CIC   05421
CENTRO DE INVESTIGACIONES CARDIOVASCULARES "DR. HORACIO EUGENIO CINGOLANI"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Omega-3 polyunsaturated fatty acids prevent adrenergic-induced arrhythmias in a mouse model of catecholaminergic polymorphic ventricular tachycardia.
Autor/es:
CURCIO A; VENETUCCI L; DE GIUSTI VC; LODOLA F; AVELINO CRUZ JE; MONTEFORTE N; BLOISE R; DENEGRI M; NAPOLITANO C; PRIORI SG
Lugar:
ROMA
Reunión:
Congreso; Congreso de la Sociedad Italiana de Cardiología.; 2012
Resumen:
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.