Nerve fibers in human myocardial scars

Vracko, Rudolf; Thorning, David; Frederickson, Richard G.

doi:10.1016/0046-8177(91)90035-n

Cited by 67 publications

(51 citation statements)

References 35 publications

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“…Major components of the response to injury in general and to the C57BL͞6 heart in this study are the inflammatory response, fibroblast proliferation, collagen synthesis by myofibroblasts, and fibrosis at the site of infarction (29,37). The extent to which these processes determine the degree of remodeling is modulated by the efficiency of resorption of necrotic foci and by the extent of revascularization following injury.…”

Section: Discussionmentioning

confidence: 98%

“…Expression levels of proteins involved in the cell cycle and specifically in the G 1 ͞S phase were shown to be different, including phosphorylated retinoblastoma protein (Rb), p107 and p130, cyclin D, and cdk2 (6). Observations in mice possessing mutations in these genes suggest the possible circumvention of the G 1 checkpoint control in mammalian myocardium as well (29,(33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

“…Very low levels of ventricular myocyte proliferation are usually found in the perinecrotic zone (29,30). Such minimal mitotic activity observed in cardiomyocytes at the margins of a wound suggest a very limited capacity for regeneration.…”

Section: Discussionmentioning

confidence: 99%

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Heart regeneration in adult MRL mice

Leferovich

Bedelbaeva

Samulewicz

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

230

190

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The reaction of cardiac tissue to acute injury involves interacting cascades of cellular and molecular responses that encompass inflammation, hormonal signaling, extracellular matrix remodeling, and compensatory adaptation of myocytes. Myocardial regeneration is observed in amphibians, whereas scar formation characterizes cardiac ventricular wound healing in a variety of mammalian injury models. We have previously shown that the MRL mouse strain has an extraordinary capacity to heal surgical wounds, a complex trait that maps to at least seven genetic loci. Here, we extend these studies to cardiac wounds and demonstrate that a severe transmural, cryogenically induced infarction of the right ventricle heals extensively within 60 days, with the restoration of normal myocardium and function. Scarring is markedly reduced in MRL mice compared with C57BL͞6 mice, consistent with both the reduced hydroxyproline levels seen after injury and an elevated cardiomyocyte mitotic index of 10 -20% for the MRL compared with 1-3% for the C57BL͞6. The myocardial response to injury observed in these mice resembles the regenerative process seen in amphibians.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Heart regeneration in adult MRL mice

Leferovich

Bedelbaeva

Samulewicz

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

230

190

View full text Add to dashboard Cite

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“…Considering the nature of the three-dimensional collagen lattice culture system, a close equivalent of the in vivo myocardial collagen network, these results further suggest that, under certain circumstances, cardiac fibroblasts residing in the interstitium of the heart could migrate and invade cellular compartments. Vracko et al (45) described an interesting phenomenon, observed in a myocardial infarction model: at the stage of tissue repair following necrosis of myocytes, fibroblast-like cells were found in the empty compartment surrounded by basement membranes, and numerous holes were observed in the membranes. Results in the present study could provide an explanation: to enter the areas of the spaces once occupied by healthy myocytes, cardiac fibroblasts "drill" holes in the surrounding basement membranes by degrading specific ECM component.…”

Section: Discussionmentioning

confidence: 99%

Type I Collagen-induced MMP-2 Activation Coincides with Up-regulation of Membrane Type 1-Matrix Metalloproteinase and TIMP-2 in Cardiac Fibroblasts

Guo

Piacentini²

2003

Journal of Biological Chemistry

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Migration of cardiac fibroblasts is implicated in infarct healing and ventricular remodeling. Activation of matrix metalloproteinases induced by three-dimensional type I collagen, the principal component of the myocardial interstitium, is hypothesized to be essential for this migration. By utilizing primary cultures of cardiac fibroblasts and collagen lattice models, we demonstrated that type I collagen induced MMP-2 activation, and cells undergoing a change from isometric tension to mechanical unloading were associated with increased levels of total and active MMP-2 species. The collageninduced MMP-2 activation coincided with up-regulated cellular levels of both membrane type 1-matrix metalloproteinase (MT1-MMP) and TIMP-2. A fraction of cellular membrane prepared from cells embedded in the collagen lattice containing active MT1-MMP and TIMP-2 was capable of activating pro-MMP-2, and exogenous TIMP-2 had a biphasic effect on this membrane-mediated MMP-2 activation. Interestingly, the presence of 43-kDa MT1-MMP species in a fraction of intracellular soluble proteins prepared from monolayer cells but not cells embedded in the lattices indicates that MT1-MMP metabolizes differently under the two different culture conditions. Treatment of cells embedded in the lattice with furin inhibitor attenuated pro-MT1-MMP processing and MMP-2 activation and impeded cell migration and invasion. These results suggest that the migration and invasion of cardiac fibroblasts is furin-dependent and that the active species of MT1-MMP and MMP-2 may be involved in both events.Cardiac fibrosis, a consequence of infarct healing and ventricular remodeling, is characterized by hyperplasia of ␣-smooth muscle actin expressing fibroblast-like cells and deposition of excessive extracellular matrix (ECM) 1 proteins by these cells in the myocardium. These cells are thought to originate from cardiac fibroblasts, which are recruited from the interstitium of the heart following myocardial injury (1). In vitro cardiac fibroblasts grown as a monolayer have been proved to be migratory cells (2, 3). However, cardiac fibroblasts in vivo reside in the interstitial fibrillar collagen network; the migratory/invasive potential of cardiac fibroblasts, by which the cells detach from the collagen network where they normally reside in vivo and then penetrate basement membrane surrounding necrotic myocytes, has not been investigated previously. Type I collagen, the principal component of the interstitial fibrillar collagen network, is a known matrix effector for MMP-2 activation in various cell types including neonatal rat cardiac fibroblasts (4). However, the mode of MMP-2 activation induced by three-dimensional type I collagen remains largely undefined (5-11). Furthermore, reorganization of the cytoskeleton subsequent to changes in mechanical tension in the collagen lattice has been reported to underlie three-dimensional type I collagen-induced MMP-2 activation in human skin fibroblasts (12) but not rat capillary endothelial cells (8), raising the possibility ...

