Effects of a reactive oxygen species generator, napabucasin (BBI608), on tolerability, safety, pharmacokinetics, and QT/QTc interval in healthy volunteers.

This study examined the safety, tolerability, and pharmacokinetics (PK) of napabucasin in healthy Asian and non-Asian participants and investigated the potential for QT/QTc interval prolongation. This five-part (A-E) study proceeded in a stepwise manner, unless stopping criteria were met. Parts A-D were randomized, double-blind, placebo-controlled, and included healthy Asian male and female and non-Asian male participants. PK parameters were measured following single-dose napabucasin (80-1200 mg) in the fasted or fed state (Part D). Potential QT/QTc interval prolongation was assessed using digital 12-lead electrocardiogram (Parts B and C). Part E was open-label, and examined the PK of single-dose napabucasin (240-720 mg) in healthy non-Asian males. Safety and tolerability were measured in Parts A-E. Changes from baseline in the Fridericia-corrected QT interval (ΔQTcF) and other electrocardiogram parameters were analyzed using a linear mixed-effects model. Napabucasin was well-tolerated across the study (n = 70), and no serious adverse events or significant safety issues were reported when administered with or without food. The most frequent treatment-emergent adverse events were diarrhea and abdominal pain, and these were mild in severity. No prolongation of the QTcF interval was reported following single-dose napabucasin (240-1200 mg) and changes in other cardiac parameters were negligible. The PK profile of napabucasin was consistent with earlier studies. Single-dose napabucasin was tolerated in healthy male and female participants, and no significant safety (including no QTcF prolongation) or tolerability issues were identified, irrespective of food intake. Clinical studies of napabucasin in advanced cancers are ongoing.

The Protective Effects of Coenzyme Q10 and Lisinopril Against Doxorubicin-Induced Cardiotoxicity in Rats: A Stereological and Electrocardiogram Study.

Doxorubicin (DOX) is used as an anticancer drug despite its several side effects, especially its irreversible impacts on cardiotoxicity. Coenzyme Q10 (Q10) as a powerful antioxidant and lisinopril (LIS) as an angiotensin-converting enzyme inhibitor seem to provide protection against DOX-induced cardiotoxicity. Therefore, this study aimed to assess the cardioprotective effects of Q10 and LIS against DOX-induced cardiotoxicity in rats. Adult male Sprague-Dawley rats were randomly assigned into the control, LIS, Q10, DOX, DOX + LIS, and DOX + Q10 groups. On day 21, ECG was recorded and the right ventricle was dissected for evaluation of catalase activity and malondialdehyde (MDA) concentration. Additionally, the left ventricle and the sinoatrial (SA) node were dissected to assess the stereological parameters. The results of ECG indicated bradycardia and increase in QRS duration and QT interval in the DOX group compared to the control group. Meanwhile, the total volumes of the left ventricle, myocytes, and microvessels and the number of cardiomyocyte nuclei decreased, whereas the total volume of the connective tissue and the mean volume of cardiomyocytes increased in the DOX group. On the other hand, the SA node and the connective tissue were enlarged, while the volume of the SA node nuclei was reduced in the DOX group. Besides, catalase activity was lower and MDA concentration was higher in the DOX-treated group. Q10 could recover most stereological parameters, catalase activity, and MDA concentration. LIS also prevented some stereological parameters and ECG changes and improved catalase activity and MDA concentration in the DOX group. The findings suggested that Q10 and LIS exerted cardioprotective effects against DOX-induced cardiac toxicity.

When Manual Analysis of 12-Lead ECG Holter Plays a Critical Role in Discovering Unknown Patterns of Increased Arrhythmogenic Risk: A Case Report of a Patient Treated with Tamoxifen and Subsequent Pneumonia in COVID-19.

