doi: 10.1161/01.ATV.0000023563.01512.1E
© 2002 American Heart Association, Inc.
Letters to the Editor |
MMP Inhibition and Lumen Loss After Balloon Angioplasty or Stenting
Department of Cardiology Utrecht Medical Center Utrecht, the Netherlands
Department of Cardiology St. Michaels Hospital Toronto, Canada
To the Editor:
With interest we read the paper by Cherr et al1 reporting the negligible effect of matrix metalloproteinase (MMP) inhibition on constrictive remodeling and intimal hyperplasia after balloon angioplasty and stenting, respectively. As the authors mentioned, the results are at odds with observations from several published studies that have reported a significant reduction of late lumen loss after intervention by MMP inhibition.2-4 Several possible explanations were proposed to account for these differences, including route of administration and lack of activity of the compound used by Cherr et al1 against tumor necrosis factor-
–converting enzyme and MMP-1. However, other explanations for these controversial results may be considered.
First, we agree with the authors that the spectrum of MMP inhibitory activity, and thus clinical effects, may significantly differ among compounds. Marimastat and GM6001 are two nonspecific MMP inhibitors with potent inhibitory MMP-1 activity that have been shown to inhibit constrictive remodeling after balloon angioplasty and in-stent intimal hyperplasia, respectively. This result may point to an important role for the breakdown of intact collagen fibers in subsequent response to injury. However, we feel that the route of administration cannot adequately explain the observed differences among studies. Significant inhibition of constrictive remodeling after balloon injury was achieved by both oral3 and parenteral2 preparations whereas subcutaneous delivery of GM6001 significantly inhibited in-stent intimal hyerplasia.4
Second, we feel that differences in animal models may also explain the lack of inhibitory effect on post-angioplasty constrictive remodeling in the study by Cherr et al.1 In an earlier publication, Geary et al5 described that, in the nonhuman primate, the vessel area did not constrict but enlarged after balloon dilation at 4 weeks. Surprisingly, the vessel area at 4 weeks did not differ compared with the area at 4 days, demonstrating the absence of constrictive remodeling in the primate arterial injury model. This is in contrast with the human and pig model in which constrictive remodeling is evident2,3 and in which constrictive remodeling progressively alters arterial structure in time.6 Based on the earlier reported absent constrictive remodeling response in the non human primate, we suggest that it would be more appropriate to conclude form the observations of Cherr et al1 that MMP inhibition in the primate model has no effect on expansive remodeling 4 weeks after balloon angioplasty.
Third, serial intravascular ultrasound examination has been used as an endpoint in other studies; it is the most accurate method to study temporal changes in vessel area.
Studies on the effect of MMP inhibition on in-stent restenosis have also resulted in contradictory observations. Cherr et al1 did not find inhibition of in-stent restenosis using their broad-spectrum MMP R0113-2908. However, MMP inhibitors have significantly inhibited in-stent hyperplasia in at least two different animals.4,7 Based on these inconsistent outcomes, we agree with the authors that additional research is needed to define the spectrum of MMP that plays a role in the response to local arterial injury.
References
1. Cherr GS, Motew SJ, Travis JA, Fingerle J, Fisher L, Brandl M, Williams JK, Geary RL. Metalloproteinase inhibition and the response to angioplasty and stenting in atherosclerotic primates. Arterioscler Thromb Vasc Biol. 2002; 22: 161–166.
2. de Smet BJ, de Kleijn D, Hanemaaijer R, Verheijen JH, Robertus L, van der Helm YJ, Borst C, Post M.J. Metalloproteinase inhibition reduces constrictive arterial remodeling after balloon angioplasty: a study in the atherosclerotic Yucatan micropig. Circulation. 2000; 101: 2962–2967.
3. Sierevogel MJ, Pasterkamp G, Velema E, de Kleijn DPV, de Jaegere PPT, de Smet BJGL, Borst C. Oral matrix metalloproteinase inhibition and arterial remodeling following balloon dilation: an intravascular ultrasound study in the pig. Circulation. 2001; 103: 302–307.
