BACKGROUND: Ibrutinib, a Bruton\'s tyrosine kinase inhibitor used in cancer therapy, exerts ventricular proarrhythmic effects; however, the underlying mechanisms remain unclear. Excitation-contraction coupling (E-C) disorders are pivotal for the genesis of ventricular arrhythmias (VAs), which arise mainly from the right ventricular outflow tract (RVOT). In this study, we aimed to comprehensively investigate whether ibrutinib regulates the electromechanical activities of the RVOT, leading to enhanced arrhythmogenesis, and explore the underlying mechanisms.
METHODS: We utilized conventional microelectrodes to synchronously record electrical and mechanical responses in rabbit RVOT tissue preparations before and after treatment with ibrutinib (10, 50, and 100 nM) and investigated their electromechanical interactions and arrhythmogenesis during programmed electrical stimulation. The fluorometric ratio technique was used to measure intracellular calcium concentration in isolated RVOT myocytes.
RESULTS: Ibrutinib (10-100 nM) shortened the action potential duration. Ibrutinib at 100 nM significantly increased pacing-induced ventricular tachycardia (VT) (from 0% to 62.5%, n = 8, p = 0.025). Comparisons between pacing-induced VT and non-VT episodes demonstrated that VT episodes had a greater increase in contractility than that of non-VT episodes (402.1 ± 41.4% vs. 232.4 ± 29.2%, p = 0.003). The pretreatment of ranolazine (10 μM, a late sodium current blocker) prevented the occurrence of ibrutinib-induced VAs. Ibrutinib (100 nM) increased late sodium current, reduced intracellular calcium transients, and enhanced calcium leakage in RVOT myocytes.
CONCLUSIONS: Ibrutinib increased the risk of VAs in the RVOT due to dysregulated electromechanical responses, which can be attenuated by ranolazine or apamin.

Background and Objectives: People with epilepsy (PWE) have a 2-3 times higher mortality rate than the general population. Sudden unexpected death in epilepsy (SUDEP) comprises a significant proportion of premature deaths, whereas sudden cardiac death (SCD) is among the leading causes of sudden death in the general population. Cardiac pathologies are significantly more prevalent in PWE. Whether electrocardiographic (ECG) parameters are associated with remote death in PWE has yet to be elucidated. The study objective was to assess whether interictal ECG parameters are associated with mortality in the long-term. Materials and Methods: The study involved 471 epilepsy patients who were hospitalized after a bilateral tonic-clonic seizure(s). ECG parameters were obtained on the day of hospitalization (heart rate, PQ interval, QRS complex, QT interval, heart rate corrected QT interval (QTc), ST segment and T wave changes), as well as reported ECG abnormalities. Mortality data were obtained from the Latvian National Cause-of-Death database 3-11, mean 7.0 years after hospitalization. The association between the ECG parameters and the long-term clinical outcome were examined. Results: At the time of assessment, 75.4% of patients were alive and 24.6% were deceased. Short QTc interval (odds ratio (OR) 4.780; 95% confidence interval (CI) 1.668-13.698; p = 0.004) was associated with a remote death. After the exclusion of known comorbidities with high mortality rates, short QTc (OR 4.631) and ECG signs of left ventricular hypertrophy (OR 5.009) were associated with a remote death. Conclusions: The association between routine 12-lead rest ECG parameters-short QTc interval and a pattern of left ventricular hypertrophy-and remote death in epilepsy patients was found. To the best of our knowledge, this is the first study to associate rest ECG parameters with remote death in an epileptic population.

This is a report of a patient with a history of hypertension and myocardial infarction and a left ventricular ejection fraction of 35% who suffered a syncopal event. Her admitting electrocardiogram was compatible with her old myocardial infarction, an anteroseptal left ventricular aneurysm, left ventricular hypertrophy, and short-QT syndrome. The present report discusses how each of these might contribute individually and to some extent synergistically to producing syncope. She was treated with an implantable cardioverter-defibrillator (ICD), though she did not meet strict Multicenter Automatic Defibrillator Implantation Trial (MADIT), MADIT II, and Multicenter Unsustained Tachycardia Trial (MUSTT) patient characteristics. Her implant, however, was consistent with the 2014 Heart Rhythm Society/American College of Cardiology/American Heart Association consensus document regarding patients who do not match clinical trial enrollees but for whom ICD consideration is appropriate.

Short QT syndrome (SQTS) is a malignant heart disorder defined by the presence of ventricular arrhythmias causing syncope and sudden cardiac arrest. The prevalence in the pediatric population is 0.05%. Quinidine is an established agent for pharmacological prophylaxis in SQTS patients, but can also terminate an electrical storm.

An otherwise healthy 64-year-old man with recently diagnosed multiple myeloma was admitted to hospital with hypercalcemia and renal failure. Despite his electrocardiogram showing short QT/QTc intervals, he was admitted without cardiac monitoring. He died suddenly a few hours later, likely from a fatal arrhythmia. This case illustrates that pronounced QT shortening from hypercalcemia is an underappreciated malignant finding that can portend a significant risk for arrhythmia and sudden cardiac death. In addition, we also discuss the causes of hypercalcemia associated short QT/QTc intervals and its ECG features.

