1630
Editorial Comment A Dilemma for the 1990s Choosing Appropriate Experimental Animal Model for the Prevention of Restenosis Margaret Ferrell, MD; Valentin Fuster, MD, PhD; Herman K. Gold, MD; and James H. Chesebro, MD Pe ercutaneous transluminal coronary angioplasty (PTCA) has become a successful and widely used treatment for patients with coronary disease since its first clinical application byAndreas Gruentzig in 1977. Despite the increase in procedure and case complexity, primary success rates have improved. However, late restenosis, which constitutes the most important problem after successful angioplasty, continues to occur in 30-40% of patients within 3-6 months. Experimental, pathological (autopsy and atherectomy specimens), angioscopic, and angiographic observations, coupled with recent observations in cell culture and in situ hybridization, indicate that restenosis after PTCA involves a fibroproliferative response to vascular injury in the setting of mural thrombosis with platelet activation, thrombin generation, and the release of mitogens.' An alternative or associated mechanism of restenosis after PTCA is recoil at the site of PTCA injury.2 Attempts to modify the fibroproliferative response to PTCA in humans by pharmacological interventions have met with very limited success. Therefore, despite more than a decade of intensive research, PTCA interventions that have shown promise in limiting restenosis in laboratory animal models have not led to similar findings in patients. Difficulty applying the results of animal models to humans is not surprising, considering the complexity of the response of the arterial wall to injury. Therefore, differences in techniques used to initiate injury, degree of stretch, and the type of injury (deep versus mild) that results may modify the outcome of pharmacological manipulation in a given animal model; complex mechanisms regulating the initial deposition of platelets and fibrin on and within the damaged vessel wall and the subsequent fibroproliferative response are not fully understood and may vary among species; the influence of atherosclerotic plaque composition on the response of the vessel wall to mechanical insult is not considered by most animal models of acute balloon injury and confounds the problem of extrapolating experimental reTIhe opinions expressed in this editorial comment are not necessarily those of the editors of the American Heart Association. From the Cardiac Unit at Massachusetts General Hospital (M.F., V.F., H.KG.), Boston, and the Division of Cardiovascular Diseases (J.H.C.), Mayo Clinic and Mayo Foundation, Rochester, Minn. Address for reprints: Valentin Fuster, MD, PhD, Cardiac Unit, Massachusetts General Hospital, Bulfinch 1, 32 Fruit Street, Boston, MA 02114.
sults to clinical settings; most importantly, drug metabolism, tissue penetration, and end-organ effects of pharmacological interventions may vary among species such that an equal dosage per kilogram does not ensure equal biological effects. Of interest, most of the data obtained in the pig and primate models of restenosis after PTCA, contrary to those obtained in the smaller size of the animal species, appear to be more closely related to the data obtained in humans. In this context, the study by Lam et a13 in this issue of Circulation considers the regulation of the fibroproliferative component of restenosis in the pig
See p 1542 model. The experiments examine the effects of pretreatment with an angiotensin converting enzyme (ACE) inhibitor, cilazapril, on vascular healing following balloon-mediated carotid artery injury. The dose of cilazapril nearly abolished plasma ACE activity and significantly lowered the mean arterial blood pressure in the treatment group. The study was not able to demonstrate any attenuation of carotid neointimal myoproliferation after either "deep" or "mild" balloon-mediated injury in the treatment group. This study is in agreement with two recent preliminary reports in which ACE inhibition did not limit restenosis in the coronary circulation in the pig model.45 Similarly, Hanson et a16 reported that ACE inhibition with cilazapril did not reduce intimal thickening over a 3-month period in arteries injured by either endarterectomy, balloon denudation, or synthetic vascular grafting in a primate model. In contrast, Powell et a17 demonstrated that pretreatment with an ACE inhibitor in the rat decreased neointima formation by 80% at 14 days after balloon injury of the carotid artery. Subsequently, others8 have confirmed a similarly profound decrease in smooth muscle cell proliferation after balloon injury by pretreatment with cilazapril in the rat model. These discordant studies have important implications for the Multicenter European Trial with Cilazapril After Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis in which more than 700 angioplasty patients have been randomly chosen to receive either cilazapril or placebo starting 4-6 hours after PTCA. A similar trial involving 1,400 patients is under way in the United States.9"10 As noted by Lam et al, the dose of cilazapril in some of the animal experiments was almost 100-fold that which might be used in the clinical setting and resulted
Downloaded from http://circ.ahajournals.org/ by guest on March 8, 2015
