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)

This study was aimed to understand the mechanism of persistent cardiac myocyte (CM) survival in myocardial infarction (MI) scars. A transmural MI was induced in 12-month-old Sprague-Dawley rats by permanent coronary artery ligation. The hearts were collected 3 days, 1, 2, 4, 8, and 12 weeks after MI and evaluated with histology, immunohistochemistry, and quantitative morphometry. Vasculature patency was assessed in 4-, 8-, and 12-week-old scars by infusion of 15-micron microspheres into the left ventricle before euthanasia. The infarcted/scarred area has a small continually retained population of surviving CMs in subendocardial and subepicardial regions. Surprisingly, whereas the transverse area of subepicardial CMs remained relatively preserved or even enlarged over 12 post-MI weeks, subendocardial CMs underwent progressive atrophy. Nevertheless, the fractional volume of viable CMs remained comparable in mature scars 4, 8, and 12 weeks after MI (3.6 ± 0.4%, 3.4 ± 0.5%, and 2.5 ± 0.3%, respectively). Despite the opposite dynamics of changes in size, CMs of both regions displayed sarcomeres and gap junctions. Most importantly, surviving CMs were always accompanied by patent microvessels linked to a venous network composed of Thebesian veins, intramural sinusoids, and subepicardial veins. Our findings reveal that long-term survival of CMs in transmural post-MI scars is sustained by a local microcirculatory bed.

Our data reveal that chronic IVA-induced HRR does not provide sustainable benefits for LV systolic performance in middle-aged rats with post-MI HF.

We previously determined that residual left ventricular (LV) myocardium of middle‐aged rats had sex‐related differences in regional tissue properties 4 weeks after a large myocardial infarction (MI). However, the impact of such differences on cardiac performance remained unclear. Therefore, our current study aimed to elucidate whether sex‐related changes in MI‐induced myocardial remodeling can influence cardiac function. A similar‐sized MI was induced in 12‐month‐old male (M‐MI) and female (F‐MI) Sprague–Dawley rats by ligation of the left coronary artery. The cardiac function was monitored for 2 months after MI and then various LV parameters were compared between sexes. We found that although two sex groups had a similar pattern of MI‐induced decline in LV function, F‐MI rats had greater cardiac performance compared to M‐MI rats, considering the higher values of EF (39.9 ± 3.4% vs. 26.7 ± 7.7%, P < 0.05), SW index (40.4 ± 2.1 mmHg • mL/kg vs. 20.2 ± 3.3 mmHg • mL/kg, P < 0.001), and CI (139.2 ± 7.9 mL/min/kg vs. 74.9 ± 14.7 mL/min/kg, P < 0.01). The poorer pumping capacity in M‐MI hearts was associated with markedly reduced LV compliance and prolonged relaxation. On the tissue level, F‐MI rats revealed a higher, than in M‐MI rats, density of cardiac myocytes in the LV free wall (2383.8 ± 242.6 cells/mm2 vs. 1785.7 ± 55.9 cells/mm2, P < 0.05). The latter finding correlated with a lower density of apoptotic cardiac myocytes in residual LV myocardium of F‐MI rats (0.18 ± 0.08 cells/mm2 vs. 0.91 ± 0.30 cells/mm2 in males, P < 0.01). Thus, our data suggested that F‐MI rats had markedly attenuated decline in cardiac performance compared to males due to ability of female rats to better retain functionally favorable intrinsic myocardial properties.

A number of studies indicate that females have a better reparative response in earlier stages of myocardial infarction (MI) compared to males. Nevertheless, little is known concerning the sex‐related differences in a later stage of MI healing (i.e. scar formation). Accordingly, we designed our study to determine whether the composition of the scar is affected by the biological sex of post‐MI 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 free wall, were evaluated. The fractional volume of fibrillar collagen (FC), cardiac myocytes (CM), myofibroblasts (MF) and vascular smooth muscle cells (VSMC) was determined in each scar. The mean scar size and thickness were comparable between F‐MI and M‐MI rats (61.3±3.9% vs. 63.8±2.5% and 0.66±0.04mm vs. 0.73±0.05mm, respectively). Although, there was a great degree of heterogeneity in spatial distribution of the analyzed structural components within each scar, their mean content showed no significant differences between F‐MI and M‐MI rats (FC: 53.3±6.6% vs. 61.6±4.5%; CM: 3.1±0.4% vs. 3.3±0.4%; MF: 9.6±1.2% vs. 9.6±1.7%; VSMC: 3.4±0.5 vs. 2.3±0.5%). Our data are the first to demonstrate that biological sex does not influence the structural composition of the MI scar in middle‐aged rats.Grant Funding Source: Internal Award from the NYCOM Office of Research (E.I. Dedkov) and NIH RO1‐HL62587 (R.J. Tomanek)

