient cohort with cardiovascular comorbidities is used. AI-based ECG analysis is a promising step for correct LQTS patient identification, especially if common diagnostic measures might be misleading.

Psychological Aspects of Syncopes and Possible Association with Recurrency-The Role of Implantable Loop Recorders.

Syncopes are a very common phenomenon and have a high recurrence rate. The differentiation between the psychogenic and physical, especially of arrhythmic origin, remains difficult. In many cases, an implantable loop recorder is used for the detection of possible arrhythmias, leading to syncopes. Yet, the existing literature suggests that psychological factors may play a significant role in recurrent syncopes. We aimed at analyzing the potential role of several psychological factors on the recurrence of arrhythmic or non-arrhythmic syncopes. Methods and results: A total of 119 patients, who had received an implantable loop recorder for recurrent syncopes at our center between 01/2018 and 12/2021, participated in this retrospective cohort study. Anxiety, depression and quality of life were assessed using extensively validated questionnaires (GAD-7, PHQ-9 and SF-12). The mean follow-up after loop recorder implantation was 710 ± 430 days and 50% of patients were female. The mean patient age was 54.8 ± 18.6 years. Most patients had no evidence of structural heart disease (84%), and normal LV function (92%). A statistical analysis revealed that the presence of structural heart disease was the strongest predictor for arrhythmic syncope during follow-up. In patients with non-arrhythmic syncopes, we found significantly higher levels of anxiety (GAD-7 score: 2.5 ± 2.6 vs. 4.8 ± 4.3) and depression (PHQ-9 score: 3.9 ± 3.6 vs. 6.8 ± 5.1), and a lower quality of life (SF-12 score: 33.7 ± 6.4 vs. 29.6 ± 7.8). Discussion: We identified factors as contributors to a better identification of patients at risk for arrhythmic as well as non-arrhythmic syncopes. Especially anxious or depressive symptoms may hinted at non-arrhythmic causes of syncope. However, the study was limited by its retrospective design and low patient number. Further trials should likewise combine the diagnostic yield of loop recorders with psychometric evaluations before implantation and combine it with additional diagnostic measures, such as video monitoring, to further examine the role of psychological factors in the pathomechanism and treatment of syncope.

Incidence and predictors of cardiac arrhythmias in patients with COVID-19 induced ARDS.

INTRODUCTION: Recent studies suggest cardiac involvement with an increased incidence of arrhythmias in the setting of coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the risk of potentially lethal arrhythmias and atrial fibrillation in patients with COVID-19-induced acute respiratory distress syndrome (ARDS) and to elicit possible predictors of arrhythmia occurrence. METHODS AND RESULTS: A total of 107 patients (82 male, mean age 60 ±â€¯12 years, median body mass index 28 kg/m2) treated for COVID-19-induced ARDS in a large tertiary university hospital intensive care unit between March 2020 and February 2021 were retrospectively analyzed. Eighty-four patients (79%) had at least moderate ARDS, 88 patients (83%) were mechanically ventilated, 35 patients (33%) received vvECMO. Forty-three patients (40%) died during their hospital stay. Twelve patients (11%) showed potentially lethal arrhythmias (six ventricular tachycardia, six significant bradycardia). Atrial fibrillation occurred in 27 patients (25%). In a multivariate logistic regression analysis, duration of hospitalization was associated with the occurrence of potentially lethal arrhythmias (p = 0.006). There was no association between possible predictive factors and the occurrence of atrial fibrillation. Invasive ventilation, antipsychotics, and the QTc interval were independently associated with acute in-hospital mortality, but this was not arrhythmia-driven as there was no association between the occurrence of arrhythmias and mortality. CONCLUSION: In this relatively young population with COVID-19-induced ARDS, the incidence of potentially lethal arrhythmias was low. While overall mortality was high in these severely affected patients, cardiac involvement and arrhythmia occurrence was not a significant driver of mortality.

Incidence and predictors of left atrial appendage thrombus on transesophageal echocardiography before elective cardioversion.

Guidelines recommend transesophageal echocardiography (TEE) before cardioversion in thrombogenic arrhythmias when the requirement of ≥ 3 weeks of anticoagulation is not met. Current data to support this approach, especially with direct oral anticoagulants (DOAC), are scarce. We analyzed consecutive elective pre-cardioversion TEE in a high-volume electrophysiology center for the occurrence of left atrial appendage (LAA) thrombi or reduced LAA flow velocity. Possible predictors were recorded and compared in a multivariate logistic regression analysis. Consecutive pre-cardioversion TEE in 512 patients (148 female, median age 69 years) were included. In all patients, indication for TEE was either intake of anticoagulation < 3 weeks before cardioversion or uncertain adherence to the prescribed anticoagulation regimen. Of the 512 TEE, 19 (3.7%) depicted a LAA thrombus. An additional 41 patients (8.0%) showed either a reduced LAA flow velocity (≤ 20 cm/s), LAA sludge, or both. In a multivariate logistic regression analysis, QRS width on admission 12-lead ECG emerged as a possible predictor of LAA thrombus and reduced LAA flow (p = 0.008). Noteworthy, a high CHA2DS2-VASc score was not associated with an increased risk of reduced LAA emptying velocity and LAA thrombi were even found in patients with a CHA2DS2-VASc score of 0 (n = 1) and 1 (n = 1). The presence of LAA thrombus before an elective cardioversion is a rare event in the age of direct oral anticoagulants. However, LAA thrombi occurred even in supposed low-risk individuals according to the CHA2DS2-VASc score. QRS width may aid in identifying patients at risk of reduced LAA flow velocity.

