Acetylcholine delays atrial activation to facilitate atrial fibrillation

Background Acetylcholine ( ACh) shortens action potential duration ( APD) in human atria. APDshortening facilitates atrial fibrillation (AF) by reducing the wavelength for reentry. However, the influence of AChon electrical conduction in human atria and its contribution to AF are unclear, particularly when combined with impaired conduction from interstitial fibrosis. Objective Investigate the effect of ACheffect on human atrial conduction and its role in AF with computational, experimental, and clinical approaches. Methods S1S2 pacing(S1=600ms and S2=variable cycle lengths) was applied to the following human AF computer models: a left atrial appendage (LAA) myocyteto quantify ACheffects on APD, maximum upstroke velocity (Vmax), and resting membrane potential (RMP); a LAA monolayer to quantify AChconduction effects; and 3) a left atrium (LA) to determine ACharrhythmogenicity. Heterogeneous AChand interstitial fibrosis were applied to the monolayer and LA models. To corroborate the simulations, APDand RMP from isolated human atrial myocyteswere recorded before and after 0.1 µM ACh. At the tissue level, LAAs from AF patients were optically mappedex vivo using Di-4-ANEPPS. The difference in total activation time (AT) was determined between AT initially recorded with S1 pacing, and AT recorded during subsequent S1 pacingwithout (n=6) or with (n=7) 100 µM ACh. Results In LAA myocytesimulations, S1 pacingwith 0.1 µM AChshortened APDby 41 ms, hyperpolarized RMP by 7 mV, and increased Vmax by 27 mV/ms. In human atrial myocytes, 0.1 µM AChshortened APDby 48 ms, hyperpolarized RMP by 3 mV, and increased Vmax by 6 mV/ms. In LAA monolayer simulations, S1 pacingwith AChhyperpolarized RMP to delay total AT by 32 ms without and 35ms with fibrosis. This led to unidirectional conduction block and sustained reentryin fibrotic LA with heterogeneous AChduring S2 pacing. In AF patient LAAs, S1 pacingwith AChincreased total AT from 39.3±26 ms to 71.4±31.2 ms (P=0.036) compared to no change without ACh(56.7±29.3 ms to 50.0±21.9 ms, P=0.140). Conclusions:In fibrotic atria with heterogeneous parasympathetic activation, AChfacilitates AF by shortening APDand slowing conduction to promote unidirectional conduction block and reentry.