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Annu. Rev. Med.1991. 42:127-32 Copyright © 1991 by Annual Reviews Inc. All rights reserved
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RESTENOSIS AFTER Annu. Rev. Med. 1991.42:127-132. Downloaded from www.annualreviews.org Access provided by Washington State University on 01/28/15. For personal use only.
CORONARY BALLOON ANGIOPLASTY Richard A. Lange, M.D., Eduardo D. Flores, M.D., and
L. David Hillis, M.D.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235 KEY WORDS:
PTCA, intimal hyperplasia
ABSTRACT
A recurrence of stenosis (restenosis) following successful coronary angio plasty continues to be a frequent problem limiting the long-term efficacy of the procedure. An overexuberant reparative response to the arterial injury induced by balloon dilatation leads to intimal hyperplasia, the major mechanism responsible for restenosis. Although none has yet been proven effective, agents designed to prevent this hyperplastic response are under investigation. INTRODUCTION
Over the past decade, percutaneous transluminal coronary angioplasty (PTCA) has emerged as the treatment of choice for many patients with atherosclerotic coronary artery disease. With increased experience and technical advances, the incidence with which the procedure is successful has risen to about 90%, and the occurrence of acute complications requiring emergent surgery has decreased to less than 4%. Although the incidence of initial success has improved, the frequency of restenosis has not changed. As a result, restenosis limits the procedure's long-term efficacy. Restenosis is defined as (a) a loss of 250% of the initial improvement 127 0066-4219/91/0401-0127$02.00
Annu. Rev. Med. 1991.42:127-132. Downloaded from www.annualreviews.org Access provided by Washington State University on 01/28/15. For personal use only.
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in the cross-sectional diameter of the arterial lumen, or (b) an increase in luminal diameter stenosis of :::::: 30% in comparison with the appearance of the arterial segment immediately after angioplasty. It occurs in 30-40% of patients who undergo PTCA of a narrowed artery and in 45-55% of those in whom a totally occluded artery is dilated. In most subjects, it occurs within six months of angioplasty ( 1). Although the patient with restenosis typically notes the reappearance of angina, he or she may be asymptomatic (2). In patients who undergo repeat PTCA, the incidence of restenosis following the second procedure is similar to that associated with the first. PATHOPHYSIOLOGIC MECHANISMS OF STENOSIS DILATATION BY PTCA
Although the factors responsible for restenosis are not completely under stood, the process appears to result from a complex series of events initiated by balloon-induced injury to the coronary artery. Pathologic examination of coronary arteries from patients dying soon after successful angioplasty usually reveals one or more of the following: (a) endothelial denudation with adherent fibrin and platelet aggregates; (b) fractures, tears, and cracks of the atherosclerotic plaque; (c) dehiscence of the intima and plaque from the underlying media; (d) dissection of the intima with variable degrees of medial penetration; (e) stretching of the media and adventitia underlying the plaque; and (f) stretching of the segment of artery that is plaque-free ( 1). In the majority of patients, this "controlled" arterial injury prompts a reparative process that results in persistent expansion of the vessel lumen. However, in some, an overexuberant reparative response causes a recur rence of the stenosis. PATHOPHYSIOLOGIC MECHANISMS OF RESTENOSIS
Restenosis following successful angioplasty may occur via several mech anisms: organization of underlying thrombus; relaxation of the over stretched segment, with concomitant vasoconstriction; intimal hyper plasia; or a combination of these responses. Thrombus
Following experimental angioplasty, fibrin-platelet thrombi are observed within minutes at the site of balloon dilatation. Although the fibrocellular transformation of thrombus was originally thought to be the primary mechanism of restenosis, it is now recognized that restenosis often occurs
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in vessels without angiographically evident thrombi and that occlusive, organized thrombi often are not found at postmortem studies of restenotic lesions (3). Thus, thrombus may contribute to the development of resten osis in some patients, but it is not the major mechanism in most.
Annu. Rev. Med. 1991.42:127-132. Downloaded from www.annualreviews.org Access provided by Washington State University on 01/28/15. For personal use only.
