Profound structural alterations of the extracellular collagen matrix in postischemic dysfunctional (“stunned”) but viable myocardium

Abstract

Ultrastructural studies of the extracellular collagen matrix were made on the "stunned" myocardium using scanning, conventional and high voltage transmission electron microscopy and light microscopy. Regional myocardial dysfunction was produced by 12 sequential 5 minute occlusions of the left anterior descending coronary artery, separated by 10 minute intervals of reperfusion. A final 90 minute reperfusion period documented persistent myocardial dysfunction. At the end of the final reperfusion period, the percent systolic shortening, measured by sonomicrometers, was depressed significantly to 35 +/- 9% of baseline. The heart was then perfusion fixed, and samples were taken from both control and stunned areas. No changes associated with irreversible cellular damage were noted in the stunned region. However, scanning electron microscopy of the stunned area showed that the extracellular collagen matrix underwent profound structural changes. Collagen cables were roughened, uncoiled and discontinuous. Linear grooves on the surface of the myocytes were frequently seen, indicating complete loss of collagen cables. The usual dense collagen weave surrounding myocytes became patchy or absent. Myocyte to myocyte struts were sparse and frequently absent, with remnant nodular or nublike structures indicative of breakage. High voltage electron microscopy of the stunned area showed that the collagen struts were discontinuous and vacuolated with rounded tips. Light microscopy of silver-stained sections of the stunned tissue demonstrated large patchy areas that were devoid of silver, indicating absence of the collagen matrix. There was a progressive increase in percent systolic bulging during each sequential coronary occlusion, suggesting increasing myocardial compliance. These results indicate that the myocardial collagen matrix is severely damaged from reversible ischemic cell injury. The greater myocardial compliance and less effective contractile effort in the stunned myocardium might be explained on a structural basis: disruption of the mechanical coupling function provided by the extracellular collagen matrix.

Ventricular Remodeling After Infarction and the Extracellular Collagen Matrix

“…24,25,30,33,34 Fifth, although a 2-to 3-fold increase in myocardial collagen above the normal level results in increased LV stiffness and mild dysfunction, 35 a very small decrease in collagen below normal can lead to drastic consequences, 36,37 including LV dilation 4,22,34 and rupture. 33,38 In reperfused MI, decreased or damaged ECCM in the IZ 5,12,39 is associated with cardiac rupture. 5,39 Key Points to Remember About Pathobiology of Cardiac ECCM First, nearly 75% of the cells in the healthy heart are nonmyocytes, which include fibroblasts 18,21 that account for 90% to 95% of nonmyocyte cell mass 17,20,21 (Table 1).…”

“…8 -10 Concurrent evidence has underscored the importance of preserving the ECCM during healing after MI. [2][3][4][5][6][7] However, the antifibrotic action of ACE-Is, aldosterone antagonists and ARBs on ECCM in the infarct zone (IZ) and noninfarct zone (NIZ), 6,7,9,11 and the reperfusion-induced damage to the ECCM in the IZ, 5,7,12 remain unreconciled with the benefits. 8 -10,13 Nevertheless, excessive ECCM, as in dilated ischemic cardiomyopathy after remote MI, 14,15 can contribute to LV diastolic dysfunction and poor outcome, 6 suggesting that antifibrotic drugs that target excess ECCM might be a logical therapeutic approach.…”

Mechanism of myocardial "stunning".

“…74 To fully evaluate this hypothesis, it will be important to explore the time course of the collagen changes and its relation to the time course of postischemic dysfunction. Because in conscious dogs undergoing one brief (c15 minutes) coronary occlusion most of the contractile recovery takes place in the first 3-4 hours of reperfusion9'12,13,52 (an interval too short for significant resynthesis or remodeling of the collagenous components), it seems improbable that structural damage to collagen plays a pathogenetic role in this model of myocardial stunning.…”

Time course of early changes in plasma markers of collagen turnover following percutaneous transluminal coronary angioplasty

“…Again, these data are entirely consistent with the pathological data on early collagen degradation following ischemia. Ischemia and infarction due to abrupt coronary artery occlusion produce changes in the extracellular matrix (1,19), causing increased production and activation of matrix metalloproteinases, the activity of which determines the extent of collagen breakdown (20)(21)(22). Matrix metalloproteinase gene expression is upregulated within a few hours of infarction (21), and the results of the present study suggest that plasma levels of CITP mirror the changes occurring at a tissue level and reflect the early remodelling process.…”