INTRODUCTION:

Myocardial infarction is usually considered as an irreversible injury to heart (1) and the treatment for Acute Myocardial Infarction (AMI) includes thrombolytic therapy and coronary angioplasty (2). Even after the treatment the heart muscles cannot be fully recovered. But recent studies have found out that myocardial regeneration occurs in humans after ischemic injury. Nowadays, stem cell therapy is considered as a better option for AMI, because it has the ability to regenerate the myocytes and repair the damaged cardiac tissues. A series of studies suggested that the adult stem cells undergo novel patterns of development by a process referred to as transdifferentiation or plasticity (3).

Received on 01.05.2015 Modified on 13.05.2015

Research J. Pharm. and Tech. 8(6): June, 2015; Page 738-741

DOI: 10.5958/0974-360X.2015.00117.1

An earlier study stated that the heart is a post mitotic organ was recently challenged by Beltrami (4), who identified the subpopulation of cardio myocytes that had not terminally differentiated and had the ability to re-enter the cell cycle and undergo nuclear mitotic division in the infarcted human heart (5). Cardiac endothelial cells, smooth-muscle cells and fibroblasts have the capacity to proliferate (6)(7). Recent studies in mice where local and intravenous administration of bone marrow derived stem cells (BMSC) or intravenous administration were given for mobilizing cytokines, suggest that myocardial regeneration is facilitated by mobilized BMSC (8-10). Myocardial regeneration is hence the most widely studied and debated example of stem cell plasticity (3). Cardiac stem cells (CSCs) are distributed throughout the heart, raising the possibility that those located within the infarction or in its proximity could divide and differentiate reconstituting dead myocardium (11).

MYOCARDIAL INFARCTION:

Myocardial infarction (MI) is a major cause of death and disability worldwide (16). It is associated with an inflammatory reaction, which is a prerequisite for healing and scar formation (17-20). When blood flow stops to some part of the heart due to blockage of coronary arteries in heart. It causes damage of heart muscles. This in-turn leads to improper function of heart. If it is untreated, the inadequate vascular supply leads to myocytes loss. In response, rupture of myocytes and deposition of fibrous connective tissue occurs, which may cause cardiac dilation, resulting in overload of heart. This condition is called as Ischemic Cardiomyopathy. It may also lead to sudden death.

Myocytes cell death can occur by three mechanisms: apoptosis, necrosis, or their combination. Apoptotic and necrotic cell death have different consequences on cardiac remodelling. Myocyte necrosis leads to an inflammatory reaction, vessel proliferation, macrophage infiltration, fibroblast activation, and ultimately, scar formation. Conversely, after apoptosis, the reparative process does not involve collagen accumulation and apoptotic bodies are removed by neighbouring cells with no apparent changes in the morphology of the tissue (33). MI may be the first manifestation of coronary artery disease (CAD) (16). MIs are less commonly caused by coronary spasm which may due to cocaine and emotional stress (12).

The mechanism of MI is often rupture of an atherosclerotic plaque which leads to complete blockage of the coronary arteries. Patient with MI are mostly diagnosed by the ST elevation in the ECG. These patients are advised coronary angioplasty to open the blocked pathway (13). In case of Non-ST elevation (i.e., NSTEMI) are managed with the blood thinner heparin, along with the use of angioplasty in those at high risk (14). In people with multiple blockage and even diabetic are recommended coronary artery bypass grafting (CABG) rather than the angioplasty (15). Blood tests which help in diagnosing MI include troponin and less often creatine kinase MB. Recent studies on treatment of MI found that the myocytes will regenerate with the help of cardiac stem cells (CSCs) (27).\

IMPORTANCE OF REGENERATION AFTER MI:

Myocyte loss in the ischemically injured mammalian heart often leads to irreversible deficits in cardiac function. Occlusion of coronary vessel and the myocardial ischemia rapidly results in myocardial necrosis followed by scar formation (22). Myocyte loss is likely to cause severe left ventricular dysfunction (LVD) (23) because the left ventricle is thicker and contains many myocytes. Severe LVD can leads to sudden death , necrosis of myocytes in left ventricle will leads to deposition of fibrous tissues that cause difficulty to pump the blood from left ventricle (LV) to systemic circulation, due to overload which decreases the cardiac output (i.e., ejection fraction). The regeneration of myocytes plays an important role in regaining the LV function to save the patient’s life. The infarcts heart has scar formation which causes difficulty in rhythmic contraction of the heart (25). Animal experiments have suggested that late reperfusion of MI after completion of the extension of cardiomyocyte death may prevent further infarct expansion and thinning (24).

