Longitudinal arrhythmogenic remodelling in a mouse model of longstanding pressure overload

Boulaksil, Mohamed; Noorman, Maartje; Engelen, Markus A.; Veen, Toon A.B. van; Vos, Marc A.; Bakker, Jacques M.T. de; Rijen, Harold V. M. van

doi:10.1007/bf03091824

Cited by 19 publications

(14 citation statements)

References 17 publications

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“…Similar to previous studies on haemodynamic remodelling in mice after TAC (Boulaksil et al 2010; Shi et al 2013), the results of the experiments reported here demonstrate that left ventricular function is depressed after several weeks of pressure overload. Interestingly, we find that cardiac remodelling and deterioration of pump function follow similar time courses in WT and KChIP2 −/− mice, thus indicating that the progression of HF is independent of KChIP2.…”

Section: Discussionsupporting

confidence: 91%

Development of heart failure is independent of K⁺ channel‐interacting protein 2 expression

Speerschneider

Grubb

Metoska

et al. 2013

The Journal of Physiology

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Key points• Previous studies have suggested that the K + channel auxiliary subunit K + channel-interacting protein 2 (KChIP2) serves as a regulator of cardiac remodelling leading to heart failure and increased risk of arrhythmias.• The results presented here show that the progression of cardiac remodelling and heart failure induced by transverse aortic constriction follows a similar time course in wild-type and KChIP2 −/− mice.• Protein expression analysis shows that ventricular KChIP2 is significantly downregulated in heart failure in wild-type mice.• The electrophysiological analysis reveals enlarged J and T wave amplitudes and lower vulnerability to pacing-induced ventricular arrhythmias in KChIP2 −/− control mice compared to wild-type control mice. Heart failure in wild-type and KChIP2 −/− mice prompted comparable prolongation of QT intervals and ventricular effective refractory periods.• Collectively, these results demonstrate that KChIP2 does not influence the structural and functional development of heart failure. Moreover, in contrast to previously reported data, downregulation of KChIP2 expression in heart failure may reduce the risk of cardiac arrhythmia.Abstract Abnormal ventricular repolarization in ion channelopathies and heart disease is a major cause of ventricular arrhythmias and sudden cardiac death. K + channel-interacting protein 2 (KChIP2) expression is significantly reduced in human heart failure (HF), contributing to a loss of the transient outward K + current (I to ). We aim to investigate the possible significance of a changed KChIP2 expression on the development of HF and proarrhythmia. Transverse aortic constrictions (TAC) and sham operations were performed in wild-type (WT) and KChIP2 −/− mice. Echocardiography was performed before and every 2 weeks after the operation. Ten weeks post-surgery, surface ECG was recorded and we paced the heart in vivo to induce arrhythmias. Afterwards, tissue from the left ventricle was used for immunoblotting. Time courses of HF development were comparable in TAC-operated WT and KChIP2 −/− mice. Ventricular protein expression of KChIP2 was reduced by 70% after 10 weeks TAC in WT mice. The amplitudes of the J and T waves were enlarged in KChIP2 −/− control mice. Ventricular effective refractory period, RR, QRS and QT intervals were longer in mice with HF compared to sham-operated mice of either genotype. Pacing-induced ventricular tachycardia (VT) was observed in 5/10 sham-operated WT mice compared with 2/10 HF WT mice with HF. Interestingly, and contrary to previously published data, sham-operated KChIP2 −/− mice were resistant to pacing-induced VT resulting in only 1/10 inducible mice. KChIP2 −/− with HF mice had similar low vulnerability to inducible VT (1/9). Our results suggest that although KChIP2 is downregulated in HF, it is not orchestrating the development of HF. Moreover, KChIP2 affects ventricular repolarization and lowers arrhythmia susceptibility. Hence, downregulation of KChIP2 expression in HF may be antiarrhythmic in mice via reduction of...

