Stress and high heart rate provoke ventricular tachycardia in mice expressing triadin.

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.

• Authors: Paulus Kirchhof, Jan Klimas, Larissa Fabritz, Melanie Zwiener, Larry R Jones, Michael Schäfers, Sven Hermann, Peter Boknik, Wilhelm Schmitz, Günter Breithardt, Uwe Kirchhefer, Joachim Neumann
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 42 Issue 5 Pg. 962-71 (May 2007) ISSN: 0022-2828 [Print] England
• PMID: 17408688 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium-Binding Proteins
• Carrier Proteins
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Muscle Proteins
• Trdn protein, mouse
• Asph protein, mouse
• Mixed Function Oxygenases

Topics

• Action Potentials
• Animals
• Calcium-Binding Proteins (genetics)
• Carrier Proteins (genetics)
• Crosses, Genetic
• Female
• Heart (physiology)
• Heart Rate
• Intracellular Signaling Peptides and Proteins
• Male
• Membrane Proteins (genetics)
• Mice
• Mice, Transgenic
• Mixed Function Oxygenases (genetics)
• Muscle Proteins (genetics)
• Physical Exertion
• Tachycardia, Ventricular (physiopathology)