Chronic myocardial infarction induces phenotypic and functional remodeling in the guinea pig cardiac plexus

Abstract

Chronic myocardial infarction (CMI) is associated with remodeling of the ventricle and evokes adaption in the cardiac neurohumoral control systems. To evaluate the remodeling of the intrinsic cardiac nervous system following myocardial infarction, the dorsal descending coronary artery was ligated in the guinea pig heart and the animals were allowed to recover for 7-9 wk. Thereafter, atrial neurons of the intrinsic cardiac plexus were isolated for electrophysiological and immunohistochemical analyses. Intracellular voltage recordings from intrinsic cardiac neurons demonstrated no significant changes in passive membrane properties or action potential configuration compared with age-matched controls and sham-operated animals. The intrinsic cardiac neurons from chronic infarcted hearts did demonstrate an increase in evoked action potential (AP) frequency (as determined by the number of APs produced with depolarizing stimuli) and an increase in responses to exogenously applied histamine compared with sham and age-matched controls. Conversely, pituitary adenylate cyclase-activating polypeptide (PACAP)-induced increases in intrinsic cardiac neuron-evoked AP frequency were similar between control and CMI animals. Immunohistochemical analysis demonstrated a threefold increase in percentage of neurons immunoreactive for neuronal nitric oxide synthase (NOS) in CMI animals compared with control and the additional expression of inducible NOS by some neurons, which was not evident in control animals. Finally, the density of mast cells within the intrinsic cardiac plexus was increased threefold in preparations from CMI animals. These results indicate that CMI induces a differential remodeling of intrinsic cardiac neurons and functional upregulation of neuronal responsiveness to specific neuromodulators.

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

“…Mechanistically, sympathetic innervation increases repolarization lability and heterogeneity (42,57) and is associated with arrhythmogenesis (56). Following cardiac injury, there is also extensive structural and functional neural remodeling throughout the cardiac neural hierarchy (1,18,41) and it is associated with increased sympathetic tone. In the heart, nerve sprouts have been identified in peri-infarct zones and associated with VAs, via poorly understood mechanisms (9).…”

Angiotensin receptors alter myocardial infarction-induced remodeling of the guinea pig cardiac plexus

“…MI was induced in a total of 32 animals by surgical ligation of the ventral descending coronary artery just distal to its first diagonal branch, as previously described (13). This procedure produces an infarct region equivalent to ϳ7-8% of the left ventricular tissue (13). Animals were treated with appropriate analgesics postoperatively and allowed to recover for ϳ7 wk.…”

“…Intracellular voltage recordings from intracardiac neurons were obtained with an AxoClamp 2B amplifier (Axon Instruments) from cells impaled with 2 M KCl-filled microelectrodes (40 -80 M⍀), as previously described (13). Input resistance was determined with small 0.1-or Ϫ0.1-nA pulses (500 ms), and single action potentials were stimulated with short, depolarizing pulses (0.3-0.9 nA, 5 ms).…”

“…Myocardial infarction was induced in guinea pigs by ligation of the descending coronary artery. Previous research found that this intervention produces an infarct that corresponds to ϳ8% of the left ventricular tissue (13). The neurons of the cardiac plexus used in this study are located primarily in the left atrium, in an area not directly impacted by the infarction.…”

“…Previous studies in our laboratory have shown that chronic myocardial infarction (MI) induces remodeling of the neurons located within the IC neural plexus of the guinea pig (13). This cardiac plexus is a primary integration site for descending parasympathetic preganglionic inputs, sympathetic efferents, and sensory afferent information (3).…”