DS0403 - Exploration des systèmes et organes leur fonctionnement normal et pathologique : physiologie, physiopathologie, vieillissement

Physiopathology of cardiac pacemaker activity: new therapeutic avenues for managing bradycardia – BradyCardia_Care

Submission summary

Cardiac automaticity results from the coordinated activity and the functional association between several classes of ion channels. The autonomic nervous system regulates channel activity to adapt the heart rate to the physiological demand of the organism. Dysfunction of heart automaticity underlies different kinds of arrhythmias and constitutes a major clinical issue. Among these, sino-atrial bradycardia, atrioventricular block, tachy-brady syndromes and ventricular tachycardias are common clinical conditions. However, the development of innovative therapeutic approaches to manage these arrhythmias is limited by our incomplete knowledge of the functional role of ion channels in the genesis and regulation of heart automaticity. Furthermore, we presently lack selective drugs able to modulate the activity of ion channels involved in cardiac pacemaking under conditions of rhythmic disease. To remove these limitations, we developed a unique collection of genetically modified mouse models where the activity of one or more ion channels involved in automaticity has been inactivated or modified. This collection of mice models allows in-depth investigation of the mechanistic bases of bradycardia and associated arrhythmias, as well as innovative testing of potential therapeutic approaches.
Recently, we showed the importance of f-channels (HCN4, pharmacologic target of Procoralan©) and that of L-type Cav1.3 and T-type Cav3.1 voltage-dependent Ca2+ channels in the generation of heart automaticity. Furthermore, the functional exploration of these mouse models showed that they faithfully reproduce bradycardia in humans, and particularly tachy-brady syndromes (Cav1.3-/-) and congenital heart block (Cav1.3-/-/Cav3.1-/-). Furthermore, we created a new and unique mouse model to study the mechanisms leading to bradycardia (HCN4-AYA) and showing a wide range of associated arrhythmias including atrial fibrillation, autonomic chronotropic incompetence, atrioventricular conduction dysfunction and ventricular tachycardia. Importantly, we showed that it is possible to normalize heart rate and rhythm of these mice by concomitant genetic inactivation or pharmacologic block of G-protein activated K+ (GIRK4) channels (Mesirca et al, Nat Commun 2014). This highly innovative result opens the way to manage bradycardia by developing GIRK4-regulating compounds.
Our project thus pursues two main aims. (i) To study the mechanistic links between ion channel loss-of-function and bradycardia, as well as the mechanisms of rescuing of this rhythmic disease by GIRK4 ablation or inhibition. (ii) To develop drugs targeting GIRK4 channels as a new pharmacologic approach to regulate and normalize heart rate in mice showing bradycardia and associated arrhythmias. The ultimate objective is to provide a better understanding of dysfunctions of the heart pacemaker mechanism and to propose an innovative therapy to manage bradycardia and associated arrhythmias in patients.
In more details, we shall investigate the mechanisms inducing bradycardia in mutant mice, as well as the mechanisms leading to normalisation of bradycardia and ventricular arrhythmia following inactivation or pharmacologic inhibition of GIRK4. We will use a wide range of in vivo and in vitro techniques to study cardiac pacemaker activity, intracellular Ca2+ release and functional crosstalk between ion channels. We will use available inhibitors of GIRK4 channels to improve heart rate of our mouse models of bradycardia. We will test modified toxins to target GIRK4. We shall also screen for new venom –based compounds active on GIRK4 to enlarge the pharmacological repertoire of available drugs. Our project will allow a better understanding of the mechanistic basis of bradycardia and promote the development of a new pharmacologic strategy to manage this invalidating arrhythmic disease.

Project coordination

Matteo Mangoni (Institut de Génomique Fonctionnelle)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


IGF - Université de Montpellier Institut de Génomique Fonctionnelle

Help of the ANR 483,000 euros
Beginning and duration of the scientific project: September 2015 - 36 Months

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