Thyroid hormones regulate cardiac repolarization and QT-interval related gene expression in hiPSC cardiomyocytes

Prolongation of cardiac repolarization (QT interval) represents a dangerous and potentially life-threatening electrical event affecting the heart. Thyroid hormones (THs) are critical for cardiac development and heart function. However, little is known about THs influence on ventricular repolarization and controversial effects on QT prolongation are reported. Human iPSC-derived cardiomyocytes (hiPSC-CMs) and multielectrode array (MEA) systems were used to investigate the influence of 3,3′,5-triiodo-l-Thyronine (T3) and 3,3′,5,5′-tetraiodo-l-Thyronine (T4) on corrected Field Potential Duration (FPDc), the in vitro analog of QT interval, and on local extracellular Action Potential Duration (APD). Treatment with high THs doses induces a significant prolongation of both FPDc and APD, with the strongest increase reached after 24 h exposure. Preincubation with reverse T3 (rT3), a specific antagonist for nuclear TH receptor binding, significantly reduces T3 effects on FPDc, suggesting a TRs-mediated transcriptional mechanism. RNA-seq analysis showed significant deregulation in genes involved in cardiac repolarization pathways, including several QT-interval related genes. In conclusion, long-time administration of high THs doses induces FPDc prolongation in hiPSC-CMs probably through the modulation of genes linked to QT-interval regulation. These results open the way to investigate new potential diagnostic biomarkers and specific targeted therapies for cardiac repolarization dysfunctions.

Association Between Obstructive Sleep Apnea and Stroke and Contributory Risk Factors

Obstructive sleep apnea (OSA), a common comorbidity in patients with stroke, has shown increasing prevalence over the past few decades. OSA is an important risk factor for stroke in addition to other well-known contributors, including hypertension, hyperlipidemia, atrial fibrillation, and diabetes mellitus. Moreover, OSA is an independent predictor of neurological outcomes and mortality. The pathological mechanisms underlying the association between OSA and stroke include autonomic dysfunction, hypertension, cardiac arrhythmia, dyslipidemia, impaired glucose tolerance, hypoxia, and inflammation. Continuous positive airway pressure (CPAP) therapy has proven clinical utility in improvement of neurological symptoms in patients with stroke. Findings from a CPAP withdrawal model have shown increased sympathetic activity in OSA with a consequent significant elevation in blood pressure, relevant cerebral hypoxia, and disturbed cardiac repolarization. In this review, we present an overview of the literature that describes an association between OSA and stroke in addition to the vascular risk factors, including hypertension, hyperlipidemia, atrial fibrillation, and diabetes mellitus. This study highlights the importance of early and accurate diagnosis and management of OSA for stroke prevention and care and will benefit physicians in clinical practice.

Safe electrophysiologic profile of dexmedetomidine in different experimental arrhythmia models

Previous studies suggest an impact of dexmedetomidine on cardiac electrophysiology. However, experimental data is sparse. Therefore, purpose of this study was to investigate the influence of dexmedetomidine on different experimental models of proarrhythmia. 50 rabbit hearts were explanted and retrogradely perfused. The first group (n = 12) was treated with dexmedetomidine in ascending concentrations (3, 5 and 10 µM). Dexmedetomidine did not substantially alter action potential duration (APD) but reduced spatial dispersion of repolarization (SDR) and rendered the action potentials rectangular, resulting in no proarrhythmia. In further 12 hearts, erythromycin (300 µM) was administered to simulate long-QT-syndrome-2 (LQT2). Additional treatment with dexmedetomidine reduced SDR, thereby suppressing torsade de pointes. In the third group (n = 14), 0.5 µM veratridine was added to reduce the repolarization reserve. Further administration of dexmedetomidine did not influence APD, SDR or the occurrence of arrhythmias. In the last group (n = 12), a combination of acetylcholine (1 µM) and isoproterenol (1 µM) was used to facilitate atrial fibrillation. Additional treatment with dexmedetomidine prolonged the atrial APD but did not reduce AF episodes. In this study, dexmedetomidine did not significantly alter cardiac repolarization duration and was not proarrhythmic in different models of ventricular and atrial arrhythmias. Of note, dexmedetomidine might be antiarrhythmic in acquired LQT2 by reducing SDR.

Species dependent cardiac electrophysiological effects elicited by various potassium channel blocking drugs

Rodents are commonly used as models in electrophysiology. However, distinct differences exist between large animals and rodents in terms of their ion channel expression and action potential shapes, possibly limiting the translational value of findings obtained in rodents. We aimed for a direct comparison of the possible impact of selective inhibition of ion channels on the cardiac repolarization in preparations from human hearts and from model species. We applied the standard microelectrode technique at 37°C on cardiac ventricular preparations (papillary muscles and trabecules) from human (n = 63), dog (n = 47), guinea pig (n = 53), rat (n = 43), and rabbit (n = 16) hearts, paced at 1 Hz. To selectively block the IKur current, 1 µM XEN-D101; IK1 current, 10 µM barium chloride; IKr current, 50 nM dofetilide; IKs current, 500 nM HMR-1556; and Ito current, 100 µM chromanol-293B were applied directly to the tissue bath. The block of IKur and IK1 elicited significantly more prominent prolongation of APD in rats (35.6% and 67.9%, respectively) when compared with the other species, including that of human (1.0% and 2.6%, respectively). On the other hand, IKr block did not affect APD in rat preparations (1.6%), whereas it elicited marked prolongation in other species (9.0–47.7%), especially being pronounced in human preparations (60.3%). IKs inhibition elicited similar but minor APD prolongation (0.3–11.4%) in all species. Inhibition of Ito moderately lengthened APD in dog (22.3%) and rabbit (17.5%) preparations but elicited no change of APD in human preparations. In contrast, block of Ito caused marked APD prolongation in rat preparations (33.2%). Our findings suggest that the specific inhibition of various ion channels elicits fundamentally different effects in rodent ventricular action potential when compared with those of other species, including human. Therefore, from a translational standpoint, rodent models in cardiac electrophysiological and arrhythmia research should be used with great caution.

