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(Circulation. 1997;96:56-60.)
© 1997 American Heart Association, Inc.

Articles

D Allele of the Angiotensin I–Converting Enzyme Is a Major Risk Factor for Restenosis After Coronary Stenting

Carole Amant, BS; Christophe Bauters, MD; Jean-Christophe Bodart, MD; Jean-Marc Lablanche, MD; Gilles Grollier, MD; Nicolas Danchin, MD; Martial Hamon, MD; Florence Richard, MD; Nicole Helbecque, PhD; Eugène P. McFadden, MRCPI; Philippe Amouyel, MD, PhD; ; Michel E. Bertrand, MD

From INSERM CJF 95-05, Institut Pasteur de Lille (C.A., F.R., N.H., P.A.); University and CHRU de Lille (C.B., J.-C.B., J.-M.L., M.H., F.R., E.P.M., P.A., M.E.B.); University and CHRU de Caen (G.G.); and University and CHRU de Nancy (N.D.), France.

Correspondence to M.E. Bertrand, MD, Service de Cardiologie B, Hôpital Cardiologique, Blvd du Professeur J Leclercq, 59037 Lille Cedex, France.

	Abstract

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Background Although intracoronary stent implantation significantly reduces restenosis compared with balloon angioplasty, a minority of patients still develop restenosis predominantly due to neointimal hyperplasia. Experimental studies suggest that the renin-angiotensin system is involved in neointimal hyperplasia after arterial injury. In humans, the plasma and cellular levels of ACE are associated with an I/D genetic polymorphism in the ACE gene, DD patients having higher levels.

Methods and Results We investigated a possible relation between the ACE I/D polymorphism and restenosis in 146 patients who underwent successful implantation of a Palmaz-Schatz stent and had 6-month follow-up angiography. The minimal lumen diameter (MLD) before and after the procedure did not differ significantly among the three groups of genotypes (DD, ID, and II). At follow-up, MLD had a significant inverse relationship to the number of D alleles present (DD, 1.65±0.71 mm; ID, 1.84±0.60 mm; II, 2.05±0.61 mm; P<.007). Late luminal loss during the follow-up period was significantly related to the number of D alleles (DD, 0.89±0.61 mm; ID, 0.60±0.52 mm; II, 0.40±0.53 mm; P<.0001). The relative risk of restenosis (defined as a >50% diameter stenosis at follow-up) approximated by the adjusted odds ratio was 2.00 per number of D alleles (95% confidence interval, 1.03 to 3.88, P<.04).

Conclusions The ACE I/D polymorphism influences the level of late luminal loss after coronary stent implantation. These results suggest that the renin-angiotensin system may be implicated in the pathogenesis of restenosis after coronary stenting.

Key Words: angiotensin • coronary disease • genetics

	Introduction

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Coronary angioplasty has become an established treatment for patients with coronary artery disease, but it remains plagued by the problem of restenosis.^{1 2} On the basis of experimental studies, restenosis was initially considered to be solely due to neointimal hyperplasia in response to balloon injury.^{2 3} Subsequent insights from intracoronary ultrasound studies in humans show that chronic remodeling (vessel constriction) rather than neointimal hyperplasia is the major mechanism of restenosis.⁴ Intracoronary stent implantation has been shown to significantly reduce angiographic restenosis in humans^{5 6} ; the better long-term angiographic result is due to a better immediate result and to the abolition of chronic remodeling despite an increase in neointimal thickening.⁷ Stent implantation thus provides a model in which the occurrence of restenosis is related primarily to neointimal hyperplasia.

The renin-angiotensin system has been implicated in the pathogenesis of neointimal hyperplasia.⁸ The activation of ACE is a critical step in this process: several reports have demonstrated the ability of ACE inhibitors to block neointimal thickening in rat, guinea pig, and rabbit.^{9 10} In humans, the level of plasma ACE is partly under genetic control.¹¹ Plasma and cellular levels of ACE are associated with an I/D polymorphism in the ACE gene^{12 13} : DD genotype bearers have higher levels of ACE than either ID or II genotype bearers.

