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Risk factors for progression of atherosclerosis six months after balloon angioplasty of coronary stenosis
Risk Factors for Progression of Atherosclerosis Six Months After Balloon Angioplasty of Coronary Stenosis Daniel Benchimol, MD, H&ne Benchimol, MD, Jacques Bonnet, MD, Jean-FranCok Dartigues, MD, Thierry Couffinhal, MS, and Henri Bricaud, MD
To assess the possible progression of coronary artery disease after psrcutaneous transluminal coronary angioplasty (PTCA) and its relation to risk factors and restenosis, 124 patients who underwent a first successful PTCA were studied. All had routine follow-up angiography 5 to 8 months after PTCA. Restenosis was deffned as a 30% decrease in diameter stenosis or a return to >50% stenosis, and progression (in any nondilated site) as a 209/o dscrease in diameter stenosis, assessed by a videodensitometric computer-assisted technique. Uni= variate and multivariate analysis with respect to progression was carried out for age, sex, initial unstable angina, previous myocardial infarction, diabetes mellitus, hypertension, hypercholesterolemia (~6.2 mmol), smoking habits, Jenkins’ score, dilated artery and restenosis. Forty-one patients (33%) had restenosis, and 23 (19%) had evidence of progression; 20 (87%) of these latter patients had restenosis and 3 (13%) did not. Univariate correlates of progression were: previous myocardial infarction (p <0.06), higher Jenkins’ score (p <0.0603) and restenosis (p
he mechanisms of percutaneous transluminal coronary angioplasty (PTCA) are similar to those used to explain the atherosclerotic lesions induced in some experimental models using balloon intima1 denudation’ according to the intimal injury theory.* The stretching process in PTCA produces fracture of the atherosclerotic plaque and often disruption of the media.3,4 PTCA might therefore initiate a fibrocellular response.5 Experimental6 and pathologic5 data suggest that immediately after PTCA, platelets are deposited’ at the site of dilatation, possibly inducing spasm and mural thrombus. Then smooth muscle cells,6 induced at least partly by growth factors released from circulating cells (mainly platelet-derived growth factor), migrate to intima, change from a contractile to a synthetic phenotype and proliferate. This fibrocellular response is thought to be a principal mechanism of restenosis. In the same way, migration and proliferation of smooth muscle cells from media to intima appear to be important in the development of atherosclerotic plaques.* Although the time courses of the 2 processes are quite different (fast in restenosis and slow in atherosclerosis) the similarity of the basic mechanisms might suggest a relation between them.8 The purpose of this study was to see whether there is significant progression of atherosclerosis in nondilated segments after PTCA and whether there are any links between progression and presence of certain factors, especially risk factors and restenosis.
T
METHODS Patients: Patients who underwent a first successful
From the Hapita Cardiologique, Pessac,INSERM U.8 de Cardiolopie, Peasac,and the Departement d’Informatique Mtiicale, Universitt de Bordeaux II, Bordeaux, France. This work was supported in part by a grant from Squibb Laboratories, Princeton, New Jersey. Manuscript received September 26,1989; revised manuscript received and accepted December 13, 1989. Address for reprints: Jacques Bonnet, MD, Hapital Cardiologique, 33604 Pessac,France. 980
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PTCA without any major complication and had repeat routine angiography 5 to 8 months later, regardless of their clinical status, were selected. Only patients in whom PTCA was performed for angina pectoris were included. We excluded patients who had PTCA for acute myocardial infarction, because in this case the dilated lesion is mainly a thrombosis. Primary success of PTCA was defined as an improvement of at least 20% in the percent diameter of the stenosis and a <50% residual stenosis.9 Acute occlusion, myocardial infarction, redilatation or coronary bypass, during PTCA or in the few days after it, were regarded as major complications. The routine repeat angiography criterion was established to evaluate at the same time both restenosis and progression when restenosis reached a plateau.‘O We also wanted to obtain a homogenous population and reduce to a minimum bias due to early or late angiographic restudy for recurrent symptoms, and bias due to patients who did not have angiographic restudy.
TABLE
I Univariate
Correlates
1
of Progression ProgressIon
No ProgressIon
Variables
(n = 23)
(n = 101)
p Value
Male (%) Age W Initial unstable angina (%) Diabetes (%) Hypercholesterolemia (%) Tobacco consumption (pack/yr) Stopped smoking (%) Hypertension (%) Prewous MI (%) Jenkrns’ score LAD angioplasty (%) Circumflex angioplasty (%) Right coronary angioplasty (“IO) Angina at restudy (%) Time to restudy (mo) Restenosis (%) No. of dilatation sites
83 61 f9 39 9 30 22*20 100 35 52 5.9 f 2.7 78 30 22 13 6.3 i 0.7 87 1.2 f 0.6
83 56 f 10 55 9 43 22&23 81 37 28 4.5 f 1.8 61 19 26 29 6.4 f 0.9 21 1.4i0.8
NS NS NS NS NS NS NS NS 0.05 0.003 NS NS NS NS NS O.ccOl NS
IAD = left anterior
descending
coronary
artery;
MI = myocardlal
infarction:
NS = not significant.