Several medicines, including cancer therapies, are known to alter the electrophysiological function of ventricular myocytes resulting in abnormal prolongation and dispersion of ventricular repolarization (quantified by multi-lead QTc measurement). This effect could be amplified by other concomitant factors (e.g., combination with other drugs affecting the QT, and/or electrolyte abnormalities, such as especially hypokalemia, hypomagnesaemia, and hypocalcemia). Usually, this condition results in higher risk of torsade de point and other life-threatening arrhythmias, related to unrecognized unpaired cardiac ventricular repolarization reserve (VRR). Being VRR a dynamic phenomenon, QT prolongation might often not be identified during the 10-s standard 12-lead ECG recording at rest, leaving the patient at increased risk for life-threatening event. We report the case of a 49-year woman, undergoing tamoxifen therapy for breast cancer, which alteration of ventricular repolarization reserve, persisting also after correction of concomitant recurrent hypokalemia, was evidenced only after manual measurements of the corrected QT (QTc) interval from selected intervals of the 12-lead ECG Holter monitoring. This otherwise missed finding was fundamental to drive the discontinuation of tamoxifen, shifting to another "safer" therapeutic option, and to avoid the use of potentially arrhythmogenic antibiotics when treating a bilateral pneumonia in recent COVID-19.

Electrocardiographic features of immune checkpoint inhibitor associated myocarditis.

BACKGROUND: Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis. METHODS: From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested. RESULTS: Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39). CONCLUSIONS: The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.

Short P-Wave Duration is a Marker of Higher Rate of Atrial Fibrillation Recurrences after Pulmonary Vein Isolation: New Insights into the Pathophysiological Mechanisms Through Computer Simulations.

Background Short ECG P-wave duration has recently been demonstrated to be associated with higher risk of atrial fibrillation (AF). The aim of this study was to assess the rate of AF recurrence after pulmonary vein isolation in patients with a short P wave, and to mechanistically elucidate the observation by computer modeling. Methods and Results A total of 282 consecutive patients undergoing a first single-pulmonary vein isolation procedure for paroxysmal or persistent AF were included. Computational models studied the effect of adenosine and sodium conductance on action potential duration and P-wave duration (PWD). About 16% of the patients had a PWD of 110 ms or shorter (median PWD 126 ms, interquartile range, 115 ms-138 ms; range, 71 ms-180 ms). At Cox regression, PWD was significantly associated with AF recurrence (P=0.012). Patients with a PWD <110 ms (hazard ratio [HR], 2.20; 95% CI, 1.24-3.88; P=0.007) and patients with a PWD ≥140 (HR, 1.87, 95% CI, 1.06-3.30; P=0.031) had a nearly 2-fold increase in risk with respect to the other group. In the computational model, adenosine yielded a significant reduction of action potential duration 90 (52%) and PWD (7%). An increased sodium conductance (up to 200%) was robustly accompanied by an increase in conduction velocity (26%), a reduction in action potential duration 90 (28%), and PWD (22%). Conclusions One out of 5 patients referred for pulmonary vein isolation has a short PWD which was associated with a higher rate of AF after the index procedure. Computer simulations suggest that shortening of atrial action potential duration leading to a faster atrial conduction may be the cause of this clinical observation.

Vascular endothelial growth factor promotes atrial arrhythmias by inducing acute intercalated disk remodeling.

Atrial fibrillation (AF) is the most common arrhythmia and is associated with inflammation. AF patients have elevated levels of inflammatory cytokines known to promote vascular leak, such as vascular endothelial growth factor A (VEGF). However, the contribution of vascular leak and consequent cardiac edema to the genesis of atrial arrhythmias remains unknown. Previous work suggests that interstitial edema in the heart can acutely promote ventricular arrhythmias by disrupting ventricular myocyte intercalated disk (ID) nanodomains rich in cardiac sodium channels (NaV1.5) and slowing cardiac conduction. Interestingly, similar disruption of ID nanodomains has been identified in atrial samples from AF patients. Therefore, we tested the hypothesis that VEGF-induced vascular leak can acutely increase atrial arrhythmia susceptibility by disrupting ID nanodomains and slowing atrial conduction. Treatment of murine hearts with VEGF (30-60 min, at clinically relevant levels) prolonged the electrocardiographic P wave and increased susceptibility to burst pacing-induced atrial arrhythmias. Optical voltage mapping revealed slower atrial conduction following VEGF treatment (10 ± 0.4 cm/s vs. 21 ± 1 cm/s at baseline, p < 0.05). Transmission electron microscopy revealed increased intermembrane spacing at ID sites adjacent to gap junctions (GJs; 64 ± 9 nm versus 17 ± 1 nm in controls, p < 0.05), as well as sites next to mechanical junctions (MJs; 63 ± 4 nm versus 27 ± 2 nm in controls, p < 0.05) in VEGF-treated hearts relative to controls. Importantly, super-resolution microscopy and quantitative image analysis revealed reorganization of NaV1.5 away from dense clusters localized near GJs and MJs to a more diffuse distribution throughout the ID. Taken together, these data suggest that VEGF can acutely predispose otherwise normal hearts to atrial arrhythmias by dynamically disrupting NaV1.5-rich ID nanodomains and slowing atrial conduction. These data highlight inflammation-induced vascular leak as a potential factor in the development and progression of AF.

