Studies on Myocardial Funny Channels and the Funny Current Inhibitor Ivabradine in Healthy Cats and Cats with Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats and is associated with high morbidity and mortality. Evidence suggests that tachycardic events may trigger syncope, decompensation, or sudden death in otherwise well compensated human patients with HCM. Bradycardic agents used in feline HCM include beta-receptor antagonists or calcium channel blockers; hoverer, their clinical use may be limited by potential adverse effects. A drug that selectively and specifically lowers heart rate (HR), without intrinsic effects on cardiac function, may therefore be superior in the long-term treatment of feline HCM. Ivabradine is a highly selective funny current (If) inhibitor that acts directly on the sinoatrial node to induce a use- and dose-dependent reduction of HR. Ivabradine has been shown to have favorable effects on cardiac function in experimental animals but its use has not yet been studied in cats. The first study describes the pharmacokinetics of ivabradine and its major metabolite S-18982 after single and repeated oral administration of ivabradine (Procorolan®, Les Laboratoires Servier, France) in healthy cats. Two-compartmental and one-compartmental models with first-order input and elimination provided the best fit to the data for both ivabradine and S-18982.The two models were combined to produce a single 4-compartment model characterizing pharmacokinetics of ivabradine and S-18982. The second study describes the use of immunoblot analysis to evaluate myocardial expression of hyperpolarization-activated, cyclic nucleotide-gated (HCN) proteins in cats. In cats with HCM, HCN4 was significantly upregulated in left ventricular (LV) myocardial tissue whereas in right ventricular tissue only a trend was found. We also observed that maturation of ventricular cardiomyocytes toward the adult phenotype regarding HCN4 expression is completed prior to the age of 2-3 months. The results of the third catheter-based study demonstrate that intravenous administration of ivabradine consistently reduces HR and the rate-pressure product in anesthetized cats with HCM. LV systolic and diastolic function as well as left atrial (LA) performance were either unchanged or only minimally affected by ivabradine. Elevation of HR induced by catecholamines was significantly blunted by ivabradine in healthy cats as well as in cats with HCM. In the last two experiments, the non-inferiority of four weeks of oral ivabradine compared to atenolol and the effects of both drugs on reproducibility of echocardiographically-derived indices are described. Ivabradine demonstrated more favorable effects on several echocardiographic variables, including indices of LV systolic wall stress, LV relaxation, and LA function. Overall, the majority of echocardiographic variables obtained had excellent to good reproducibility justifying their use in the clinical setting. However, although unexpected, both drugs failed to increase reproducibility of the majority of echocardiographically-derived indices. Ivabradine was specifically useful in the separation of diastolic filling waves, making assessment of LV diastolic function clinically feasible. Based on these studies, oral ivabradine appears to be clinically well tolerated, safe and useful for effective HR control in cats. This may make ivabradine attractive in the treatment of feline HCM, although its long-term effects in cats with HCM and in particular in cats with dynamic LV outflow obstruction require further investigation.