Regenerative healing following foetal myocardial infarction☆☆☆

Abstract

Objectives The adult response to myocardial infarction results in inflammation, scar formation, left ventricular dilatation, and loss of regional and global function. Regenerative scarless healing has been demonstrated in fetal dermis and tendon and is associated with diminished inflammation. We hypothesized that following fetal myocardial infarction there would be minimal inflammation, regenerative healing, and preservation of function. Methods Anteroapical myocardial infarction encompassing 20% of the left ventricle were created in adult or early gestation fetal sheep. Myocardial function was serially assessed using quantitative echocardiography. Infarct architecture was examined histologically for evidence of scar formation. Cellular inflammation, cellular proliferation, and apoptosis were assessed using immunohistochemistry. Results In the adult sheep 4 weeks following myocardial infarction, there was a significant decline in ejection fraction (41±7.4% to 26±7.4%, p<0.05), and the akinetic myocardial segment increased in size (6.9±0.8 cm to 7.9±1.1 cm, p<0.05). In contrast, there was no decline in the fetal ejection fraction (53±8.1% to 55±8.8%) and no akinetic fetal myocardial segment 4 weeks post-infarction. The fetal infarcts lacked an inflammatory cell infiltrate and healed with minimal fibrosis, compared to the adults. Fetal infarcts also demonstrated BrdU+ proliferating cells, including cardiomyocytes, within the infarct. Conclusions These data demonstrate that the fetal response to myocardial infarction is dramatically different than the adult and is characterized by minimal inflammation, lack of fibrosis, myocardial proliferation, and restoration of cardiac function. Diminished inflammation is associated with fetal regenerative cardiac healing following injury. Understanding the mechanisms involved in fetal myocardial regeneration may lead to applications to alter the adult response following myocardial infarction.

The Cardiomyocyte Cell Cycle in Hypertrophy, Tissue Homeostasis, and Regeneration

“…Four weeks after MI, regeneration was completed and heart function recovered. Heart regeneration was accompanied by increase in DNA synthesis in cardiomyocytes indicating extensive cardiomyocyte proliferation (Herdrich et al 2010). Collectively, these observations indicate that the fetal heart has significant regenerative capacity and that cardiomyocyte proliferation contributes to this process.…”

Macrophage interactions with polylactic acid and chitosan scaffolds lead to improved recruitment of human mesenchymal stem/stromal cells: a comprehensive study with different immune cells

“…Importantly, it was shown in a murine model that upon biomaterial subcutaneous implantation there is first recruitment of inflammatory cells, which is then correlated with recruitment of MSC [4][5][6][7]. MSC recruitment can then lead to subsequent modulation of inflammation and is essential to promote the constructive remodelling of the tissue [8,9].…”

Fetal trans-apical stent delivery into the pulmonary artery: prospects for prenatal heart-valve implantation

“…The patients of these interventions mainly include either fetuses with high-grade aortic stenosis with evolving hypoplastic left-heart syndrome (HLHS) or patients with pulmonary atresia with evolving hypoplastic right-heart syndrome (HRHS) (reviewed by McElhinney et al [1]). The prenatal correction of these congenital cardiac defects, as a definite surgical repair at the earliest time point, could be associated with several therapeutic advantages, including prevention of fetal demise in selected cases [1,5], prevention of intrauterine cardiac maldevelopment and reduction of severity of postnatal disease [1], enhanced (scarless) healing reactions in early-gestational fetuses [18], capacity for myocyte proliferation [19] as well as a high regenerative capacity [20] in fetuses promoted by high blood levels of progenitor cells [21]. Although first clinical experiences of fetal heart-valve intervention, including balloon valvuloplasty, seem highly promising [1,5], restenoses of the obstructed segments have been repeatedly reported after prenatal cardiacballoon interventions [4,14].…”