Effect of thyrotropin suppressive therapy on heart rate variability and QT dispersion in patients with differentiated thyroid cancer.

The effects of thyrotropin (TSH) suppressive therapy on autonomic regulation and ventricular repolarization in patients with differentiated thyroid cancer (DTC) have not been elucidated. The aim of present study was to evaluate variation in heart rate variability (HRV) and QT dispersion after TSH suppressive therapy in patients with DTC.Cases, defined as 271 patients with DTC within 1 year of exogenous levothyroxine, and all patients underwent a full history, physical examination, including standard 12 lead electrocardiogram (ECG), and 24 h ambulatory ECG monitoring (Holter) with normal free thyroxine (FT4) and free triiodothyronine (FT3) with levothyroxine. To evaluate effects of TSH suppressive therapy on HRV and QT dispersion, patients were divided into three groups according to different levels of TSH: TSH < 0.1 mIU/L group and 0.1 ≤ TSH < 0.5 mIU/L group were as TSH suppression groups, and 0.5 ≤ TSH < 2.0 mIU/L group was as TSH replacement group.Comparing with 0.5 ≤ TSH < 2.0 mIU/L group, significant changes in both time and frequency domain of HRV and QT dispersion were observed in TSH < 0.1 mIU/L group (P < .001: SDNN, SDANN, HF, LF/HF, QTd, and QTcd; P < .05: rMSSD) and 0.1 ≤ TSH < 0.5 mIU/L group (P < .001: SDNN, HF, LF/HF, QTd, and QTcd), and especially were more pronounced in TSH < 0.1 mIU/L group. Moreover, we found that TSH level was proportional to SDNN (ß = 15.829, P < .001), but inversely proportional to LF/HF (ß = -0.671, P < .001), QTd (ß = -16.674, P < .001) and QTcd (ß = -18.314, P < .001) in DTC patients with exogenous levothyroxine.Compared with euthyroid state, patients with suppressed serum TSH have increased sympathetic activity in the presence of diminished vagal tone, ultimately showed sympathovagal imbalance and with an increased inhomogeneity of ventricular recovery times. These findings revealed that TSH suppression therapy had a significant impact on cardiovascular system and had certain guiding role in the treatment and management of patients with DTC.

Estimates of population-based incidence of malignant arrhythmias associated with medication use-a narrative review.

Certain medications are reported to be associated with acquired long-QT syndrome (ALQTS), which can degenerate into a potentially severe 'malignant' arrhythmia known as torsades de pointes (TdP). However, population-based estimations of the incidence of medication-associated malignant arrhythmia are limited. The purpose of this article is to review the clinical symptoms, cellular mechanism, categorization, and risk factors of these malignant arrhythmias, as well as illustrate results and methodological limitations of epidemiological literature which have previously estimated population-based incidence of ALQTS and malignant arrhythmia. Administrative databases in universal healthcare systems (such as Canada) can be used to provide a robust estimate of this incidence. We present a valid operational definition of medication-associated malignant arrhythmia, using Canadian hospital administrative data linked to prescription databases that can be used to estimate the population-based incidence. An estimation of incidence may have important implications with regard to understanding the potential widespread distribution of this adverse effect-which may influence medication prescribing patterns.

Evolution of Electrocardiographic Repolarization Parameters During Antiandrogen Therapy in Patients with Prostate Cancer and Hypogonadism.

