Denervation supersensitivity of refractoriness in noninfarcted areas apical to transmural myocardial infarction.

Abstract

Denervation supersensitivity was demonstrated in anesthetized dogs 5 to 10 days after transmural myocardial infarction produced by latex embolization of a diagonal branch of the left anterior descending coronary artery. Sympathetic efferent denervation in noninfarcted myocardium apical to the infarction was demonstrated by a 90% depletion of myocardial norepinephrine content in the apical (45 ± 15 pg norepinephrine/g tissue) vs basal (437 ± 76 pg/g tissue) regions and by the lack of effective refractory period (ERP) shortening during bilateral ansae subclaviae stimulation in 34% of sites apical to the infarction. Supersensitivity in the area apical to the infarction was manifested by an exaggerated shortening of the ERP during both norepinephrine and isoproterenol infusions, with an upward and leftward shift in the dose-response curves in the apical vs basal regions (p < .001). The cellular mechanism for denervation supersensitivity did not involve detectable changes in the ,Badrenergic receptor adenylate cyclase system. There was no difference in the density of /3-adrenergic receptors ([1251]-cyanopindolol) in the apical (268.6 ± 22.7 fmol/mg protein) vs the basal (253.5 ± 24.8 fmol/mg protein) regions. Adenylate cyclase activity stimulated by guanosine triphosphate plus isoproterenol was slightly greater in the apical (58.7 ± 17.4%) than in the basal (49.6 ± 10.9%) region, but this difference did not reach statistical significance (p = .068). Muscarinic modulation of fl-receptor coupling (oxotremorine attenuation of guanosine triphosphate plus isoproterenol-stimulated adenylate cyclase activity) also was not significantly different at the apical (31.6 ± 17.5% inhibition) and basal (21.4 ± 20.9% inhibition) sites. These data show that a transmural myocardial infarction produces denervation supersensitivity in areas apical to the infarction, but in this preparation no differences in the total number or a redistribution of ,B-adrenergic receptors or adenylate cyclase activity were detected. Data from several studies indicate that efferent sympathetic nerves of the left ventricle course in the superficial subepicardium before diving transmurally, and travel in a basal-to-apical direction.0 15. 16 We have demonstrated that transmural myocardial infarction, presumably by affecting the postganglionic sympathetic nerves that traverse the area of infarction, produces sympathetic denervation in viable myocardium apical to the infarction. 7 We therefore reasoned that this area of myocardium might exhibit an exaggerated response to infused norepinephrine. We chose to investigate an electrophysiologic end point, shortening of effective refractory period (ERP), because it may be important in the development of arrhythmias.'`The purpose of this study was to test the hypothesis that transmural myocardial infarction produces sympathetic denervation supersensitivity in noninfarcted myocardium apical to the infarction.

The Role of the Autonomic Nervous System in Sudden Cardiac Death

“…Interestingly, the cellular mechanisms for this exaggerated response did not involve detectable differences in β-adrenergic receptor density or α subunit of the stimulatory G protein density or affinity in the apical vs basal areas. [31][32][33] Myocardial infarction produced loss of efferent sympathetic innervation in noninfarcted apical sites as early as 5 to 20 minutes after coronary occlusion, with more significant loss occurring over the following 3 hours. 33 Hence, disruption of neurotransmission, likely due disruption of sympathetic fibers that run along the coronaries, can lead to a heterogenous response in ERP even in areas of viable noninfarcted myocardium situated apical to the infarct.…”

Heterogeneous Sympathetic Innervation Influences Local Myocardial Repolarization in Normally Perfused Rabbit Hearts

“…This infusion rate of NE was selected because it is within the range of rates used in previous experimental studies of denervation supersensitivity. 11 After Ն10 minutes of NE infusion to allow a steady state to be achieved, arterial blood pressure, sinus cycle length, and ARI were repeated.…”

Brief Episode of Myocardial Ischemia Before Prolonged Ischemia Attenuates Cardiac Sympathetic Nerve Injury

“…31 The peri-infarct area with normal flow tracer uptake but reduced MIBG uptake is considered to be "denervated but viable" myocardium that may be supersensitive to catecholamines, and therefore, may be arrhythmogenic. 32 …”