ML277 regulates KCNQ1 single-channel amplitudes and kinetics, modified by voltage sensor state

KCNQ1 is a pore-forming K+ channel subunit critically important to cardiac repolarization at high heart rates. (2R)-N-[4-(4-methoxyphenyl)-2-thiazolyl]-1-[(4-methylphenyl)sulfonyl]-2 piperidinecarboxamide, or ML277, is an activator of this channel that rescues function of pathophysiologically important mutant channel complexes in human induced pluripotent stem cell–derived cardiomyocytes, and that therefore may have therapeutic potential. Here we extend our understanding of ML277 actions through cell-attached single-channel recordings of wild-type and mutant KCNQ1 channels with voltage sensor domains fixed in resting, intermediate, and activated states. ML277 has profound effects on KCNQ1 single-channel kinetics, eliminating the flickering nature of the openings, converting them to discrete opening bursts, and increasing their amplitudes approximately threefold. KCNQ1 single-channel behavior after ML277 treatment most resembles IO state-locked channels (E160R/R231E) rather than AO state channels (E160R/R237E), suggesting that at least during ML277 treatment, KCNQ1 does not frequently visit the AO state. Introduction of KCNE1 subunits reduces the effectiveness of ML277, but some enhancement of single-channel openings is still observed.

Thorough QT Study to Evaluate the Effect of Zoliflodacin, a Novel Therapeutic for Gonorrhea, on Cardiac Repolarization in Healthy Adults

Zoliflodacin is a novel spiropyrimidinetrione antibiotic being developed as single oral dose treatment to address the growing global threat of Neisseria gonorrhoeae . To evaluate the cardiac safety of zoliflodacin, a thorough QT/QTc (TQT) study was performed in healthy subjects. In this randomized, double-blind, placebo-controlled, 4-period crossover study, 72 subjects in a fasted state received a single dose of zoliflodacin 2 g (therapeutic), zoliflodacin 4 g (supratherapeutic), placebo, and moxifloxacin 400 mg as a positive comparator. Cardiac repolarization was measured by duration of the corrected QT interval by Fridericia’s formula (QTcF). At each time point up to 24 hours after zoliflodacin administration, the upper limit of the one-sided 95% confidence interval (CI) for the placebo-corrected change from the pre-dose baseline in QTcF (ΔΔQTcF) was less than 10 ms, indicating an absence of a clinically meaningful increase in QT prolongation. The lower limit of the one-sided multiplicity-adjusted 95% CI of ΔΔQTcF for moxifloxacin was longer than 5 ms at four time points from 1-4 hours after dosing, demonstrating adequate sensitivity of the QTc measurement. There were no clinically significant effects on heart rate, PR and QRS intervals, ECG morphology, or laboratory values. Treatment-emergent adverse events (AEs) were mild or moderate in severity and transient. This was a negative TQT study according to regulatory guidelines (E14) and confirms that a single oral dose of zoliflodacin is safe and well-tolerated. These findings suggest zoliflodacin is not proarrhythmic and contribute to the favorable assessment of cardiac safety for a single oral dose of zoliflodacin.

Estimation of anaerobic threshold by cardiac repolarization instability: a prospective validation study

Background Assessing lactate (LT) or anaerobic thresholds (AT) in athletes is an important tool to control training intensities and to estimate individual performance levels. Previously we demonstrated that ECG-based assessment of cardiac repolarization instability during exercise testing allows non-invasive estimation of AT in recreational athletes. Here, we validate this method in professional and amateur team sports athletes. Methods We included 65 team sports athletes (32 professionals and 33 amateur athletes; 51 men, 14 women, mean age 22.3 ± 5.2 years) undergoing a standardized incremental cycle exercise test. During exercise testing a high-resolution ECG (1000 Hz) was recorded in Frank-leads configuration and beat-to-beat vector changes of cardiac repolarization (dT°) were assessed by previously established technologies. Repolarization-based AT (ATdT°) was estimated by its typical dT°-signal pattern. Additionally, LT was detected in accordance to methods established by Mader (LTMader) and Dickhuth (LTDickhuth). Results All athletes performed exercise testing until exhaustion with a mean maximum workload of 262.3 ± 60.8 W (241.8 ± 64.4 W for amateur athletes and 283.4 ± 49.5 W for professional athletes). Athletes showed ATdT° at 187.6 ± 44.4 W, LTDickhuth at 181.1 ± 45.6 W and LTMader at 184.3 ± 52.4 W. ATdT° correlated highly significantly with LTDickhuth (r = 0.96, p < 0.001) and LTMader (r = 0.98, p < 0.001) in the entire cohort of athletes as well as in the subgroups of professional and amateur athletes (p < 0.001 for all). Conclusions ATdT°, defined by the maximal discordance between dT° and heart rate, can be assessed reliably and non-invasively via the use of a high-resolution ECG in professional and amateur athletes.