DOES REGENERATION OCCURS:

Myocardial regeneration within the infarct could have escaped in earlier observations because the heart was not viewed as a self-renewing organ (36). Cardiac myocytes are thought to be terminally differentiated cells and have been often compared to neurons for their inability to regenerate itself and replace the damaged myocardium (27). Even if a few myocytes are created, the growth reserve of the heart is severely limited and the intrinsic mechanisms of repair are inadequate for reconstitution of the injured myocardium (26). But recent results in humans and animals have provided evidence that Myocyte replication does occur under physiological and pathological condition of the heart (28-30). The use of Ki67 and 5-bromodeoxyuridine (BrdU) as markers of cell proliferation, together with the use of contractile protein antibodies for recognizing myocytes, has allowed identification of multiplying myocytes by high-resolution confocal microscopy (28-30). Although most Myocytes seem to be terminally differentiated, there is a fraction of younger myocytes that retain the capacity to replicate (31, 32).

In general, after myocardial infarction, the mammalian cardiac tissue has a particularly limited regenerative capacity. Hence, the heart reconstitutes itself by the inflammatory reaction. Starting within the first day after MI, inflammatory cells invade the infarct and the myofibroblasts appear in the wound. Alterations of connective tissue are present early after an experimental coronary occlusion and degradation of collagen in the rat. The normal collagen structure virtually disappears during the first week after the infarct. The extent of collagen damage correlates with the degree of infarct expansion (34). Increased activities of collagenases and other neutral proteinases have been made responsible for the rapid degradation of extracellular matrix collagen in MI. Inflammatory cells release proteases and contribute to removal of necrotic tissue; myofibroblasts to the reconstruction of a new collagen network. The actions of the myofibroblasts are admirably systematic and are essential for the organization of scar formation under the difficult condition of the rhythmic contraction of the heart. After several weeks, a solid scar has been formed with a stable collagen structure, overall little cellularity, but some myofibroblasts remain in the scar tissue (35).

The issue at hand is whether strategies can be developed to modulate the regenerative potential of the human heart. Interventions have to promote translocation of Cardiac Stem Cells (CSCs) from the site of storage to the infarct, their activation and differentiation into myocytes and coronary vessels, ultimately, mending the “broken heart" (26).

NEWER METHODS IN REGENERATION:

A new therapy of myocardial infarction is the implantation of stem cells in the infarcted are derived from skeletal myoblasts and bone-marrow-derived cardiomyocytes (BMCs) (37, 38), embryonic stem cells (ESC).

Recent studies indicates that adult BMSC treatment seems to be safe and improves heart function moderately but significantly in patients suffering from AMI (39). The growth potential of adult BMCs offers a promising new tool (27). These cells reach the infarcted region by local injection (10), by mobilization due to cytokines (8) or by spontaneous translocation after injury (9). The BMCs proliferate and differentiate into myocytes, smooth muscle cells and endothelial cells, resulting in the partial regeneration of the destroyed myocardium (8, 10). In addition, the growth response mediated by BMCs interferes with ventricular scarring and decompensation (8, 10).

Comparing BMCs with cardiac stem cells (CSCs), CSCs might be more effective than BMCs in rebuilding dead tissue (27). CSCs may be faster than BMCs in reaching functional competence and structural characteristics of mature myocytes (27).

The most primitive of all stem cell populations are the embryonic stem cells (ESC) that develop as the inner cell mass at day 5 after fertilization in the human blastocyst. At this early stage, ESC has vast developmental potential. They give rise to cells of the three embryonic germ layers. When isolated and transferred to appropriate culture media, mouse and human ESC can undergo an undetermined number of cell doublings while retaining the capacity to differentiate into specific cell types, including cardiomyocytes (40, 41). The regenerative property of myocytes by stem cell therapy has been a growing study in MI management.

Three available lines of evidence converge in favour of the interpretation that the transplanted BMCs participate directly and indirectly in the regeneration of cardiac myocytes and micro vasculature post-MI: 1) the recent observations that cardiac endogenous stem cells present in the normal myocardium and involved in the maintenance of the cardiac cellular homeostasis are also able to expand and regenerate myocytes and micro vasculature in the infarcted myocardium (21); 2) the evidence that cardio myocyte repopulation by extra cardiac progenitors of hematopoietic origin can take place in the human;(42,43-45) and 3) the demonstration that it is possible to increase the efficiency of the intrinsic cardiac regeneration capacity in animals with acute MI by both local delivery of BMCs (10,46) and bone marrow mobilization with cytokines, (8) resulting in a reduction of infarct size and clear improvement in LV performance and survival.

CONCLUSION:
Myocardial infarction is considered as a irreversible injury to heart (1) and also that the heart has only a limited regenerative capacity. Nowadays many studies conducted in animals have found that regeneration will occur in infarcted heart. Stem cell therapy is introduced as a new technique which helps in regeneration of myocytes after infarction. Myocyte proliferation may be a component of the growth reserve of the human heart; this mechanism could replace damaged myocardium (30).

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