Heart rate reduction (HRR) by ivabradine (IVA), a selective inhibitor of the pacemaker If current, for 4 weeks after myocardial infarction (MI) was associated with the reduced collagen accumulation in surviving left ventricular (LV) myocardium. Although this effect is considered to benefit LV performance, the decrease in fibrillar collagen (FC) can diminish a tensile strength of the scar. Therefore, we designed our study to determine whether chronic HRR with IVA affects a structural composition of the MI scar. A large MI (>; 50% of the LV free wall) was induced in 12‐month‐old male Sprague‐Dawley rats by ligation of the left coronary artery and the rats were then assigned in two experimental groups. In the first group, rats were treated with IVA i.p. via osmotic pumps in a dose of 10.5 mg/kg/d for 3 months (MI+IVA), while in the second group, rats received placebo (MI). After three months, the fractional volume of FC was determined in the myocardium of LV free wall and the scar. The scar size and thickness were comparable between MI and MI+IVA rats (63.1±2.7% vs. 59.6±1.8% and 0.93±0.09mm vs. 0.90±0.05mm, respectively). Although, there was a significant reduction of FC in LV free wall of IVA‐treated rats (5.1±0.5% vs. 7.8±0.8%, p≤0.01) the content of FC was comparable in scars of MI and MI+IVA rats (71.8±3.9% vs. 71.7±6.9%, respectively). Our data show that chronic IVA‐induced HRR does not reduce the content of collagen in MI scar.Grant Funding Source: Internal Award from the NYCOM Office of Research (E.I. Dedkov) and Research Grant from IRI Servier (R.J. Tomanek)

Background: We have previously demonstrated that heart rate reduction (HRR) with the selective cardiac pacemaker I f current inhibitor ivabradine (IVA) improved LV function and coronary perfusion reserve in post-MI middle-aged rats. The beneficial effects of IVA treatment were associated with attenuated collagen accumulation in the surviving LV myocardium and inhibition of the circulatory renin-angiotensin system. However, sustainability of these positive changes after a period of IVA treatment interruption remains to be determined. Methods: MI was induced in 12-month-old male Sprague-Dawley rats by left coronary artery ligation. Twenty four hours later, the rats with a confirmed large transmural MI were randomly assigned in two experimental groups. In a first group, rats were treated with IVA i.p. via osmotic pumps in a dose of 10.5 mg/kg/d for 4 weeks followed by a 4-week period without treatment (MI+IVA). In a second group, rats received placebo for 4 weeks (MI). Sham-operated rats served as a control. Eight weeks after MI, the various LV parameters were examined. Results: During 4 weeks of treatment, heart rate in MI+IVA rats was consistently reduced compared to untreated MI rats (mean of HRR was 27%). After IVA withdrawal, heart rate increased to the levels of the placebo group. Eight weeks after MI, the IVA treated group demonstrated smaller LV free wall infarct size (57.5 ± 2.7% vs. 72.5 ± 2.5%, p<0.01) and greater LV weight/body weight ratio (2.54 ± 0.06 vs. 2.26 ± 0.11 mg/g, p<0.05), indicating greater myocardial compensatory hypertrophy. Furthermore, the interstitial collagen content was significantly lower in the remote LV myocardium of MI+IVA rats compared to MI rats (7.5 ± 0.7% vs. 13.3 ± 1.0% in free wall and 7.3 ± 0.8% vs. 11.2 ± 0.9% in septum, p < 0.01). However, compared to non-infarcted controls, rats of both MI groups had markedly lower LV ejection fraction and coronary perfusion reserve. Conclusions: Our data demonstrate that although beneficial structural changes induced by IVA in post-MI myocardium can be sustainable for a long period of time they cannot prevent deterioration of LV function after withdrawal of treatment. Therefore, we believe that continuous treatment with IVA may be essential for attenuation of heart failure after a large MI.

Background: We have previously shown that 1-month treatment with ivabradine (IVA), the selective cardiac pacemaker I f current inhibitor, preserved myocardial perfusion and coronary perfusion reserve in post-MI middle-aged rats. However, the persistence of this cardioprotective effect after a prolonged period of IVA treatment remains to be determined. Methods: Acute MI was induced in 12-month-old male Sprague-Dawley rats by left coronary artery ligation. Twenty four hours later, the rats with a confirmed large transmural MI (>50% of the left ventricular (LV) free wall) were randomly assigned in two experimental groups. In a first group, rats were treated with IVA i.p. via osmotic pumps in a dose of 10.5 mg/kg/day for 3 months (MI+IVA). In a second group, rats received placebo treatment (5% dextrose) during the same time period (MI). Sham-operated rats served as an age-matched control. At the end of experimental period, myocardial perfusion (baseline and maximal coronary conductance per 100g of tissue) and coronary perfusion reserve (fold increase between baseline and maximal coronary conductance) were determined in non-infarcted LV free wall and interventricular septum by using the neutron-activated stable isotope-labeled microsphere technique. Results: During 3 months of IVA treatment, heart rate in MI+IVA rats was consistently reduced compared to untreated MI rats by mean of 30.6%. Nevertheless, we found that the infarct size and the extent of LV remodeling were relatively comparable between MI and MI+IVA rats three months after surgery. Moreover, the levels of baseline and maximal coronary conductance were similar in LV free wall and septum between two experimental groups. Consequently, IVA-treated rats revealed no difference in coronary perfusion reserve as compared to untreated post-MI animals (2.22±0.46 vs. 2.59±0.41 in LV free wall and 2.30±0.59 vs. 2.68±0.44 in septum, respectively). However, the rats of both post-MI groups had markedly reduced levels of maximal coronary blood flow as compared to non-infarcted controls (p≤0.01). Conclusion: Our data demonstrate that long-term IVA treatment does not provide sustainable improvement in LV myocardial perfusion and coronary perfusion reserve in middle-aged rats following large MI.