The following patients were excluded: those in whom complete occlusion of the dilated artery at angiographic restudy was not considered restenosis (the exact mechanism of occlusion could not be defined accurately from the angiographic data) or in whom the time of occlusion suggested an acute but asymptomatic occlusion; patients who had coronary bypass (the potential effect of coronary surgery in grafted and nongrafted coronary vessels is recognized) l l and patients with poor quality angiograms. Of the 347 first consecutive patients who underwent successful PTCA in our hospital, only 246 (71%) had angiographic restudy (101 refused). Of these, 124 patients (103 men and 21 women, mean age 57 f 10)
stenodsoftlDemidrigMcoroMry restemis at the angiographtc
were selected and 122 patients were excluded (5 1 for early repeat angiography due to recurrence of symptoms, 35 for late restudy mostly for recurrent angina, 11 for PTCA performed on bypass graft, 13 for occlusion of a dilated vessel at restudy and 12 with unavailable angiograms) . Coronary
arteriogram
and angiophsty
procedure:
All patients underwent initial diagnostic coronary angiography a few days before PTCA (6 f 4 days) performed by the femoral approach. Patients were treated with oral nitrates and oral calcium antagonists; sublingual nitroglycerin was given to avoid coronary spasm. Several projections were made for each coronary vessel. Angiograms were recorded on 35mm cinefilm. Angio-
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gion to be analyzed by the computer, and the general axis and direction of the vessel. Edges were then automatically detected along the defined segment, perpendicular to its axis, on the monoplane videodensitometric profile using a first derivate algorithm. Among the various parameters calculated, percent stenosis diameter was used in lesion assessment. We tested the accuracy of the method on plexiglass phantom models filled with contrast medium (12 holes made in a block of plexiglass, with a large diameter of 3.5 mm and a small diameter from 3 to 0.5 mm). In diameter, the accuracy was 0.08 f 0.12 mm and in area 0.30 f 0.49 mm2. To Angiogram analysis: DETERMINATION OF PROGRFS SON: Progression in nondilated segments was defined as evaluate, in percent diameter stenosis, the intra- and a 20% decrease in the stenosis diameter.13 Two indepen- interobserver variability in the analysis of angiograms, 80 and 72 stenoses were assessed at random a second dent observers, unaware of the clinical data, examined the cinefilms alone and then together to select all lesions time, 3 months later. The linear correlations were, re observed on both the preangioplasty and the restudy spectively, r = 0.97, standard error of the estimate = angiograms, or on the restudy angiogram in a place that 4.7%, and r = 0.97, standard error of the estimate = appeared normal on the first angiogram according to 5.4%. the American Heart Association coding system.14 The RESTENOSIS ANALYSIS: Restenosis was defined as a slightest irregularity was considered a lesion and was 30% decrease in the stenosis diameter or a return to assessed. Thus, 130 sites were selected for progression >50% stenosis. Patients were included in the restenosis analysis. Two end-diastolic frames were chosen, one group if restenosis occurred in at least one of the dilated from the diagnostic angiogram and the other from the sites. The PTCA site was evaluated using the same follow-up angiogram in the same projection showing the method on 3 frames (before PTCA, at the end of the narrowest image of the stenosis. procedure and at restudy). After this visual screening, the severity of each seOVERALL EXTENT OF CORONARY ARTERY DISEASE: The lected lesion was assessedby a computer-assisted meth- overall extent of coronary artery disease was assessed od developed in our hospital following Nichols et al.‘5 from the Jenkins’ score,16 based on the severity of leAn optical system on a Tagamo 35 XR projector fo- sions in 8 proximal segments of coronary vessels. cussed and magnified a selected part of the frame conClinical data: Clinical fmdings analyzed included: taining the stenosis. This part of the frame was project- unstable angina (defined as an increasing severity at exed into a charge coupled device video camera, which ercise or rest, or as a de novo angina [onset <2 along with a Matrox image processor (512 X 5 12 pix- months]); previous myocardial infarction (known histoels, 256 gray levels), converted the analog signal into ry of acute myocardial infarction with electrocardiodigital form. Hard copies were printed on a video print- graphic and cardiac enzyme modifications); previous or er from a control video monitor to ensure that the same new onset diabetes (fasting glycemia >7 mmol/liter at segments were analyzed on consecutive angiograms. repeated determinations); previous or recent hypertenThe digital images were stored and processed using an sion (systolic blood pressure >160 mm Hg and diastolic IBM PC AT. The operator selected points on the coro- blood pressure >95 mm Hg); known and treated hypernary segment containing the stenosis, to define the re- cholesterolemia or a total cholesterol level 16.2 mmol/ plasty was performed according to Gruentzig et a1.12All patients received 500 mg of aspirin 12 hours before the procedure. They were treated by intravenous nitrate (20 pg/min), intravenous heparin (3 mg/kg/day) and either nifedipine (10 mg) or diltiazem (60 mg) 4 times/ day for 12 hours before and 24 hours after PTCA. All patients had a routine angiographic restudy between 5 and 8 months after PTCA (6 f 1 months). Angiograms were performed under the same conditions as for the diagnostic angiogram using the same technique and treatment.
FIGURE 2. LeR coronal awiogramrin~same
paumtasinRgwe1 -theofamodemtastenohin theaMusemarginal.A, --B,ti
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liter and tobacco consumption estimated in cigarette pack-years. Cholesterolemia before PTCA and at reexamination was studied. Statistical analysis: A univariate analysis was performed by nonpaired Student t test or Mann Whitney U test for the quantitative variables and by the chisquare test for the qualitative variables. A multivariate analysis by logistic regression with respect to progression was carried out on 12 variables: age, sex, unstable angina at PTCA, previous myocardial infarction, diabetes, hypertension, hypercholesterolemia, smoking habits, left anterior descending artery dilatation, right coronary artery dilatation, Jenkins’ score and restenosis. Circumflex artery dilatation was excluded from the multivariate analysis for an excessive colinearity toward the 2 other coronary vessels.