We assessed the effects of antiandrogen therapy on ECG parameters of ventricular repolarization related to arrhythmic risk in 35 patients aged 70.3 ± 7 years with advanced prostate cancer treated with degarelix associated with enzalutamide (group A, 26 patients) or degarelix monotherapy (group B, 9 patients). We analyzed Fridericia corrected Q-T interval (QTc), Q-T dispersion (QTd), J-Tpeak interval (JTp), mean and maximum Tpeak-Tend interval (Tpe) and Tpe/QT ratio, Tpeak-Tend dispersion (Tped), index of cardio-electrophysiological balance (iCEB) from ECG tracings, and occurrence of ventricular premature beats (VPB) recorded by Holter ECG, before initiation of medication (M0) and after 6 months of treatment (M1). The groups had similar demographics except for a higher prevalence of prior myocardial infarction in group B (p = 0.01). All patients had low serum testosterone at M1. Baseline QTc, QTd, maxTpe/QT, meanTpe, maxTpe, Tped values were higher in B compared to A. They had a significant prolongation at M1 only in A. 20 patients in A and 6 in B had a 10% prolongation or decrease of iCEB (p = 0.66). In 5 patients, VPB severity increased from non-complex to complex: 3 in A and 2 in B (p = 0.31), but no sustained ventricular arrhythmia was registered. In conclusion, after 6 months of treatment, patients with hypogonadism on degarelix associated with enzalutamide had significant prolongation of QTc, QTd, maxTpe, meanTpe/QT, maxTpe/QT, Tped compared to patients on degarelix alone. The proportion of patients with 10% iCEB variation was similar between groups. There was no record of severe arrhythmias during the first 6 months of treatment.

Atrial fibrillation in Brugada syndrome: Current perspectives.

The incidence of atrial fibrillation (AF) in Brugada syndrome (BrS) has been reported at between 9% and 53% by different series, but the true prevalence is unknown. However, AF may be the presenting feature in some patients. The underlying mechanisms for AF may be a combination of multiple factors, genetic or acquired, that may impact upon autonomic function, atrial structure, and conduction velocities or other unknown factors. The presence of AF has been associated with a more malignant course, with a greater incidence of syncope and ventricular arrhythmias, thus acting as marker of more advanced disease. Regarding the management of patients with AF, antiarrhythmic drugs effective in preventing malignant arrhythmias in BrS such as quinidine or invasive treatment with pulmonary vein isolation (PVI) may be useful in AF treatment. In this review, we aim to present the current perspectives regarding the genetics, pathophysiology, management, and prognosis of AF in patients with BrS.

Prevalence and clinical impact of spontaneous and adenosine-induced pulmonary vein reconduction in the Contact-Force vs. Cryoballoon Atrial Fibrillation Ablation (CIRCA-DOSE) study.

BACKGROUND: Use of intraprocedural observation and pharmacologic challenges have been proposed as means to differentiate permanent pulmonary vein (PV)-left atrial conduction block from inadequate ablation lesions. OBJECTIVE: The purpose of this study was to determine the prevalence and clinical impact of spontaneous and adenosine-provoked reconnection using contemporary atrial fibrillation (AF) ablation technologies. METHODS: The CIRCA-DOSE (Cryoballoon vs. Irrigated Radiofrequency Catheter Ablation: Double Short vs. Standard Exposure Duration) study enrolled 346 patients with paroxysmal AF and randomized them to contact force-guided radiofrequency ablation (CF-RF) or cryoballoon ablation. Patients underwent provocative testing with adenosine after a 20-minute observation period. All patients received an implantable cardiac monitor for arrhythmia monitoring. RESULTS: Spontaneous reconnection was observed in 5.4% of PVs (71/1318) during the 20-minute postprocedure observation period, and dormant conduction was elicited in 5.7% of PVs (75/1318). Both spontaneous reconnection and dormant conduction were more common after CF-RF compared to cryoballoon ablation (P = .03 and P <.0001, respectively). Acute PV reconnection (spontaneous or adenosine-provoked) was associated with a significantly higher incidence of recurrent atrial tachyarrhythmia in the cryoballoon group (hazard ratio [HR] 2.39; 95% confidence interval [CI] 1.44-3.96; P = .0007) but not in the CF-RF group (HR 1.47; 95% CI 0.84-2.58; P = .16). In the absence of acute reconnection, the freedom from recurrent arrhythmia did not differ between groups (HR 0.95; 95% CI 0.6057-1.495; P = .83). CONCLUSION: Patients without spontaneous or adenosine-provoked reconnection had better outcomes compared to those with acute PV reconnection, suggesting that efforts should be directed toward ensuring an ideal ablation lesion at the first attempt in order to achieve durable PV isolation.

