Role of apoptosis in left ventricular remodeling after acute myocardial infarction

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 [[1]Reimer K. Vander Heide R. Richard V. Reperfusion in acute myocardial infarction: effect of timing and modulating factors in experimental models.Am J Cardiol. 1993; 72: 3G-21GAbstract Full Text PDF PubMed Scopus (120) Google Scholar]. PCI has reduced the mortality of AMI, however, the incidence of heart failure is increasing and has become a serious problem in recent years [[2]Velagaleti R. Pencina M. Murabito J. Wang T. Parikh N. D’Agostino R. Levy D. Kannel W.B. Vasan R.S. Long-term trends in the incidence of heart failure after myocardial infarction.Circulation. 2008; 118: 2057-2062Crossref PubMed Scopus (366) Google Scholar]. 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 [3McKay R. Pfeffer M. Pasternak R. Markis J. Come P. Nakao S. Alderman J.D. Ferguson J.J. Safian R.D. Grossman W. Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion.Circulation. 1986; 74: 693-702Crossref PubMed Scopus (651) Google Scholar, 4Cheng W. Kajstura J. Nitahara J. Li B. Reiss K. Liu Y. Clark W.A. Krajewski S. Reed J.C. Olivetti G. Anversa P. Programmed myocyte cell death affects the viable myocardium after infarction in rats.Exp Cell Res. 1996; 226: 316-327Crossref PubMed Scopus (317) Google Scholar]. In particular, apoptotic cell death in infarcted tissue is reported to play an important role in progression of LV remodeling after AMI [[5]Takemura G. Ohno M. Hayakawa Y. Misao J. Kanoh M. Ohno A. Uno Y. Minatoguchi S. Fujiwara T. Fujiwara H. Role of apoptosis in the disappearance of infiltrated and proliferated interstitial cells after myocardial infarction.Circ Res. 1998; 82: 1130-1138Crossref PubMed Scopus (169) Google Scholar]. 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 [[6]Hayakawa K. Takemura G. Kanoh M. Li Y. Koda M. Kawase Y. Maruyama R. Okada H. Minatoguchi S. Fujiwara T. Fujiwara H. Inhibition of granulation tissue cell apoptosis during the subacute stage of myocardial infarction improves cardiac remodeling and dysfunction at the chronic stage.Circulation. 2003; 108: 104-109Crossref PubMed Scopus (91) Google Scholar]. 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 [[7]Granville D. Carthy C. Hunt D. McManus B. Apoptosis: molecular aspects of cell death and disease.Lab Invest. 1998; 78: 893-913PubMed Google Scholar]. 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 [[8]Kondo H. Hojo Y. Tsuru R. Nishimura Y. Shimizu H. Takahashi N. Hirose M. Ikemoto T. Ohya K. Katsuki T. Yashiro T. Shimada K. Elevation of plasma granzyme B levels after acute myocardial infarction.Circ J. 2009; 73: 503-507Crossref PubMed Scopus (34) Google Scholar]. Soeki et al. have reported increased FasL levels in patients with LV remodeling 2–3 weeks after AMI [[9]Soeki T. Tamura Y. Shinohara H. Sakabe K. Onose Y. Fukuda N. Relation between circulating soluble Fas ligand and subsequent ventricular remodelling following myocardial infarction.Heart Vessels. 2003; 89: 339-341Crossref Scopus (11) Google Scholar]. 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 [[10]Bradham W. Bozkurt B. Gunasinghe H. Mann D. Spinale F. Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective.Cardiovasc Res. 2002; 53: 822-830Crossref PubMed Scopus (147) Google Scholar]. 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 [[11]Anker S. Coats A. How to RECOVER from RENAISSANCE? The significance of the results of RECOVER, RENAISSANCE, RENEWAL and ATTACH.Int J Cardiol. 2002; 86: 123-130Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar]. So far, inhibition of TNFα has not been effective for prevention of LV remodeling and heart failure in humans. 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 [9Soeki T. Tamura Y. Shinohara H. Sakabe K. Onose Y. Fukuda N. Relation between circulating soluble Fas ligand and subsequent ventricular remodelling following myocardial infarction.Heart Vessels. 2003; 89: 339-341Crossref Scopus (11) Google Scholar, 12Kanamori H. Takemura G. Li Y. Okada H. Maruyama R. Aoyama T. Miyata S. Esaki M. Ogino A. Nakagawa M. Ushikoshi H. Kawasaki M. Minatoguchi S. Fujiwara H. 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-H2194Crossref PubMed Scopus (30) Google Scholar, 13Li Y. Takemura G. Kosai K. Takahashi T. Okada H. Miyata S. Yuge K. Nagano S. Esaki M. Khai N.C. Goto K. Mikami A. Maruyama R. Minatoguchi S. Fujiwara T. et al.Critical roles for the Fas/Fas ligand system in postinfarction ventricular remodeling and heart failure.Circ Res. 2004; 95: 627-636Crossref PubMed Scopus (99) Google Scholar]. 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 [14Lamblin N. Bauters A. Fertin M. de Groote P. Pinet F. Bauters C. Circulating levels of hepatocyte growth factor and left ventricular remodelling after acute myocardial infarction (from the REVE-2 study).Eur J Heart Fail. 2011; 13: 1314-1322Crossref PubMed Scopus (22) Google Scholar, 15Fertin 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].Google Scholar]. 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 [[6]Hayakawa K. Takemura G. Kanoh M. Li Y. Koda M. Kawase Y. Maruyama R. Okada H. Minatoguchi S. Fujiwara T. Fujiwara H. Inhibition of granulation tissue cell apoptosis during the subacute stage of myocardial infarction improves cardiac remodeling and dysfunction at the chronic stage.Circulation. 2003; 108: 104-109Crossref PubMed Scopus (91) Google Scholar]. 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 [[16]Hayashida K. Sano M. Ohsawa I. Shinmura K. Tamaki K. Kimura K. Endo J. Katayama T. Kawamura A. Kohsaka S. Makino S. Ohta S. Ogawa S. Fukuda K. Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia–reperfusion injury.Biochem Biophys Res Commun. 2008; 373: 30-35Crossref PubMed Scopus (395) Google Scholar]. 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 [14Lamblin N. Bauters A. Fertin M. de Groote P. Pinet F. Bauters C. Circulating levels of hepatocyte growth factor and left ventricular remodelling after acute myocardial infarction (from the REVE-2 study).Eur J Heart Fail. 2011; 13: 1314-1322Crossref PubMed Scopus (22) Google Scholar, 15Fertin 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].Google Scholar]. 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.