The present study was designed to determine whether the ACE I/D polymorphism influences angiographic restenosis after coronary stenting. We analyzed, with quantitative coronary angiography, the occurrence of restenosis in consecutive patients who underwent successful coronary stenting.

	Methods

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Study Population
Between April 1994 and December 1995, 171 consecutive white patients underwent successful implantation of a Palmaz-Schatz stent in our institution. Coronary stenting was performed as a bailout procedure after failed balloon angioplasty, or because there was a suboptimal result after balloon angioplasty, or electively. All the patients were prospectively asked to undergo systematic 6-month angiographic follow-up, which was actually performed in 146 patients (85%). Coronary stenting was performed at 158 lesions in these 146 patients by standard techniques, as previously described.¹⁴

Angiographic Analysis
Quantitative computer-assisted angiographic measurements were performed on end-diastolic frames with use of the CAESAR (Computer-Assisted Evaluation of Stenosis and Restenosis) system. A detailed description of this system has been reported previously.¹⁵ We routinely perform angiography in at least two projections after the intracoronary injection of isosorbide dinitrate (2 mg). These projections are recorded in our database, and the follow-up angiogram is performed, after injection of isosorbide dinitrate, in the same projections. The following definitions were used: the acute gain associated with the procedure was defined as the difference between the MLD immediately after stent implantation and the MLD before the procedure; the late loss during the follow-up period as the difference between the MLD immediately after stent implantation and the MLD at follow-up; the net gain as the difference between the acute gain and the late loss; and the loss index as the ratio of late loss to acute gain. To define restenosis, we used a categorical approach with the classic criterion of >50% diameter stenosis at follow-up.^{5 6}

Genetic Study
Genomic DNA was extracted from white blood cells.¹⁶ The ACE fragment containing the I/D polymorphism was amplified with a Perkin-Elmer DNA thermal cycler and Thermus aquaticus DNA polymerase (Amersham). ACE polymorphism was detected as previously described,¹⁷ except for addition of DMSO to enhance amplification of the ACE I allele.^{18 19} Reaction products were analyzed on agarose gel for allele identification. To avoid mistyping of ACE polymorphism,^{19 20} all patients were regenotyped with a three-primer system²¹ ; the amplification products were run on 4% NuSieve agarose gels (FMC BioProducts). Both techniques yielded identical results.

Statistical Analysis
Statistical analyses were performed with SAS software, version 6.10 (SAS Institute Inc). Mean and SD values of quantitative data were calculated. Quantitative data were compared with a general linear model according to the ACE genotypes. Subjects were categorized in three classes according to their genotype (ie, DD, ID, and II). Statistical analyses were performed per lesion (n=158) and per patient (only one lesion for each subject; n=146). For the per-patient analysis, when more than one lesion was stented, the first treated lesion was selected. The tests were performed assuming an allele-dose effect. The effects of the D allele on MLD at follow-up, diameter stenosis at follow-up, late loss, net gain, and loss index were adjusted for diabetes, unstable angina, previous myocardial infarction, ACE inhibitor treatment, reference diameter, MLD after PTCA, indication for stenting, and number of stents. Adjusted mean and SEM values of quantitative data were calculated. Qualitative data were tested by Pearson's ² test and Mantel-Haenszel linear test. Adjusted odds ratios were computed from a multivariate logistic regression model to provide an estimate of the relative risk of restenosis. In the logistic regression model, restenosis was defined as a diameter stenosis >50% at follow-up; the same confounding covariates as for the quantitative angiographic variables were used.

