Focal myocardial infarction induces global remodeling of cardiac sympathetic innervation: neural remodeling in a spatial context

Abstract

Myocardial infarction (MI) induces neural and electrical remodeling at scar border zones. The impact of focal MI on global functional neural remodeling is not well understood. Sympathetic stimulation was performed in swine with anteroapical infarcts (MI; n ϭ 9) and control swine (n ϭ 9). A 56-electrode sock was placed over both ventricles to record electrograms at baseline and during left, right, and bilateral stellate ganglion stimulation. Activation recovery intervals (ARIs) were measured from electrograms. Global and regional ARI shortening, dispersion of repolarization, and activation propagation were assessed before and during sympathetic stimulation. At baseline, mean ARI was shorter in MI hearts than control hearts (365 Ϯ 8 vs. 436 Ϯ 9 ms, P Ͻ 0.0001), dispersion of repolarization was greater in MI versus control hearts (734 Ϯ 123 vs. 362 Ϯ 32 ms 2 , P ϭ 0.02), and the infarcted region in MI hearts showed longer ARIs than noninfarcted regions (406 Ϯ 14 vs. 365 Ϯ 8 ms, P ϭ 0.027). In control animals, percent ARI shortening was greater on anterior than posterior walls during right stellate ganglion stimulation (P ϭ 0.0001), whereas left stellate ganglion stimulation showed the reverse (P ϭ 0.0003). In infarcted animals, this pattern was completely lost. In 50% of the animals studied, sympathetic stimulation, compared with baseline, significantly altered the direction of activation propagation emanating from the intramyocardial scar during pacing. In conclusion, focal distal anterior MI alters regional and global pattern of sympathetic innervation, resulting in shorter ARIs in infarcted hearts, greater repolarization dispersion, and altered activation propagation. These conditions may underlie the mechanisms by which arrhythmias are initiated when sympathetic tone is enhanced. autonomic nervous system; sympathetic nerves; cardiac innervation; neural remodeling REMODELING of the cardiac sympathetic nervous system after myocardial infarction (MI) has been linked to ventricular arrhythmias in animal models (29) and in humans (4,12,24). Modulation of cardiac sympathetic signaling is a major therapeutic strategy to prevent and treat ventricular arrhythmias (1,8,22). Despite its importance, the global electrophysiological consequences of postinfarct neural remodeling from a focal infarct remain poorly characterized.Patchy myocardial scars with surviving islands of myocytes characterize human infarcts (10, 17). Heterogeneous intramyocardial sympathetic nerve sprouting at scar border zones leads to labile repolarization, increased peak Ca 2ϩ current, and susceptibility to ventricular fibrillation in hypercholesterolemic rabbits (15). Increased transmural dispersion of repolarization has also been reported (13, 28), along with alterations in transient outward and inward rectifier K ϩ currents (21) in a postinfarct model with nerve sprouts.However, the electrophysiological responses to sympathetic activation exhibited by myocytes at and remote to a focal infarction have not been characterized. Specifically, the functi...

Long noncoding NONRATT021972 siRNA normalized abnormal sympathetic activity mediated by the upregulation of P2X7 receptor in superior cervical ganglia after myocardial ischemia

“…Sympathetic nerve remodeling occurs in the ischemic area after MI injury [47,48]. MI increases cardiac GAP43 expression in the infarcted area [48,49].…”

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

“…These experiments were, however, limited by discordance of the ganglion stimulated and the region mapped, the decentralization of the LSG, and in some cases the complete removal of the RSG. Using electrophysiologic indexes to examine the functional innervation patterns of left and right sympathetic nerves on the heart, our group and others have demonstrated that the anterior wall of the heart is innervated predominantly by the RSG, while the posterior wall is innervated by the LSG (2,53,63). Cardiac sympathetic denervation is frequently performed for intractable arrhythmias, however, left cardiac sympathectomy is still widely performed.…”

“…LSGS and RSGS were performed with repeated square-wave pulses at a frequency of 4-Hz, 4-ms duration for 30 s. Stimulation amplitude was set at the amplitude at which blood pressure and/or heart rate increased by 10% (generally 1-8 mA). Cardiac sympathetic activation was also confirmed by surface T-wave changes and increases in heart rate and blood pressure as previously described (2). Bipolar electrodes were placed around each stellate ganglion (superior and inferior) for stimulation, with the cathode being superior.…”

“…EGMs were recorded with a customized multiplexer (University of Utah, Salt Lake City, UT) (19,32). Using a previously described customized program (2) to generate the first derivative of the QRS, and second derivative of the T wave, activation time (AT) was measured as the time interval between the onset of ventricular activation and the minimum dV/dt of the QRS and repolarization time (RT) as the maximum dV/dt of the T wave. The activation recovery interval (ARI), a surrogate for APD (27,32), was taken as the difference between RT and AT (ARI ϭ RT Ϫ AT), as previously described.…”

Inflammation, oxidative stress, and glial cell activation characterize stellate ganglia from humans with electrical storm

“…These findings support the use of denervation via partial resection of the stellate ganglion to control arrhythmias (5,34,35) and to mitigate the progression of dilated CMY (36). Pathological changes within stellate ganglia that act to enhance neurotransmission create further electrical instability (37), increasing the risk of arrhythmias. Removal of a segment of the sympathetic chain may also eliminate these regions of the nervous system, which can potentially amplify sympathoexcitation.…”