4. Li C, Cantor WJ, Nili N, Robinson R, Fenkall L, Le Tran Y, Whittingham HA, Tsui W, Cheema AN, Sparkes JD, Pritzker K, Levy DE, Strauss BH. Arterial repair after stenting and the effects of GM6001, a MMP inhibitor. J Am Coll Cardiol. In press.
5. Geary RL, Williams JK, Golden D, Brown DG, Benjamin ME, Adams MR. Time course of cellular proliferation, intimal hyperplasia, and remodeling following angioplasty in monkeys with established atherosclerosis: a nonhuman primate model of restenosis. Arterioscler Thromb Vasc Biol. 1996; 16: 34–43.
6. de Smet BJ, van der Zande J, van der Helm YJ, Kuntz RE, Borst C, Post MJ. The atherosclerotic Yucatan animal model to study the arterial response after balloon angioplasty: the natural history of remodeling. Cardiovasc Res. 1998; 39: 224–232.
7. Gobeil F, Laflamme M, Bouchard M, Campbell E, Wood M, St-Jacques P, Vincent J, Leclerc G. BiodivYsio stent coated with metalloproteinase inhibitor reduces neointimal hyperplasia in a porcine coronary artery restenosis model. Circulation. 2001; 104: II-388.Abstract 1848.
In Response
Departments of Surgery and Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC
We recently documented that a broad-spectrum MMP inhibitor had no effect on artery wall remodeling and intimal hyperplasia after angioplasty or stenting in nonhuman primates.1 Thirty one cynomolgus monkeys had consumed an atherogenic diet for more than two years to create large and complicated iliac atherosclerotic lesions. Angioplasty and stenting were then performed, and animals were randomly assigned to a 4-week continuous infusion of a potent MMP inhibitor (RO113-2908) or vehicle. Despite demonstrating significant plasma MMP inhibitory activity and a marked inhibition of angiogenesis, treatment did not prevent constrictive artery wall remodeling or neointimal accumulation at sites of angioplasty or stenting.
As outlined in their letter, our results are at odds with reports by Pasterkamp and colleagues.2-4 It is important to first acknowledge that a number of earlier studies not referenced in their letter failed to show that MMP inhibition causes durable improvement in the response to angioplasty (refer to Discussion1). Consistent with these studies and our results, Pasterkamp and colleagues did not achieve a significant reduction in neointimal hyperplasia after iliac angioplasty by treating micropigs, pigs, or rabbits with the broad-spectrum MMP inhibitors batimastat,2 marimastat,3 and GM6001,4 respectively. However, in contrast to our results, they did achieve improved artery wall remodeling after angioplasty in pigs treated with batimastat2 or marimastat.3 The effect of GM6001 on constrictive remodeling in their rabbit double-injury model was not reported.4
In their letter, Pasterkamp and colleagues suggest the failure of RO113-2908 to improve artery wall remodeling after angioplasty in atherosclerotic monkeys may reflect a lack of constrictive remodeling in this model. This is not the case. In a previous study from our group, Mondy et al5 characterized the remodeling response in 37 atherosclerotic monkeys one month after iliac angioplasty (as in the present study) and documented frequent artery wall shrinkage. The correlation between late changes in artery wall size and lumen area was highly significant (r=0.72, P<0.001) with 14 of 37 arteries shrinking to a size smaller than their baseline before angioplasty.5 Moreover, 12 of 29 injured arteries in the present study1 had constricted to a size smaller than their reference artery (EEL area ratio) 4 weeks after angioplasty and of these more than half were in the treatment group. Thus, constrictive remodeling did occur and it was not inhibited by treatment.
Our study was the first to report the effects of a MMP inhibitor on stent neointimal thickening.1 Pasterkamp and colleagues contrast our negative result with their recent study in rabbits in which GM6001 reduced stent neointimal area by 29% but failed to significantly alter the response to angioplasty.4 They also refer to an abstract summarizing a small study of batimastat-coated stents placed in pig coronary arteries.6 A "low-dose" coating reduced neointimal area by 33% compared with control stents, but the effect was not significant for a "high-dose" coating. Furthermore, lumen caliber was similar in all groups.6
Given marked differences in experimental design, we do not find it surprising that treatment effects have varied. Responses to angioplasty and stenting in primates with preexisting advanced atherosclerosis1 are being compared with those following angioplasty in Yucatan micropigs with lesions first induced by balloon injury and high-fat diet2 or to those following angioplasty in nonatherosclerotic Landrace pigs3 and following double balloon injury and stenting in nonatherosclerotic New Zealand White rabbits.4 Each model also used a different MMP inhibitor, drug dose, and drug delivery protocol.