	Results

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The mean age of the patients was 60±10 years; 84% were men. Thirty-six percent had unstable angina, and 38% had experienced a previous myocardial infarction. Coronary stenting was performed as a bailout procedure after failed balloon angioplasty in 12%; because there was a suboptimal result after balloon angioplasty in 72%; and electively in 16%. Eighty-four percent of the lesions were treated with a single stent, 14% with two stents, and 2% with three stents. Of the 146 patients, 30% had the DD genotype, 51% had the ID genotype, and 19% had the II genotype. These genotype frequencies were compatible with the Hardy-Weinberg distribution and close to values reported in other white populations of French origin.^{17 22} The baseline characteristics for the three groups of patients are shown in Table 1. There were no statistically significant differences among genotypes.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics

The results of quantitative coronary angiography for the 158 lesions are shown in Table 2 and the Figure. There were no significant differences in reference diameter among the three groups of genotypes at any of the three time points studied (before the procedure, after the procedure, and at 6-month follow-up). The MLD before and after the procedure and the acute gain did not differ significantly among the three groups. At follow-up angiography, the MLD had a significant inverse relationship to the number of D alleles (P<.007). Late loss during the follow-up period was more than twofold greater in the DD (0.89±0.61 mm) than in the II group (0.40±0.53 mm), the ID group being intermediate (0.60±0.52 mm) (P<.0001). Similar results were obtained when the analysis was performed per patient (one lesion per patient): the MLD at follow-up was 1.63±0.69, 1.83±0.60, and 2.08±0.57 mm for DD, ID, and II patients, respectively (P<.004); the late loss during the follow-up period was 0.88±0.58, 0.62±0.52, and 0.38±0.53 mm for DD, ID, and II patients, respectively (P<.0002).

View this table: [in this window] [in a new window]   Table 2. Quantitative Angiography

View larger version (16K): [in this window] [in a new window]   Figure 1. Cumulative distribution curves of MLD before stenting and immediately after stenting (A) and at follow-up (B) as a function of the ACE I/D genotype.

All these results were homogeneous across covariates (smoking, diabetes, hypertension, unstable angina, previous myocardial infarction, ACE inhibitor treatment, indication for stenting). The quantitative angiographic variables adjusted for diabetes, unstable angina, previous myocardial infarction, ACE inhibitor treatment, reference diameter, MLD after PTCA, indication for stenting, and number of stents are presented in Table 3. The association of the number of D alleles with the restenotic process was independent of other risk factors known to influence this phenomenon. The relative risk of restenosis (defined as a >50% diameter stenosis at follow-up) approximated by the adjusted odds ratio was 2.00 per number of D alleles (95% CI, 1.03 to 3.88, P<.04).

View this table: [in this window] [in a new window]   Table 3. Quantitative Angiography Adjusted for Covariates

	Discussion

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Our results show that the ACE I/D polymorphism is an independent predictor of the degree of late luminal narrowing after coronary stenting. Late loss increased significantly as the number of D alleles increased.

We and others have previously shown that the ACE I/D polymorphism was not associated with restenosis after conventional balloon angioplasty.^{22 23} Moreover, two recent randomized trials (MERCATOR²⁴ and MARCATOR²⁵ ) have failed to demonstrate any beneficial effect of ACE inhibition on the occurrence of angiographic restenosis after balloon angioplasty. New insights into the mechanisms of restenosis after balloon angioplasty help to explain why drugs that effectively prevented neointimal hyperplasia in experimental studies have consistently failed in the clinical setting. Recent experimental^{26 27} and clinical⁴ studies have suggested that the contribution of neointimal hyperplasia to restenosis after balloon angioplasty is relatively limited and that lumen renarrowing is in fact related primarily to vessel remodeling (ie, chronic sclerosis with vessel constriction). Conversely, because the stent prevents the remodeling process, restenosis after coronary stenting is primarily a consequence of neointimal hyperplasia within the stent.⁷ Thus, factors that directly affect the degree of neointimal hyperplasia will be more likely to influence restenosis after coronary stenting than restenosis after balloon angioplasty.

