Risk factors for restenosis after percutaneous transluminal coronary angioplasty: Role of lipoprotein (a)

Risk factors for restenosis after percutaneous transluminal coronary angioplasty: Role of lipoprotein (a) Hideya Yamamoto, MD, Michinori Imazu, MD, PhD, Takashi Yamabe, MD, PhD, Hironori Ueda, MD, Yoshihiro Hattori, MD, and Michio Yamakido, MD, PhD Hiroshima, Japan To evaluate serum levels of lipoprotein (a) (Lp[a]) as a predictor of restenosis after percutaneous transluminal coronary angioplasty (PTCA), we evaluated 71 patients who underwent elective single-vessel angioplasty. Patients were divided into two groups according to the presence (n-- 24 [34%]; group R) or absence (n = 47 [66%]; group N) of restenosis. Serum insulin levels were similar before and after the glucose challenge test in both groups. The median level of serum Lp(a) was 34.9 mg/dl in group R compared with 19.4 mg/dl in group N (p < 0.01). The frequency of the apo E4 allele was 4 (17%) in group R and 4 (9%) in group N (p= NS). The incidence of restenosis was significantly higher in patients with Lp(a) levels ->30 mg/dl than in those with Lp(a) levels <30 mg/dl (65% vs 26%; p < 0.01). Our results indicate that a serum Lp(a) level ->30 mg/dl is a risk factor for restenosis. [AM HEARTJ 1995; 130:1168-73.)

Serial angiographic studies after percutaneous transluminal coronary angioplasty (PTCA) have shown a 6-month restenosis rate of 30% to 40%. 1 The pathogenesis ofrestenosis after mechanical injury is incompletely understood. Medial smooth muscle cells at the site of an injured artery exhibit uncontrolled migration, proliferation, and extracellural matrix synthesis. 2 Injury may lead to mural thrombus that may then induce the production of cytokines, chemoattractants, and growth factors t h a t initiate and sustain the neointimal growth process. 3 An elevated serum level of lipoprotein (a) [Lp(a)] has been found to be a risk factor for myocardial infarction,4 coronary artery disease, 5 and vein graft stenosis after bypass procedures. 6 On the other hand, two studies showed no evidence of association between

From the Second Department of Internal Medicine, Hiroshima University, School of Medicine. Received for publication Feb. 7, 1995; accepted June 2, 1995. Reprint requests: Hideya Yamamoto, 2nd Department of Internal Medicine, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima-city, 734 Japan. Copyright © 1995 by Mosby-Year Book, Inc. 0002-8703/95/$5.00 + 0 4/1/67142

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Lp(a) level and risk of future myocardial infarction.7, 8 Lp(a) is a low-density lipoprotein (LDL)-like lipoprotein characterized by its specific apolipoprotein (a) [apo(a)], which is bound by disulfide linkage to apolipoprotein B-100 in the shell of the LDL particle. Apo(a) has 80% to 90% homology with plasminogen. It has been suggested t h a t Lp(a) competitively inhibits the binding of plasminogen to the surfaces of endothelial cells, thereby modulating fibrinolysis.9, 10 These findings suggested t h a t Lp(a) may provide a link between the pathologic processes of thrombosis and atherosclerosis. Whereas some studies suggested that serum Lp(a) is an independent predictor of restenosis after PTCA,11, 12 others13, 14 reported t h a t restenosis is unrelated to Lp(a) level. The relation between Lp(a) and restenosis after coronary angioplasty is not clear. We investigated the usefulness of serum Lp(a), apolipoprotein E (apo E) isoform, and serum insulin levels for predicting restenosis after PTCA. Apo E serves as a receptor ligand for the uptake oflipoproteins from the circulation. 15 The three common allelic variants of apo E in humans are E2, E3, and E4.16 These isoforms differ in their interaction with the LDL receptor. Individuals with apo E4 exhibit a high total cholesterol and high LDL cholesterol and are predisposed to the early development of coronary artery disease. 17 METHODS Patient population. Between December 1991 and July

1993, 463 patients underwent elective PTCA. Exclusion criteria were unstable angina, recent myocardial infarction within 1 month, multivessel procedure, and cases of repeated PTCA. A total of 199 patients underwent their first elective single-vessel PTCA procedure. Serum samples for the measurement of Lp(a) and apo E isoform could not be drawn in 54 patients. Ultimately, 85 patients were enrolled in this study. PTCA was unsuccessful in five patients, and follow-up angiograms were not obtained in nine patients. Finally, data were evaluated on 71 patients (48