Electrophysiology Translational Considerations in Cardio-Oncology: QT and Beyond.

With improved screening and the advent of many novel therapeutics, patients with cancer are living longer and often surviving their disease. Cardiovascular complications have significant impact on both short- and long-term morbidity and mortality in these patients. While a great deal of attention has been paid to cardiomyopathy and heart failure, many other cardiotoxicities can occur, often at higher rates. Arrhythmias are a particularly common cardiovascular complication of cancer therapeutics and can range from benign to life threatening. Moreover, management of these rhythm disturbances can be challenging in cancer patients for various reasons including drug interactions, as well as underlying hematologic and metabolic disturbances. In this review, we describe the most common therapeutics associated with arrhythmias in cancer patients and provide a discussion about the potential basic and translational mechanisms leading to the development of the various rhythm disturbances which may help to guide prevention and treatment decisions. Clinicaltrials.gov Identifier: NCT02928497.

The acute toxic effects of platinum nanoparticles on ion channels, transmembrane potentials of cardiomyocytes in vitro and heart rhythm in vivo in mice.

BACKGROUND: Platinum nanoparticles (PtNPs) have been considered a nontoxic nanomaterial and been clinically used in cancer chemotherapy. PtNPs can also be vehicle exhausts and environmental pollutants. These situations increase the possibility of human exposure to PtNPs. However, the potential biotoxicities of PtNPs including that on cardiac electrophysiology have been poorly understood. METHODS: Ion channel currents of cardiomyocytes were recorded by patch clamp. Heart rhythm was monitored by electrocardiogram recording. Morphology and characteristics of PtNPs were examined by transmission electron microscopy, dynamic light scattering and electrophoretic light scattering analyses. RESULTS: In cultured neonatal mice ventricular cardiomyocytes, PtNPs with diameters 5 nm (PtNP-5) and 70 nm (PtNP-70) concentration-dependently (10-9 - 10-5 g/mL) depolarized the resting potentials, suppressed the depolarization of action potentials and delayed the repolarization of action potentials. At the ion channel level, PtNPs decreased the current densities of INa, IK1 and Ito channels, but did not affect the channel activity kinetics. In vivo, PtNP-5 and PtNP-70 dose-dependently (3-10 mg/kg, i.v.) decreased the heart rate and induced complete atrioventricular conduction block (AVB) at higher doses. Both PtNP-5 and PtNP-70 (10-9 - 10-5 g/mL) did not significantly increase the generation of ROS and leak of lactate dehydrogenase (LDH) from cardiomyocytes within 5 mins after exposure except that only very high PtNP-5 (10-5 g/mL) slightly increased LDH leak. The internalization of PtNP-5 and PtNP-70 did not occur within 5 mins but occurred 1 hr after exposure. CONCLUSION: PtNP-5 and PtNP-70 have similar acute toxic effects on cardiac electrophysiology and can induce threatening cardiac conduction block. These acute electrophysiological toxicities of PtNPs are most likely caused by a nanoscale interference of PtNPs on ion channels at the extracellular side, rather than by oxidative damage or other slower biological processes.

Regulating the Warburg effect on metabolic stress and myocardial fibrosis remodeling and atrial intracardiac waveform activity induced by atrial fibrillation.

