A vast body of evidence suggests an essential role for the immune response in the reparative process following myocardial infarction [334
]. Although no specific immunomodulatory approach is currently part of our therapeutic armamentarium for patients with myocardial infarction, established therapeutic strategies, such as β-adrenergic blockade and ACE inhibition, may exert their beneficial effects in part by interfering with the inflammatory cascade. β-adrenergic blockade attenuated TNF-α and IL-1β expression in failing hearts [335
] and decreased IL-1 expression levels in the infarcted myocardium [336
]. Several studies have demonstrated that ACE inhibition and angiotensin receptor blockade result in decreased TGF-β expression in healing infarcts [306
]. However, the contribution of TGF-β signaling inhibition in mediating the salutary effects of ACE inhibitors remains unknown.
Over the past thirty years numerous experimental studies have shown dramatic reduction in infarct size, or attenuation of adverse remodeling, with the use of specific strategies that modulate the inflammatory response. Initially the main concept guiding these interventions was the notion that inflammatory cells and mediators may induce injury of viable cardiomyocytes. As the role of the inflammatory cascade in cardiac repair was recognized, attempts to optimize the healing response were introduced, aimed at attenuating adverse remodeling. Recently, the concept of cell-based cardiac repair has evolved and strategies enhancing the regenerative capacity of the heart have been tested in both experimental animal models and in clinical settings. In order to identify suitable therapeutic targets for patients with myocardial infarction several important questions need to be answered:
Do anti-inflammatory approaches reduce cardiomyocyte injury?
Although extensive experimental evidence suggested that infiltrating leukocytes and inflammatory mediators may induce injurious effects on viable cardiomyocytes in the infarcted heart, attempts to mitigate inflammatory injury in clinical practice have been in general unsuccessful. The catastrophic experience of the methylprednisolone trial [337
] emphasized the need for better understanding of the cellular and molecular events associated with the inflammatory response in order to achieve effective suppression of injurious processes without interfering with healing and cardiac repair. Recently, the disappointing results of the anti-CD18 trials led to criticism regarding the usefulness of strategies targeting the inflammatory cascade in myocardial infarction [201
]. It has been suggested that these failures may represent the inherent risk of using animal models, which may have fundamental differences from the respective human disease process. Although species-specific effects may be in some cases significant, the most important lesson we have learned from studying experimental myocardial infarction is that a sound understanding of the biology is necessary before a specific intervention is pursued on a therapeutic basis. So, why did anti-inflammatory strategies fail in reducing cardiac injury?
First, the significance of inflammatory cardiomyocyte injury may have been overstated. Although many published experimental studies demonstrated an impressive reduction in infarct size upon inhibition of specific inflammatory mediators, these findings may not adequately represent our collective experience. In contrast to clinical trials, experimental studies may not be published when the data do not reveal an effect of the intervention. This bias against “negative” findings may have prevented publication of reports that showed no significant effects of anti-inflammatory strategies.
Second, one has to consider that the inflammatory cascade is based on a complex network of molecular mediators with pleiotropic effects, dictated by critical cellular, spatial and temporal variables. Typical properties of cytokines in networks are redundancy, pleiotropic, synergistic activity and antagonistic effects upon each other. Thus, cytokines and other inflammatory mediators that may appear reasonable therapeutic targets considering their injurious role in the early stages of the inflammatory response may also be essential regulators of cardiac repair. Interventions attenuating early inflammatory injury may also result in impaired healing, leading to accentuated adverse remodeling through alterations in the qualitative characteristics of the scar. For many anti-inflammatory interventions, the possible benefit from reduction of inflammatory cardiomyocyte injury may not outweigh the detrimental effects on the reparative response.
Third, the complexity of the clinical scenario cannot be adequately simulated in experimental studies. Variables such as age, gender, the presence of comorbid conditions such as diabetes, obesity and hyperlipidemia, the timing of reperfusion and genetic variations between individuals greatly complicate prediction of the potential effects of a therapeutic intervention. Our recent investigation on the effects of aging on infarct healing provides insight into the challenges of predicting the effects of a therapeutic intervention on the basis of experimental animal studies [338
]. We demonstrated that enhanced post-infarction remodeling in senescent mice is associated with suppressed inflammation, delayed granulation tissue formation and markedly reduced collagen deposition, in part due to blunted responses of senescent fibroblasts to growth factors. In contrast, young animals exhibit a robust post-infarction inflammatory response and form dense collagenous scars. Animal studies are almost always performed in young adult animals and, although they provide valuable insight into the mechanisms involved in cardiac injury and repair, they may not accurately reflect the pathology of myocardial infarction in middle aged or elderly human populations. Thus, the injurious potential of inflammatory mediators in patients with myocardial infarction may have been overstated due to extrapolation from young animals to human patients. In addition, senescent ischemic hearts show impairment of important cardioprotective pathways involving TNF-α [339
] and PDGF-AB [340
] and have a decreased anti-apoptotic response to administration of Granulocyte-Colony Stimulating Factor (G-CSF) and SCF [341
] in comparison with young animals.