Pasterkamp and colleagues used broad-spectrum inhibitors with activity against MMPs and other proteases including the sheddases such as TNF-–converting enzyme (TACE). Thus, high-dose marimastat, batimastat, and GM6001 may have indirectly altered inflammatory responses to angioplasty and stenting. RO113-2908 is a more selective agent with no activity against TACE and relatively less activity against MMP-1.1 This may help explain differences in treatment effects in the stent models1,4 in which chronic inflammation is thought to play a more important role in promoting neointimal hyperplasia. Lastly, Pasterkamp and colleagues used very high drug doses and potentially achieved greater MMP inhibition. However, these doses have been associated with toxicity in animals and humans.7 We selected the dose of RO113-2908 based on safety studies in nonhuman primates and achieved steady-state plasma levels above the IC50 for relevant MMPs.1 Drug activity was validated at the tissue level where we documented significant inhibition of angiogenesis in subcutaneous polyvinyl alcohol sponges.1
Clearly, a negative result in a primate model that so closely depicts the pathology in human restenosis warrants discussion in light of positive effects observed in lower species. Pasterkamp and colleagues have raised important questions, and we appreciate the opportunity to provide our perspective. Additional studies will be necessary to reconcile these differences and to provide guidance for preclinical development of MMP inhibitors to prevent restenosis.
References
1. Cherr GS, Motew SJ, Travis JA, Fingerle J, Fisher L, Brandl M, Williams JK, Geary RL. Metalloproteinase (MMP) inhibition and restenosis following angioplasty and stenting in atherosclerotic nonhuman primates. Arterioscler Thromb Vasc Biol. 2002; 22: 161-166.
2. de Smet BJ, de Kleijn D, Hanemaaijer R, Verheijen JH, Robertus L, van der Helm YJ, Borst C, Post MJ. Metalloproteinase inhibition reduces constrictive arterial remodeling after balloon angioplasty: a study in the atherosclerotic Yucatan micropig. Circulation. 2000; 101: 2962-2967.
3. Sierevogel MJ, Pasterkamp G, Velema E, de Kleijn DPV, de Jaegere PPT, de Smet BJGL, Borst C. Oral matrix metalloproteinase inhibition and arterial remodeling following balloon dilation: an intravascular ultrasound study in the pig. Circulation. 2001; 103: 302–307.
4. Li C, Cantor WJ, Nili N, Robinson R, Fenkall L, Le Tran Y, Whittingham HA, Tsui W, Cheema AN, Sparkes JD, Pritzker K, Levy DE, Strauss BH. Arterial repair after stenting and the effects of GM6001, a MMP inhibitor. J Am Coll Cardiol. 2002; 39: 1852–1858.
5. Mondy JS, Williams, JK, Adams MR, Dean RH, Geary RL. Structural determinants of lumen narrowing after angioplasty in atherosclerotic nonhuman primates. J Vasc Surg. 1997; 26: 875-883.[CrossRef][Medline] [Order article via Infotrieve]
6. Gobeil F, Laflamme M, Bouchard M, Campbell E, Wood M, St-Jacques P, Vincent J, Leclerc G. BiodivYsio stent coated with metalloproteinase inhibitor reduces neointimal hyperplasia in a porcine coronary artery restenosis model. Circulation. 2001; 104: II-388.Abstract 1848.
7. Nemunaitis J, Poole C, Primrose J, Rosemurgy A, Malfetano J, Brown P, Berrington A, Cornish A, Lynch K, Rasmussen H, Kerr D, Cox D, Millar A. Combined analysis of studies of the effects of matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer-term studies. Clin Cancer Res. 1998; 4: 1101–1109.[Abstract]
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