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Despite the development of percutaneous coronary intervention (PCI), left ventricular (LV) remodeling after acute myocardial infarction (AMI) is a serious complication that causes cardiac thrombosis, heart failure, and ventricular arrhythmia, leading to an unfavorable clinical outcome. The size of infarction determined within several hours after the attack is the most critical determinant of subsequent LV remodeling [
]. Mechanical factors, medical interventions, and humoral factors such as vasoactive substances and cytokines have been reported to be associated with LV remodeling in the chronic phase after AMI [
]. Hayakawa et al. have reported that inhibition of granulation tissue cell apoptosis by a pancaspase inhibitor significantly improved LV remodeling and heart failure in the chronic stage after AMI [
Inhibition of granulation tissue cell apoptosis during the subacute stage of myocardial infarction improves cardiac remodeling and dysfunction at the chronic stage.
Immune cells can initiate apoptosis of target cells through various stimulations including tumor necrosis factor α (TNFα), Fas/Fas ligand (FasL), granzymes, anti-cancer drugs, and oxidative stress [
]. As shown in Fig. 1, several mechanisms are involved in initiation of apoptosis. To date two major pathways are known for induction of apoptosis: extrinsic pathway and intrinsic pathway. Death ligands and receptors induce the extrinsic pathway, whereas mitochondrial cytochrome C is a major signaling molecule in the intrinsic pathway. In both pathways, cascade reaction of caspases is necessary. Kondo et al. showed the significant association between plasma granzyme B level and the extent of LV remodeling with AMI [
]. The number of patients was small in these two studies. The role of TNFα in heart failure has been studied enthusiastically in animal models as well as human studies [
]. TNFα has been reported to alter spatial alignment of cardiac myocytes in LV wall by reducing the collagen cross-linking. Upregulation of matrix metalloproteinases plays a critical role in TNFα-mediated matrix remodeling. Nonetheless, clinical trials (RECOVER, RENAISSANCE, RENEWAL, and ATTACH) using neutralizing antibody against TNFα failed to reduce mortality of patients with congestive heart failure [
]. So far, inhibition of TNFα has not been effective for prevention of LV remodeling and heart failure in humans.
Fig. 1Signal transduction pathways for apoptosis. Apoptosis is induced by various stimulations including tumor necrosis factor α (TNFα), Fas/Fas ligand (FasL), granzymes, anti-cancer drugs, and oxidative stress. There are two major pathways for induction of apoptosis: extrinsic pathway and intrinsic pathway. Death ligands and receptors induce the extrinsic pathway, whereas mitochondrial cytochrome C is a major signaling molecule in the intrinsic pathway.
Similar to TNFα, FasL activates the extrinsic apoptosis pathway through binding to Fas that belongs to the death-receptor family. Binding of ligands to death-receptor allows complex formation with FADD (Fas-associated protein with death domain) and intracellular domain of death receptors. The receptor and FADD complex activates caspase 8 and down-stream caspases. Previous studies have demonstrated the association of Fas/FasL axis in LV remodeling [
Inhibition of Fas-associated apoptosis in granulation tissue cells accompanies attenuation of postinfarction left ventricular remodeling by olmesartan.
Am J Physiol Heart Circ Physiol.2007; 292: H2184-H2194
]. In the REVE-2 study, the authors enrolled a large number of patients with typical first anterior myocardial infarction and failed to show a significant association between circulating soluble FasL and LV remodeling after AMI [
Fertin M, Bauters A, Pinet F, Bauters C. Circulating levels of soluble Fas ligand and left ventricular remodeling after acute myocardial infarction (from the REVE-2 study). J Cardiol 2012 April 2, http://dx.doi.org/10.1016/j.jjcc.2012.03.001 [Epub ahead of print].
There are several possibilities to explain the discrepancy between previous studies regarding cardiac apoptosis and the REVE-2 study. (1) Most previous studies were performed in rodent models. Thus the discrepancy might be caused by species difference. (2) As indicated by the authors, blood sampling was performed only once in the REVE-2 study (1 month after AMI). Different results might be obtained if changes in circulating levels of Fas/FasL were monitored by serial blood sampling after AMI. (3) Also Fas/FasL pathway (extrinsic pathway) was not involved; the intrinsic pathway might play a critical role in apoptosis of cardiac myocytes, because pancaspase inhibitor has attenuated the LV remodeling [
Inhibition of granulation tissue cell apoptosis during the subacute stage of myocardial infarction improves cardiac remodeling and dysfunction at the chronic stage.
Inflammation and matrix remodeling after AMI consists of complex mechanisms including increased oxidative stress, cytokine storms, and geometric changes of left ventricle. To date, various therapies have been attempted to prevent LV remodeling such as inhibition of renin–angiotensin–aldosterone system, cardiac regeneration therapy, gene therapy, and administration of nitric oxide, natriuretic peptide, and scavengers of reactive oxygen species [
]. Interestingly, the REVE-2 study also showed that hepatocyte growth factor was significantly associated with LV remodeling and can be a prognostic biomarker after AMI [
Fertin M, Bauters A, Pinet F, Bauters C. Circulating levels of soluble Fas ligand and left ventricular remodeling after acute myocardial infarction (from the REVE-2 study). J Cardiol 2012 April 2, http://dx.doi.org/10.1016/j.jjcc.2012.03.001 [Epub ahead of print].
In experimental studies, the percentage of apoptotic cells relative to total cardiac myocytes is quite small after AMI. The precise role of apoptosis in LV remodeling after AMI should be clarified in humans. In addition to the measurement of circulating biomarkers, a novel modality such as molecular imaging is needed to clarify the role of apoptosis in LV remodeling. Understanding the complex process of LV remodeling will lead to novel therapeutic approaches to treat the increasing number of patients with heart failure after AMI.
References
Reimer K.
Vander Heide R.
Richard V.
Reperfusion in acute myocardial infarction: effect of timing and modulating factors in experimental models.
Inhibition of granulation tissue cell apoptosis during the subacute stage of myocardial infarction improves cardiac remodeling and dysfunction at the chronic stage.
Inhibition of Fas-associated apoptosis in granulation tissue cells accompanies attenuation of postinfarction left ventricular remodeling by olmesartan.
Am J Physiol Heart Circ Physiol.2007; 292: H2184-H2194
Fertin M, Bauters A, Pinet F, Bauters C. Circulating levels of soluble Fas ligand and left ventricular remodeling after acute myocardial infarction (from the REVE-2 study). J Cardiol 2012 April 2, http://dx.doi.org/10.1016/j.jjcc.2012.03.001 [Epub ahead of print].
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