Atrial fibrillation (AF) is associated with metabolic stress and induces myocardial fibrosis reconstruction by increasing glycolysis. One goal in the treatment of paroxysmal AF (p-AF) is to improve myocardial fibrosis reconstruction and myocardial metabolic stress caused by the Warburg effect. Adopted male canine that rapid right atrial pacing (RAP) for 6 days to establish a p-AF model. The canines were pre-treated with phenylephrine (PE) or dichloroacetic acid (DCA) before exposure to p-AF or non-p-AF. P-wave duration (Pmax), minimum P-wave duration (Pmin), P wave dispersion (PWD), atrial effective refractory period (AERP) and AERP dispersion (AERPd) were measured in canine atrial cardiomyocytes. Pyruvate dehydrogenase kinase-1 (PDK-1), PDK-4, lactate dehydrogenase A (LDHA), pyruvate dehydrogenase (PDH), citrate synthase (CS), isocitrate dehydrogenase (IDH), and matrix metalloproteinase 9 (MMP-9) were evaluated by western blotting and reverse transcription polymerase chain reaction (RT-PCR), content of adenosine monophosphate (AMP), adenosine triphosphate (ATP), lactic acid and glycogen, and activity of LDHA, PDK-1 and PDK-4 were evaluated by enzyme-linked immunosorbent assay (ELISA), myocardial tissue glycogen content was evaluated by PAS, myocardial fibrosis remodeling was evaluated by hematoxylin and eosin (H&E) and Masson staining. Our findings demonstrated that p-AF increases the Warburg effect-related metabolic stress and myocardial fibrosis remodeling by increasing the expression and activity of PDK-1, PDK-4, and LDHA, content of AMP and lactic acid, and the ratio of AMP/ATP and decreasing the expression of PDH, CS, and IDH, and glycogen content. In addition, p-AF can induce cardiomyocyte fibrosis remodeling and increase MMP-9 expression, and p-AF also increases atrial intracardiac waveform activity by prolonging Pmax, Pmin, PWD, and AERPd and shortening AERP. PDK isoforms agonists (PE) produce a similar p-AF pathological effect and can produce synergistic effects with p-AF, further increasing Warburg effect-related metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity. In contrast, the use of PDK-specific inhibitors (DCA) completely reverses these pathophysiological changes induced by p-AF. We demonstrate that p-AF can induce the Warburg effect in canine atrial cardiomyocytes and significantly improve p-AF-induced metabolic stress, myocardial fibrosis remodeling, and atrial intracardiac waveform activity by inhibiting the Warburg effect.

Underuse of ECG monitoring in oncology patients receiving QT-interval prolonging drugs.

OBJECTIVE: We examined use of ECG monitoring in oncology patients prescribed QT-prolonging drugs. METHODS: Patients ≥66 years diagnosed with cancer between 2005 and 2011 were identified through the Ontario Cancer Registry and linked to multiple population-based administrative databases to ascertain demographics, comorbidities, prescription drug use, systemic therapy and ECG. QT-prolonging drugs were identified as per drug lists developed by the Arizona Center for Education and Research on Therapeutics. Univariable and multivariable analyses were used to examine factors associated with ECG use in patients on first-line systemic therapy. RESULTS: A total of 48 236 patients (median age 74; 49% women) received one or more drugs associated with a risk of QT-interval prolongation but only 27% of patients had an ECG performed. Factors associated with more ECG use on multivariable analysis included recent cancer diagnosis (p for trend <0.001 between 2005 and 2011), use of concurrent QT-prolonging drugs (OR=1.15 per each additional QT-prolonging drug, 95% CI 1.12 to 1.17) and the presence of coronary artery disease (OR 1.31; 95% CI 1.25 to 1.38) and heart failure (OR 1.25; 95% CI 1.17 to 1.35). Use of anticancer (OR 0.74; 95% CI 0.70 to 0.79) and antiemetic (OR 0.93; 95% CI 0.88 to 0.99) QT-prolonging drugs was paradoxically associated with less ECG use. CONCLUSIONS: Our study highlights common use of QT-prolonging drugs and underuse of ECG in oncology patients. Since ECG is an inexpensive, non-invasive and widely available test, it may be readily incorporated in the monitoring of patients for toxicities in routine clinical practice.

Bupivacaine Toxicity Increases Transmural Dispersion of Repolarization, Developing of a Brugada-like Pattern and Ventricular Arrhythmias, Which is Reversed by Lipid Emulsion Administration. Study in an Experimental Porcine Model.

