An N-/L-Type calcium channel blocker, cilnidipine, reduces electrical and structural atrial remodeling associated with atrial fibrillation in a chronic dog model

Abstract

Drugs that suppress AF-promoting remodeling are currently lacking. Cilnidipine is a clinically available Ca 2+ channel blocker that inhibits N-type channels which regulate autonomic function. To assess the effect of cilnidipine on AF-related atrial remodeling. 3 groups of 8 dogs were followed for 3 weeks: – AF maintained by 600 bpm atrial tachypacing treated with placebo (AF + P) ; – cilnidipine 10 mg twice a day (AF + C) ; – instrumented control dogs (Sham). At terminal open-chest study, typical electrophysiological remodeling was observed ( Fig. 1 A) with AF + P: reduced left atrial (LA) effective refractory period (ERP: 69 ± 14 ms vs. 126 ± 15 Sham); enhanced AF vulnerability (inducibility by single extrastimuli: (77 ± 19 vs. 2 ± 6%); and increased AF duration after burst pacing (12.7 ± 10.1 min vs. 0.1 ± 0 min). All these changes were suppressed in AF + C: (ERP 90 ± 15; vulnerability 52 ± 27%; AF duration 5.3 ± 9.1 min). Ex vivo optical mapping ( Fig. 1 B) showed that conduction velocity was decreased in AF + P (68 ± 6 cm/s) vs. Sham (119 ± 9 cm/s, P 0.01); AF + C was protective (97 ± 9 cm/s). SCN5A was decreased in AF + P ( P < 0.01) but not in AF + C vs. Sham ( Fig. 1 C). GJA1 and Connexin43 were down regulated in AF + P ( P < 0.05), but not in AF + C, vs. Sham. Fibrous tissue content (Masson Trichrome) was increased in AF + P (17 ± 4%) vs. Sham (3 ± 1%, P < 0.001) ( Fig. 1 D); AF + C reduced fibrosis (10 ± 4%, P < 0.01). This study shows for the first that cilnidipine, a commercially available N-/L-type Ca 2+ channel blocker, attenuates AF-induced electrical and structural remodeling, introducing a novel potential therapeutic target for this unmet need.