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“…39,40 Excessive and uncontrolled regeneration could lead to hyperinnervation of the myocardium. Vracho et al 41,42 demonstrated abnormal patterns of neurilemma proliferation in the scars of human myocardium. These studies were confirmed by Cao et al 43 who showed local increases in sympathetic nerves in the periphery of necrotic tissues and in perivascular regions of the hearts of 53 patients with heart failure who underwent cardiac transplantation by using immunochemical staining for S-100 protein, neurofilament protein, and tyrosine hydroxylase on explanted hearts.…”

Section: Myocardial Infarction Heart Failure and Sympathetic Innervmentioning

confidence: 99%

The Role of the Autonomic Nervous System in Sudden Cardiac Death

Vaseghi

Shivkumar²

2008

Progress in Cardiovascular Diseases

322

233

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The cardiac autonomic nervous system consists of 2 branches-the sympathetic and the parasympathetic systems-that work in a delicately tuned, yet opposing fashion in the heart. This extrinsic control mechanism can dominate intrinsic regulatory mechanisms that modulate heart rate and cardiac output. These branches differ in their neurotransmitters (norepinephrine and acetylcholine) and exert stimulatory or inhibitory effects on target tissue via adrenergic and muscarinic receptors. Stimulation of the sympathetic branch exerts facilitatory effects on function, increasing heart rate and myocardial contractility, whereas the stimulation of the parasympathetic branch exerts inhibitory effects that decrease heart rate and contractility. The interplay between these two branches is complex and susceptible to control at several levels, from centrally mediated baroreceptors and chemoreceptors to local interneuronal interactions.Alterations in autonomic function occur in several interrelated cardiac conditions including sudden cardiac death, congestive heart failure, diabetic neuropathy, and myocardial ischemia. Although the full extent of these changes has not been elucidated, multiple autonomic remodeling mechanisms have been observed at both the neuronal fiber and myocardial cellular level that contribute to an arrhythmogenic substrate. We describe the anatomy of both systems in this review. However, the review will premdominantly focus on the sympathetic system, whose role in the modulation of cardiac arrhythmias is slightly better delineated. Cardiac Autonomic Innervation: NeuroanatomyBoth branches of the autonomic nervous system are composed of both afferent and efferent as well interneuronal fibers (Fig 1). Sympathetic innervation originates mainly in the right and left stellate ganglia. These fibers travel along the epicardial vascular structures of the heart and penetrate into the underlying myocardium similar to coronary vessels and end as sympathetic nerve terminals reaching the endocardium. Based on norepinephrine content studies, a gradient exists in sympathetic innervation from atria to the ventricles and from base to apex of the heart. Therefore, the atria are most densely innervated, but the ventricles are also supplied with a sympathetic network, most densely at the base. 1 Parasympathetic effects are carried by the right and left vagus nerves, originating in the medulla. The vagus nerve further divides into the superior and inferior cardiac nerves, finally merging with the postganglionic sympathetic neurons to form a plexus of nerves at the base of the heart, known as the cardiac plexus. In contrast to sympathetic neurons, after parasympathetic fibers cross the atrioventricular (AV) groove along the surface of the heart,

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Nerve fibers in human myocardial scars

Cited by 67 publications

References 35 publications

Heart regeneration in adult MRL mice

Heart regeneration in adult MRL mice

Type I Collagen-induced MMP-2 Activation Coincides with Up-regulation of Membrane Type 1-Matrix Metalloproteinase and TIMP-2 in Cardiac Fibroblasts

The Role of the Autonomic Nervous System in Sudden Cardiac Death

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