Unintentional administration of bupivacaine may be associated with electrocardiogram changes that promote the development cardiac arrhythmias. Ventricular repolarization markers (corrected QT, QT dispersion, Tpeak-Tend and Tpeak-Tend dispersion) are useful to predict cardiac arrhythmias. We aim to investigate the effects of bupivacaine on the transmural dispersion of repolarization and their reversion following intravenous lipid emulsion (ILE) administration. Fourteen pigs were anaesthetized with thiopental and sevoflurane and underwent tracheal intubation. After instrumentation, a 4 mg kg-bolus of bupivacaine was administrated followed by an infusion of 100 µg kg-1 min-1. QT interval, QTc:QT corrected by heart rate, Tpeak-to-Tend interval and QT and Tpeak-to-Tend dispersion were determined in a sequential fashion: after bupivacaine (at 1 min, 5 min and 10 min) and after ILE (1.5 mL kg-1 over 1 min followed by an infusion of 0.25 mL kg-1 min-1). Three additional animals received only ILE (control group). Bupivacaine significantly prolonged QT interval (∆:36%), QT dispersion (∆:68%), Tpeak-to-Tend (∆:163%) and Tpeak-to-Tend dispersion (∆:98%), from baseline to 10 min. Dispersion of repolarization was related to lethal arrhythmias [three events, including asystole, sustained ventricular tachycardia (VT)] and repeated non-sustained VT (4/14, 28%). A Brugada-like-ECG pattern was visualized at V1-4 leads in 5/14 pigs (35%). ILE significantly decreased the alterations induced by bupivacaine, with the termination of VT within 10 min. No ECG changes were observed in control group. Bupivacaine toxicity is associated with an increase of transmural dispersion of repolarization, the occurrence of a Brugada-like pattern and malignant VA. ILE reverses the changes in dispersion of repolarization, favouring the disappearance of the Brugada-like pattern and VT.

Effects of Dexmedetomidine on Myocardial Repolarization in Children Undergoing General Anesthesia: A Randomized Controlled Trial.

BACKGROUND: Dexmedetomidine is a highly selective α2-adrenergic agonist, which is increasingly used in pediatric anesthesia and intensive care. Potential adverse effects that have not been rigorously evaluated in children include its effects on myocardial repolarization, which is important given that the drug is listed as a possible risk factor for torsades de pointes. We investigated the effect of 3 different doses of dexmedetomidine on myocardial repolarization and transmural dispersion in children undergoing elective surgery with total IV anesthesia. METHODS: Sixty-four American Society of Anesthesiologists I-II children 3-10 years of age were randomized to receive dexmedetomidine 0.25 µg/kg, 0.5 µg/kg, 0.75 µg/kg, or 0 µg/kg (control), as a bolus administered over 60 seconds, after induction of anesthesia. Pre- and postintervention 12-lead electrocardiograms were recorded. The interval between the peak and the end of the electrocardiogram T wave (Tp-e; transmural dispersion) and heart rate-corrected QT intervals (myocardial repolarization) were measured by a pediatric electrophysiologist blinded to group allocation. Data were analyzed using an analysis of covariance regression model. The study was powered to detect a 25-millisecond difference in Tp-e. RESULTS: Forty-eight children completed the study, with data analyzed from 12 participants per group. There were no instances of dysrhythmias. Tp-e values were unaffected by dexmedetomidine administration at any of the studied doses (F = 0.09; P = .96). Mean (99% CI) within-group differences were all <2 milliseconds (-5 to 8). Postintervention, corrected QT interval increased in the control group, but decreased in some dexmedetomidine groups (F = 7.23; P < .001), specifically the dexmedetomidine 0.5 and 0.75 µg/kg doses. Within groups, the mean (99% CI) differences between pre- and postintervention corrected QT interval were 12.4 milliseconds (-5.8 to 30.6) in the control group, -9.0 milliseconds (-24.9 to 6.9) for dexmedetomidine 0.25 µg/kg, -18.6 milliseconds (-33.7 to -3.5) for dexmedetomidine 0.5 µg/kg, and -14.1 milliseconds (-27.4 to -0.8) for dexmedetomidine 0.75 µg/kg. CONCLUSIONS: Of the bolus doses of dexmedetomidine studied, none had an effect on Tp-e and the dexmedetomidine 0.5 and 0.75 µg/kg doses shortened corrected QT intervals when measured at 1 minute after dexmedetomidine bolus injection during total IV anesthesia. There is no evidence for an increased risk of torsades de pointes in this context.

A current understanding of drug-induced QT prolongation and its implications for anticancer therapy.

