Ventricular Remodeling After Infarction and the Extracellular Collagen Matrix

Abstract

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...

Time course of serum collagen types I and III metabolism products after reperfused acute myocardial infarction in patients with and without systemic hypertension

“…2 In contrast, we did not observe any relationship between S serum PIIINP and echocardiographic parameters; this result cannot be elucidated from this study. However, it is at odds with recent reports from the Framingham Heart Study.…”

“…1 Although the mechanisms of post-myocardial infarction remodelling are multifactorial, it has now been established that changes in the extracellular collagen matrix (ECCM) contribute greatly to LV remodelling. 2 Systemic arterial hypertension causes significant alteration in cardiac geometry and function, 3 as well as in the ECCM composition. 4 Antecedent hypertension increases the risk of heart failure after acute myocardial infarction (AMI).…”

The extracellular matrix in myocardial injury, repair, and remodeling

“…In all mammalian species studied to date, type I collagen is the major structural component of the cardiac interstitium, accounting for approximately 85% to 90% of the collagenous matrix (7), and is predominantly localized in the epimysium and perimysium. In contrast, type III collagen represents 5% to 11% of total myocardial collagen and is more prominent in the endomysium (7)(8)(9). In addition to collagens, the cardiac ECM also contains fibronectin, glycosaminoglycans, and proteoglycans, and it serves as a reservoir for growth factors and proteases, which are stored in the normal matrix and can be activated following injury.…”

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

“…To induce MSC differentiation into the osteogenic lineage, cells were cultured in DMEM/F12 medium supplemented with 10% FBS, 10 nmol/L dexamethasone, 10 mmol/L ␤-glycerophosphate, 50 g/mL ascorbate phosphate, and 10 nmol/L 1␣,25-dihydroxyvitamin D 3 . To induce adipogenesis, cells were placed in DMEM/F12 medium supplemented with 10% FBS, 10 mol/L dexamethasone, 1 g/mL insulin, and 0.5 mmol/L isobutylmethylxanthine.…”

“…After several weeks, a mature scar is formed, and most of the myofibroblasts undergo apoptosis. [3][4][5] We have previously established in a model of mouse MI that, compared with young animals, aged mice demonstrate greater infarct expansion and less effective myocardial repair. 6 Defective scar formation arises from a decreased number of myofibroblasts and diminished collagen deposition in the infarct, which results in a structurally unstable scar formed by loose connective tissue.…”