Ferrell et al Choosing Appropriate Experimental Animal Model in significant blood pressure-lowering effects and therefore may have little physiological relevance for humans. Moreover, the variable effects of ACE inhibition on restenosis in various animal species (beneficial in small animals but ineffective in the pig and primate) serve to highlight the problems of extrapolating data from experimental animal models of restenosis to the clinical setting. Recent reviews have underscored the paucity of interventions that have been effective in preventing or attenuating restenosis in clinical trials after PTCA, in contrast to the numerous methods that have been of benefit in small animal models.9"0 Although it seems logical to initiate investigations of new interventions for preventing restenosis in small animal models for reasons of cost-effectiveness, ease of experimentation, and the ability to generate statistically significant numbers of animals, the pitfalls of this approach are now evident as the complexities of restenosis are unraveled and differences between species become apparent. Before undertaking large and costly patient PTCArestenosis trials, it would be ideal to conduct trials in an experimental animal model of arterial injury that closely simulates this condition in humans with regard to natural history, thrombus deposition, and fibroproliferative response to injury. In addition, the model should have a similar pharmacological profile. Unfortunately, no such model exists. At present, research conducted in the pig and the primate appears to be the most predictive of results in humans, and it would seem prudent to verify laboratory findings obtained using smaller animals in these models before undertaking large-scale human trials. Furthermore, measurements of a specific biological activity and duration that are measurable in animals may also be measurable and translatable to smaller studies in humans for assessment of dosage and duration of therapy before embarking on large-scale and expensive trials with clinical efficacy end points. In the absence of an ideal experimental animal model, the ongoing challenge for investigators is to identify effective therapies within the constraints of available models that will translate into patient benefit in clinical trials of restenosis after PTCA. However, given the complex biology of restenosis and the multiple
1631
influences that are active, including injury, thrombosis, cellular proliferation, growth factors, coronary spasm, and vessel recoil, it is unlikely that a single intervention will be effective in limiting restenosis in humans. The solution will more likely involve a multifactorial approach predicated on an understanding of the basic biological processes involved and targeted at the individual components. References 1. Ip JH, Fuster V, Israel D, Badimon L, Badimon J, Chesebro JH: The role of platelets, thrombin, and hyperplasia in restenosis after coronary angioplasty. JAm Coll Cardiol 1991;16:77B-88B 2. Waller BF, Pinkerton CA, Orr CM, Slack JD, VanTassel JW, Peters T: Restenosis 1 to 24 months after clinically successful coronary balloon angioplasty: A necropsy study of 20 patients. JAm Coil Cardiol 1991;17:58B-70B 3. Lam JYT, Lacoste L, Bourassa MG: Cilazapril and early atherosclerotic changes after balloon injury of porcine carotid arteries. Circulation 1992;85:1542-1547 4. Santoian EC, Gravanis MB, Karas SP, Anderberg K, Schneider JE, Hearn JM, King SB III: Enalapril does not inhibit smooth muscle cell proliferation in a balloon-injured coronary artery swine model of intimal hyperplasia (abstract). Circulation 1991;84(suppl II):II-70 5. Churchill DA, Siegel CO, Dougherty KG, Raizner AE, Minor ST: Failure of enalapril to reduce coronary restenosis in a swine model (abstract). Circulation 1991;84(suppl II):II-1183 6. Hanson SR, Powell JS, Dodson T, Lumsden A, Kelly AB, Anderson JS, Clowes AW, Harker LA: Effects of angiotensin converting enzyme inhibition with cilazapril on intimal hyperplasia in injured arteries and vascular grafts in the baboon. Hypertension 1991;
18(suppl II):II-70-II-76 7. Powell JS, Clozel JP, Muller RK, Kuhn H, Hefti F, Hosang M, Baumgartner HR: Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science 1989;245:186-188 8. Clowes AW, Clowes MM, Vergel SC, Muller RKM, Powell JS, Hefti F, Baumgartner HR: Heparin and cilazapril together inhibit injury-mediated intimal hyperplasia. Hypertension 1991;18(suppl II):II-65-II-69 9. Hermans WRM, Rensing BJ, Strauss BH, Serruys PW: Prevention of restenosis after percutaneous transluminal coronary angioplasty: The search for the "magic bullet." Am Heart J 1991;122: 171-187 10. Popma JJ, Califf RM, Topol EJ: Clinical trials of restenosis following coronary angioplasty. Circulation 1991;84:1426-1436 KEY WORDS * angiotensin converting enzymes percutaneous transluminal coronary angioplasty * clinical trials * restenosis Editorial Comments
Downloaded from http://circ.ahajournals.org/ by guest on March 8, 2015
A dilemma for the 1990s. Choosing appropriate experimental animal model for the prevention of restenosis. M Ferrell, V Fuster, H K Gold and J H Chesebro Circulation. 1992;85:1630-1631 doi: 10.1161/01.CIR.85.4.1630 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1992 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/85/4/1630.citation
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/
Downloaded from http://circ.ahajournals.org/ by guest on March 8, 2015