Multiple factors have been implicated in the pathogenesis of neointimal hyperplasia.²⁸ Among these, the renin-angiotensin system is of particular interest, because pharmacological inhibitors are now clinically available. Administration of ACE inhibitors in rat, guinea pig, and rabbit inhibits neointimal development after arterial balloon denudation.^{9 10} Potential mechanisms by which ACE inhibition reduces neointimal hyperplasia in these models may be related to the role of this enzyme in the formation of angiotensin II, a potent growth factor for smooth muscle cells,²⁹ and in the degradation of bradykinin, a growth inhibitor for smooth muscle cells.³⁰ The implication of ACE in neointimal hyperplasia has been further supported by gene transfer studies showing that overexpression of the ACE gene increased DNA synthesis in the rat carotid artery.³¹

In humans, the level of plasma ACE is stable in an individual but is highly variable between individuals.¹² A high proportion of the interindividual variability of plasma ACE concentration is determined by a major gene effect.¹¹ The I/D polymorphism located in intron 16 of the ACE gene is associated with plasma ACE levels and activity¹⁷ : the mean plasma ACE level in DD subjects is about twice that of II subjects, heterozygotes having intermediate levels.¹² This increased activity of ACE may account for the higher degree of neointimal thickening observed in D allele bearers. It has recently been suggested that long-term exposure to high levels of plasma ACE may be involved in structural changes in the arterial wall.^{32 33} In one study, high plasma concentrations of ACE were associated with a statistically significant increase of common carotid artery intima-media thickening.³² Another study reported an association between the DD genotype and the extent of common carotid artery intima-media thickening.³³ Our results, which demonstrate that the ACE I/D polymorphism is associated with neointimal hyperplasia in human coronary arteries, are consistent with these previous observations.

In conclusion, the D allele of the ACE gene is associated with a greater late luminal loss after intracoronary stent implantation. Although further studies are needed to confirm this observation in independent populations, these findings have two potential clinical implications: first, they may help to identify patients who are at particular risk of restenosis after coronary stenting; second, they identify a population in which the effects of drugs such as ACE inhibitors could be tested.

	Selected Abbreviations and Acronyms

 

D = deletion polymorphism I = insertion polymorphism MLD = minimal lumen diameter PTCA = percutaneous transluminal coronary angioplasty

	Acknowledgments

 
Carole Amant was supported by the Conseil Régional du Nord-Pas de Calais. This work was supported in part by a grant from the Direction de la Recherche et des Etudes Doctorales, by the Institut National de la Santé et de la Recherche Médicale (INSERM), and by the Institut Pasteur de Lille. We thank Claudine Mercier and Valérie Codron for their excellent scientific and technical assistance.

Received November 4, 1996; revision received January 30, 1997; accepted February 3, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. McBride W, Lange RA, Hillis LD. Restenosis after successful coronary angioplasty: pathophysiology and prevention. N Engl J Med. 1988;318:1734-1737.[Medline] [Order article via Infotrieve]
   
2. Liu MW, Roubin GS, King SB III. Restenosis after coronary angioplasty: potential biologic determinants and role of intimal hyperplasia. Circulation. 1989;79:1374-1387.[Abstract/Free Full Text]
   
3. Austin GE, Norman NB, Hollman J, Tabei S, Phillips VF. Intimal proliferation of smooth muscle cells as an explanation for recurrent coronary artery stenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol. 1985;6:369-375.[Abstract]
   
4. Mintz GS, Popma JJ, Pichard AD, Kent KM, Satler LF, Wong SC, Hong MK, Kovach JA, Leon MB. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation. 1996;75:299-306.[Abstract/Free Full Text]
   
5. Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, Belardi J, Sigwart U, Colombo A, Goy JJ, van den Heuvel P, Delcan J, Morel MA, for the Benestent Study Group. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med. 1994;331:489-495.[Abstract/Free Full Text]
   
6. Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M, Cleman M, Heuser R, Almond D, Teirstein PS, Fish RD, Colombo A, Brinker J, Moses J, Shaknovich A, Hirshfeld J, Bailey S, Ellis S, Rake R, Goldberg S, for the Stent Restenosis Study Investigators. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med. 1994;331:496-501.[Abstract/Free Full Text]
   
7. Hoffmann R, Mintz GS, Dussaillant GR, Popma JJ, Pichard AD, Satler LF, Kent KM, Griffin J, Leon M. Patterns and mechanisms of in-stent restenosis: a serial intravascular ultrasound study. Circulation. 1996;94:1247-1254.[Abstract/Free Full Text]
   
8. Pratt RE, Dzau VJ. Pharmacological strategies to prevent restenosis: lessons learned from blockade of the renin-angiotensin system. Circulation. 1996;93:848-852.[Free Full Text]
   
9. Powell JS, Clozel JP, Muller RKM, Kuhn H, Hefti F, Hosang M, Baumgartner HR. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science. 1989;245:186-188.[Abstract/Free Full Text]
   
10. Clozel JP, Hess P, Michael C, Schietinger K, Baumgartner HR. Inhibition of converting enzyme and neointima formation after vascular injury in rabbits and guinea pigs. Hypertension. 1991;18(suppl I):I-155-I-159.
    
