Heart Ventricle Remodeling – an overview | ScienceDirect …

T.D. Vu, T. Kofidis, in Cardiac Regeneration and Repair, 2014

Cardiac remodeling (CR) after myocardial infarction (MI) is a series of changes in the structures and function of the heart, in response to myocardial injuries. CR is a progressive and multifactorial process occurring at genetic, molecular, cellular and intercellular levels, starting a few hours after MI and continuing for years (Hochman and Bulkley, 1982; Weisman et al., 1985; Korup et al., 1997; Giannuzzi et al., 2001). The development of CR is determined by a series of mechanical and biological factors through a number of signaling pathways. CR affects the structure of the whole heart, including infarct, border and non-infarct areas.

The loss of contractile tissue is initially compensated by an adaptive cardiac remodeling process to maintain cardiac output, predominantly by hypertrophy of myocytes and stabilization of the infarct area by scar tissue (McKay et al., 1986; Kai, 2006). However, CR might become maladaptive with pathological changes in size, shape and deterioration of the heart function. Yet, it is unknown when cardiac remodeling starts to change from an adaptive to a maladaptive status (Cohn et al., 2000a; Dorn et al., 2003; Opie et al., 2006).

Adverse cardiac remodeling is the key predictor of late adverse outcomes after myocardial infarction and increased cardiac sudden death in patients with heart failure (White et al., 1987). Cardiac myocytes and extracellular matrix are the two key domains where most cardiac remodeling events happen.

Billions of CMs died after myocardial perfusion (Laflamme and Murry, 2005). The end diastolic left ventricular volume will increase in compensation for the lost myocardium to maintain stroke volume, according to FrankStarlings law. Stretching of myocytes due to ventricular dilatation and wall stress increase results in elongation or hypertrophy of CMs (Reiss et al., 1993; Opie et al., 2006). Overstretching of the ventricular wall and CMs will destroy the functional sarcomeres and further impair the contractility (Harding et al., 1989). Subsequently, non-ischemic expansion of the scar occurs because CM loss continues after MI as the result of both necrosis (Tan et al., 1991) and apoptosis (Olivetti et al., 1997).

Cardiac fibroblasts are stimulated by cytokines released from necrotic tissue and mechanical stretching to proliferate and transdifferentiate into myofibroblasts, and contribute to scar formation in the infarct area as well as fibrosis in the non-infarct area (Anderson et al., 1979; Weber et al., 1990; Sadoshima and Izumo, 1993; Sadoshima et al., 1993). Soon after infarction, fibroblasts and myofibroblasts deposit a large quantity of fibrillar collagen (type I, III) to form a new ECM. Non-fibrillar collagens (type IV, VI) are also produced and play a key role in differentiation and organization of the fibrillar collagen network (Shamhart and Meszaros, 2010). In acute infarction, quick scar formation in the infarct area is crucial to retain integrity of myocardium, and prevent extensive dilatation and possible ventricular rupture.

The synthesis and deposition of ECM parallel the increase of extracellular proteases (Zamilpa and Lindsey, 2010). Matrix metalloproteinases (MMPs) are proteases excreted from CMs and mainly from CFs (Polyakova et al., 2004). The MMPs contribute to the degradation of both matrix and non-matrix proteins in cardiac remodeling. Certain MMP types have diverse effects on cardiac remodeling and their modulation results in changes in the ECM structure and LV function (Zavadzkas et al., 2011). ADAMs (A Disintegrin And Metalloproteinase) belong to a group of glycoproteins that have a metalloprotease domain. ADAMs have essential roles in cardiac remodeling via effects on ECM degradation, activation of growth factors, cytokines and peptides, as well as CM viability and proliferation, hypertrophic responses and ischemic preconditioning (Manso et al., 2006).

Tissue inhibitors of metalloproteinases (TIMPs) have diverse and complex interaction with MMPs in proteolytic processes. TIMPs are excreted mainly from CFs (Polyakova et al., 2004). The imbalance between MMPs and TIMPs may facilitate adverse cardiac remodeling (Spinale, 2011). In other words, the ultimate changes in ECM during cardiac remodeling are the results of balancing between synthesis and degradation of matrix proteins (Zamilpa and Lindsey, 2010). Therefore, the effects of stem cell treatment on post-MI cardiac remodeling might be related to the modification of proteolytic pathways (Dixon and Spinale, 2011).

The abrupt disruption of perfusion to the myocardium results in damage of the vasculature within the infarct area. The collaterals at a microvascular level between occluded and non-occluded coronary arteries, which determine the survival of tissue, are minimal at the time of acute infarction. Low perfusion and hypoxia also occur at the border area of an infarct, without signs of capillary proliferation. Moreover, responsive hypertrophy in the non-infarct area is not accompanied by the adequate growth of capillaries. As a result, coronary reserve is reduced and micro-ischemic areas may form, that worsen the underlying pathological condition (Hudlicka et al., 1992; Kehat and Molkentin, 2010). Of note, LV remodeling can be initiated even by the regional dysfunctional hibernating myocardium (Chen et al., 1997).

As a consequence of cardiac remodeling, myocardial mass increases in the normal area as the result of compensatory hypertrophy (Opie et al., 2006), which is normally established within the first 4 weeks after the MI (Ertl et al., 1993). If there is more than 40% myocyte loss, the compensatory growth of the remaining CMs is insufficient to normalize the wall stress. The scar area becomes thinner because of both stretching of the wall and loss of CMs. The increase in LV size and thinning of the LV wall in the infarct area, according to La Places law, result in an increase in wall tension, up to nine-fold, and further impair LV function (Anversa et al., 1991).

Overloading of the ventricular chamber causes persistent increase in wall stretch and stress; and the resultant ventricular hypertrophy and dilatation lead to a vicious cycle of energy imbalance, expansion of infarction and finally end-stage heart failure (Anversa et al., 1991; Sadoshima et al., 1993). Therefore, unloading the ventricles either by drugs or mechanical ventricular support devices may ceases or reverses the process of cardiac remodeling (Malliaras et al., 2009).

The progress of cardiac remodeling and subsequent heart failure are primarily dependent on the extent of the infarction, early ventricular dilatation (McKay et al., 1986; Anversa et al., 1991; Gaudron et al., 1993), other local and systemic factors (Sutton and Sharpe, 2000), and the treatment after infarction (Jugdutt, 1995). During the first year post-MI, dilatation continues progressively in both infarct and non-infarct areas, until the counterbalance between intraventricular forces and tensile strength of the scar is established. Finally, the heart loses its elliptical shape and becomes spherical when cardiac remodeling progresses and patients develop heart failure years after the onset of MI (Mitchell et al., 1992; Cohn et al., 2000b).

In conclusion, post-MI cardiac remodeling is a multi-factorial, multi-level and progressive process that involves both cells and ECM. Considering the complexity of cardiac structure and post-MI cardiac remodeling, it would require a multimodal therapy involving molecular, cellular, medical and surgical approaches to treat the heart after myocardial infarction. Timely addressing of factors in the remodeling process might prevent progression of adverse remodeling and subsequent heart failure. In the next section, we will see how cells and biomaterials act to restore the infarcted myocardium.

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Heart Ventricle Remodeling - an overview | ScienceDirect ...