TABLE
of the population: Sixty-five patients (52%) had unstable angina at PTCA, 40 (33%) had a previous myocardial infarction; 11 (9%) had diabetes and 45 (36%) had hypertension. Clinical improvement was noticed in 117 patients (95%). During follow-up, 92 patients (74%) were asymptomatic, 21 (17%) had stable angina and 11 (9%) had recurrent stable angina after an asymptomatic period. No acute myocardial infarction occurred during follow-up. Hypercholesterolemia was found in 50 patients (40%). Among 82 (66%) current or former cigarette smokers, 44 had stopped smoking before PTCA, and 32 stopped after it. One hundred fifty-one stenoses were successfully dilated. The mean Jenkins’ score was 4.8 f 2.1. Eightyfive stenoses (56%) were dilated in the left anterior descending artery, 38 (25%) in the right coronary artery and 28 (19%) in the circumflex artery. There was 1 PTCA site in 107 patients (86%), 2 sites in 9 patients (7%), 3 sites in 6 patients (5%) and 4 sites in 2 patients (2%). The mean severity of preangioplasty stenosis was 61 f 12%, the mean residual stenosis was 19 f 13% and the mean gain was 43 f 16%. The mean degree of stenosis at restudy time was 35 f 20%. Analysis of progression: Progression was observed in 23 patients (19%); 20 also had restenosis. Among the 130 nondilated segments analyzed, 29 had progression confirmed on computer assessment (initial stenosis: 20 f 15%; stenosis at restudy: 55 f 14%) and 101 had no progression (initial stenosis: 32 f 14%; stenosis at restudy: 30 f 14%). Sixteen (55%) progressions occurred in vessels dilated in another segment: 4 (25%) proximal to the PTCA segment and 12 (75%) distal to the PTCA segment. Thirteen (45%) progressions occurred in segments of arteries free from any procedure. They appeared mainly in the midleft anterior descending artery (lo), the proximal right coronary artery (4) and the obtuse marginal artery (4). Restenosis was observed in 41 patients (33%). Among the 151 dilated stenoses, 46 (31%) had restenosis at angiographic restudy with a mean severity of 58 f 13%. The 105 stenoses without restenosis had a mean severity of 25 f 12% on restudy. Twenty-eight restenoses (33%) occurred in the left ante-
Correlates
of Progression
Covanables
0 Coefficient
Chl-Square
p Value
Male Age angina Initial unstable Dtabetes Hypercholesterolemia Tobacco consumption Hypertension Previous myocardlal InfarctIon LAD angloplasty Right coronary angioplasty Restenosis Jenkins’ score
-0.96 0.02 -1.22 -0.77 -0.28 -0.008 -0.47 101 1.25 0.29 3.49 0 15
0.81 0.35 2.75 0.34 0.14 0.18 0.45 1.64 1.51 0.07 17.75 0.78
NS NS NS NS NS NS NS
LAD = left antemr
TABLE
RESULTS Characteristics
II Multivariate
Ill
Restenosis
descendmg
coronary
Multivariate in the
NS NS o.cCQo3 NS
artery. NS = not slgnlflcant
Analysis
Logistic
NS
of Progression
i
Without
Regression
Covanables
fi Coefficient
Chi-Square
p Value
Male Age lnitlal unstable anglna Diabetes Hypercholesterolemla Tobacco consumption Hypertension Prewous myocardial infarction LAD angioplasty Right coronary angioplasty Jenkins’ score
-0.29 0.05 -0.9 -0.69 -0.51 0.004 -0.01 1.09 1.73 1.06 0.31
0.12 3.01 2.26 0.4 0.62 0.09 0.002 3.21 4.38 1.46 4.94
NS NS NS NS NS NS NS
LAD = left anterior
descending
coronary
NS 0.04 NS 0.03
artery; NS = not sgnifmnt
rior descending artery, 11 (29%) in the right coronary artery and 7 (25%) in the circumflex artery. Figures 1, 2 and 3 illustrate the association between progression and restenosis. The univariate correlates of progression are listed in Table I. Progression appeared to be correlated with a previous myocardial infarction (52 vs 28%, chi square = 3.94, p <0.05) and a higher Jenkins’ score (5.9 f 2.7 vs 4.5 f 1.8, t = 3, p <0.003). It correlated more significantly with restenosis (87 vs 21%, chi square = 34.1, p
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limits 1.1 to 28.7) were found to be correlated with progression. Thus, restenosis appears to be the strongest correlate of progression at 6-month routine restudy. The initial extent of coronary artery disease, the most frequently dilated artery and a previous myocardial infarction appear to be less strongly correlated.
been previously reported. The correlation with the extent of coronary atherosclerosis is in agreement with other studies.13J9,24Since 6-month routine angiographic restudy was the essential criterion of inclusion, we could not test a time factor. However, we did not find any correlation with the usual risk factors for atherosclerosis. This is not altogether surprising since even though such risk factors predict the appearance of the disease DISCUSSION Our results indicate that angiographic progression in the general population25 or progression in patients after PTCA, irrespective of its clinical consequences, is with minimally diseased coronary vessels,23 they are, not rare. Although angiography only evaluates the ef- with the exception of cholesterolemia,*’ only poorly corfect of the atherosclerotic lesions on the contour of the related with progression in patients with extensive disarterial lumen, giving an indirect assessment of the true ease.26 Nevertheless, because the selection criteria instate of the arterial wa11,i7it is at present the only meth- duced a homogenous population, they probably reduced od that can be used in man to study the progression of the differences in risk factors among patients. In fact, coronary atherosclerosis with any accuracy.r3,r8J9 A the strongest correlate of progression was restenosis. methodologic problem stems from the definition of pro- The incidence of restenosis is quite different in this segression. Some investigators used a visual assessment, ries. Several factors contributed to the differences: the some assessthe lesions by class’* and define progression various definitions, the rate of patients undergoing angias a shift of the lesion to a more severe class, and ographic restudy and the visual or quantitative assesssome13J9 define progression as an increase in percent ment of the angiograms. Our results-a 33% restenosis diameter stenosis with