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Updated: Jul 15, 2026
Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk
Published on: July 27, 2022
Stress and high heart rate provoke ventricular tachycardia in mice expressing triadin
Paulus Kirchhof1, Jan Klimas, Larissa Fabritz
1Department of Cardiology and Angiology, Hospital of the University of Münster, Germany. kirchhp@uni-muenster.de
Abstract:
Reduced function of the cardiac ryanodine receptor or calsequestrin causes catecholaminergic ventricular tachycardia (VT). These proteins regulate sarcoplasmic Ca(2+) release in close conjunction with two accessory proteins, triadin and junctin. Based on data from cardiomyocytes, we hypothesized that enhanced triadin expression could cause VT. We assessed arrhythmias and electrophysiological changes in vivo and in the beating heart in mice expressing junctin, triadin, or both proteins (TRDxJCN), and measured calcium transients in isolated ventricular cardiomyocytes. TRDxJCN mice were studied to compensate the down-regulation of junctin expression in triadin-expressing mice. Exercise or stress provoked repetitive VT in freely roaming TRDxJCN mice whenever heart rate increased above approximately 600 bpm (p<0.05 vs. the three other genotypes). TRDxJCN mice expressed total triadin 2.9-fold (p<0.05) and total junctin not different to wildtype (p=ns). Left ventricular systolic function was not different between lineages. beta-adrenoreceptor stimulation (orciprenaline 1.7 microM) provoked early-coupled ventricular ectopy and repetitive VT in isolated, Langendorff-perfused TRDxJCN hearts (p<0.05). Under conditions associated with VT (high pacing rate, catecholamine stimulation), action potential duration was shorter in TRDxJCN with VT than in the other genotypes and shorter than in TRDxJCN hearts without VT (p<0.05). Ca(2+) transient duration was prolonged in Indo1-loaded TRDxJCN cardiomyocytes under VT-provoking conditions. Action potential prolongation by mexiletine (2 microM or 4 microM) or clarithromycine (150 microM) suppressed VT. Expression of triadin provokes stress- and tachycardia-related ventricular arrhythmias in mice. An imbalance between prolonged intracellular calcium release and shortening of the ventricular action potential may contribute to genesis of arrhythmias in this model.
Insights
Enhanced triadin expression in mice causes stress-induced ventricular tachycardia (VT). This occurs due to an imbalance in intracellular calcium release and shortened action potential duration, suggesting triadin
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Arrhythmogenesis
Background:
- Reduced function of cardiac ryanodine receptor or calsequestrin is linked to catecholaminergic ventricular tachycardia (VT).
- Triadin and junctin are accessory proteins crucial for sarcoplasmic reticulum Ca(2+) release, alongside ryanodine receptors and calsequestrin.
- Previous studies suggest a potential role for triadin in arrhythmogenesis, but in vivo evidence is limited.
Purpose of the Study:
- To investigate the hypothesis that enhanced triadin expression can induce VT.
- To assess the in vivo and ex vivo electrophysiological consequences of altered triadin and junctin expression.
- To elucidate the underlying mechanisms of VT development in a mouse model with modified triadin/junctin levels.
Main Methods:
- Generation and characterization of transgenic mice expressing junctin, triadin, or both (TRDxJCN).
- In vivo assessment of arrhythmias during exercise or stress.
- Ex vivo electrophysiological studies on isolated hearts and cardiomyocytes, including calcium transient measurements and drug interventions.
Main Results:
- TRDxJCN mice exhibited stress- and tachycardia-induced repetitive VT at heart rates >600 bpm.
- Enhanced triadin expression (2.9-fold) with normal junctin levels provoked VT in response to beta-adrenergic stimulation.
- VT was associated with shortened action potential duration and prolonged Ca(2+) transient duration in TRDxJCN cardiomyocytes; VT was suppressed by drugs prolonging action potential.
Conclusions:
- Overexpression of triadin provokes stress- and tachycardia-related ventricular arrhythmias in mice.
- An imbalance between prolonged intracellular calcium release and shortened ventricular action potential duration contributes to VT genesis in this model.
- Triadin's role in regulating calcium handling and action potential dynamics is critical for cardiac electrical stability.