11. Cambien F, Alhenc-Gelas F, Herbeth B, Andre JL, Rakotoao R, Gonzales MF, Allegrini J, Bloch C. Familial resemblance of plasma angiotensin-converting enzyme level: the Nancy study. Am J Hum Genet. 1988;43:774-780.[Medline] [Order article via Infotrieve]
    
12. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F. An insertion/deletion polymorphism in the angiotensin-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86:1343-1346.
    
13. Costerousse O, Allegrini J, Lopez M, Alhenc-Gelas F. Angiotensin-converting enzyme in human circulating mononuclear cells: genetic polymorphism of expression in T lymphocytes. Biochem J. 1993;290:33-40.
    
14. Van Belle E, Mc Fadden EP, Lablanche JM, Bauters C, Hamon M, Bertrand ME. Two-pronged antiplatelet therapy with aspirin and ticlopidine without systemic anticoagulation: an alternative therapeutic strategy after bailout stent implantation. Coron Artery Dis. 1995;6:341-345.[Medline] [Order article via Infotrieve]
    
15. Bertrand ME, Lablanche JM, Bauters C, Leroy F, Mc Fadden EP. Discordant results of visual and quantitative estimates of stenosis severity before and after coronary angioplasty. Cathet Cardiovasc Diagn. 1993;28:1-6.[Medline] [Order article via Infotrieve]
    
16. Marcadet A, O'Connell P, Cohen D. Standardized Southern blot workshop technique. In: Dupont B, ed. Histocompatibility Testing. New York, NY: Springer-Verlag; 1987:553-560.
    
17. Tiret L, Rigat B, Visikis S, Breda C, Corvol P, Cambien F, Soubrier F. Evidence from combined segregation and linkage analysis that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet. 1992;51:197-205.[Medline] [Order article via Infotrieve]
    
18. Fogarty DG, Maxwell AP, Doherty CC, Hugues AE, Nevin NC. ACE gene typing. Lancet. 1994;343:851. Letter.[Medline] [Order article via Infotrieve]
    
19. Shanmugam V, Sell KW, Saha BK. Mistyping ACE heterozygotes. PCR Methods Appl. 1993;3:120-121.[Medline] [Order article via Infotrieve]
    
20. Dutka DP, Morgan K. ACE gene and cardiovascular disease. Circulation. 1996;94:1787. Letter.
    
21. Evans AE, Poirier O, Kee F, Lecerf L, McCrum E, Falconer T, Crane J, O'Rourke DF, Cambien F. Polymorphisms of the angiotensin-converting enzyme gene in subjects who die from coronary heart disease. Q J Med. 1994;87:211-214.[Abstract/Free Full Text]
    
22. Hamon M, Bauters C, Amant C, Mc Fadden EP, Helbecque N, Lablanche JM, Bertrand ME, Amouyel P. Relation between the deletion polymorphism of the angiotensin-converting enzyme gene and late luminal narrowing after coronary angioplasty. Circulation. 1995;92:296-299.[Abstract/Free Full Text]
    
23. Samani NJ, Martin DS, Brack M, Cullen J, Chauhan A, Lodwick D, Harley A, Swales JD, de Borno DP, Gershlick AH. Insertion/deletion polymorphism in the angiotensin-converting enzyme gene and risk of restenosis after coronary angioplasty. Lancet. 1995;345:1013-1016.[Medline] [Order article via Infotrieve]
    
24. The MERCATOR Study Group. Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: a multicenter, randomized, double-blind, placebo-controlled trial. Circulation. 1992;86:100-110.[Abstract/Free Full Text]
    