various cut off points. Only a few rate and a 31% lesion rate-are in agreement with the studies of progression20*21 used a quantitative assess- rates reported in 3 large series27-29using the same criteria as ours. Only 26% of our patients were symptomatic ment. Spontaneous progression in medically treated pa- at restudy, and this agrees with the rate reported by tients has been found to be correlated with time be- Serruys et allo in their prospective study, which estabtween the 2 angiograms,18~19 unstable angina,19*** lower lished that the restenosis rate should be assessed from age gmup,r9 smoking habits,23s24cholesterolemia at first routine angiographic reexaminations with a quantitative study*4 and extent of coronary artery disease at first method. Thus, our restenosis rate may reflect the inciangiogram.13 We found that progression was correlated dence of restenosis in our whole population of patients with a previous myocardial infarction, which has not undergoing FICA. The progression of atherosclerosis after FTCA has been investigated in only a few series. Our progression rate (19%) is within the rates reported: 11% for Cequier et a130 and 51% for Hwang et al.*O In a study of 39 patients, Hwang et al*O reported that progression was comparable in 2 groups (with or without restenosis) but the selection of symptomatic patients introduced a significant bias. In 98 patients Cequier et aP” did not find any difference in the incidence of progression in patients with or without restenosis at early and late restudy. This appears to contradict our results; however, in that study both the selection criteria-patients with only 1 restenosis of their dilated stenoses or with only an early repeat angiography excluded-and the angiogram assessment by visual analysis are different from ours. The reaction in the arterial wall after PTCA is neither continuous nor linear with time.1°13* A relation between restenosis and progression may only exist early after PTCA, which is in line with our results. Two possibilities are suggested. The first is that restenosis, especially at routine repeat angiography, occurs in patients with more progressive coronary atherosclerosis. Kimbiris et a13* showed rapid progression before the procedure in patients selected for PTCA, which tends to support this hypothesis. Thus progression and restenosis would tend to increase in parallel. The second possibility is that there is a direct relation between progression and restenosis via some common mechanism. The relation could be accounted for by the induction of local processes, which induce both restenosis and an acute transitory progression. This hy984
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pothesis is supported by several case reports5,33,34suggesting that direct intimal injury proximal or distal to the PTCA site induces fibrocellular proliferation and accelerates the formation of atherosclerotic lesions. Waller et al5 suggested that such PTCA-induced proliferation may extend to adjacent segments. In our study, about half of the progressions, however, were observed in an untreated coronary vessel. Therefore either these 2 kinds of progression are different, or other mechanisms inducing a more diffuse response are invoked. They may involve the action of circulating factors or activated cells liberated from the site of dilatation with local or systemic effects. Some studies provide evidence for this. Lambert et a129showed that after multiple PTCA the occurrence of restenosis at any site is not independent of the outcome of other dilated lesions. It implies that systemic factors influence restenosis. In dogs, Bates et a135demonstrated the effect of arterial, especially medial, injury on regional blood flow in both the dilated and nondilated vessel; this indicates that circulating factors from a coronary vessel undergoing balloon PTCA could influence other coronary vessels. These 2 hypotheses are not, however, mutually exclusive. In a particular group of patients with more progressive and greater extent of initial coronary atherosclerosis, balloon angioplasty could simultaneously enhance restenosis at the dilatation site and induce progression processes in both nondilated and dilated vessels over a short time after the procedure. In fact, restenosis at 6-month routine angiography is a major correlate of progression at this time. However, further prospective studies will be necessary to determine the time courses of these 2 phenomena before a possible relation can be established with any certainty. Acknowledgment: We gratefully acknowledge G. Le Goff and P. Besse for assistance in angiogram analysis and J. Toyes and J. Likre for excellent secretarial assistance.
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10. Serruys PW, Luijten KJ, Beatt KJ, Geuskens R, De Feyter PJ, Van den Brand M, Reiber JHC, Ten Katen HJ, Van Es GA, Hugenholtz PG. Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon. Circulation 1988:77:36/L371. 11. Maurer BJ, Oberman A, Holt Jr JH, Kouchoukos NT, Jones WR, Russel Jr RO, Reeves JT. Changes in grafted and nongrafted coronary arteries following saphenous vein bypass grafting. Circukfion 1974;50:293-300. 12. Gruentzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary artery stenosis. Percutaneous transluminal angioplasty. N Eng/ J Med 1979;301:61~68. 13. Moise A, Clement B, Saltiel J. Clinical and angiographic correlates and prognostic significance of the coronary extent score. Am J Cardiol/988,61:12551259. 14. Austen WG, Edwards JE, Frye RL, Gensini GT, Gott VL, Griffith LSC, McGoon DC, Murphy ML, Roe BB. A reporting system on patients evaluated for coronary artery disease. Circulation 1975;51:7-40. 15. Nichols AB, Gabrieli CFO, Fenoglio Jr JJ, Esser PD. Quantification of relative coronary arterial stenosis by cinevideodensitometric analysis of coronary arteriograms. Circulation 1984,69:512-522. 16. Jenkins PJ, Harper RW, Nestel PJ. Severity of coronary atherosclerosis related to lipoprotein concentration. Br Med J 1978;2:288-391. 17. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987:316:1371-1375. 