The fungicide Tebuconazole induces electromechanical cardiotoxicity in murine hearts

Tebuconazole (TEB) is an important fungicide that belongs to the triazole family. It is largely applied in agriculture and its use has increased in the last decade. Since TEB is stable in water and soil, long-term exposure of humans to this pesticide is a real threat. Acute toxicological studies to uncover the toxicity of TEB are limited, and there is evidence of an association between long-term exposure to TEB and damage of several biological systems, including hepatotoxicity and cardiotoxicity. In this paper, the effects of acute exposure of cardiomyocytes and murine hearts to TEB were addressed to elucidate its impact on electromechanical properties of the cardiac tissue. In whole-cell patch-clamp records, TEB inhibited both the total outward potassium current (IC50=5.7±1.5 μmol.l−1) and the L-type calcium current (IC50=33.2±7.4 μmol.l−1). Acute exposure to TEB at 30 μmol.l−1 prolonged the action potential duration as well as an induced out-of-pace action potential, and increased the sodium/calcium exchanger current in its forward and reverse modes. Moreover, sarcomere shortening and calcium transient in isolated cardiomyocytes was enhanced when cells were exposed to TEB at 30 μmol.l−1. In ex vivo experiments, TEB 30 μmol.l−1 caused significant electrocardiogram remodeling with prolonged PR, QRS, and QT interval duration. Accordingly, TEB exposure was prone to the appearance of arrhythmias. Combined, our results demonstrate that acute TEB exposure affects the cardiomyocyte's electro-contractile properties and triggers the appearance of ECG abnormalities, including conduction defects and arrhythmias.

Monogenic and Polygenic Contributions to QTc Prolongation in the Population

Background: Rare sequence variation in genes underlying the long QT syndrome (LQTS) and common polygenic variation influence QT interval duration. It is unclear how rare and common variation contribute to QT interval duration in the general population. Objectives: Investigate monogenic and polygenic contributions to QT interval duration and the role of polygenic variation in modulating phenotypic expression of rare monogenic variation. Methods: We performed a genome wide association study (GWAS) of QTc duration in 44,979 United Kingdom Biobank (UKBB) participants and created a polygenic risk score (PRS). The PRS was validated in 39,800 independent UKBB participants. Among 26,976 participants with whole genome sequencing and ECG data in the TransOmics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 LQTS genes. We examined QTc associations with the PRS and with LQTS rare variants in TOPMed. Results: Twenty independent loci (4 novel) were identified by GWAS. The PRS comprising 565 common variants was significantly associated with QTc duration in TOPMed (p=1.1x10-64). Carriers of LQTS rare variants had longer QTc intervals than non-carriers (deltaQTc=10.9 ms [7.4-14.4] for all LQTS genes; deltaQTc=26.5 ms [20.7-32.3] for KCNQ1, KCNH2 and SCN5A). 16.7% of individuals with QTc>480 ms carried either a rare variant in a LQTS gene or had a PRS in the top decile (3.4% monogenic, 13.6% top decile of PRS). We observed a greater effect of rare variants on the QTc among individuals with a higher polygenic risk (lowest PRS tertile:deltaQTccarrier/non-carrier=4.8 ms [-1.2-10.7];highest PRS tertile:deltaQTccarrier/non-carrier=18.9 ms [12.8-25.1];p-interaction=0.001). Conclusions: QTc duration is influenced by both rare variants in established LQTS genes and polygenic risk. The phenotypic expression of monogenic variation is modulated by polygenic variation. Nevertheless, over 80% of individuals with prolonged QTc do not carry a rare monogenic variant or polygenic risk equivalent.

Sexual Dimorphisms, Anti-Hormonal Therapy and Cardiac Arrhythmias

Significant variations from the normal QT interval range of 350 to 450 milliseconds (ms) in men and 360 to 460 ms in women increase the risk for ventricular arrhythmias. This difference in the QT interval between men and women has led to the understanding of the influence of sex hormones on the role of gender-specific channelopathies and development of ventricular arrhythmias. The QT interval, which represents the duration of ventricular repolarization of the heart, can be affected by androgen levels, resulting in a sex-specific predilection for acquired and inherited channelopathies such as acquired long QT syndrome in women and Brugada syndrome and early repolarization syndrome in men. Manipulation of the homeostasis of these sex hormones as either hormonal therapy for certain cancers, recreational therapy or family planning and in transgender treatment has also been shown to affect QT interval duration and increase the risk for ventricular arrhythmias. In this review, we highlight the effects of endogenous and exogenous sex hormones in the physiological and pathological states on QTc variation and predisposition to gender-specific pro-arrhythmias.

