Objectives: 

Widely used murine models of adrenergic-induced cardiomyopathy offer little insight into electrical remodeling seen in human heart failure (HF) owing to a profound difference in the characteristics of ventricular repolarization in mice and rats vs. humans. We therefore sought to determine whether sustained adrenergic activation may produce a clinically relevant HF phenotype in the guinea-pig, an animal species whose ventricular action potential shape and electrical restitution properties resemble those determined in humans.

Methods: 

Male guinea pigs were injected daily with isoproterenol (ISO), a b-adrenoceptor agonist, in incremental doses (up to 1 mg/kg, i.p.) over a 12-week period. Echocardiography and isolated, perfused heart preparations were used to assess myocardial structural, contractile and electrophysiological changes produced by sustained ISO administration.

Results: 

Chronic adrenergic activation promoted HF as evidenced by cardiac hypertrophy, dilatation, basal systolic dysfunction, reduced contractile reserve in the presence of acute ISO stimulation, and pulmonary edema. These changes were associated with prolongation of left ventricular epicardial action potential, QT interval, an upward shift of electrical restitution curve, and reduced maximal restitution slope. The physiological difference in action potential duration between right and left ventricle (RV and LV) was eliminated in ISO-treated hearts, thereby contributing to impaired activation-to-repolarization coupling and reversed RV-to-LV difference in repolarization time.

Conclusion: 

We establish the guinea-pig model of ISO-induced HF, which enables the correlation of detrimental structural and contractile changes to repolarization abnormalities typically seen in HF.