16. Bruschke AV, Wijers TS, Kolters W, Landmann J. The anatomic evolution of coronary artery disease demonstrated by coronary arteriography in 256 nonoperated patients. Circulation 1981;63:527-536. 19. Moi’se A, Thtroux P, Taeymans Y, Waters DD, Lesperance J, Fines P, Descoings B, Robert P. Clinical and angiographic factors associated with progression of coronary artery disease. JACC 1984;3:659-667. 20. Hwang MJ, Sihdu P, Pacold I, Jonshon S, Scalon PJ, Loeb HS. Progression of coronary artery disease after percutanous transluminal coronary angioplasty. Am Heart J 1988;115:297~301. 21. Arntzenius AC, Kromhout D, Barth JD, Reibcr JHC, Bruschke AVG. Buis B, Van Gent CM, Kempen-Voogd N, Strikwerda SD, Van der Velde EA. Diet, lipoproteins, and the progression of coronary atherosclerosis. The Leiden Intervention Trial. N Engl J Med 1985:312:805-811. 22. MoIse A, Thboux P, Taeymans Y, Descoings B, Lesperance J, Waters DD, Pelletier GB, Bourassa MG. Unstable angina and progression of coronary atherosclerosis. N Engl J Med 1983;309:685-689. 23. Morse A, Thdroux P, Taeymans Y, Waters DD. Factors associated with progression of coronary artery disease in patients with normal or minimally narrowed coronary arteries. Am J Cardiol 1985;56:30-34. 24. Raichlen JS, Healy B, Achuff SC, Pearson TA. Importance of risk factors in the angiographic progression of coronary artery disease. Am J Cardiol 1986; 57:66-70. 25. Truett J, Cornetield J, Kannel W. A multivariate analysis of the risk of coronary heart disease in Framingham. J Chronic Dis 1967;20:511-524. 26. Moise A, Bourassa MG, Thtroux P, Taeymans Y, Pasternac A, Campeau L, Buis MA, Dyrda I, David PR. Prognostic significance of progression of coronary artery disease. Am J Cardiol 1985;55:94lb946. 27. Holmes DR, Vlietstra RE, Smith HE, Vetsovec GW, Kent KM, Cowley MJ, Faxon DP, Gruentzig AR, Kelsey SF, Detre KM, Van Raden MJ, Mock MB. Restenosis after percutaneous transluminal coronary angioplasty (PTCA): a report from the PTCA registry of the National Heart, Lung and Blood Institute. Am J Cardiol 1984:53:77C-81C. 26. Leimgruber PP, Roubin GS, Hollman J, Cotsonis GA, Meier B, Douglas JS, King 111 SB, Gruentzig A. Restenosis after successful coronary angioplasty in patients with single vessel disease. Circulation 1986;73:710-717, 29. Lambert M, Bonan R, C&t G, Crepeau J, De Guise P, Mundth E, Lesperante J, David PR, Waters DD. Multiple coronary angioplasty: a model to discriminate systemic and procedural factors related to restenosis. JACC 1988;12:310m 314. 30. Ccquier A, Bonan R, Crtpeau J, CBt& G, De Guise P, Jolly P, Lesperance J, Waters DD. Restenosis and progression of coronary atherosclerosis after angioplasty. JACC 1988;12:49-55. 31. Nobuyoshi M, Kimura T, Nosaka M, Mioka S, Ueno K, Yokoi H, Hamasaki N. Horiuchi H, Ohishi H. Restenosis after successful percutaneous transluminal coronary angioplasty: serial angiographic follow-up of 229 patients. JACC 1988;12:616-623. 32. Kimbiris D, Iskandrian A, Saras H. Inder G, Bemis GE, Segal BL. Rapid progression of coronary stenosis in patients with unstable angina pectoris selected for coronary angioplasty. Cathet Cardiouasc Diagn 1984;10:101-114. 33. Graf RH. Verani MS. Left main coronary artery stenosis: a possible complication of transluminal coronary angioplasty. Cuthet Cardiouasc Diagn 1984; 10:163~/66. 34. Hamby RI, Amin HS, Gulotta SJ, Ricciardi R. 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To assess the possible progression of coronary artery disease after psrcutaneous transluminal coronary angioplasty (PTCA) and its relation to risk factors and restenosis, 124 patients who underwent a first successful PTCA were studied. All had routine follow-up angiography 5 to 8 months after PTCA. Restenosis was deffned as a 30% decrease in diameter stenosis or a return to >50% stenosis, and progression (in any nondilated site) as a 209/o dscrease in diameter stenosis, assessed by a videodensitometric computer-assisted technique. Uni= variate and multivariate analysis with respect to progression was carried out for age, sex, initial unstable angina, previous myocardial infarction, diabetes mellitus, hypertension, hypercholesterolemia (~6.2 mmol), smoking habits, Jenkins’ score, dilated artery and restenosis. Forty-one patients (33%) had restenosis, and 23 (19%) had evidence of progression; 20 (87%) of these latter patients had restenosis and 3 (13%) did not. Univariate correlates of progression were: previous myocardial infarction (p <0.06), higher Jenkins’ score (p <0.0603) and restenosis (p
he mechanisms of percutaneous transluminal coronary angioplasty (PTCA) are similar to those used to explain the atherosclerotic lesions induced in some experimental models using balloon intima1 denudation’ according to the intimal injury theory.* The stretching process in PTCA produces fracture of the atherosclerotic plaque and often disruption of the media.3,4 PTCA might therefore initiate a fibrocellular response.5 Experimental6 and pathologic5 data suggest that immediately after PTCA, platelets are deposited’ at the site of dilatation, possibly inducing spasm and mural thrombus. Then smooth muscle cells,6 induced at least partly by growth factors released from circulating cells (mainly platelet-derived growth factor), migrate to intima, change from a contractile to a synthetic phenotype and proliferate. This fibrocellular response is thought to be a principal mechanism of restenosis. In the same way, migration and proliferation of smooth muscle cells from media to intima appear to be important in the development of atherosclerotic plaques.* Although the time courses of the 2 processes are quite different (fast in restenosis and slow in atherosclerosis) the similarity of the basic mechanisms might suggest a relation between them.8 The purpose of this study was to see whether there is significant progression of atherosclerosis in nondilated segments after PTCA and whether there are any links between progression and presence of certain factors, especially risk factors and restenosis.