The QT interval, a global index of ventricular repolarization, varies among individuals and is influenced by diverse physiologic and pathophysiologic stimuli such as gender, age, heart rate, electrolyte concentrations, concomitant cardiac disease, and other diseases such as diabetes. Many drugs produce a small but reproducible effect on QT interval but in rare instances this is exaggerated and marked QT prolongation can provoke the polymorphic ventricular tachycardia 'torsades de pointes', which can cause syncope or sudden cardiac death. The generally accepted common mechanism whereby drugs prolong QT is block of a key repolarizing potassium current in heart, IKr, generated by expression of KCNH2, also known as HERG. Thus, evaluation of the potential that a new drug entity may cause torsades de pointes has relied on exposure of normal volunteers or patients to drug at usual and high concentrations, and on assessment of IKr block in vitro. More recent work, focusing on anticancer drugs with QT prolonging liability, is defining new pathways whereby drugs can prolong QT. Notably, the in vitro effects of some tyrosine kinase inhibitors to prolong cardiac action potentials (the cellular correlate of QT) can be rescued by intracellular phosphatidylinositol 3,4,5-trisphosphate, the downstream effector of phosphoinositide 3-kinase. This finding supports a role for inhibition of this enzyme, either directly or by inhibition of upstream kinases, to prolong QT through mechanisms that are being worked out, but include enhanced inward 'late' sodium current during the plateau of the action potential. The definition of non-IKr-dependent pathways to QT prolongation will be important for assessing risk, not only with anticancer therapies but also with other QT prolonging drugs and for generating a refined understanding how variable activity of intracellular signalling systems can modulate QT and associated arrhythmia risk.

Cardiac arrhythmia considerations of hormone cancer therapies.

Breast and prostate cancers are among the most prevalent cancers worldwide. Oestradiol and progesterone are major drivers for breast cancer proliferation, and androgens for prostate cancer. Endocrine therapies are drugs that interfere with hormone-activated pathways to slow cancer progression. Multiple new breakthrough drugs improving overall survival have recently been developed within this class. As the use of these latter drugs grows, incidence of cardiac arrhythmias has emerged as an unappreciated complication. These changes are not surprising given that sex hormones alter ventricular repolarization. Testosterone shortens action potential duration and QT interval duration, while oestradiol has an opposite effect. In patients with breast cancer, selective oestrogen receptor modulators are associated with more reports for long QT and torsade de pointes (TdP) than aromatase inhibitors, likely through an oestradiol-like effect on the heart. Cyclin-dependent kinase 4/6 inhibitors, a new class of anticancer drugs used in combination with endocrine therapies in hormone receptor positive breast cancer, are also variably associated with drug-induced long QT, particularly with ribociclib. In prostate cancer, androgen deprivation therapy is associated with long QT and TdP, and possibly atrial fibrillation for abiraterone. In this review, we have summarized the clinical and preclinical data focusing on cardiac arrhythmia considerations of hormone cancer therapies.

German Cardiac Society Working Group on Cellular Electrophysiology state-of-the-art paper: impact of molecular mechanisms on clinical arrhythmia management.

Cardiac arrhythmias remain a common challenge and are associated with significant morbidity and mortality. Effective and safe rhythm control strategies are a primary, yet unmet need in everyday clinical practice. Despite significant pharmacological and technological advances, including catheter ablation and device-based therapies, the development of more effective alternatives is of significant interest to increase quality of life and to reduce symptom burden, hospitalizations and mortality. The mechanistic understanding of pathophysiological pathways underlying cardiac arrhythmias has advanced profoundly, opening up novel avenues for mechanism-based therapeutic approaches. Current management of arrhythmias, however, is primarily guided by clinical and demographic characteristics of patient groups as opposed to individual, patient-specific mechanisms and pheno-/genotyping. With this state-of-the-art paper, the Working Group on Cellular Electrophysiology of the German Cardiac Society aims to close the gap between advanced molecular understanding and clinical decision-making in cardiac electrophysiology. The significance of cellular electrophysiological findings for clinical arrhythmia management constitutes the main focus of this document. Clinically relevant knowledge of pathophysiological pathways of arrhythmias and cellular mechanisms of antiarrhythmic interventions are summarized. Furthermore, the specific molecular background for the initiation and perpetuation of atrial and ventricular arrhythmias and mechanism-based strategies for therapeutic interventions are highlighted. Current "hot topics" in atrial fibrillation are critically appraised. Finally, the establishment and support of cellular and translational electrophysiology programs in clinical rhythmology departments is called for to improve basic-science-guided patient management.