Spatial distribution of nerve sprouting after myocardial infarction in mice.

BACKGROUND: Myocardial infarction (MI) elicits nerve sprouting. OBJECTIVES: The purpose of this study was to determine the spatial distribution of nerve sprouting and neurotrophic gene expression after MI. METHODS: We created MI in mice by coronary artery ligation. The hearts were removed 3 hours to 2 months after MI and examined for nerve fiber density and neurotrophic factor gene expression using Affymetrix microarray and mRNA analyses. RESULTS: The density of nerve fibers immunopositive for growth-associated protein (GAP)-43 was the highest 3 hours after MI both in the peri-infarct area and in the area remote to infarct, resulting in sympathetic (but not parasympathetic) hyperinnervation in the ventricles. The GAP-43-positive nerve fiber density of myocardium was greater in the outer transverse loop than in the inner vertical loop. The differences between these two myocardial loops peaked within 3 hours after MI and persisted for 2 months afterward. Gene expression of nerve growth factor, insulin-like growth factor, leukemia inhibitory factor, transforming growth factor-beta(3), and interleukin-1alpha was increased up to 2 months after MI compared with normal control. Expression of these growth factors was more pronounced and persistent in the peri-infarct area than in the remote area. CONCLUSION: MI induces sympathetic nerve sprouting in both peri-infarct and remote areas, more in the outer transverse loop. Selective up-regulation of nerve growth factor, insulin-like growth factor, leukemia inhibitory factor, transforming growth factor-beta(3), and interleukin-1alpha occurred in the peri-infarct area and, to a lesser extent, in the remote area.

Sympathetic nerve sprouting after orthotopic heart transplantation.

BACKGROUND: Although many studies have documented sympathetic re-innervation in transplanted hearts (allografts) using chemical, imaging, and electrophysiologic methods, little histopathologic proof of this process exists. METHODS AND RESULTS: We used immunohistochemical techniques with antibodies to S-100 protein, to growth-associated protein 43 (GAP43), and to tyrosine hydroxylase (TH) to detect nerves in the left ventricles in allografts from 29 consecutive recipients. Reasons for transplantation included ischemic heart disease (IHD, n=16), non-ischemic dilated cardiomyopathy (DCM, n=12), and both (n=1). We assessed nerve densities (nerves/mm2) with respect to time after transplantation in the endocardium; in the mid-myocardium; and around intramyocardial blood vessels, scars, foci of rejection, and Quilty lesions. Six normal hearts were used for comparison. As in normal hearts, all 29 allografts had epicardial nerve trunks that extended into the mid-myocardium around blood vessels. Although the total number of nerves (S100-positive) progressively decreased over time, GAP43-positive nerves around the blood vessels increased with time (p <0.005). We also observed abundant TH-positive nerves. The density of S100-positive nerves around blood vessels was greater in those undergoing transplantation for IHD (113 +/- 88) than in those with prior DCM (54 +/- 49, p <0.05). Nerve density in each area varied greatly. CONCLUSIONS: Heterogeneous sympathetic nerve sprouting and re-innervation occurred around blood vessels in the allografts. The magnitude of nerve sprouting increased with time and varied greatly from patient to patient. Patients with IHD had greater nerve sprouting and re-innervation than did those with DCM.

Patterns of spiral tip motion in cardiac tissues.

In support of the spiral wave theory of reentry, simulation studies and animal models have been utilized to show various patterns of spiral wave tip motion such as meandering and drifting. However, the demonstration of these or any other patterns in cardiac tissues have been limited. Whether such patterns of spiral tip motion are commonly observed in fibrillating cardiac tissues is unknown, and whether such patterns form the basis of ventricular tachycardia or fibrillation remain debatable. Using a computerized dynamic activation display, 108 episodes of atrial and ventricular tachycardia and fibrillation in isolated and intact canine cardiac tissues, as well as in vitro swine and myopathic human cardiac tissues, were analyzed for patterns of nonstationary, spiral wave tip motion. Among them, 46 episodes were from normal animal myocardium without pharmacological perturbations, 50 samples were from normal animal myocardium, either treated with drugs or had chemical ablation of the subendocardium, and 12 samples were from diseased human hearts. Among the total episodes, 11 of them had obvious nonstationary spiral tip motion with a life span of >2 cycles and with consecutive reentrant paths distinct from each other. Four patterns were observed: (1) meandering with an inward petal flower in 2; (2) meandering with outward petals in 5; (3) irregularly concentric in 3 (core moving about a common center); and (4) drift in 1 (linear core movement). The life span of a single nonstationary spiral wave lasted no more than 7 complete cycles with a mean of 4.6+/-4.3, and a median of 4.5 cycles in our samples. Conclusion: (1) Patently evident nonstationary spiral waves with long life spans were uncommon in our sample of mostly normal cardiac tissues, thus making a single meandering spiral wave an unlikely major mechanism of fibrillation in normal ventricular myocardium. (2) A tendency toward four patterns of nonstationary spiral tip motion was observed. (c) 1998 American Institute of Physics.

Mesenchymal stem cell injection induces cardiac nerve sprouting and increased tenascin expression in a Swine model of myocardial infarction.

UNLABELLED: Stem Cell Induces Cardiac Nerve Sprouting. INTRODUCTION: Mesenchymal stem cell (MSC) transplantation is a promising technique to improve cardiac function. Whether MSC can increase cardiac nerve density and contribute to the improved cardiac function is unclear. METHODS AND RESULTS: Anterior wall myocardial infarction was created in 16 swine. One month later, 6 swine were given MSC and fresh bone marrow (BM) into infarcted myocardium (MSC group). Four swine were given fresh BM only (BM group), and 6 swine were given culture media (MI-only group). The swine were sacrificed 95.8 +/- 3.5 days after MI. Six normal swine were used as control. Immunocytochemical staining was performed using antibodies against growth-associated protein 43 (GAP43), tyrosine hydroxylase (TH), and three subtypes of tenascin (R, C, and X). Five fields per slide were counted for nerve density. The results show the following. (1). There were more GAP43-positive nerves in the MSC group than in the BM, MI-only, or Control group (P < 0.0001). TH staining showed higher nerve densities in the MSC group than in the MI-only (P < 0.01) or Control group (P < 0.0001) in the atria. (2). There were more sympathetic (TH-positive) nerves in myocardium distant from infarct than in the peri-infarct area (P < 0.05). (3). Optical intensity and color analyses showed significantly higher tenascin R and tenascin C expression in the MSC and BM groups than in the MI-only or Control group (P < 0.01). CONCLUSION: MSC injected with BM into swine infarct results in overexpression of cardiac tenascin, increased the magnitude of cardiac nerve sprouting in both atria and ventricles, and increased the magnitude of atrial sympathetic hyperinnervation 2 months after injection.