Recoil
With eccentric atherosclerotic lesions, balloon dilatation stretches the seg ments of artery that are plaque-free. Over the ensuing days to weeks, these stretched segments may gradually relax (so called "recoil" or "restitution of tone"), which leads to a reduction in luminal diameter. At angiography, progressive diminution in luminal caliber has been observed within 30 minutes of balloon dilatation (4). In addition, the local release of vaso constrictors by aggregating platelets (e.g. serotonin and thromboxane) as well as the decreased production of endogenous vasodilators (e.g. endothelial-derived relaxant factor and prostacyclin) promotes vaso constriction at the site of angioplasty. The role that these humoral sub stances play in the development of restenosis is undefined. Intimal Hyperplasia
Intimal hyperplasia appears to be the predominant mechanism responsible for the recurrence of stenosis following PTCA. Specimens obtained during the healing phase of angioplasty demonstrate smooth muscle proliferation in the intima of the artery (5). In postmortem specimens acquired weeks to months after angioplasty, a layer of smooth muscle cells and fibroblasts extends beneath the outer acellular layer of fractured atherosclerotic plaque into the luminal space around the inner circumference of the vessel (5). In addition, tissue specimens from restenotic lesions obtained by atherectomy consist largely of hyperplastic smooth muscle (4). Intimal hyperplasia can be induced by multiple stimuli. At the site of balloon injury, platelet activation and degranulation result in the release of growth factors (3)-such as platelet-derived growth factor (PDGF), epidermal growth factor, and beta-transforming growth factor-that are mitogenic and chemotactic for macrophages and neutrophils. With injury to the media, these growth factors induce (a) the migration and pro liferation of smooth muscle cells from the media to the intima and (b) increased synthesis of collagen, elastin, and a proteoglycan matrix. Injured smooth muscle cells and activated macrophages also produce mitogenic and growth factors-such as PDGF-like molecules, basic fibroblast growth factor, and interleukin-l-that induce smooth muscle and fibro blast proliferation. The migration of smooth muscle cells from the media to the intima occurs within a few days of angioplasty, and proliferation begins shortly
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Annu. Rev. Med. 1991.42:127-132. Downloaded from www.annualreviews.org Access provided by Washington State University on 01/28/15. For personal use only.
thereafter (i.e. at 7-14 days). The number of smooth muscle cells peaks at 2-3 weeks and remains constant for up to a year. Intimal thickening is maximal at 2-3 months, which suggests that increases in cell volume as well as deposition of extracellular matrix and connective tissue are responsible for subsequent encroachment on the arterial lumen (3). The processes responsible for restenosis are most active during the initial 3-4 months following balloon dilatation. In a series of patients undergoing sequential angiographic studies, the incidence of restenosis at 1, 3, 6, and 12 months was 12%, 43%, 49%, and 52%, respectively (6). FACTORS INFLUENCING THE INCIDENCE OF RESTENOSIS
Retrospective studies have identified certain clinical, anatomic, and pro cedural variables that are associated with an increased likelihood of resten osis (l) (Table I). Of the clinical factors examined, unstable angina, vaso spastic angina, and diabetes mellitus are consistently associated with an Table 1
Variables associated with an increased incidence of
restenosis following successful angioplasty
A. Clinical variables I. Unstable angina 2. Vasospastic angina 3. Diabetes mellitus
4. Chronic dialysis 5. Male sex (?) 6. Cigarette smoking (?)
7. Hypercholesterolemia (?)
B.
Anatomic variables 1. Location a. Left main> LAD> RCA, LCx' b. Proximal location c. Bifurcation
2. Severity of pre-PTCA stenosis 3. Saphenous vein graft
4. Totally occluded artery C. Procedural variables
I. Extensive dissection 2. Severity ofpost-PTCA stenosis a. Residual stenosis z 30% b. Transstenotic pressure gradient> 15 mm Hg. •
Abbreviations: LAD
flex; RCA
=
=
left anterior descending; Lex
right coronary artery.
=
left circum
Annu. Rev. Med. 1991.42:127-132. Downloaded from www.annualreviews.org Access provided by Washington State University on 01/28/15. For personal use only.