Editorial Comment A Dilemma for the 1990s Choosing Appropriate Experimental Animal Model for the Prevention of Restenosis Margaret Ferrell, MD; Valentin Fuster, MD, PhD; Herman K. Gold, MD; and James H. Chesebro, MD Pe ercutaneous transluminal coronary angioplasty (PTCA) has become a successful and widely used treatment for patients with coronary disease since its first clinical application byAndreas Gruentzig in 1977. Despite the increase in procedure and case complexity, primary success rates have improved. However, late restenosis, which constitutes the most important problem after successful angioplasty, continues to occur in 30-40% of patients within 3-6 months. Experimental, pathological (autopsy and atherectomy specimens), angioscopic, and angiographic observations, coupled with recent observations in cell culture and in situ hybridization, indicate that restenosis after PTCA involves a fibroproliferative response to vascular injury in the setting of mural thrombosis with platelet activation, thrombin generation, and the release of mitogens.' An alternative or associated mechanism of restenosis after PTCA is recoil at the site of PTCA injury.2 Attempts to modify the fibroproliferative response to PTCA in humans by pharmacological interventions have met with very limited success. Therefore, despite more than a decade of intensive research, PTCA interventions that have shown promise in limiting restenosis in laboratory animal models have not led to similar findings in patients. Difficulty applying the results of animal models to humans is not surprising, considering the complexity of the response of the arterial wall to injury. Therefore, differences in techniques used to initiate injury, degree of stretch, and the type of injury (deep versus mild) that results may modify the outcome of pharmacological manipulation in a given animal model; complex mechanisms regulating the initial deposition of platelets and fibrin on and within the damaged vessel wall and the subsequent fibroproliferative response are not fully understood and may vary among species; the influence of atherosclerotic plaque composition on the response of the vessel wall to mechanical insult is not considered by most animal models of acute balloon injury and confounds the problem of extrapolating experimental reTIhe opinions expressed in this editorial comment are not necessarily those of the editors of the American Heart Association. From the Cardiac Unit at Massachusetts General Hospital (M.F., V.F., H.KG.), Boston, and the Division of Cardiovascular Diseases (J.H.C.), Mayo Clinic and Mayo Foundation, Rochester, Minn. Address for reprints: Valentin Fuster, MD, PhD, Cardiac Unit, Massachusetts General Hospital, Bulfinch 1, 32 Fruit Street, Boston, MA 02114.
sults to clinical settings; most importantly, drug metabolism, tissue penetration, and end-organ effects of pharmacological interventions may vary among species such that an equal dosage per kilogram does not ensure equal biological effects. Of interest, most of the data obtained in the pig and primate models of restenosis after PTCA, contrary to those obtained in the smaller size of the animal species, appear to be more closely related to the data obtained in humans. In this context, the study by Lam et a13 in this issue of Circulation considers the regulation of the fibroproliferative component of restenosis in the pig
See p 1542 model. The experiments examine the effects of pretreatment with an angiotensin converting enzyme (ACE) inhibitor, cilazapril, on vascular healing following balloon-mediated carotid artery injury. The dose of cilazapril nearly abolished plasma ACE activity and significantly lowered the mean arterial blood pressure in the treatment group. The study was not able to demonstrate any attenuation of carotid neointimal myoproliferation after either "deep" or "mild" balloon-mediated injury in the treatment group. This study is in agreement with two recent preliminary reports in which ACE inhibition did not limit restenosis in the coronary circulation in the pig model.45 Similarly, Hanson et a16 reported that ACE inhibition with cilazapril did not reduce intimal thickening over a 3-month period in arteries injured by either endarterectomy, balloon denudation, or synthetic vascular grafting in a primate model. In contrast, Powell et a17 demonstrated that pretreatment with an ACE inhibitor in the rat decreased neointima formation by 80% at 14 days after balloon injury of the carotid artery. Subsequently, others8 have confirmed a similarly profound decrease in smooth muscle cell proliferation after balloon injury by pretreatment with cilazapril in the rat model. These discordant studies have important implications for the Multicenter European Trial with Cilazapril After Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis in which more than 700 angioplasty patients have been randomly chosen to receive either cilazapril or placebo starting 4-6 hours after PTCA. A similar trial involving 1,400 patients is under way in the United States.9"10 As noted by Lam et al, the dose of cilazapril in some of the animal experiments was almost 100-fold that which might be used in the clinical setting and resulted
Downloaded from http://circ.ahajournals.org/ by guest on March 8, 2015
