PRECLINICAL STUDY: EDITORIAL COMMENT
The Janus Face of Drug-Eluting Stents*
James S. Forrester, MD, FACC*,
Michael S. Lee, MD,
Nikhil Kapoor, MD and
Raj R. Makkar, MD
Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California.
* Reprint requests and correspondence: Dr. James S. Forrester, Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. (Email: forrester{at}cshs.org).
Janus is the Roman god of gates and doors, of beginnings and endings, represented as a double-faced head looking in opposite directions. In this issue of the Journal, Cho et al. (1) lead us to look both forward and backward as they compare the effect of a 6-day course of granulocyte colony stimulating factor (GCSF) on neointimal hyperplasia and endothelial healing after vascular injury by bare-metal stent (BMS) and paclitaxel-eluting stent (PES) in the rabbit. Remarkably, the drug had substantially different effects in the two groups at 2 months. Substantial intimal hyperplasia and delayed endothelial recovery occurred in the BMS group but not in the PES group. The study bears directly on two of the most important yet seemingly unrelated issues in current clinical interventional cardiology research: in-stent restenosis and myocardial regenerative therapy. To understand how this came to be, we need to revisit the history of GCSF-related cardiovascular research in the past decade.
In the late 1990s, GCSF was reported to be effective in animal models of therapeutic angiogenesis (2). Intense interest in the cardiovascular use of GCSF, however, can perhaps be traced to late 2001, when two near-simultaneous publications showed its efficacy in restoring myocardial perfusion and function in the rat infarct model. In one study, human bone marrow-derived angioblasts mobilized by administration of GCSF were delivered via intravenous injection (3). At 15 weeks, new capillary formation was three-fold greater in the treated group than in the control group, the number of apoptotic cells was reduced six-fold, and infarct size was reduced from 36% to 12%. In the other study, GCSF and rat stem cell factor were given for 8 days in the peri-infarct period, with the goal of stimulating bone marrow cells to home to the infarcted myocardium (4). At 1 month, rat mortality was decreased by 68% , infarct size by 40%, and ejection fraction improved progressively by 48%, 62%, and 114% versus control subjects at 1, 2, and 4 weeks, respectively. These results were confirmed by other investigators (5,6). Thus, two streams of research flowed together to create a river of intense pressure for clinical trials in both myocardial infarction (MI) and stable coronary disease. The idea had particular appeal, because GCSF had a long prior record of safe and successful use in hematology (7) and in principle it could be given in any hospital. Clinical investigators around the world vied to be the first to report the results of cardiovascular GCSF therapy in man.
There were, of course, cautionary theoretical questions raised. The cytokine cousin of GCSF, granulocyte-macrophage colony stimulating factor (GMCSF) had been reported to have adverse effects in the animal model of infarction (8). More directly, we speculated that GCSF could also have adverse effects in man (9), because increased leukocyte count is associated with increased risk of mortality (10), acute coronary syndromes are often preceded by systemic inflammation (11), and multiple unstable plaques characterize acute MI in man (12). Ironically, the first data-based cautionary note in man, however, was not an increased incidence of re-infarction. Rather, it was an entirely unanticipated complication. In March 2004, Kang et al. (13) reported the results of randomizing 27 BMS infarct patients into treatment, with intracoronary bone marrow cells mobilized by GCSF infusion (n = 10), G-CSF alone (n = 10), and 7 control subjects. In the treated groups, the myocardial perfusion defect diminished (12% vs. 5%) and ejection fraction increased significantly (49% vs. 55%), as predicted by the rat MI studies; but at 6 month follow-up, 7 of 10 treated patients had in-stent restenosis, leading to termination of the study. The authors speculated that "although G-CSF might accelerate growth of neointima with bare metal stents, it might be beneficial with drug-eluting stents in promoting re-endothelialization, resulting in significant reduction of inflammation and restenosis." Indeed their speculation seems to have been proved accurate by the current study.
As other randomized clinical trials continued, however, the initial dramatic effects of GCSF reported in the rat infarct model were not being reproduced in larger animals. With the porcine infarct model, other investigative groups, including our own, found no significant difference in early or late post-infarction left ventricular ejection fraction between G-CSF treated groups and control subjects, despite significant differences in regional myocardial function (14).
Then, in November 2005, the other shoe dropped. Two randomized clinical trials, both published in the Journal of the American College of Cardiology, were terminated early because of an increased incidence of acute coronary events in the treatment group. The first, a multinational trial aimed at therapeutic revascularization in 16 stable angina patients, found that although indices of platelet activation and coagulation remained unchanged, C-reactive protein nearly doubled (15). Two patients sustained an MI, one of whom died. In the same issue, a Swiss team reported that two of seven stable angina patients given GMCSF sustained an acute coronary syndrome during treatment (16). Editorials in the Journal of the American College of Cardiology (17) and The Lancet (18) concluded that GCSF and GMCSF trials should be restricted to patients with no other therapeutic options. In sum, it now seems unlikely that systemic administration of GCSF will find a role in the management of either stable coronary disease or acute MI. In retrospect, animal laboratory studies failed to test whether systemic GCSF increased either the risk of in-stent restenosis or plaque destabilization before initiation of clinical trials.
With the future of cardiovascular GCSF therapy so seriously in question, it might seem surprising that a study of systemic GCSF therapy in rabbits provides both important insight and new directions for interventional cardiology. The study of Cho et al. (1), however, provides a provocative new idea: the processes of intimal hyperplasia and endothelial healing can be separated. The authors hypothesize—and their results strongly support—the idea that paclitaxel inhibited intimal hyperplasia, whereas GCSF promoted endothelial healing. This important insight seems to provide a foundation for the ultimate solution to stenting’s most important limitations: intimal hyperplasia and impaired endothelial healing, the proximate causes of in-stent restenosis and late stent thrombosis, respectively. The issue of impaired endothelial healing with drug-eluting stents is paramount, because in a recent report of 2,229 consecutive patients, 29 (1.3%) patients had stent thrombosis (1.7% of PES), of whom 45% died (19). We might speculate that local delivery and timing of process-specific agents will be critical components of the solution to these two problems. As if on cue, in the past year the capacity to test this hypothesis became available through third generation stents that can deliver several different substances locally at predetermined times after stent implantation (20). As we look to the future, it might be that GCSF and even paclitaxel will be only historical signposts, whereas the physiologic processes exposed by the Cho et al. (1) study, driven by the failure of past clinical trials, will be central to that final resolution. Such is the wonderful illogic of scientific progress, in which the past is prologue and failures are sometimes more important than successes.
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Footnotes
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* Editorials published in the Journal of American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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