25. The MARCATOR Study Group. Effect of high dose angiotensin-converting enzyme inhibition on restenosis: final results of the MARCATOR study, a multicenter, double-blind, placebo-controlled trial of cilazapril. J Am Coll Cardiol. 1995;25:362-369.[Abstract]
    
26. Kakuta T, Currier JW, Haudenschild CC, Ryan TJ, Faxon DP. Differences in compensatory vessel enlargement, not intimal formation, account for restenosis after angioplasty in the hypercholesterolemic rabbit model. Circulation. 1994;89:2809-2815.[Abstract/Free Full Text]
    
27. Lafont A, Guzman LA, Whitlow PL, Goormastic M, Cornhill JF, Chisolm GM. Restenosis after experimental angioplasty: intimal, medial, and adventitial changes associated with constrictive remodeling. Circ Res. 1995;76:996-1002.[Abstract/Free Full Text]
    
28. Schwartz SM, deBlois D, O'Brien ERM. The intima: soil for atherosclerosis and restenosis. Circ Res. 1995;77:445-465.[Free Full Text]
    
29. Daemen MJAP, Lombardi DM, Bosman FT, Schwartz SM. Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Circ Res. 1991;68:450-456.[Abstract/Free Full Text]
    
30. Farhy RD, Carretero OA, Ho KL, Scicli AG. Role of kinins and nitric oxide in the effects of angiotensin converting enzyme inhibitors on neointima formation. Circ Res. 1993;72:1202-1210.[Abstract/Free Full Text]
    
31. Morishita R, Gibbons GH, Ellison KE, Lee W, Zhang L, Yu H, Kaneda Y, Ogihara T, Dzau V. Evidence for direct local effect of angiotensin in vascular hypertrophy: in vivo gene transfer of angiotensin converting enzyme. J Clin Invest. 1994;94:978-984.
    
32. Bonithon-Kopp C, Ducimetiere P, Touboul PJ, Feve JM, Billaud E, Courbon D, Heraud V. Plasma angiotensin-converting enzyme activity and carotid wall thickening. Circulation. 1994;89:952-954.[Abstract/Free Full Text]
    
33. Castellano M, Muiesan ML, Rizzoni D, Beschi M, Pasini G, Cinelli A, Salvetti M, Porteri E, Bettoni G, Kreutz R, Lindpaintner K, Rosei EA. Angiotensin-converting enzyme I/D polymorphism and arterial wall thickness in a general population: the Vobarno Study. Circulation. 1995;91:2721-2724.[Abstract/Free Full Text]
    

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				E. Jorgensen, H. Kelbaek, S. Helqvist, G. V. H. Jensen, K. Saunamaki, J. Kastrup, O. Havndrup, H. Bundgaard, J. Kyst Madsen, M. Christiansen, et al. Predictors of coronary in-stent restenosis: importance of angiotensin-converting enzyme gene polymorphism and treatment with angiotensin-converting enzyme inhibitors J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1434 - 1439. [Abstract] [Full Text] [PDF]

				J. M. Ahmed, G. S. Mintz, R. Waksman, R. Mehran, B. Leiboff, A. D. Pichard, L. F. Satler, K. M. Kent, and N. J. Weissman Serial Intravascular Ultrasound Assessment of the Efficacy of Intracoronary {gamma}-Radiation Therapy for Preventing Recurrence in Very Long, Diffuse, In-Stent Restenosis Lesions Circulation, August 21, 2001; 104(8): 856 - 859. [Abstract] [Full Text] [PDF]

				R. Y. L. Zee, A. Fernandez-Ortiz, C. Macaya, E. Pintor, K. Lindpaintner, and A. Fernandez-Cruz ACE D/I Polymorphism and Incidence of Post-PTCA Restenosis : A Prospective, Angiography-Based Evaluation Hypertension, March 1, 2001; 37(3): 851 - 855. [Abstract] [Full Text] [PDF]

				D. Crisan and J. Carr Angiotensin I-Converting Enzyme: Genotype and Disease Associations J. Mol. Diagn., August 1, 2000; 2(3): 105 - 115. [Full Text]

