SDF-1a is constitutively expressed by many tissues, including the heart [1]. Following MI, cardiac SDF-1a is thought to contribute to a stem cell cytokine gradient that causes homing of stem cells to the heart [2,3]. For this to occur, SDF-1a must be produced in the heart and released into the circulation. Experimental models have yielded conflicting data about cardiac expression of SDF-1a, with some finding increased expression after MI [2,4-6] and others finding decreased expression [1,7]. Furthermore, the data concerning serum levels of circulating SDF-1a are also conflicting. In patients, some studies find increased levels after MI [8,9], while others find no change [10]. In rodent experimental MI, the serum level of SDF-1a is actually reduced [2], whereas in the canine model it is increased [1]. Thus, whether SDF-1a is released from the heart to create a cytokine gradient following MI remains unknown.

The role of MCP-1 in post-infarction left ventricular (LV) remodeling is complex. MCP-1 has been implicated in numerous steps along the way to post-infarction heart failure: in the development of atherosclerosis [11], in atherosclerotic plaque instability [12], in recruitment of monocytes to the heart following MI [13] and in post-infarction LV remodeling [14]. In experimental animal models, MCP-1 is also chemoattractant for stem cells [15,16]. MCP-1 levels are increased in peripheral blood following MI, both in rats [17] and in patients [18-20] and these levels correlate with prognosis [21]. It has been assumed that these peripheral blood levels are reflective of cardiac release causing a chemo-attractant cytokine gradient towards the heart. Thus modulation of the MCP-1/CCR2 axis has been proposed as a novel therapeutic target to treat post-infarction LV remodeling [14,21].

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 [2]) 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 [24] and anti-apoptotic for cardiac myocytes [25]. 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 [25]. 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 [21]. 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 [26]. 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.