Cardiovascular risk of energy drinks: Caffeine and taurine facilitate ventricular arrhythmias in a sensitive whole-heart model.

BACKGROUND: Several case reports have suggested an increased risk of sudden cardiac death due to energy drinks. Therefore, the purpose of this study was to assess acute electrophysiologic effects of caffeine and taurine, two of the main ingredients of energy drinks, in an experimental whole-heart model. METHODS AND RESULTS: Twenty-five rabbit hearts were excised, retrogradely perfused, and assigned to two groups. Hearts were perfused with caffeine (2, 10, and 50 µM) or taurine (2, 10, and 50 µM) after generating baseline data. Eight monophasic action potentials and electrocardiography recordings showed a significant abbreviation of action potential duration (APD90 ), QT interval, and effective refractory periods (ERP) after caffeine treatment. With taurine, cardiac repolarization duration and ERP were significantly shortened. A ventricular vulnerability was assessed by a predefined pacing protocol. With caffeine, we observed a trend towards more ventricular arrhythmias in a dose-dependent manner. After treatment with taurine, significantly more episodes of ventricular arrhythmias occurred. CONCLUSION: In this experimental whole-heart study, treatment with caffeine and taurine provoked ventricular arrhythmias. The underlying mechanism was an abbreviation of cardiac repolarizations and effective refractory periods that may facilitate re-entry and thereby provokes arrhythmias. These findings help to understand the potentially hazardous and fatal outcomes after intoxication with energy drinks.

Machine learning in the detection and management of atrial fibrillation.

Machine learning has immense novel but also disruptive potential for medicine. Numerous applications have already been suggested and evaluated concerning cardiovascular diseases. One important aspect is the detection and management of potentially thrombogenic arrhythmias such as atrial fibrillation. While atrial fibrillation is the most common arrhythmia with a lifetime risk of one in three persons and an increased risk of thromboembolic complications such as stroke, many atrial fibrillation episodes are asymptomatic and a first diagnosis is oftentimes only reached after an embolic event. Therefore, screening for atrial fibrillation represents an important part of clinical practice. Novel technologies such as machine learning have the potential to substantially improve patient care and clinical outcomes. Additionally, machine learning applications may aid cardiologists in the management of patients with already diagnosed atrial fibrillation, for example, by identifying patients at a high risk of recurrence after catheter ablation. We summarize the current state of evidence concerning machine learning and, in particular, artificial neural networks in the detection and management of atrial fibrillation and describe possible future areas of development as well as pitfalls. Typical data flow in machine learning applications for atrial fibrillation detection.

Incidence and Predictors of Left Atrial Appendage Thrombus before Catheter Ablation of Thrombogenic Arrhythmias.

Introduction: Transesophageal echocardiography (TEE) is routinely performed before catheter ablation of atrial tachyarrhythmias to rule out the presence of left atrial thrombi. However, data to support this practice are inconsistent. Methods: We analyzed consecutive pre-procedural TEE in a high-volume electrophysiology center for the presence of left atrial thrombi and a relevant flow reduction in the left atrial appendage (LAA) defined as LAA sludge or LAA emptying velocity (LAAEV) < 20 cm/s. The possible predictors of reduced flow were recorded and compared in a multivariate logistic regression analysis. Results: 1676 TEE were included (1122 before pulmonary vein isolation, 436 before atrial flutter ablation, 166 before other ablations). 543 patients (32%) were female and 991 (59%) were on DOAC. Nine patients (0.5%) had an LAA thrombus on pre-procedural TEE. Ninety-five further patients (5.7%) had a relevant reduction in LAA flow. The underlying rhythm showed a significant association with the presence of LAA thrombus or reduced LAA flow (p = 0.003). Patients in sinus rhythm and cavotricuspid isthmus-dependent atrial flutter exhibited the lowest risk. Additionally, reduced kidney function was associated with a reduction in LAA flow velocities (p = 0.04). Of note, two LAA thrombi occurred in patients in sinus rhythm and six out of nine patients with an LAA thrombus were on vitamin-K antagonists. Conclusions: LAA thrombus is a rare occurrence before an elective catheter ablation. The underlying rhythm and kidney function may serve as markers of a higher likelihood of significantly reduced LAAEV and LAA thrombus.

Accuracy of Deep Learning Echocardiographic View Classification in Patients with Congenital or Structural Heart Disease: Importance of Specific Datasets.

