Remodeling of the Myocardium and Potential Targets in the Collagen Degradation and Synthesis Pathways

Abstract

Remodeling of the myocardium is the major mechanism for disability and death in prevalent cardiovascular diseases such as hypertension, heart failure and myocardial infarction (MI). It is a complex process that involves changes in structure, shape and topography at the global level and changes in myocytes and non-myocytes at cellular and subcellular levels that impact negatively on function. Although the myocytes subserve the heart's pump function, the predominant cell type in the heart is the fibroblast (not the myocyte). The fibroblast's major role is deposition of the extracellular matrix (ECM) of which collagen is the principal component. The cardiac extracellular collagen matrix (ECCM) maintains structural and functional integrity, and contributes to coordinated mechanical action with every systole during life. Excessive collagen deposition or pathological fibrosis is an important contributor to left ventricular (LV) dysfunction and poor outcome in hypertension, MI and heart failure. It is also an important problem in the aging heart. Antifibrotic agents that target steps in the collagen synthesis and degradation pathways therefore represent promising strategies for these diseases. Because reparative fibrosis is an essential component of healing of the infarct zone (IZ) after MI, the design of approaches that separately target the IZ and non-infarct zone (NIZ) is challenging. It may be possible in future to target the collagen pathways in the heart or regions of the heart, and not other areas or organs, by delivering drugs or genes locally to specific regions.

Ventricular Remodeling After Infarction and the Extracellular Collagen Matrix

“…First, the LV remodeling process after MI is complex, dynamic, and time dependent, and progresses in parallel with healing over months. 1,2,7,16 Notably, it involves differential changes between the IZ and NIZ with respect to the following: (1) LV structure, shape, and topography 1,2 ( Figure 1); (2) cell type, such as myocytes and nonmyocytes (Table 1) 6,7,[17][18][19][20][21][22][23] ; (3) proteins, cytokines, and growth factors 7,24,25 ; and (4) the ECCM. 5-7,13-17,19 -23 Differential regional remodeling of the ECCM contributes significantly to global LV structural remodeling after MI (Figure 2) 7,9,26 and plays a pivotal role in paradigm 1.…”

“…7 Third, several endogenous molecules that affect collagen synthesis and are upregulated after MI, and several agents that are used therapeutically for MI, affect collagen turnover (Table 2, Figure 3) and exert an antifibrotic effect. 2,7,9,10,28 This can potentially alter ECCM remodeling in the IZ 9,28 and impair healing, 29 and thereby promote adverse remodeling and outcome, depending on their timing relative to pathophysiological stages of healing (Table 3).Fourth, a fine balance, between matrix metalloproteinases (MMPs) that degrade ECCM and endogenous tissue inhibitors of MMPs (TIMPs) that inhibit MMPs, 30 -32 maintains normal remodeling and function, and an imbalance can result in adverse remodeling. 24,25,30,33,34 Fifth, although a 2-to 3-fold increase in myocardial collagen above the normal level results in increased LV stiffness and mild dysfunction, 35 a very small decrease in collagen below normal can lead to drastic consequences, 36,37 including LV dilation 4,22,34 and rupture.…”

“…Paradigm 1, LV remodeling is a major mechanism for disability and death, 1,2 has received a great deal of attention. In contrast, paradigm 2, remodeling of the extracellular collagen matrix (ECCM) plays a major role in LV remodeling, [3][4][5][6][7] whereby decrease, disruption, and/or defective composition of the ECCM promote LV dilation and rupture, 4 -7 has received little attention. A host of clinical trials showed that angiotensin-converting enzyme (ACE) inhibitors (ACE-Is) with or without aldosterone antagonists, angiotensin II (AngII) type 1 (AT 1 ) receptor blockers (ARBs), ␤-adrenergic blockers or reperfusion improve outcome in survivors of MI.…”

“…8 -10 Concurrent evidence has underscored the importance of preserving the ECCM during healing after MI. [2][3][4][5][6][7] However, the antifibrotic action of ACE-Is, aldosterone antagonists and ARBs on ECCM in the infarct zone (IZ) and noninfarct zone (NIZ), 6,7,9,11 and the reperfusion-induced damage to the ECCM in the IZ, 5,7,12 remain unreconciled with the benefits. 8 -10,13 Nevertheless, excessive ECCM, as in dilated ischemic cardiomyopathy after remote MI, 14,15 can contribute to LV diastolic dysfunction and poor outcome, 6 suggesting that antifibrotic drugs that target excess ECCM might be a logical therapeutic approach.…”

Relaxin remodels fibrotic healing following myocardial infarction

“…Following myocardial infarction (MI), reparative fibrotic healing occurs in the infarct region (IR) to maintain structural integrity, denoting an irreversible loss of tissue function while preventing myocardial regeneration. [1][2][3] Reactive fibrosis occurs in the non-infarcted myocardium in response to biomechanical and/or hormonal stimulation, contributing to increased myocardial stiffness and global dysfunction. Hence, interventions targeting excessive fibrosis as a result of MI are of major therapeutic importance.…”