Abstract 17253: The Late Sodium Current Contributes to Electromechanical Defects Occurring With Aging

To establish the contribution of the late sodium current (I NaL ) on cardiovascular defects occurring with aging, mice with phosphomimetic mutation of Na + channel Nav1.5 at Ser571 (S571E), which causes I NaL enhancement in cardiomyocytes (I NaL gain-of-function), and mice with ablation of the Nav1.5 Ser571 (S571A), preventing CaMKII-mediated I NaL increase under stress condition (I NaL loss-of-function) were studied together with C57Bl/6 mice (wild-type, WT). Male mice at 2-6 (~4 m), 10-16 (~12 m), 17-20 (~18 m), and 20-27 (~24 m) months of age underwent electrocardiographic and echocardiographic evaluation. In WT mice, the QT interval duration of the ECG in the anesthetized state was similar at ~4 and ~12 months (56±5 ms and 58±5 ms, respectively) and was prolonged at ~18 and ~24 months (66±4 ms and 67±3 ms, respectively). In S571E mice, QT interval at ~4 months was prolonged with respect to WT animals (67±4 ms) and remained protracted at ~12, ~18, and ~24 months (65±3 ms, 68±6 ms, and 69±5 ms). S571A animals at ~4 months presented intermediate QT interval duration with respect to the other two strains (61±3 ms), and remained unchanged at ~12, ~18, and ~24 months (63±4 ms, 62±4 ms, and 64±4 ms). Ejection fraction was not altered with age and was comparable for the three mouse groups. In contrast, by transmitral flow Doppler echocardiography diastolic function, quantified here by the isovolumic relaxation time, was normal in WT mice at ~4 (17.4±1.6 ms) and ~12 months (16.8±1.6 ms) and became depressed at ~18 (21.5±2.5 ms) and ~24 months (21.4±1.7 ms). Defective diastolic function was apparent in S571E mice at ~4 months (19.7±2.9 ms) and persisted at ~12, ~18, and ~24 months (19.1±1.7 ms, 21.0±1.9 ms, and 22.1±2.2 ms, respectively). Interestingly, S571A mice at ~4 months had normal diastolic function (16.2±2.2 ms) and minor alterations were observed at ~12, ~18, and ~24 months (17.1±1.5 ms, 18.4±1.6 ms, and 19.3±3.3 ms, respectively). Overall, collected results suggest that I NaL enhancement in S571E mice is associated with premature appearance of prolonged electrical recovery and defective diastolic function, with respect to aging WT animals. In contrast, S571A mice, with inability to increase I NaL , are protected from electromechanical defects occurring with aging.

Abstract 16495: Activation of Notch Signaling in the Heart Promotes Electrical Disturbances

Notch1 receptor signaling is active in the heart during embryonic development, is progressively silenced after birth, and it is partly restored in the adult myocardium following ischemic damage, a condition characterized by occurrence of arrhythmias. We previously reported that inducible overexpression of Notch1 intracellular domain (gain-of-function, NGoF) in adult mouse cardiomyocytes alters ionic currents and action potential profile. But the consequences of Notch1 signaling activation on electrical properties and arrhythmogenicity of the entire heart remain to be defined. For this purpose, electrocardiograms were obtained in NGoF (n=25) and corresponding control (Ctrl, n=13) mice in the conscious state, over a 10 min period. Electrical signals were obtained at baseline and following administration of an arrhythmogenic cocktail (120 mg/kg BW caffeine and 2 mg/kg BW epinephrine) to test the propensity of these animals to develop electrical disturbances. Moreover, information was also obtained in mice with inducible Notch1 gene deletion for complete silencing of Notch1 signaling (Notch1 loss-of-function, NLoF, n=5). At baseline, heart rate and QT interval duration were comparable in NGoF (689±30 bpm; 49±2 ms), Ctrl (703±29 bpm; 48±1 ms), and NLoF (697±50 bpm; 48±1 ms) animals. Only a small fraction (~8%) of NGoF mice presented isolated premature ventricular complexes (PVCs) or junctional rhythm, but these events were not observed in Ctrl and NLoF mice. Administration of the arrhythmogenic cocktail induced PVCs in the majority of Ctrl (~56%) and NLoF (~60%) mice and in almost all NGoF animals (~92%). Also recurrent PVCs (≥10/10 min) were 1.7-2.1-fold higher in NGoF mice, with respect to NLoF and Ctrl. Importantly, 77% of NGoF mice developed ventricular tachycardia (VT), whereas VT occurrence was attenuated in Ctrl (56%) and NLoF (~40%) animals. Incidence of sustained VT was 1.7-fold higher in NGoF mice, with respect to Ctrl. Similarly, bidirectional VT was higher in NGoF (~62%), with respect to Ctrl (~52%) and NLoF (~40%). Thus, Notch signaling activation in the heart of experimental animals tends to enhance the occurrence of electrical disturbances, a factor that may be involved in the arrhythmogenic behavior of the post-infarcted myocardium.