L eft ventricular (LV) remodeling after myocardial infarction (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][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. 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 co...

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.

SUMMARY To study endocardial wall motion and thickness as indexes of infarction, we used two-dimensional echocardiography to examine regional percentages of systolic wall thickening (%Th) and endocardial motion (%EM) in infarcted canine hearts. Thirteen dogs were studied 48 hours after occlusion of the circumflex or left anterior descending coronary artery. Two-dimensional echocardiographic cross sections obtained every 16 msec at 1-cm intervals from apex to base in an open-chest, anesthetized preparation were analyzed with a computer-aided contouring system for quantification of segmental %EM and %Th at 16 equally spaced points per slice. Slices corresponding to each two-dimensional echocardiographic cross section were examined pathologically for evidence of infarction.Comparing histologically infarcted with distant normal zones in each slice, %Th and %EM both yielded clear separation with little overlap (-12.5% infarcted vs 37.4% normal for thickness; -11.3 vs 25.7% for motion, p << 0.001 for both). Endocardial motion was less precise than thickening, however, in distinguishing infarct from either distant normal zones or zones directly adjacent to infarct.Although wall thickening was useful in separating out true subendocardial infarct, change in systolic thickening was not accurate in detecting the transmural extent of infarction. In 827 individual two-dimensional echocardiographic segments with varying degrees of transmural involvement, segments with 1-20% extent of transmural infarction showed reduced thickening compared with noninfarcted segments (39.9 vs 15.2%, p < 0.001), whereas myocardial segments with 21-100% transmural infarction showed systolic thinning (-8.9 to -13.3%). There was no significant augmentation in the severity of systolic thinning as the extent of transmural infarction increased from 21% to 100%.We conclude that: (1) Wall motion abnormalities are less precise than thickening in discriminating between infarcted and noninfarcted zones and could lead to overestimation of infarct size. (2) There is an abrupt deterioration in systolic thickening in segments containing more than 20% transmural extent of infarction. (3) There is no significant augmentation in the degree of systolic thinning as the transmural extent of infarct increases from 21% to 100%. This "threshold" phenomenon may therefore preclude accurate estimation of infarct size by two-dimensional echocardiography. (4

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To determine 1) whether the effect of intravenous nitroglycerin (NG) therapy during acute myocardial infarction on creatine kinase infarct size is influenced by infarct location (anterior vs.