Acute isoproterenol leads to age-dependent arrhythmogenesis in guinea pigs

Abstract

Sudden cardiac death from ventricular arrhythmias is more common in adult patients with with heart failure compared with pediatric patients with heart failure. We identified age-specific differences in arrhythmogenesis using a guinea pig model of acute β-adrenergic stimulation. Young and adult guinea pigs were exposed to the β-adrenergic agonist isoproterenol (ISO; 0.7 mg/kg) for 30 min in the absence or presence of flecainide (20 mg/kg), an antiarrhythmic that blocks Na and ryanodine channels. Implanted cardiac monitors (Reveal LINQ, Medtronic) were used to monitor heart rhythm. Alterations in phosphorylation and oxidation of ryanodine receptor 2 (RyR2) were measured in left ventricular tissue. There were age-specific differences in arrhythmogenesis and sudden death associated with acute β-adrenergic stimulation in guinea pigs. Young and adult guinea pigs developed arrhythmias in response to ISO; however, adult animals developed significantly more premature ventricular contractions and experienced higher arrhythmia-related mortality than young guinea pigs treated with ISO. Although there were no significant differences in the phosphorylation of left ventricular RyR2 between young and adult guinea pigs, adult guinea pigs exposed to acute ISO had significantly more oxidation of RyR2. Flecainide treatment significantly improved survival and decreased the number of premature ventricular contractions in young and adult animals in association with lower RyR2 oxidation. Adult guinea pigs had a greater propensity to develop arrhythmias and suffer sudden death than young guinea pigs when acutely exposed to ISO. This was associated with higher oxidation of RyR2. The incidence of sudden death can be rescued with flecainide treatment, which decreases RyR2 oxidation. NEW & NOTEWORTHY Clinically, adult patients with heart failure are more likely to develop arrhythmias and sudden death than pediatric patients with heart failure. In the present study, older guinea pigs also showed a greater propensity to arrhythmias and sudden death than young guinea pigs when acutely exposed to isoproterenol. Although there are well-described age-related cardiac structural changes that predispose patients to arrhythmogenesis, the present data suggest contributions from dynamic changes in cellular signaling also play an important role in arrhythmogenesis.

Effects of exercise training on behavior and brain function after high dose isoproterenol-induced cardiac damage

“…ISO, administered twice with 24 h in between, evoked inflammation and cytokine production and cardiac fibrosis 1 , that over a period of weeks developed into left ventricular hypertrophy and dilatation, and ultimately heart failure 2 . Effects of ISO appeared age dependent 23 , 24 . Accordingly, in the present study mortality in the adult (12 months old) animals was substantially higher than in the young (3 months old) rats.…”

Age-dependent changes in electrophysiology and calcium handling: implications for pediatric cardiac research

“…Maturation of the cardiovascular system can have a profound effect on the efficacy and potency of pharmacological agents. Previous studies have documented an age-dependent cardiovascular re-sponse to isoproterenol, a nonspecific ␤-adrenergic agonist, in both in vivo [e.g., canine, guinea pig (10,63)] and isolated cardiomyocyte preparations [e.g., rat (28)]. Isoproterenol exerted a greater effect on the coronary vasculature in adult isolated whole hearts, increasing the coronary flow rate in adults by 104% compared with 12% in juvenile hearts (P Ͻ 0.0001; Fig.…”

Effects of Exercise Training on Behavior and Brain Function after High Dose Isoproterenol-Induced Cardiac Damage

“…ISO, administered twice with 24h in between, evoked in ammation and cytokine production and cardiac brosis [1], that over a period of weeks developed into left ventricular hypertrophy and dilatation, and ultimately heart failure [4]. Effects of ISO appeared age dependent [17,18]. Accordingly, in the present study mortality in the adult (12 months old) animals was substantially higher than in the young (3 months old) rats.…”