Rescuing cardiac automaticity in L‐type Cav1.3 channelopathies and beyond

Abstract

Pacemaker activity of the sino-atrial node generates the heart rate. Disease of the sinus node and impairment of atrioventricular conduction induce an excessively low ventricular rate (bradycardia), which cannot meet the needs of the organism. Bradycardia accounts for about half of the total workload of clinical cardiologists. The 'sick sinus' syndrome (SSS) is characterized by sinus bradycardia and periods of intermittent atrial fibrillation. Several genetic or acquired risk factors or pathologies can lead to SSS. Implantation of an electronic pacemaker constitutes the only available therapy for SSS. The incidence of SSS is forecast to double over the next 50 years, with Abstract figure legend Genetically modified mice carrying loss-of-function in Ca v 1.3 or HCN4 channels display bradycardia and heart block (experimental channelopathy). This condition is similar to some forms of inherited sino-atrial node dysfunction in humans. The G protein-activated K + current I KACh constantly imposes negative chronotropic and dromotropic effects on the heart rhythmogenic centres under physiological conditions (normal heart rate). However, the action of I KACh becomes detrimental under conditions of diseased heart impulse generation and eventually causes symptoms associated with bradycardia. In humans, these symptoms are managed by implantation of an electronic pacemaker, which constitutes the only currently available therapy. In mice, 'compensatory' genetic or pharmacological targeting of I KACh can rescue bradycardia. This strategy may open the way for new therapeutic options to handle disease of heart automaticity in humans.

Pregnancy and oestrogen regulate sinoatrial node calcium homeostasis and accelerate pacemaking

“… 22 , 23 , 29 Indeed, as previously reported Ca V 1.3 constitutes the major L-type Ca 2+ channel isoform in the diastolic depolarization of the mouse SAN AP and in support of this observation, previous studies have shown that deletion of Ca V 1.3 resulted in bradycardia and dysrhythmic SAN pacemaking. Furthermore, Ca V 1.3 was demonstrated to play a critical role in modulating intra-cellular Ca 2+ dynamics by regulating Ca 2+ release from the SR. 22 , 23 , 29 Although it was shown that Ca V 1.3 deletion resulted in an inhibition of Ca 2+ transients, it is very likely that the increase in Ca V 1.3 we observed here, along with the increase in RyR2, serves the opposite purpose: increasing Ca 2+ transient rate and robustness of the Ca V 1.3/RyR2 coupling, thereby sustaining the elevated HR during pregnancy. In support of this notion, Torrente et al 22 recently reported that Ca V 1.3 channels co-localize with RyR2 in mouse SAN cells, which would favour the Ca 2+ -induced Ca 2+ release from the SR.…”

Inhibition of G protein-gated K+ channels by tertiapin-Q rescues sinus node dysfunction and atrioventricular conduction in mouse models of primary bradycardia

“…We have chosen mice (Mus musculus) as the model animal species for this study. Mice were considered for our experiments, because of the availability in our laboratory of genetically modified strains recapitulating congenital primary SND 53 . To the best of our knowledge, no alternative animal models of primary SND are available.…”

Génération de la fonction sinusale et perspectives thérapeutiques

“…Comme indiqué dans les paragraphes précédents, la perte de fonction des canaux f-HCN4 et Ca v 1.3 induit des dysfonctions sinusales chez les souris génétiquement modifiées et chez l’homme. Nous avons montré que l’ablation génétique ou l’inhibition pharmacologique des canaux Girk4 codant pour I KACh normalise la fréquence et le rythme cardiaque des souris Ca v 1.3 −/− et HCN4-AYA [5,14]. Nos résultats montrent que la normalisation de la fonction sinu-sale et l’amélioration de la conduction s’expliquent par un phénomène de rétablissement de l’équilibre entre courants entrants et sortants activés dans la dépolarisation diastolique (Fig.…”