We analyzed electropharmacological characteristics of microminipigs under halothane-anesthesia using anti-influenza virus drug oseltamivir, which has been known to possess multi-channel blocking properties, including Na+, Ca2+ and K+ channels (n = 4). Oseltamivir in doses of 0.3, 3 and 30 mg/kg was intravenously infused over 10 min with an interval of 20 min, which provided peak plasma concentrations 1.4, 7.4 and 125.5 µg/mL, respectively. The low dose did not alter any of the cardiovascular variables. The middle dose decreased the heart rate at 30 min after the start of the infusion. The high dose transiently returned the heart rate toward the baseline for 10-15 min, but decreased it for 20-60 min; decreased the mean blood pressure for 5-60 min; prolonged the PR interval for 10-60 min, and the QRS width for 10-20 min; but shortened the QT interval for 10-30 min, and the QTc for 5-60 min. Thus, oseltamivir can suppress the sinus automaticity, and atrioventricular nodal and intraventricular conduction; and decrease the mean blood pressure, extents of which were greater in microminipigs than in beagle dogs in our previous observation in spite of similar plasma concentrations, reflecting higher sensitivity of microminipigs for Na+ and Ca2+ channel inhibition than that of beagle dogs. In contrast to beagle dogs, oseltamivir shortened the repolarization period in microminipigs, indicating that oseltamivir can more potently inhibit the inward currents than the outward ones in the hearts of microminipigs. This information may help improve utilizatione of microminipigs as a laboratory animal.

Syncope is a common presentation to the emergency room. Unlike in the adult population, most pediatric syncope has non-life-threatening causes, and minimal evaluation in the emergency department is appropriate with parental reassurance. Despite this benign prognosis, care must be made to find uncommon and potentially fatal causes. The primary purpose of evaluation of the patient with syncope is to determine whether the patient is at increased risk for death and needs either admission to the hospital or an expedited outpatient evaluation. This article reviews some of the most dangerous causes of syncope in the pediatric patient.

The current regulatory guidelines recommend the use of QT interval to assess the risk of arrhythmogenic potential of new chemical entities. Recently, the electromechanical window (EMW), the difference in duration between electrical and mechanical systole, has been proposed as markers for drug-induced torsades de pointes (TdP); however, data of EMW in short QT model are not available. This study aimed to characterize the EMW as a marker for drug-induced ventricular arrhythmias in anesthetized rabbit model of long QT syndrome type 2 (LQT2) and short QT syndrome (SQTS) infused with reference compounds known to lengthen or shorten QT intervals. After rabbits were anesthetized with isoflurane, body surface electrocardiograms and left ventricular pressure were recorded. The LQT2 was produced by intravenous infusion with dofetilide (n = 6), quinidine (n = 6) and sotalol (n = 6) whereas the SQTS was induced by intravenous escalating concentrations of nicorandil (n = 7), pinacidil (n = 5) and cromakalim (n = 5). The EMW in anesthetized rabbits ranged from 1.3 to 53.3 msec. All three drugs known to lengthen QT intervals prolonged QT and QTcF interval while the EMW was markedly decreased to negative values. Pinacidil significantly produced QT and QTcF shortening and significantly abbreviated the EMW (p < 0.05). This study demonstrated that the EMW is associated with QT intervals (p < 0.001). It is negative in the presence of QT-prolonging drugs while it is more positive in the presence of QT-shortening drugs. The results suggest that the EMW in anesthetized rabbits can be used in drug safety evaluation in addition to the QT interval.

Persistent elevation of Ca(2+) influx due to prolongation of the action potential (AP), chronic activation of the β-adrenergic system and molecular remodeling occurs in stressed and diseased hearts. Increases in Ca(2+) influx are usually linked to prolonged myocyte action potentials and arrhythmias. However, the contribution of chronic enhancement of Cav1.2 activity on cardiac electrical remodeling and arrhythmogenicity has not been completely defined and is the subject of this study. Chronically increased Cav1.2 activity was produced with a cardiac specific, inducible double transgenic (DTG) mouse system overexpressing the β2a subunit of Cav (Cavβ2a). DTG myocytes had increased L-type Ca(2+) current (ICa-L), myocyte shortening, and Ca(2+) transients. DTG mice had enhanced cardiac performance, but died suddenly and prematurely. Telemetric electrocardiograms revealed shortened QT intervals in DTG mice. The action potential duration (APD) was shortened in DTG myocytes due to significant increases of potassium currents and channel abundance. However, shortened AP in DTG myocytes did not fully limit excess Ca(2+) influx and increased the peak and tail ICa-L. Enhanced ICa promoted sarcoplasmic reticulum (SR) Ca(2+) overload, diastolic Ca(2+) sparks and waves, and increased NCX activity, causing increased occurrence of early and delayed afterdepolarizations (EADs and DADs) that may contribute to premature ventricular beats and ventricular tachycardia. AV blocks that could be related to fibrosis of the AV node were also observed. Our study suggests that increasing ICa-L does not necessarily result in AP prolongation but causes SR Ca(2+) overload and fibrosis of AV node and myocardium to induce cellular arrhythmogenicity, arrhythmias, and conduction abnormalities.

Evidence for seizure-induced cardiac dysrhythmia leading to sudden unexpected death in epilepsy (SUDEP) has been elusive. We present a patient with focal cortical dysplasia who has had epilepsy for 19 years and was undergoing presurgical evaluation. The patient did not have any cardiologic antecedents. During long-term video-electroencephalography (EEG) monitoring, following a cluster of secondarily generalized tonic-clonic seizures (GTCS), the patient had prolonged postictal generalized EEG suppression, asystole, followed by arrhythmia, and the patient died despite cardiopulmonary resuscitation. Analysis of heart rate variability showed a marked increase in the parasympathetic activity during the period preceding the fatal seizures, compared with values measured 1 day and 7 months before, and also higher than the preictal values in a group of 10 patients with GTCS without SUDEP. The duration of the QTc interval was short (335-358 msec). This unfortunate case documented during video-EEG monitoring indicates that autonomic imbalance and seizure-induced cardiac dysrhythmias contribute to the pathomechanisms leading to SUDEP in patients at risk (short QT interval).