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Section: Discussionsupporting

confidence: 91%

Development of heart failure is independent of K⁺ channel‐interacting protein 2 expression

Speerschneider

Grubb

Metoska

et al. 2013

The Journal of Physiology

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“…Moreover, CYP2J2 TG mice displayed less severe QRS interval prolongation than WT mice. QRS prolongation indicates ventricular conduction slowing and has been considered as a predictor of mortality in congestive heart failure patients [21], [22]. In agreement with the antiarrhythmic effect, CYP2J2 overexpression increased ventricular refractoriness.…”

Section: Discussionmentioning

confidence: 91%

CYP2J2 Overexpression Protects against Arrhythmia Susceptibility in Cardiac Hypertrophy

et al. 2013

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Maladaptive cardiac hypertrophy predisposes one to arrhythmia and sudden death. Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) promote anti-inflammatory and antiapoptotic mechanisms, and are involved in the regulation of cardiac Ca2+-, K+- and Na+-channels. To test the hypothesis that enhanced cardiac EET biosynthesis counteracts hypertrophy-induced electrical remodeling, male transgenic mice with cardiomyocyte-specific overexpression of the human epoxygenase CYP2J2 (CYP2J2-TG) and wildtype littermates (WT) were subjected to chronic pressure overload (transverse aortic constriction, TAC) or β-adrenergic stimulation (isoproterenol infusion, ISO). TAC caused progressive mortality that was higher in WT (42% over 8 weeks after TAC), compared to CYP2J2-TG mice (6%). In vivo electrophysiological studies, 4 weeks after TAC, revealed high ventricular tachyarrhythmia inducibility in WT (47% of the stimulation protocols), but not in CYP2J2-TG mice (0%). CYP2J2 overexpression also enhanced ventricular refractoriness and protected against TAC-induced QRS prolongation and delocalization of left ventricular connexin-43. ISO for 14 days induced high vulnerability for atrial fibrillation in WT mice (54%) that was reduced in CYP-TG mice (17%). CYP2J2 overexpression also protected against ISO-induced reduction of atrial refractoriness and development of atrial fibrosis. In contrast to these profound effects on electrical remodeling, CYP2J2 overexpression only moderately reduced TAC-induced cardiac hypertrophy and did not affect the hypertrophic response to β-adrenergic stimulation. These results demonstrate that enhanced cardiac EET biosynthesis protects against electrical remodeling, ventricular tachyarrhythmia, and atrial fibrillation susceptibility during maladaptive cardiac hypertrophy.

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“…Transverse aortic constriction (TAC) has been described previously (Boulaksil et al 2010). Briefly, mice were anaesthetized with 2% isoflurane and intubated.…”

Section: Induction Of Heart Failurementioning

confidence: 99%

Physiology and analysis of the electrocardiographic T wave in mice

Speerschneider

Thomsen

2013

Acta Physiologica

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Longitudinal arrhythmogenic remodelling in a mouse model of longstanding pressure overload

Cited by 19 publications

References 17 publications

Development of heart failure is independent of K⁺ channel‐interacting protein 2 expression

Development of heart failure is independent of K⁺ channel‐interacting protein 2 expression

CYP2J2 Overexpression Protects against Arrhythmia Susceptibility in Cardiac Hypertrophy

Physiology and analysis of the electrocardiographic T wave in mice

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Longitudinal arrhythmogenic remodelling in a mouse model of longstanding pressure overload

Cited by 19 publications

References 17 publications

Development of heart failure is independent of K+ channel‐interacting protein 2 expression

Development of heart failure is independent of K+ channel‐interacting protein 2 expression

CYP2J2 Overexpression Protects against Arrhythmia Susceptibility in Cardiac Hypertrophy

Physiology and analysis of the electrocardiographic T wave in mice

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Development of heart failure is independent of K⁺ channel‐interacting protein 2 expression

Development of heart failure is independent of K⁺ channel‐interacting protein 2 expression