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a Children's Memorial Hospital, Division of Cardiovascular-Thoracic Surgery, 2300 Children's Plaza, MC 22, Chicago, IL 60614
b The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, Ohio State University, 700 Children's Dr, W321, Columbus, OH 43205
(Email: skaushal{at}childrensmemorial.org; loren.wold{at}nationwidechildrens.org).
Despite significant medical advancements, myocardial ischemic disease is still a leading cause of death in the world. The regenerative capacity of the heart is now generally believed to exist; however, its capacity to regenerate an adequate amount of myocardial tissue during ischemic insults is insufficient. Subsequently, cardiomyocytes are lost as a result of myocardial ischemia, triggering cardiac dysfunction and eventual cardiac failure. One of the most promising novel therapies for cardiac failure is cellular cardiomyoplasty, which relies on transferring cells into the compromised myocardium to improve function.
Although initial results have shown promise, the effect of cellular cardiomyoplasty has been limited due to the conflicting results seen in experimental animal models and clinical trials. Many questions remain unanswered in this approach to treating heart failure. First, the mechanism whereby cellular cardiomyoplasty improves myocardial performance is still unknown. Second, the optimal cell type—skeletal myoblasts vs bone marrow-derived cells vs endogenous cardiomyocyte precursors—is unclear. Third, the optimal route of delivery (coronary delivery or direct myocardial) is unknown. Fourth, the ability of the injected cells to remain at the site of injury is not optimal. Therefore, how the mechanism of improved myocardial function may occur is still undetermined, whether potentially by way of cytokine release, angiogenesis stimulation, or another unknown mechanism.
The article by Chen and colleagues [1] addresses one mechanism of how marrow stromal cells could improve myocardial function by determining the ratio of cytokine levels. The authors measured proinflammatory and antiinflammatory cytokine gene expression in an acute rat model of myocardial infarction and showed that cytokine ratios decrease with time, which was associated with improved cardiac function and less scar formation. They further showed that less scar formation correlated with significantly lower extracellular matrix deposition, resulting in decreased cytokine ratios.
Although the experiments in this article are suggestive of a cytokine-mediated mechanism, they do not prove that this is the definitive mechanism leading to improved myocardial performance as observed. The more definitive proof would involve myocardial improvement dependent solely on the cytokines, with no cell therapy. Another experiment that would prove this hypothesis would be to selectively inhibit the cytokine actions. Finally, the use of another cell type that does not improve myocardial performance (eg, fibroblasts) will further support this hypothesis.
Despite these limitations, this article advances our understanding of how marrow stromal cells may increase myocardial performance during ischemia. As this field continues to grow, understanding the mechanisms involved in improved cardiac function after cellular therapy will be critical to prove the best future clinical therapy. Furthermore, a more mechanistic approach will improve the success of cellular regeneration and the future of myocardial ischemic patient trials.
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