T
METHODS Patients: Patients who underwent a first successful
From the Hapita Cardiologique, Pessac,INSERM U.8 de Cardiolopie, Peasac,and the Departement d’Informatique Mtiicale, Universitt de Bordeaux II, Bordeaux, France. This work was supported in part by a grant from Squibb Laboratories, Princeton, New Jersey. Manuscript received September 26,1989; revised manuscript received and accepted December 13, 1989. Address for reprints: Jacques Bonnet, MD, Hapital Cardiologique, 33604 Pessac,France. 980
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PTCA without any major complication and had repeat routine angiography 5 to 8 months later, regardless of their clinical status, were selected. Only patients in whom PTCA was performed for angina pectoris were included. We excluded patients who had PTCA for acute myocardial infarction, because in this case the dilated lesion is mainly a thrombosis. Primary success of PTCA was defined as an improvement of at least 20% in the percent diameter of the stenosis and a <50% residual stenosis.9 Acute occlusion, myocardial infarction, redilatation or coronary bypass, during PTCA or in the few days after it, were regarded as major complications. The routine repeat angiography criterion was established to evaluate at the same time both restenosis and progression when restenosis reached a plateau.‘O We also wanted to obtain a homogenous population and reduce to a minimum bias due to early or late angiographic restudy for recurrent symptoms, and bias due to patients who did not have angiographic restudy.
TABLE
I Univariate
Correlates
1
of Progression ProgressIon
No ProgressIon
Variables
(n = 23)
(n = 101)
p Value
Male (%) Age W Initial unstable angina (%) Diabetes (%) Hypercholesterolemia (%) Tobacco consumption (pack/yr) Stopped smoking (%) Hypertension (%) Prewous MI (%) Jenkrns’ score LAD angioplasty (%) Circumflex angioplasty (%) Right coronary angioplasty (“IO) Angina at restudy (%) Time to restudy (mo) Restenosis (%) No. of dilatation sites
83 61 f9 39 9 30 22*20 100 35 52 5.9 f 2.7 78 30 22 13 6.3 i 0.7 87 1.2 f 0.6
83 56 f 10 55 9 43 22&23 81 37 28 4.5 f 1.8 61 19 26 29 6.4 f 0.9 21 1.4i0.8
NS NS NS NS NS NS NS NS 0.05 0.003 NS NS NS NS NS O.ccOl NS
IAD = left anterior
descending
coronary
artery;
MI = myocardlal
infarction:
NS = not significant.
The following patients were excluded: those in whom complete occlusion of the dilated artery at angiographic restudy was not considered restenosis (the exact mechanism of occlusion could not be defined accurately from the angiographic data) or in whom the time of occlusion suggested an acute but asymptomatic occlusion; patients who had coronary bypass (the potential effect of coronary surgery in grafted and nongrafted coronary vessels is recognized) l l and patients with poor quality angiograms. Of the 347 first consecutive patients who underwent successful PTCA in our hospital, only 246 (71%) had angiographic restudy (101 refused). Of these, 124 patients (103 men and 21 women, mean age 57 f 10)
stenodsoftlDemidrigMcoroMry restemis at the angiographtc
were selected and 122 patients were excluded (5 1 for early repeat angiography due to recurrence of symptoms, 35 for late restudy mostly for recurrent angina, 11 for PTCA performed on bypass graft, 13 for occlusion of a dilated vessel at restudy and 12 with unavailable angiograms) . Coronary
arteriogram
and angiophsty
procedure:
All patients underwent initial diagnostic coronary angiography a few days before PTCA (6 f 4 days) performed by the femoral approach. Patients were treated with oral nitrates and oral calcium antagonists; sublingual nitroglycerin was given to avoid coronary spasm. Several projections were made for each coronary vessel. Angiograms were recorded on 35mm cinefilm. Angio-
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gion to be analyzed by the computer, and the general axis and direction of the vessel. Edges were then automatically detected along the defined segment, perpendicular to its axis, on the monoplane videodensitometric profile using a first derivate algorithm. Among the various parameters calculated, percent stenosis diameter was used in lesion assessment. We tested the accuracy of the method on plexiglass phantom models filled with contrast medium (12 holes made in a block of plexiglass, with a large diameter of 3.5 mm and a small diameter from 3 to 0.5 mm). In diameter, the accuracy was 0.08 f 0.12 mm and in area 0.30 f 0.49 mm2. To Angiogram analysis: DETERMINATION OF PROGRFS SON: Progression in nondilated segments was defined as evaluate, in percent diameter stenosis, the intra- and a 20% decrease in the stenosis diameter.13 Two indepen- interobserver variability in the analysis of angiograms, 80 and 72 stenoses were assessed at random a second dent observers, unaware of the clinical data, examined the cinefilms alone and then together to select all lesions time, 3 months later. The linear correlations were, re observed on both the preangioplasty and the restudy spectively, r = 0.97, standard error of the estimate = angiograms, or on the restudy angiogram in a place that 4.7%, and r = 0.97, standard error of the estimate = appeared normal on the first angiogram according to 5.4%. the American Heart Association coding system.14 The RESTENOSIS ANALYSIS: Restenosis was defined as a slightest irregularity was considered a lesion and was 30% decrease in the stenosis diameter or a return to assessed. Thus, 130 sites were selected for progression >50% stenosis. Patients were included in the restenosis analysis. Two end-diastolic frames were chosen, one group if restenosis occurred in at least one of the dilated from the diagnostic angiogram and the other from the sites. The PTCA site was evaluated using the same follow-up angiogram in the same projection showing the method on 3 frames (before PTCA, at the end of the narrowest image of the stenosis. procedure and at restudy). After this visual screening, the severity of each seOVERALL EXTENT OF CORONARY ARTERY DISEASE: The lected lesion was assessedby a computer-assisted meth- overall extent of coronary artery disease was assessed od developed in our hospital following Nichols et al.‘5 from the Jenkins’ score,16 based on the severity of leAn optical system on a Tagamo 35 XR projector fo- sions in 8 proximal segments of coronary vessels. cussed and magnified a selected part of the frame conClinical data: Clinical fmdings analyzed included: taining the stenosis. This part of the frame was project- unstable angina (defined as an increasing severity at exed into a charge coupled device video camera, which ercise or rest, or as a de novo angina [onset <2 along with a Matrox image processor (512 X 5 12 pix- months]); previous myocardial infarction (known histoels, 256 gray levels), converted the analog signal into ry of acute myocardial infarction with electrocardiodigital form. Hard copies were printed on a video print- graphic and cardiac enzyme modifications); previous or er from a control video monitor to ensure that the same new onset diabetes (fasting glycemia >7 mmol/liter at segments were analyzed on consecutive angiograms. repeated determinations); previous or recent hypertenThe digital images were stored and processed using an sion (systolic blood pressure >160 mm Hg and diastolic IBM PC AT. The operator selected points on the coro- blood pressure >95 mm Hg); known and treated hypernary segment containing the stenosis, to define the re- cholesterolemia or a total cholesterol level 16.2 mmol/ plasty was performed according to Gruentzig et a1.12All patients received 500 mg of aspirin 12 hours before the procedure. They were treated by intravenous nitrate (20 pg/min), intravenous heparin (3 mg/kg/day) and either nifedipine (10 mg) or diltiazem (60 mg) 4 times/ day for 12 hours before and 24 hours after PTCA. All patients had a routine angiographic restudy between 5 and 8 months after PTCA (6 f 1 months). Angiograms were performed under the same conditions as for the diagnostic angiogram using the same technique and treatment.