INTRODUCTION: Automated echocardiography image interpretation has the potential to transform clinical practice. However, neural networks developed in general cohorts may underperform in the setting of altered cardiac anatomy. METHODS: Consecutive echocardiographic studies of patients with congenital or structural heart disease (C/SHD) were used to validate an existing convolutional neural network trained on 14,035 echocardiograms for automated view classification. In addition, a new convolutional neural network for view classification was trained and tested specifically in patients with C/SHD. RESULTS: Overall, 9793 imaging files from 262 patients with C/SHD (mean age 49 years, 60% male) and 62 normal controls (mean age 45 years, 50.0% male) were included. Congenital diagnoses included among others, tetralogy of Fallot (30), Ebstein anomaly (18) and transposition of the great arteries (TGA, 48). Assessing correct view classification based on 284,250 individual frames revealed that the non-congenital model had an overall accuracy of 48.3% for correct view classification in patients with C/SHD compared to 66.7% in patients without cardiac disease. Our newly trained convolutional network for echocardiographic view detection based on over 139,910 frames and tested on 35,614 frames from C/SHD patients achieved an accuracy of 76.1% in detecting the correct echocardiographic view. CONCLUSIONS: The current study is the first to validate view classification by neural networks in C/SHD patients. While generic models have acceptable accuracy in general cardiology patients, the quality of image classification is only modest in patients with C/SHD. In contrast, our model trained in C/SHD achieved a considerably increased accuracy in this particular cohort.

Electrophysiologic effects of sacubitril in different arrhythmia models.

BACKGROUND: Previous studies report conflicting data regarding anti- or proarrhythmic effects of sacubitril. Aim of this study was to assess the impact of acute sacubitril treatment in different arrhythmia models. METHODS: Sacubitril was administered (3, 5, 10 µM) in 12 isolated rabbit hearts. Further 12 hearts were treated with erythromycin to simulate long-QT-syndrome-2 (LQT2). Other 12 hearts were perfused with veratridine to mimic long-QT-syndrome-3 (LQT3). Both LQT-groups were treated with sacubitril (5 µM) additionally. Ventricular vulnerability was assessed by a pacing protocol. AV-blocked bradycardic hearts were perfused with a hypokalemic solution to trigger torsade de pointes (TdP). In further 13 hearts, AF was induced by a combination of acetylcholine and isoproterenol and sacubitril (5 µM) was added afterwards. RESULTS: With sacubitril, action potential duration (APD) was abbreviated whereas spatial dispersion of repolarisation (SDR) remained stable. In both LQT groups, APD and SDR were increased. Infusion of sacubitril reduced APD (- 21 ms, p < 0.01) and SDR (- 8 ms) in the LQT2-group and did not alter APD (+2 ms) but reduced SDR (-19 ms, p < 0.01) in the LQT3-group. Ventricular vulnerability was not altered by sacubitril. No TdP were observed with sacubitril or under baseline conditions in any group. Sacubitril significantly suppressed TdP in the LQT2-group (3 vs. 43 episodes, p < 0.05) but not in the LQT3-group (10 vs. 16 episodes, p = ns). Sacubitril reduced inducibility of AF (9 vs. 31 episodes). CONCLUSION: Sacubitril abbreviated APD. In addition, sacubitril exhibits potential antiarrhythmic effects in LQT2 and may be beneficial in LQT3 and AF.

Experimental evidence for proarrhythmic effects of nonsteroidal anti-inflammatory drugs in a sensitive whole-heart model.

BACKGROUND: Previous studies have raised serious concerns on cardiovascular safety of widely prescribed nonsteroidal anti-inflammatory drugs (NSAIDs). Therefore, the aim of this study was to characterize the electrophysiological effects of certain NSAIDs in an established whole heart model of proarrhythmia. METHODS AND RESULTS: Thirty-eight hearts of New Zealand White rabbits were harvested and retrogradely perfused employing a Langendorff setup, and electrophysiology studies were performed to investigate action potential duration at 90% of repolarization (APD90 ), QT intervals, and effective refractory period (ERP). After generating baseline data, hearts were perfused with ibuprofen (Group 1, n = 12; 10 and 30 µM), indomethacin (Group 2, n = 13; 10 and 20 µM) and diclofenac (Group 3, n = 13; 10 and 20 µM), respectively, and the pacing protocols were repeated for each concentration. In all groups, perfusion with the NSAIDs resulted in a significant and reproducible shortening of APD90 and QT interval. In all groups, the arrhythmia susceptibility was significantly raised as occurrence of monomorphic ventricular tachycardia under programmed ventricular stimulation was significantly increased under perfusion with ibuprofen, indomethacin and diclofenac in all concentrations. CONCLUSION: The perfusion with ibuprofen, indomethacin and diclofenac in commonly used doses raised the arrhythmia susceptibility in an established rabbit whole-heart model while APD shortening and shortened ERP seem to be crucial for arrhythmogenesis.