Description:
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<jats:bold>Background:</jats:bold>
Cathecolaminergic polymorphic ventricular (CPVT) is characterized by an increase in the ventricular arrhythmia burden with a gradual rise in the heart rate. However it has been observed that in young patients reaching maximum heart rate during exercise test CPVT may paradoxically be abolished. In addition, we previously reported that in isolated Casq2-/- hearts, a CPVT mouse model, an increase in heart rate can prevent the induction of CPVT. Here we hypothesize that increasing heart rate by vagolytic therapy can prevent CPVT in vivo.
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<jats:bold>Methods:</jats:bold>
Surface ECGs were recorded from 11 anaesthetized Casq2-/- mice (4 males and 7 females; 24±2 month of age). Vagolytic therapy was performed with an i.p. injection of 0.5mg/kg of atropine. After the heart rate increase had reached its plateau (~10 min post atropine), catecholamine challenge was carried out with 1.5mg/kg isoproterenol (Atr/ISO group). The incidence of PVC and VT was analyzed and compared with that obtained in the same mice after injection of only 1.5mg/kg of isoproterenol (ISO group).
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<jats:bold>Results:</jats:bold>
Administration of atropine in Casq2-/- mice increased the heart rate by 23% (±4%) but did not induce any arrhythmia (Fig. A). On the other hand, ISO alone, as expected, caused PVCs in all mice and VT episodes in 4/11 mice. Pretreatment with atropin significantly reduced PVC incidence during ISO challenge (Atr/ISO: 1.13±0.46 PVC/min vs. ISO: 4.93±1.74 PVC/min, p<0.05) (Fig. B) and completely prevented VT induction. Conversely, slowing the sinus heart by infusion of the muscarinic agonist carbachol significantly increased the incidence of ISO-induced CPVT in isolated perfused Casq2-/- hearts (n = 20 hearts, p<0.01).
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<jats:bold>Conclusions:</jats:bold>
A catecholamine-independent increase in the sinus heart rate, obtained by muscarinic receptor block with atropine, is sufficient to protect Casq2-KO mice from CPVT during catecholamine challenge in vivo.
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