Steroid administration after myocardial infarction promotes early infarct expansion. A study in the rat.

Mannisi, John A.; Weisman, Harlan F.; Bush, David E.; Dudeck, Pamela; Healy, Bernadine

doi:10.1172/jci112971

Cited by 61 publications

(26 citation statements)

References 25 publications

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“…One possibility is that the greater number of macrophages detected in healing post-MI scars of female animals during an inflammatory phase (Cavasin et al 2004) could underlie current observations, because macrophages facilitate inward remodeling in arterial vessels experiencing a reduction in blood flow (Bakker et al 2008). Such an assumption is also supported by the fact that the slightly higher fractional volume of mummified dead CM seen in post-MI scars of middle-aged male rats (as compared with females) may be a result of reduced macrophage response during MI healing similar to that observed in rats after inhibition of immune response with high doses of corticosteroids (Kloner et al 1978;Mannisi et al 1987) or in monocyte chemotactic protein 1-deficient mice showing an impeded phagocytic response (Dewald et al 2005).…”

Section: Effect Of Biological Sex On the Structural Composition Of A supporting

confidence: 60%

Structural Composition of Myocardial Infarction Scar in Middle-aged Male and Female Rats

Bogatyryov

Tomanek

Dedkov

2013

J Histochem Cytochem.

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ArticleSudden obstruction of coronary blood flow causes ischemic death of cardiomyocytes followed by a universal cascade of reparative events (Frangogiannis 2006) leading to infarct healing and scar formation in the heart. Nevertheless, a growing body of evidence from animal studies suggests that females exhibit a different pattern of myocardial infarction (MI) healing and left ventricular (LV) remodeling than males. For instance, post-MI female mice reveal less exaggerated inflammation and enhanced reparative fibrotic response during infarct healing, contributing to a lower rate of cardiac rupture and a lesser degree of LV remodeling in comparison with males (Cavasin et al. 2004;Gao et al. 2005;Fang et al. 2007;Wang F et al. 2007). In addition, despite comparable infarct size and LV cavity dilatation, the thickness of noninfarcted myocardium is less in post-MI female than male rats (Litwin et al. 1999), indicating a smaller increase in compensatory hypertrophy in response to post-MI cardiac remodeling in the females.Although most of these studies were focused on earlier reparative events taking place in male and female hearts during the overlapping phases of MI healing (i.e., inflammatory, proliferative and maturation phases), surprisingly little attention has been paid to providing a comparative assessment of the structural components in a mature scar. However, it has been previously shown that the tissue composition of a mature scar is an important determinant of its mechanical properties (Connelly et al. 1985) and, thereby, can drastically influence overall ventricular performance SummaryThe present study was designed to determine whether the structural composition of the scar in middle-aged post-myocardial infraction (MI) rats is affected by the biological sex of the animals. A large MI was induced in 12-month-old male (M-MI) and female (F-MI) Sprague-Dawley rats by ligation of the left coronary artery. Four weeks after the MI, rats with transmural infarctions, greater than 50% of the left ventricular (LV) free wall, were evaluated. The extent of LV remodeling and fractional volumes of fibrillar collagen (FC), myofibroblasts, vascular smooth muscle (SM) cells, and surviving cardiac myocytes (CM) in the scars were compared between the two sexes. The left ventricle of post-MI male and female rats underwent a similar degree of remodeling as evidenced by the analogous scar thinning ratio (0.46 ± 0.02 vs. 0.42 ± 0.05) and infarct expansion index (1.06 ± 0.07 vs. 1.12 ± 0.08), respectively. Most important, the contents of major structural components of the scar revealed no evident difference between M-MI and F-MI rats (interstitial FC, 80.74 ± 2.08 vs. 82.57 ± 4.53; myofibroblasts, 9.59 ± 1.68 vs. 9.56 ± 1.15; vascular SM cells, 2.27 ± 0.51 vs. 3.38 ± 0.47; and surviving CM, 3.26 ± 0.39 vs. 3.05 ± 0.38, respectively). Our data are the first to demonstrate that biological sex does not influence the structural composition of a mature scar in middleaged post-MI rats. (J Histochem Cytochem 61:833-848, 2013)

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Section: Effect Of Biological Sex On the Structural Composition Of A supporting

confidence: 60%

Structural Composition of Myocardial Infarction Scar in Middle-aged Male and Female Rats

Bogatyryov

Tomanek

Dedkov

2013

J Histochem Cytochem.