FIGURE 2. LeR coronal awiogramrin~same
paumtasinRgwe1 -theofamodemtastenohin theaMusemarginal.A, --B,ti
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liter and tobacco consumption estimated in cigarette pack-years. Cholesterolemia before PTCA and at reexamination was studied. Statistical analysis: A univariate analysis was performed by nonpaired Student t test or Mann Whitney U test for the quantitative variables and by the chisquare test for the qualitative variables. A multivariate analysis by logistic regression with respect to progression was carried out on 12 variables: age, sex, unstable angina at PTCA, previous myocardial infarction, diabetes, hypertension, hypercholesterolemia, smoking habits, left anterior descending artery dilatation, right coronary artery dilatation, Jenkins’ score and restenosis. Circumflex artery dilatation was excluded from the multivariate analysis for an excessive colinearity toward the 2 other coronary vessels.
TABLE
of the population: Sixty-five patients (52%) had unstable angina at PTCA, 40 (33%) had a previous myocardial infarction; 11 (9%) had diabetes and 45 (36%) had hypertension. Clinical improvement was noticed in 117 patients (95%). During follow-up, 92 patients (74%) were asymptomatic, 21 (17%) had stable angina and 11 (9%) had recurrent stable angina after an asymptomatic period. No acute myocardial infarction occurred during follow-up. Hypercholesterolemia was found in 50 patients (40%). Among 82 (66%) current or former cigarette smokers, 44 had stopped smoking before PTCA, and 32 stopped after it. One hundred fifty-one stenoses were successfully dilated. The mean Jenkins’ score was 4.8 f 2.1. Eightyfive stenoses (56%) were dilated in the left anterior descending artery, 38 (25%) in the right coronary artery and 28 (19%) in the circumflex artery. There was 1 PTCA site in 107 patients (86%), 2 sites in 9 patients (7%), 3 sites in 6 patients (5%) and 4 sites in 2 patients (2%). The mean severity of preangioplasty stenosis was 61 f 12%, the mean residual stenosis was 19 f 13% and the mean gain was 43 f 16%. The mean degree of stenosis at restudy time was 35 f 20%. Analysis of progression: Progression was observed in 23 patients (19%); 20 also had restenosis. Among the 130 nondilated segments analyzed, 29 had progression confirmed on computer assessment (initial stenosis: 20 f 15%; stenosis at restudy: 55 f 14%) and 101 had no progression (initial stenosis: 32 f 14%; stenosis at restudy: 30 f 14%). Sixteen (55%) progressions occurred in vessels dilated in another segment: 4 (25%) proximal to the PTCA segment and 12 (75%) distal to the PTCA segment. Thirteen (45%) progressions occurred in segments of arteries free from any procedure. They appeared mainly in the midleft anterior descending artery (lo), the proximal right coronary artery (4) and the obtuse marginal artery (4). Restenosis was observed in 41 patients (33%). Among the 151 dilated stenoses, 46 (31%) had restenosis at angiographic restudy with a mean severity of 58 f 13%. The 105 stenoses without restenosis had a mean severity of 25 f 12% on restudy. Twenty-eight restenoses (33%) occurred in the left ante-
Correlates
of Progression
Covanables
0 Coefficient
Chl-Square
p Value
Male Age angina Initial unstable Dtabetes Hypercholesterolemia Tobacco consumption Hypertension Previous myocardlal InfarctIon LAD angloplasty Right coronary angioplasty Restenosis Jenkins’ score
-0.96 0.02 -1.22 -0.77 -0.28 -0.008 -0.47 101 1.25 0.29 3.49 0 15
0.81 0.35 2.75 0.34 0.14 0.18 0.45 1.64 1.51 0.07 17.75 0.78
NS NS NS NS NS NS NS
LAD = left antemr
TABLE
RESULTS Characteristics
II Multivariate
Ill
Restenosis
descendmg
coronary
Multivariate in the
NS NS o.cCQo3 NS
artery. NS = not slgnlflcant
Analysis
Logistic
NS
of Progression
i
Without
Regression
Covanables
fi Coefficient
Chi-Square
p Value
Male Age lnitlal unstable anglna Diabetes Hypercholesterolemla Tobacco consumption Hypertension Prewous myocardial infarction LAD angioplasty Right coronary angioplasty Jenkins’ score
-0.29 0.05 -0.9 -0.69 -0.51 0.004 -0.01 1.09 1.73 1.06 0.31
0.12 3.01 2.26 0.4 0.62 0.09 0.002 3.21 4.38 1.46 4.94
NS NS NS NS NS NS NS
LAD = left anterior
descending
coronary
NS 0.04 NS 0.03
artery; NS = not sgnifmnt
rior descending artery, 11 (29%) in the right coronary artery and 7 (25%) in the circumflex artery. Figures 1, 2 and 3 illustrate the association between progression and restenosis. The univariate correlates of progression are listed in Table I. Progression appeared to be correlated with a previous myocardial infarction (52 vs 28%, chi square = 3.94, p <0.05) and a higher Jenkins’ score (5.9 f 2.7 vs 4.5 f 1.8, t = 3, p <0.003). It correlated more significantly with restenosis (87 vs 21%, chi square = 34.1, p
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limits 1.1 to 28.7) were found to be correlated with progression. Thus, restenosis appears to be the strongest correlate of progression at 6-month routine restudy. The initial extent of coronary artery disease, the most frequently dilated artery and a previous myocardial infarction appear to be less strongly correlated.