Does modulation of the inflammatory response attenuate adverse remodeling?
Even if interventions targeting the inflammatory response do not reduce cardiomyocyte death, modulation of the reparative process in order to optimize the mechanical and functional properties of the infarcted heart remains an interesting direction. Experimental evidence suggests that inhibition of chemokine signaling, modulation of extracellular matrix remodeling, and enhancement of the endogenous protective mechanisms that contribute to resolution and containment of the inflammatory response may be promising therapeutic strategies [334
]. Timing and topography are key determinants of the success of a specific approach. Effective healing is dependent on a well-orchestrated cellular response and on timely induction and suppression of specific mediators in a locally restricted manner. Thus, interventions targeting inflammatory mediators should take into account both topographic and temporal parameters. An approach that may have favorable effects if locally applied in the center of the infarct may result in deleterious changes in the border zone or the non-infarcted remodeling myocardium. For example, a strategy that decreases the collagen content in the infarcted heart may attenuate interstitial fibrosis in the non-infarcted areas, but may also result in enhanced remodeling by suppressing collagen deposition in the center of the infarct, leading to decreased tensile strength and subsequent left ventricular dilation.
Is cardiac regeneration a realistic therapeutic target?
Cardiac myocytes are thought to be terminally differentiated cells unable to regenerate and replace damaged myocardium. This concept was challenged by recent evidence suggesting that a fraction of cardiomyocytes may be able to re-enter the cell cycle, and that limited cardiac regeneration may occur through recruitment of resident and circulating stem cells [342
]. Although the issue of cardiomyocyte regeneration remains highly controversial [344
] these concepts led to basic and clinical studies exploring the effects of cell-therapy strategies in cardiac repair following infarction [345
]. Cell-based therapy began with the transplantation of autologous skeletal myoblasts; these cells did not appear to transdifferentiate into cardiomyocytes after cardiac grafting [347
] and remained functionally isolated from their host [348
]. Several groups have independently studied the potential of bone marrow-derived cells to promote cardiac regeneration. Orlic and co-workers suggested that hematopoietic stem cells can transdifferentiate into cardiomyocytes when injected into the infarcted myocardium resulting in extensive cardiac regeneration and improved function [221
]. Unfortunately several other groups could not reproduce these findings and concluded that there was no significant cardiac differentiation of bone marrow-derived cells [349
], although endogenously derived circulating cells were noted to fuse with host myocytes in the infarct border zone. Thus, the ability of injected bone marrow-derived cells to give rise to cardiac myocytes after myocardial infarction remains controversial [345
]. Mesenchymal stem cells have recently attracted significant interest as a promising cell-based therapeutic strategy for patients with myocardial infarction [351
]. Enthusiasm from the early experimental findings fueled numerous small clinical studies examining the effects of cell therapy in patients with acute myocardial infarction [342
]. Although some of these studies have reported beneficial effects of progenitor cell transfer in the infarcted heart [354
], the mechanisms responsible for these actions remain poorly understood [356
]. Carefully conducted clinical trials will clarify the role of cell therapy in the treatment of patients with myocardial infarction.
The discovery of the beneficial effects of marrow-derived progenitors in cardiac repair led to attempts to mobilize these cells using cytokines and growth factors. Inflammatory mediators play an important role in mobilizing progenitor cells and may regulate their homing into the infarcted myocardium [357
]. Several studies demonstrated that treatment with SCF and G-CSF results in improved function and attenuated left ventricular remodeling following myocardial infarction [220
]. Whether these beneficial effects are mediated through enhanced recruitment of progenitor cells remains unclear. Growth factors are pleiotropic and multifunctional and induce a diverse range of effects on a variety of cell types involved in infarct healing. In addition to its actions on progenitor cell recruitment, G-CSF may prevent post-infarction remodeling by exerting direct anti-apoptotic effects on cardiomyocytes [358
]. Thus, the potential beneficial actions of growth factor therapy in the infarcted myocardium may not be mediated through stem cell mobilization.
The field of cell-based therapy in myocardial infarction is rapidly evolving. Although the initial ambitious goal to rebuild the heart from its component parts remains elusive, extensive experimental evidence suggests beneficial effects from therapeutic strategies injecting a wide variety of cell types. The benefit is usually not associated with cardiomyocyte regeneration, but may be mediated through paracrine effects of the injected cells, inducing enhanced repair and attenuating dilative remodeling of the infracted ventricle. Many challenging questions remain to be answered. What is the mechanism responsible for functional improvement in the absence of cardiomyocyte transdifferentiation? Are the benefits from cell therapy simply due to alterations in the mechanical properties of the infarcted heart? Considering the significant species differences in the biology of progenitor cells and tissue regeneration, are the conclusions derived from studies in rodents applicable to human patients? How can we ensure optimal vascularization of the grafted cells? Do the injected cells serve as a vehicle for continuous delivery of specific soluble mediators that exert protective effects? Which combination of cytokines and growth factors would provide optimal enhancement of the reparative response? These and other critical issues need to be addressed in order to fulfill the visionary goal of cardiac regeneration.