Cardiac fibrosis in myocardial infarction—from repair and remodeling to regeneration

Abstract

Ischemic cell death during a myocardial infarction leads to a multiphase reparative response in which the damaged tissue is replaced with a fibrotic scar produced by fibroblasts and myofibroblasts. This also induces geometrical, biomechanical, and biochemical changes in the uninjured ventricular wall eliciting a reactive remodeling process that includes interstitial and perivascular fibrosis. Although the initial reparative fibrosis is crucial for preventing rupture of the ventricular wall, an exaggerated fibrotic response and reactive fibrosis outside the injured area are detrimental as they lead to progressive impairment of cardiac function and eventually to heart failure. In this review, we summarize current knowledge of the mechanisms of both reparative and reactive cardiac fibrosis in response to myocardial infarction, discuss the potential of inducing cardiac regeneration through direct reprogramming of fibroblasts and myofibroblasts into cardiomyocytes, and review the currently available and potential future therapeutic strategies to inhibit cardiac fibrosis.Graphical abstractReparative response following a myocardial infarction. Hypoxia-induced cardiomyocyte death leads to the activation of myofibroblasts and a reparative fibrotic response in the injured area. Right top In adult mammals, the fibrotic scar formed at the infarcted area is permanent and promotes reactive fibrosis in the uninjured myocardium. Right bottom In teleost fish and newts and in embryonic and neonatal mammals, the initial formation of a fibrotic scar is followed by regeneration of the cardiac muscle tissue. Induction of post-infarction cardiac regeneration in adult mammals is currently the target of intensive research and drug discovery attempts

Retracted: Tanshinone IIA prevents left ventricular remodelling via the TLR4/MyD88/NF‐κB signalling pathway in rats with myocardial infarction

“…Therefore, we speculate that tanshinone IIA may prevent ventricular remodelling by reducing the area of fibrosis. A previous study indicated that the ideal therapy for MI‐induced cardiac injury was to inhibit the reactive fibrosis (and other remodelling processes) as well as the regeneration of the infarct area in non‐infarcted areas 32. Tanshinone IIA suppresses cardiac fibrosis by regulating the paracrine factors released by cardiomyocytes that go on to activate the TGF‐b/Smads signalling pathway 9.…”

The Structure-function remodeling in rabbit hearts of myocardial infarction

“…The Masson trichrome staining (Prabhu and Frangogiannis 2016; Talman and Ruskoaho 2016) showed a huge amount of tissues with fibrosis at border zones of rabbit hearts at postoperative 12 weeks given post‐MI inflammation (Anker and von Haehling 2004). An increase in cardiac fibrosis altered the constitutive relation of myocardium and further increased the ventricle wall shear, which impaired coronary vasculature (e.g., a vascular rarefaction) at border zones and contributed to the vicious cycle of ischemia and HF with time.…”

Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats

“…38 In this respect, LDE-MTX treatment led to a reduction in fibrosis in both subendocardial and interstitial areas, as documented by the local reduction of collagen I and III. Because fibrosis is stimulated by hypoxia and cell death, 39 the reduction of both by LDE-MTX accounted for the decrease in subendocardial fibrosis. Increase in VEGF expression by LDE-MTX was presumably involved in this effect.…”