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increased incidence of restenosis. In addition, a high incidence of restenosis has been reported in patients undergoing chronic dialysis (7). Some studies suggest that hypercholesterolemia, cigarette smoking, and male gender increase the incidence of restenosis, but other studies do not (1). Several anatomic factors are known to increase the incidence of resten osis. Lesions that are (a) located in the left main or left anterior descending coronary arteries, (b) proximal, or (c) at the site of vessel bifurcation show an increased incidence of restenosis in comparison to those that are distal or that are located in the right or left circumflex coronary arteries. Severe stenoses and total occlusions have a high incidence of restenosis following angioplasty. The incidence of restenosis appears to be higher in saphenous vein bypass grafts than in native vessels. Procedural factors also influence the long-term success of PTCA. Both the absence of a dissection and the presence of an extensive dissection increase the likelihood of restenosis. Likewise, a suboptimal result of PTCA, as evidenced by a persistent transstenotic pressure gradient or a significant residual stenosis, increases the incidence of restenosis. STRATEGIES FOR THE PREVENTION OF RESTENOSIS Pharmacologic Approaches
Numerous pharmacologic agents have been used in an attempt to prevent or reduce the incidence of restenosis (1). Although platelet inhibitors reduce the incidence of acute occlusion following angioplasty, neither aspirin-dipyridamole nor ticlopidine has been shown to influence the inci dence of restenosis. An l8-24-hour infusion of heparin, an inhibitor of thrombus formation and smooth muscle proliferation in vitro, exerted no effect on the incidence of restenosis. Similarly disappointing rcsults were observed with prolonged (six months) warfarin administration. Studies in rabbits suggest that corticosteroids may reduce the incidence of restenosis, but intravenous methylprednisolone prior to PTCA was not beneficial in humans (8). The calcium antagonists, diltiazem and nifedipine, have not been effective in reducing the incidence of restenosis (1). Great interest has developed in the omega-3 fatty acids (fish oils), which inhibit platelet aggregation and favorably alter lipid profiles. Although one study showed that fish oils reduce the incidence of restenosis when initiated one week before PTCA, others have not shown them to be useful if they are begun just prior to the procedure (4). Nonpharmacologic Approaches
Several mechanical devices are under investigation, including hot-tipped balloons, rotational and excisional atherectomy catheters, intravascular
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stents, ultrasonic and radiofrequency devices, and laser catheters. Although experience is limited, preliminary reports suggest that restenosis occurs frequently following the use of these devices. Balloon catheters that permit direct application of pharmacologic agents into the vessel wall at the time of dilatation are under investigation.
Annu. Rev. Med. 1991.42:127-132. Downloaded from www.annualreviews.org Access provided by Washington State University on 01/28/15. For personal use only.
Future Approaches
A better understanding of the pathophysiologic mechanism(s) responsible for restenosis will help develop strategies to reduce or prevent its occur rence. Under development or investigation are monoclonal antibodies against adhesive molecules (von Willebrand factor), monoclonal anti bodies that block platelet membrane receptors responsible for aggregation (lIb-lIla receptors), agents that inhibit platelet aggregation (ciprostene), thrombin inhibitors (hirudin), antioxidant lipid-lowering agents (pro bucol), inhibitors of smooth muscle cell proliferation (mevinolin), antag onists to platclct-derived growth factor (triazolopyrimidine), and agents that inhibit the production of extracellular matrix (colchicine). Literature Cited
L McBride, W., Lange, R. A., Hillis, L. D.
2.
3.
4.
5.
1988. Restenosis after successful coronary angioplasty: pathophysiology and pre vention. N. Engl. J. Med. 318: 1734-37 Blackshear, 1. L., O'Caliaghan, W. G., Califf, R. M. 1987. Medical approaches to prevention of restenosis after coronary angioplasty. J. Am. Call. Cardiol. 9: 83448 Liu, M. W., Roubin, G. S., King, S. B. III. 1989. Restenosis after coronary angi oplasty: potential biologic determinants and role of intimal hyperplasia. Cir culation 79: 1374-87 Popma, 1. 1., Topol, E. 1. 1990. Factors influencing restenosis after coronary angi oplasty. Am. J. Med. 88(1): 16N�24N Waller, B. F. 1989. "Crackers, breakers, stretchers, drillers, scrapers, shavers, bur ners, welders and melters"-The future treatment of atherosclerotic coronary
artery disease?: A clinical-morphologic assessment. J. Am. Call. Cardiol. 13: 969�
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6. Nobuyoshi, M., Kimura, T., Nosaka, H., Mioka, S., Veno, K., et al. 1988. Resten osis after successful percutaneous trans luminal coronary angioplasty: serial angiographic follow-up of 229 patients. J. Am. Call. Cardiol. 12: 616 23 7. Kahn, 1. K., Rutherford, B. D., McCon ahay, D. R., 1ohnson, W. L., Giorgi, L. V Hartzler, G. O. 1990. Short- and long term outcome of percutaneous trans luminal coronary angioplasty in chronic dialysis patients. Am. Heart J. 119: 48489 8. Pepine, C. 1., Hirshfeld, 1. W., MacDon ald, R. G., et al. 1990. A controlled trial of corticosteroids to prevent restenosis following coronary angioplasty. Cir culation 81: 1753-61 .•