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“…Inhibition of this inflammatory response has been shown to impair wound healing and to induce severe consequences such as wall rupture [20,21]. Importantly, in our study, sPLA 2 -IIA inhibition by PX-18 did not result in reduced ventricular wall thickness, nor in aneurysmatic infarcts, indicating that wound healing was not impaired.…”

Section: Discussionmentioning

confidence: 41%

Inhibition of type 2A secretory phospholipase A2 reduces death of cardiomyocytes in acute myocardial infarction

et al. 2009

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During acute myocardial infarction (AMI), ischemia leads to necrotic areas surrounded by border zones of reversibly damaged cardiomyocytes, showing membrane flip-flop. During reperfusion type IIA secretory phopholipase A 2 (sPLA 2 -IIA) induces direct cell-toxicity and facilitates binding of other inflammatory mediators on these cardiomyocytes. Therefore, we hypothesized that the specific sPLA 2 -IIA-inhibitor PX-18 would reduce cardiomyocyte death and infarct size in vivo. Wistar rats were treated with PX-18 starting minutes after reperfusion, and at day 1 and 2 post AMI. After 28 days hearts were analyzed. Furthermore, the effect of PX-18 on membrane flipflop and apoptosis was investigated in vitro. PX-18 significantly inhibited sPLA 2 -IIA activity and reduced infarct size (reduction 73 ± 9%, P \ 0.05), compared to the vehicle-treated group, without impairing wound healing. In vitro, PX-18 significantly reduced reversible membrane flip-flop and apoptosis in cardiomyocytes. However, no sPLA 2 -IIA activity could be detected, suggesting that PX-18 also exerted a protective effect independent of sPLA 2 -IIA. In conclusion, PX-18 is a potent therapeutic to reduce infarct size by inhibiting sPLA 2 -IIA, and possibly also by inhibiting apoptosis of cardiomyocytes in a sPLA 2 -IIA independent manner.

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“…In our study, the increase in cell density in the infarct zone not accounted for by cell stretch would explain a decrease in wall thickness of approximately 12% and seemed to be largely due to the loss in intravascular volume. In a previous study with the same infarct model, 18 we found that the infarct zone increases in water content by about 6-7% in hearts 1 day after infarction, and it is possible that interstitial edema partially prevents the decrease in intercellular space produced by intravascular collapse. Consistent with this possibility is the observation in the present study that the nonvascular space between cells appeared to be slightly increased.…”

Section: Discussionmentioning

confidence: 57%

“…Approximately 11% of myocytes encountered were at or near branch points, and we used a method described previously to correct for branching. 18 The cell counts were performed twice for each region. In most cases, identical counts were obtained; however, if the two counts dilfered by more than 5%, cells were recounted another two times.…”

Section: Rat Infarct Modelmentioning

confidence: 99%

Cellular mechanisms of myocardial infarct expansion.

et al. 1988

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Infarct expansion is acute regional dilatation and thinning of the infarct zone. There are several possibilities for the mechanism of this alteration in cardiac shape: thinning could be caused by 1) cell rupture, 2) a reduction in the intercellular space, or 3) stretching of myocytes or 4) slippage of groups of myocytes so that less cells are distributed across the wall. To determine the relative contributions of these cellular mechanisms of wall thinning and dilatation, detailed study of transverse histological sections of rat hearts with infarct expansion was performed 1, 2, and 3 days after coronary ligation. The number of cells across the wall was determined in six regions within, adjacent to, and remote from the infarct. Cell counting was performed so that the total number of cells across the wall and the number of cells per unit length (cell density) across the wall were determined. The transmural cell count and the cell density were correlated with the wall thickness in each region. Myocyte cross-sectional areas and sarcomere lengths were also measured. The results from the infarct expansion hearts were compared with those of sham-operated control hearts that had been similarly analyzed. To ensure that mechanisms identified in the rat were applicable to human infarct expansion, five hearts from patients who died within 3 days of infarction and two hearts from patients without coronary disease were studied histologically in a similar fashion. Wall thinning occurred in all regions of the rat infarct expansion hearts compared with controls (p <0.0001) but, as expected, was most pronounced in the infarct zone. A decrease in the number of cells across the wall accompanied the wall thinning at each site (p <0.0001), and this change in cell number was highly correlated with the changes in wall thickness (r= 0.915, p <0.001). Cell density increased from controls only within the infarct zone (p <0.001) and accounted for at most 20% of the thinning in that region. The change in cell density was attributable to both cell stretch (measured by increased sarcomere length and decreased myocyte cross-sectional area) and a decrease in the intercellular space. A similar strong correlation between wall thinning and decreased number of cells across the wall was identified in the human hearts (r= 0.94, p <0.001). Thus, a decrease in the number of cells across the wall accounts for most wall thinning in the infarct zone and all thinning in noninfarcted regions. In noninfarcted regions, cell slippage accounts for all thinning. Cell stretch and loss of intercellular space are confined to the infarct zone and contribute less to wall thinning than does cell slippage. (Circulation 1988;78:186-201) I nfarct expansion describes the disproportionate thinning and dilatation of acutely infarcted myocardium that occurs within the first 24 hours after infarction1 2 and leads to early cardiac dilatation.34 These early structural changes within the infarct zone are accompanied by similar but less pronounced changes in wall thickness and ...

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Steroid administration after myocardial infarction promotes early infarct expansion. A study in the rat.

Cited by 61 publications

References 25 publications

Structural Composition of Myocardial Infarction Scar in Middle-aged Male and Female Rats

Structural Composition of Myocardial Infarction Scar in Middle-aged Male and Female Rats

Inhibition of type 2A secretory phospholipase A2 reduces death of cardiomyocytes in acute myocardial infarction

Cellular mechanisms of myocardial infarct expansion.

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