Cardiac sympathetic nerve transdifferentiation reduces action potential heterogeneity after myocardial infarction

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 318; no. 3; pp. H558 - H565
• Main Authors: Wang, Lianguo, Olivas, Antoinette, Francis Stuart, Samantha D., Tapa, Srinivas, Blake, Matthew R., Woodward, William R., Habecker, Beth A., Ripplinger, Crystal M.
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.03.2020
• Series: Integrative Cardiovascular Physiology and Pathophysiology
• Subjects: Action Potentials - physiology; Adrenergic Neurons - metabolism; Animals; Calcium Signaling - physiology; Cell Transdifferentiation - physiology; Choline O-Acetyltransferase - genetics; Choline O-Acetyltransferase - metabolism; Cholinergic Neurons - metabolism; Disease Models, Animal; Heart - innervation; Mice; Mice, Knockout; Myocardial Infarction - metabolism; Myocardial Infarction - physiopathology; Sympathetic Nervous System - metabolism; transdifferentiation; sympathetic activity; intracellular calcium; action potential; arrhythmia
• ISSN: 0363-6135; 1522-1539; 1522-1539
• DOI: 10.1152/ajpheart.00412.2019

Cardiac sympathetic nerves undergo cholinergic transdifferentiation following reperfused myocardial infarction (MI), whereby the sympathetic nerves release both norepinephrine (NE) and acetylcholine (ACh). The functional electrophysiological consequences of post-MI transdifferentiation have never been explored. We performed MI or sham surgery in wild-type (WT) mice and mice in which choline acetyltransferase was deleted from adult noradrenergic neurons [knockout (KO)]. Electrophysiological activity was assessed with optical mapping of action potentials (AP) and intracellular Ca 2+ transients (CaT) in innervated Langendorff-perfused hearts. KO MI hearts had similar NE content but reduced ACh content compared with WT MI hearts (0.360 ± 0.074 vs. 0.493 ± 0.087 pmol/mg; KO, n = 6; WT, n = 4; P < 0.05). KO MI hearts also had higher basal ex vivo heart rates versus WT MI hearts (328.5 ± 35.3 vs. 247.4 ± 62.4 beats/min; KO, n = 8; WT, n = 6; P < 0.05). AP duration at 80% repolarization was significantly shorter in the remote and border zones of KO MI versus WT MI hearts, whereas AP durations (APDs) were similar in infarct regions. This APD heterogeneity resulted in increased APD dispersion in the KO MI versus WT MI hearts (11.9 ± 2.7 vs. 8.2 ± 2.3 ms; KO, n = 8; WT, n = 6; P < 0.05), which was eliminated with atropine. CaT duration at 80% and CaT alternans magnitude were similar between groups both with and without sympathetic nerve stimulation. These results indicate that cholinergic transdifferentiation following MI prolongs APD in the remote and border zone and reduces APD heterogeneity. NEW & NOTEWORTHY Cardiac sympathetic neurons undergo cholinergic transdifferentiation following myocardial infarction; however, the electrophysiological effects of corelease of norepinephrine and acetylcholine (ACh) have never been assessed. Using a mouse model in which choline acetyltransferase was deleted from adult noradrenergic neurons and optical mapping of innervated hearts, we found that corelease of ACh reduces dispersion of action potential duration, which may be antiarrhythmic.