Ventricular Remodeling After Infarction and the Extracellular Collagen Matrix: When Is Enough Enough?

Abstract

Ventricular Remodeling After Infarction and the Extracellular Collagen MatrixWhen Is Enough Enough?Bodh I. Jugdutt, MD L eft ventricular (LV) remodeling after myocardial in- farction (MI) contributes significantly to LV dilation and dysfunction, and disability and death.Two paradigms, pertinent to antiremodeling therapy after MI (Figure 1), have evolved over the last 3 decades.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.This review focuses on the role of the ECCM in the evolution of LV remodeling after MI and the potential impact of therapies that target the ECCM. Ventricular Remodeling After MI and the Role of ECCMFive points merit emphasis.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) 6,7,17-23 ; (3) proteins, cytokines, and growth factors 7,24,25 ; and (4) the ECCM.5-7,13-17,19 -23 Differential re-gional 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. 3,6,7 Second, the post-MI heart shows remarkable capacity to adapt to the rather sudden development of an IZ and a NIZ.Thus, MI results in time-dependent damage to myocytes, nonmyocytes, and the ECCM in the IZ; ventricular dysfunction followed by volume overload and progressive dilation; reactive hypertrophy with interstitial fibrosis and increased collagen in the NIZ; gradual reparative fibrosis in the IZ 27 ; and vascular remodeling in the IZ and NIZ.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.33,38 In reperfused MI, decreased or damaged ECCM in the IZ 5,12,39 is associated with cardiac rupture.5,39