				W. Koch, A. Kastrati, J. Mehilli, C. Bottiger, N. von Beckerath, and A. Schomig Insertion/Deletion Polymorphism of the Angiotensin I-Converting Enzyme Gene Is Not Associated With Restenosis After Coronary Stent Placement Circulation, July 11, 2000; 102(2): 197 - 202. [Abstract] [Full Text] [PDF]

				P. J. Goldschmidt-Clermont, G. E. Cooke, G. M. Eaton, and P. F. Binkley PlA2, a variant of GPIIIa implicated in coronary thromboembolic complications J. Am. Coll. Cardiol., July 1, 2000; 36(1): 90 - 93. [Full Text] [PDF]

				B. Agerholm-Larsen, B. G. Nordestgaard, and A. Tybjarg-Hansen ACE Gene Polymorphism in Cardiovascular Disease : Meta-Analyses of Small and Large Studies in Whites Arterioscler. Thromb. Vasc. Biol., February 1, 2000; 20(2): 484 - 492. [Abstract] [Full Text] [PDF]

				R. Mehran, G. Dangas, A. S. Abizaid, G. S. Mintz, A. J. Lansky, L. F. Satler, A. D. Pichard, K. M. Kent, G. W. Stone, and M. B. Leon Angiographic Patterns of In-Stent Restenosis : Classification and Implications for Long-Term Outcome Circulation, November 2, 1999; 100(18): 1872 - 1878. [Abstract] [Full Text] [PDF]

				A. Okamura, M. Ohishi, H. Rakugi, T. Katsuya, Y. Yanagitani, S. Takiuchi, Y. Taniyama, K. Moriguchi, H. Ito, Y. Higashino, et al. Pharmacogenetic Analysis of the Effect of Angiotensin-Converting Enzyme Inhibitor on Restenosis After Percutaneous Transluminal Coronary Angioplasty Angiology, October 1, 1999; 50(10): 811 - 822. [Abstract] [PDF]

				J W. JUKEMA Matching treatment to the genetic basis of (lipid) disorder in patients with coronary artery disease Heart, August 1, 1999; 82(2): 126 - 127. [Full Text] [PDF]

				M. E. Bertrand and C. Bauters Cytomegalovirus Infection and Coronary Restenosis Circulation, March 16, 1999; 99(10): 1278 - 1279. [Full Text] [PDF]

				S. Kasaoka, J. M. Tobis, T. Akiyama, B. Reimers, C. Di Mario, N. D. Wong, and A. Colombo Angiographic and intravascular ultrasound predictors of in-stent restenosis J. Am. Coll. Cardiol., November 15, 1998; 32(6): 1630 - 1635. [Abstract] [Full Text] [PDF]

				A. Lafont and D. Faxon Why do animal models of post-angioplasty restenosis sometimes poorly predict the outcome of clinical trials? Cardiovasc Res, July 1, 1998; 39(1): 50 - 59. [Full Text] [PDF]

				J. P. O'Malley, J. P. BS, C. L. Maslen, and D. R. Illingworth Angiotensin-Converting Enzyme DD Genotype and Cardiovascular Disease in Heterozygous Familial Hypercholesterolemia Circulation, May 19, 1998; 97(18): 1780 - 1783. [Abstract] [Full Text] [PDF]

				M. Challah, E. Villard, M. Philippe, A. Ribadeau-Dumas, B. Giraudeau, P. Janiak, J.-P. Vilaine, F. Soubrier, and J.-B. Michel Angiotensin I-Converting Enzyme Genotype Influences Arterial Response to Injury in Normotensive Rats Arterioscler. Thromb. Vasc. Biol., February 1, 1998; 18(2): 235 - 243. [Abstract] [Full Text] [PDF]

F. Ribichini, G. Steffenino, A. Dellavalle, G. Matullo, E. Colajanni, T. Camilla, A. Vado, G. Benetton, E. Uslenghi, and A. Piazza Plasma Activity and Insertion/Deletion Polymorphism of Angiotensin I–Converting Enzyme : A Major Risk Factor and a Marker of Risk f