CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Omega-3 polyunsaturated fatty acids prevent adrenergic-induced arrhythmias in a mouse model of catecholaminergic polymorphic ventricular tachycardia.
CURCIO A; VENETUCCI L; DE GIUSTI VC; LODOLA F; AVELINO CRUZ JE; MONTEFORTE N; BLOISE R; DENEGRI M; NAPOLITANO C; PRIORI SG
Congreso; Congreso de la Sociedad Italiana de Cardiología.; 2012
BACKGROUND: Adrenergically mediated ventricular tachyarrhythmias are associated to syncope and sudden cardiac death in patients affected by catecholaminergic polymorphic ventricular tachycardia (CPVT). We reported that CPVT is caused by mutations of the cardiac ryanodine receptor gene (hRyR2), and that these mutations led to arrhythmias by facilitating the onset of calcium waves and delayed afterdepolarizations (DADs) in cardiac myocytes during adrenergic stimulation. Anti-adrenergic treatment with beta-blockers represents the main therapy for clinical management of CPVT. However, arrhythmia control can be unsatisfactory, hence suggesting that additional therapies are needed. Omega-3 polyunsaturated fatty acids (PUFA) have been shown to prevent calcium waves and delayed afterdepolarizations (DADs) in vitro and to reduce the incidence of reperfusion arrhythmias in animal models. Therefore, we evaluated whether dietary PUFA reduce the occurrence of malignant ventricular tachycardias in the RyR2 R4496C mutation knock-in mouse model of CPVT. MATERIALS AND METHODS: Nineteen RyR2/RyR2R4496C mice at three weeks of age were randomly selected to standard or PUFA-enriched diet for 12 weeks, then subcutaneous telemetric recorders were implanted and electrocardiograms were acquired in both basal condition and upon intraperitoneal epinephrine (2 mg/kg) plus caffeine (120 mg/kg) challenge one week after surgery. Additional experiments were conducted on ventricular myocytes enzymatically dissociated using aortic retrograde perfusion and action potentials were recorded with patch-clamp technique in current-clamp configuration. RESULTS: Baseline heart rate (HR) was 675±58 beats per minute (bpm) in RyR2/RyR2R4496C mice (N=10) and 648±32 bpm in RyR2/RyR2R4496C mice treated with PUFA (N=9). Interestingly, pharmacologic stimulation induced a significant HR increase in RyR2/RyR2R4496C mice (11% change compared to basal, p<0.008) as opposed to RyR2/RyR2R4496C mice treated with PUFA (4% change compared to basal, p=0.19). Moreover, bidirectional ventricular tachyarrhythmias (BiVTachs) and polymorphic ventricular tachycardias were dramatically prevented by chronic PUFA administration in RyR2/RyR2R4496C treated mice (only one mouse out of 9 developed arrhythmias), which displayed only ventricular ectopic beats and bigeminism phenomena. Finally, electrophysiological assessments on isolated cardiomyocytes demonstrated that addition of PUFA in the external solution prevented the onset of DADs and triggered activity upon challenge with 30 nmol/L isoproterenol. CONCLUSIONS: We demonstrated for the first time that incorporated PUFA reduce BiVTachs elicited in a knock-in mouse model carrier of a mutation in the cardiac RyR2. This observation strengthens the assumption that the in vivo antiarrhythmic effects of PUFA are due to prevention of DADs. We are currently evaluating PUFA effectiveness in CPVT patients unresponsive to beta-blockers.