Ferrell et al Choosing Appropriate Experimental Animal Model in significant blood pressure-lowering effects and therefore may have little physiological relevance for humans. Moreover, the variable effects of ACE inhibition on restenosis in various animal species (beneficial in small animals but ineffective in the pig and primate) serve to highlight the problems of extrapolating data from experimental animal models of restenosis to the clinical setting. Recent reviews have underscored the paucity of interventions that have been effective in preventing or attenuating restenosis in clinical trials after PTCA, in contrast to the numerous methods that have been of benefit in small animal models.9"0 Although it seems logical to initiate investigations of new interventions for preventing restenosis in small animal models for reasons of cost-effectiveness, ease of experimentation, and the ability to generate statistically significant numbers of animals, the pitfalls of this approach are now evident as the complexities of restenosis are unraveled and differences between species become apparent. Before undertaking large and costly patient PTCArestenosis trials, it would be ideal to conduct trials in an experimental animal model of arterial injury that closely simulates this condition in humans with regard to natural history, thrombus deposition, and fibroproliferative response to injury. In addition, the model should have a similar pharmacological profile. Unfortunately, no such model exists. At present, research conducted in the pig and the primate appears to be the most predictive of results in humans, and it would seem prudent to verify laboratory findings obtained using smaller animals in these models before undertaking large-scale human trials. Furthermore, measurements of a specific biological activity and duration that are measurable in animals may also be measurable and translatable to smaller studies in humans for assessment of dosage and duration of therapy before embarking on large-scale and expensive trials with clinical efficacy end points. In the absence of an ideal experimental animal model, the ongoing challenge for investigators is to identify effective therapies within the constraints of available models that will translate into patient benefit in clinical trials of restenosis after PTCA. However, given the complex biology of restenosis and the multiple
1631
influences that are active, including injury, thrombosis, cellular proliferation, growth factors, coronary spasm, and vessel recoil, it is unlikely that a single intervention will be effective in limiting restenosis in humans. The solution will more likely involve a multifactorial approach predicated on an understanding of the basic biological processes involved and targeted at the individual components. References 1. Ip JH, Fuster V, Israel D, Badimon L, Badimon J, Chesebro JH: The role of platelets, thrombin, and hyperplasia in restenosis after coronary angioplasty. JAm Coll Cardiol 1991;16:77B-88B 2. Waller BF, Pinkerton CA, Orr CM, Slack JD, VanTassel JW, Peters T: Restenosis 1 to 24 months after clinically successful coronary balloon angioplasty: A necropsy study of 20 patients. JAm Coil Cardiol 1991;17:58B-70B 3. Lam JYT, Lacoste L, Bourassa MG: Cilazapril and early atherosclerotic changes after balloon injury of porcine carotid arteries. Circulation 1992;85:1542-1547 4. Santoian EC, Gravanis MB, Karas SP, Anderberg K, Schneider JE, Hearn JM, King SB III: Enalapril does not inhibit smooth muscle cell proliferation in a balloon-injured coronary artery swine model of intimal hyperplasia (abstract). Circulation 1991;84(suppl II):II-70 5. Churchill DA, Siegel CO, Dougherty KG, Raizner AE, Minor ST: Failure of enalapril to reduce coronary restenosis in a swine model (abstract). Circulation 1991;84(suppl II):II-1183 6. Hanson SR, Powell JS, Dodson T, Lumsden A, Kelly AB, Anderson JS, Clowes AW, Harker LA: Effects of angiotensin converting enzyme inhibition with cilazapril on intimal hyperplasia in injured arteries and vascular grafts in the baboon. Hypertension 1991;
18(suppl II):II-70-II-76 7. Powell JS, Clozel JP, Muller RK, Kuhn H, Hefti F, Hosang M, Baumgartner HR: Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science 1989;245:186-188 8. Clowes AW, Clowes MM, Vergel SC, Muller RKM, Powell JS, Hefti F, Baumgartner HR: Heparin and cilazapril together inhibit injury-mediated intimal hyperplasia. Hypertension 1991;18(suppl II):II-65-II-69 9. Hermans WRM, Rensing BJ, Strauss BH, Serruys PW: Prevention of restenosis after percutaneous transluminal coronary angioplasty: The search for the "magic bullet." Am Heart J 1991;122: 171-187 10. Popma JJ, Califf RM, Topol EJ: Clinical trials of restenosis following coronary angioplasty. Circulation 1991;84:1426-1436 KEY WORDS * angiotensin converting enzymes percutaneous transluminal coronary angioplasty * clinical trials * restenosis Editorial Comments
Downloaded from http://circ.ahajournals.org/ by guest on March 8, 2015
A dilemma for the 1990s. Choosing appropriate experimental animal model for the prevention of restenosis. M Ferrell, V Fuster, H K Gold and J H Chesebro Circulation. 1992;85:1630-1631 doi: 10.1161/01.CIR.85.4.1630 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1992 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/85/4/1630.citation
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/
Downloaded from http://circ.ahajournals.org/ by guest on March 8, 2015
