This study has several important novel findings. Firstly, myocardial release of SDF-1a into the circulation is decreased in humans following MI and in all stages of coronary artery disease. Secondly, myocardial release of MCP-1 is also suppressed in patients post-MI and in the presence of coronary artery disease. Thirdly, and perhaps most importantly, the human release pattern of cytokines sometimes reflects the pattern seen in rodent models, but in other cases it does not. This has significance for the progression of all translational research from murine studies.
Several authors have described different findings from ours; in particular, they have described increased SDF1a expression following MI [2, 4, 5]. However, we believe that this may be due to differences in strain of mouse used (CD1 mice in ) or species studied (rats in [4, 5]). In contrast, we used C57Bl6 mice in our studies and found a decrease in RNA and protein expression. However, discrepancies between strains and species lend weight to our conclusions that interspecies variations are significant, and that observational translational clinical trials are paramount before progressing to clinical trials of therapies based on rodent data.
SDF-1a has been shown to be chemoattractant for stem cells [2, 4, 23], pro-angiogenic  and anti-apoptotic for cardiac myocytes . Whilst the stem cell chemotactic properties capture the imagination, the absence of release of SDF-1a from the human heart suggest that this may not be its primary mechanism of action following MI. Confounding the issue, and further emphasizing the difference between rodent models and man, is the presence of coronary artery disease in humans. The suppression of SDF-1a release from the heart in both stable and unstable coronary artery syndromes suggests that coronary artery disease itself reduces the release of SDF-1a. Perhaps the coronary artery plaques themselves sequester SDF-1a from the circulation. The mechanism of SDF-1a inducing cardiac repair remains incompletely understood, but our data demonstrates that in humans, SDF-1a release from the heart is reduced after MI. Some prior observational studies have shown increased peripheral blood levels of SDF-1a after MI [8, 9] but our data would suggest that if elevated levels of SDF-1a are detected in peripheral blood, it originates from tissues other than the heart.
It is not known whether the reduction in cytokine release of SDF-1a and MCP-1 are beneficial or detrimental to the LV remodeling process. In the case of SDF-1a, we and others [1, 7] have shown that there is reduced myocardial SDF-1a production, and there is experimental evidence that myocardial delivery of SDF-1a can repair damaged myocardium . With our human data mimicking the murine data, it would be reasonable to speculate that SDF-1a delivery to damaged human myocardium would result in improved LV function. However, with respect to MCP-1, quite the opposite is true. Elevated levels of MCP-1 have been demonstrated in peripheral blood following MI [18–20] and higher levels correlate with poorer prognosis . The animal model shows increased MCP-1 RNA in the hearts of rodents subjected to MI, and one might logically speculate that the elevated peripheral blood level of MCP-1 in humans after MI is produced by, and released from, the damaged heart tissue. A knockout animal model has shown that deletion of MCP-1 has a beneficial effect on post-infarction LV remodeling . Extrapolating from all this, one might expect a strategy of MCP-1 antagonism after MI to be therapeutically effective. However, our data shows that there is no increased release of MCP-1 from the human heart following MI, in fact there is a decrease. Therefore, it would likely not be appropriate to pursue blockade of myocardial MCP-1 based on our current results. This underscores the importance of human observational clinical studies to ensure that the animal model is actually reflective of the human disease. Performing this step in the advancement from the bench to the bedside will prevent costly studies that, although reasonable based on animal study data, are unlikely to succeed based on the human data. This will avoid exposing patients to unnecessary risk and may save considerable amounts for ever-shrinking research budgets.
For all who study animal models of human disease, it is imperative to acknowledge that all models have limitations. While it is easy and relatively inexpensive to perform quantitative studies on murine cardiac mRNA, it is comparatively difficult and expensive to perform such studies on human cardiac tissue. Furthermore, there are ethical and logistic difficulties in procuring human heart samples. Thus, we frequently presume that the murine findings will apply to the human situation; our results suggest that this may not be the case. A limitation to our study is that we have not directly compared human mRNA to murine mRNA. This is because of the aforementioned difficulties in procuring human heart tissue. We also did not directly compare the transmyocardial release of these cytokines between species, because the coronary sinus in the mouse is simply too small to access. We therefore chose the most appropriate available samples to compare between species, but our results should be interpreted with these limitations in mind. Another limitation of our study is that there were more males in the 3 coronary artery disease groups than in the normal control group (which is reflective of coronary artery disease's predilection for male subjects); therefore we cannot exclude gender differences as playing a small role in the differences between groups. However, we used all male mice in the murine study and showed similar response to MI with SDF-1a, but different response with MCP-1. This suggests that gender differences are less likely to have confounded our clinical results, but we cannot fully exclude the possibility of a gender effect in cytokine release profiles. This possibility warrants further study.