been previously reported. The correlation with the extent of coronary atherosclerosis is in agreement with other studies.13J9,24Since 6-month routine angiographic restudy was the essential criterion of inclusion, we could not test a time factor. However, we did not find any correlation with the usual risk factors for atherosclerosis. This is not altogether surprising since even though such risk factors predict the appearance of the disease DISCUSSION Our results indicate that angiographic progression in the general population25 or progression in patients after PTCA, irrespective of its clinical consequences, is with minimally diseased coronary vessels,23 they are, not rare. Although angiography only evaluates the ef- with the exception of cholesterolemia,*’ only poorly corfect of the atherosclerotic lesions on the contour of the related with progression in patients with extensive disarterial lumen, giving an indirect assessment of the true ease.26 Nevertheless, because the selection criteria instate of the arterial wa11,i7it is at present the only meth- duced a homogenous population, they probably reduced od that can be used in man to study the progression of the differences in risk factors among patients. In fact, coronary atherosclerosis with any accuracy.r3,r8J9 A the strongest correlate of progression was restenosis. methodologic problem stems from the definition of pro- The incidence of restenosis is quite different in this segression. Some investigators used a visual assessment, ries. Several factors contributed to the differences: the some assessthe lesions by class’* and define progression various definitions, the rate of patients undergoing angias a shift of the lesion to a more severe class, and ographic restudy and the visual or quantitative assesssome13J9 define progression as an increase in percent ment of the angiograms. Our results-a 33% restenosis diameter stenosis with various cut off points. Only a few rate and a 31% lesion rate-are in agreement with the studies of progression20*21 used a quantitative assess- rates reported in 3 large series27-29using the same criteria as ours. Only 26% of our patients were symptomatic ment. Spontaneous progression in medically treated pa- at restudy, and this agrees with the rate reported by tients has been found to be correlated with time be- Serruys et allo in their prospective study, which estabtween the 2 angiograms,18~19 unstable angina,19*** lower lished that the restenosis rate should be assessed from age gmup,r9 smoking habits,23s24cholesterolemia at first routine angiographic reexaminations with a quantitative study*4 and extent of coronary artery disease at first method. Thus, our restenosis rate may reflect the inciangiogram.13 We found that progression was correlated dence of restenosis in our whole population of patients with a previous myocardial infarction, which has not undergoing FICA. The progression of atherosclerosis after FTCA has been investigated in only a few series. Our progression rate (19%) is within the rates reported: 11% for Cequier et a130 and 51% for Hwang et al.*O In a study of 39 patients, Hwang et al*O reported that progression was comparable in 2 groups (with or without restenosis) but the selection of symptomatic patients introduced a significant bias. In 98 patients Cequier et aP” did not find any difference in the incidence of progression in patients with or without restenosis at early and late restudy. This appears to contradict our results; however, in that study both the selection criteria-patients with only 1 restenosis of their dilated stenoses or with only an early repeat angiography excluded-and the angiogram assessment by visual analysis are different from ours. The reaction in the arterial wall after PTCA is neither continuous nor linear with time.1°13* A relation between restenosis and progression may only exist early after PTCA, which is in line with our results. Two possibilities are suggested. The first is that restenosis, especially at routine repeat angiography, occurs in patients with more progressive coronary atherosclerosis. Kimbiris et a13* showed rapid progression before the procedure in patients selected for PTCA, which tends to support this hypothesis. Thus progression and restenosis would tend to increase in parallel. The second possibility is that there is a direct relation between progression and restenosis via some common mechanism. The relation could be accounted for by the induction of local processes, which induce both restenosis and an acute transitory progression. This hy984
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pothesis is supported by several case reports5,33,34suggesting that direct intimal injury proximal or distal to the PTCA site induces fibrocellular proliferation and accelerates the formation of atherosclerotic lesions. Waller et al5 suggested that such PTCA-induced proliferation may extend to adjacent segments. In our study, about half of the progressions, however, were observed in an untreated coronary vessel. Therefore either these 2 kinds of progression are different, or other mechanisms inducing a more diffuse response are invoked. They may involve the action of circulating factors or activated cells liberated from the site of dilatation with local or systemic effects. Some studies provide evidence for this. Lambert et a129showed that after multiple PTCA the occurrence of restenosis at any site is not independent of the outcome of other dilated lesions. It implies that systemic factors influence restenosis. In dogs, Bates et a135demonstrated the effect of arterial, especially medial, injury on regional blood flow in both the dilated and nondilated vessel; this indicates that circulating factors from a coronary vessel undergoing balloon PTCA could influence other coronary vessels. These 2 hypotheses are not, however, mutually exclusive. In a particular group of patients with more progressive and greater extent of initial coronary atherosclerosis, balloon angioplasty could simultaneously enhance restenosis at the dilatation site and induce progression processes in both nondilated and dilated vessels over a short time after the procedure. In fact, restenosis at 6-month routine angiography is a major correlate of progression at this time. However, further prospective studies will be necessary to determine the time courses of these 2 phenomena before a possible relation can be established with any certainty. Acknowledgment: We gratefully acknowledge G. Le Goff and P. Besse for assistance in angiogram analysis and J. Toyes and J. Likre for excellent secretarial assistance.
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