Cellular preservation therapy in acute myocardial infarction.

THE PAST DECADE has been characterized by unprecedented progress in cardiac cell biology and pathophysiology. The dogma of the heart being a terminally differentiated organ has been challenged by compelling evidence generated in several different laboratories around the world (6). These findings were received with a mixture of skepticism and enthusiasm, which has led to an exponential development in the field of cardiac regeneration. The relative ease of using autologous cells to promote cardiac regeneration paired with promising preclinical data has prompted multiple translational studies in patients with acute myocardial infarction (AMI) (5, 12). While the results of clinical studies with bone marrow-derived stem cells or mobilizing factors [such as granulocyte colony-stimulating factor (G-CSF)] produced only marginal positive benefits (5, 12), clinical observations have led to a reexploration of the original hypotheses generated in the laboratory (from bedside to bench). Some investigators now question the efficiency of cardiomyocyte regeneration and progenitor cell transdifferentiation (16). Furthermore, the paradigm shifted from a substantial role of cardiomyocyte regeneration to a combined role of cellular preservation and regeneration of resident cells mediated by paracrine mechanisms (9). Most important, the complexity of the events in infarct healing suggests that no single intervention may be sufficient to halt the course of post-AMI remodeling (Fig. 1). Ischemic necrosis. Ischemic necrosis is the hallmark of acute myocardial infarction. A sudden obstruction to coronary flow leads to decreased tissue oxygen content, decreased ATP levels, tissue acidosis, and hypoglycemia, which trigger the activation of the mitochondrial apoptosis pathway (caspase-9 mediated) and alterations in cell membrane permeability leading to oncosis cell death. Cell membrane rupture releases cytosolic content into the surrounding tissue and stimulates further inflammation. The constellation of cell membrane rupture and tissue inflammation constitutes ischemic necrosis, which is the trigger for the process of infarct healing. Inflammation, granulation tissue, and scar formation. Necrosis is a powerful chemotactic factor for inflammatory cells that infiltrate the damaged area in the attempt to remove debris and coordinate the reparative fibrosis. While inflammation is an essential step for infarct healing, a limitation of the inflammatory response may be a potential therapeutic intervention to limit unfavorable remodeling. Polymorphynucleates, monocytes, and lymphocyte infiltrate the infarct area at different times. This infiltrate is paired with neoangiogenesis, hyperplasia of fibroblast, and increased collagen production and deposition. The inflammatory infiltrate disappears over time by means of cell apoptosis. Ultimate scar formation is characterized by a prevalence of connective tissues fibers and supporting cells. The fate of the infiltrate and the granulation tissue are major determinants for cardiac remodeling after AMI. For example, the inhibition of granulation tissue apoptosis is associated with the formation of a thicker scar, which ultimately reduces wall stress (10). However, the inflammatory infiltrate also stimulates the local production of inflammatory cytokines (i.e., interleukin-1) that further induce receptor-dependent caspase-8-mediated apoptosis in cardiomyocytes (4). Cardiomyocyte hypertrophy, apoptosis, autophagy, and degeneration. Many cardiomyocytes are lost during the early course of AMI in the central area where tissue levels of oxygen are lowest. However, neither the region of the myocardium bordering this central area nor the remote myocardium is spared from damage. Increased wall stress leads to an increased metabolic demand of the surviving cardiomyocytes that leads to cell hypertrophy. This is more evident in the border zone in which there is a combination of hypertrophic stimuli (stretch, angiotensin, and norepinephrine) and inflammatory stimuli (interleukins and tumor necrosis factor) paired with a suboptimal tissue perfusion. Cardiomyocytes in the border zone have been described as metabolically impaired (usually with anaerobic metabolism, electromechanical dissociation, and fetal gene switch) and morphologically abnormal (degenerated, with aberrant nuclei). These cells have multiple overlapping phenotypes, such as mitochondrial abnormalities, suggestive of oncosis; nuclear alterations and DNA fragmentation, suggestive of apoptosis; and cytoplasmic vacuolization, suggestive of autophagy (7– 8, 11). While the presence of “degenerated” cardiomyocytes is generally accepted, many investigators debate the exact role of each cell death modality. This debate stems from inconsistencies between studies that vary in subjects studied, overlapping pathways and phenotypes, methods used, and interpretations given (1, 2). Nevertheless, the degree of cardiomyocyte degeneration correlates with clinical signs of adverse cardiac remodeling and predicts outcome independent of the markers used to detect cardiomyocyte degeneration (i.e., in situ end-labeling for DNA fragments, caspase-3 activation, annexin V staining for apoptosis, or ubiquitin staining for autophagy) (2–3, 8, 14). The most compelling evidence supporting a significant role for cardiomyocyte apoptosis derives from the elegant study by Wencker et al. (17) demonstrating mechanistically that cardiomyocyte apoptosis induced by caspase-8 overexpression is sufficient to cause dilated cardiomyopathy, heart failure, and death in the mouse. Address for reprint requests and other correspondence: A. Abbate, Div. of Cardiology/VCU Pauley Heart Ctr., Virginia Commonwealth Univ., 1200 E. Broad St. West Hospital, 10th Fl., East Wing, Rm. 1041, PO Box 980281 Richmond, VA 23298-0281 (e-mail address: [email protected]). Am J Physiol Heart Circ Physiol 296: H563–H565, 2009; doi:10.1152/ajpheart.00066.2009.