Cardiac sympathetic nerve transdifferentiation reduces action potential heterogeneity after myocardial infarction

Abstract

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 Ca2+ 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.

Adrenergic supersensitivity and impaired neural control of cardiac electrophysiology following regional cardiac sympathetic nerve loss

“…6 B); however, control hearts had faster maximal HRs with SNS compared to DBH-Sap hearts (Control SNS: 442.0 ± 45.1 BPM vs. DBH-Sap: 333.2 ± 62.0 BPM, p < 0.05). We previously showed that SNS in the normal mouse heart leads to APD prolongation and CaTD shortening, while HR is increased 28 . Control hearts responded as expected, with APD prolongation and CaTD shortening at both the base and apex during SNS (Fig.…”

Stop the beat to see the rhythm: excitation-contraction uncoupling in cardiac research

“…As shown in Figure 1, since its first use for optical mapping in 2007, blebbistatin has all but replaced the other available EC uncouplers. In fact, in the last three years alone, blebbistatin was used twice as often (1,29,36,41,51,56,59,69,74,76,78,83,85,87) as any other uncoupler for imaging applications (25,27,33,46,54,55,80). The use of BDM/DAM and CytoD for optical mapping has essentially ceased, yet due to its lower cost, BDM/DAM may still be a reasonable choice for larger animal (i.e., non-rodent) studies (10,23,25,35,52,70,77), which require larger amounts of an EC uncoupler (72).…”

“…In contrast, the development of optical mapping offered a new mapping approach with superior spatial resolution (53) that is determined by the image sensor specifications (sensor size, number of pixels, and quantum efficiency) and the optical field of view (9). Additionally, the use of calciumsensitive probes enabled simultaneous measurements of electrical activity and intracellular calcium cycling, as demonstrated by Choi and Salama at the turn of the century (15), and now provides unprecedented insight into ECC parameters in normal and diseased hearts (31,42,56,74,76,83).…”

Autonomic Modulation for Cardiovascular Disease

“…In porcine models of chronic ischemia, as well as humans with ischemic cardiomyopathy, histologic changes in stellate ganglia neurons have been observed resulting in inflammation, glial cell activation, and oxidative stress (Ajijola et al, 2012(Ajijola et al, , 2015. Cholinergic transdifferentiation has been described following myocardial infarction, and, in animal models, co-release of acetylcholine with norepinephrine may be antiarrhythmic by reducing actional potential duration dispersion (Olivas et al, 2016;Wang et al, 2020).…”