Abstract 2512: Anti-arrhythmic Effects of 4-phenylbutyrate (4PB) in Cardiac Myocytes
A clinically approved anti-cancer agent, 4-phenylbutyrate (4PB), has recently been reported to promote the expression of connexin 43 (Cx43) when used in small doses. Cx43 is the main gap junction forming protein in ventricular myocytes and is critical in maintaining synchronization in heart function, especially in acidosis and other uncoupling-related conditions. We hypothesized that low dose 4PB (order of magnitude lower than clinically used) may be effective in improving conduction and in suppressing arrhythmogenic alternans, without adverse effects. Optical mapping was used in vitro on 4PB-treated and control cardiac cell monolayers. The development of spatiotemporal alternans was quantified under progressively increasing pacing frequencies by a custom-developed alternans detection and phase recognition algorithm. 4PB treatment significantly increased conduction velocity in cell monolayers at 30°C (p<0.001, >30% increase) without concomitant changes in the morphology of intracellular Ca2+ transients (Fig 1A⇓). Analysis of alternans evolution revealed that 4PB treatment improved tolerance to higher pacing rates and suppressed the occurrence of arrhythmogenic alternans (Fig 1B⇓). Control samples exhibited more alternans (at a fine spatial scale and over consolidated large areas), at earlier time points (lower frequencies) and developed conduction blocks earlier than 4PB-treated samples. Although further experiments are needed to fully characterize 4PB effects on cardiac function, the results reported here indicate that 4PB may be a promising candidate for treating cardiac arrhythmias, especially in conditions of compromised conduction.
This research has received full or partial funding support from the American Heart Association, Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).