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men, 23 women; age, 63.6 _+ 7.7 years) who u n d e r w e n t follow-up angiography at 6.0 -+ 2.2 months after the initial coronary angioplasty. Target lesions were located in the left descending a r t e r y in 43 patients, in the left circumflex a r t e r y in 15 patients, and in the right coronary a r t e r y in 13 patients. Angioplasty procedure and angiography. Intravenous h e p a r i n (10,000 units) and intracoronary isosorbide dinit r a t e (5 mg) were a d m i n i s t e r e d at the initiation ofconventional PTCA. The size of the balloon was adjusted to the dimension of the coronary a r t e r y to be dilated. Angiograms were obtained before and i m m e d i a t e l y after angioplasty and at follow-up. Follow-up angiography was recommended 6 months after successful PTCA b u t was performed earlier if clinically indicated. Stenotic coronary segments were analyzed quantitatively by using CARDIO 500 (Kontron I n s t r u m e n t s , Inc., Everett, Mass.). The percentage d i a m e t e r stenosis m e a s u r e m e n t was obtained by comparing the m i n i m a l lumen d i a m e t e r (MLD) value at the site of obstruction with the corresponding value of the reference d i a m e t e r (RD) in this position. A successful angioplasty was defined as a residual d i a m e t e r stenosis of <50%. Restenosis was defined as the presence of stenosis ->50% at follow-up. Is The lesion was classified according to the definitions established by a t a s k force of the American H e a r t Association/American College of Cardiology. 19 Blood sample. Before the performance of PTCA, blood samples were obtained in the morning after a 12-hour fast; fasting levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were m e a s u r e d by enzymatic methods. Fibrinogen levels were m e a s u r e d with a fibrometer. Lp(a) levels were m e a s u r e d by an enzymelinked i m m u n o s o r b e n t a s s a y (TintElize Lp(a), Biopool International, Ventura, Calif.). LDL cholesterol was calculated with Friedewald's formula. Apolipoprotein A-I (Apo A-I), Apo B, and Apo E were m e a s u r e d by immunoturbidimetry. Apo E phenotype was d e t e r m i n e d by isoelectric focusing 2° a n d classified into three categories: E2 allele (E2/2, E2/3), E3 allele (E3/3), and E4 allele (E4/3, E4/4). P l a s m a glucose and serum insulin concentrations were m e a s u r e d in 57 patients before and after an oral challenge with 75 gm of glucose monohydrate. P a t i e n t s with diabetes receiving oral hypoglycemic drugs or insulin were excluded. P l a s m a glucose was m e a s u r e d by the glucokinase method, and serum insulin was m e a s u r e d by an enzyme immunoassay. Statistics. D a t a are presented as the m e a n ÷ SD, and u n p a i r e d t tests were performed on continuous clinical and serum variables exhibiting normal distributions. D a t a (serum insulin, Lp[a]) were presented as the m e d i a n for variables having a highly skewed distribution and evaluated by M a n n - W h i t n e y r a n k sum test. Chi-square analysis or Fisher's exact test were performed for discrete variables. Multivariate analysis was performed by using the multiple logistic regression model with a J M P 3.0 for the Macintosh (Apple Computer, Cupertino, Calif.). A p value of <0.05 was considered statistically significant.

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Table I. Clinical characteristics

Age (year) Gender (male) Previous MI Hypertension Diabetes mellitus History of smoking Vessel disease One Two Three Medication Aspirin Antiplatelet agents ~-blockers Calcium antagonists Long-acting nitrates Antihyperlipidemic drugs ACE inhibitors Total cholesterol (mg/dl) Triglyceride (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Apo B/A1 Apo E (mg/dl) E2 allele E3 allele E4 allele Fibrinogen (mg/dl)

Group R

Group N

(n = 24)

(n = 47)

65.5 _+ 7.9 17 (71%) 13 (54%) 16 (67%) 5 (21%) 10 (43%)

62.6 +_ 7.5 31 (66%) 21 (45%) 24 (52%) 15 (33%) 23 (52%)

15 (65%) 6 (23%) 3 (12%)

32 (68%) 12 (26%) 3 (6%)

17 (72%) 15 (61%) 0 (0%) 23 (94%) 23 (94%) 4 (17%) 9 (42%) 204.3 ÷ 42.3 139.5 ÷ 47.8 40.7 _+ 11.6 138.7 _+49.4 1.0 ÷ 0.28 5.4 _+ 1.4 0 (0%) 20 (83%) 4 (17%) 344.6 + 101.9

35 (74%) 24 (51%) 3 (5%) 47 (100%) 41 (87%) 5 (11%) 24 (61%) 213.0 _+34.7 138.4 _+ 73.4 44.6 + 10.6 140.4 + 39.4 1.0 ÷ 0.26 6.3 + 2.2 2 (4%) 41 (87%) 4 (9%) 323.2 _+ 78.1

MI, Myocardial infarction; ACE, angiotensin-converting enzyme; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

RESULTS Patient characteristics ( T a b l e I). A m o n g t h e 71 p a t i e n t s , r e s t e n o s i s w a s o b s e r v e d i n 24 (36%; g r o u p R) p a t i e n t s a n d n o t o b s e r v e d i n t h e r e m a i n i n g 47 (64%; g r o u p N) p a t i e n t s . T h e r e w e r e n o s i g n i f i c a n t differe n c e s b e t w e e n t h e t w o g r o u p s w i t h r e g a r d to a g e , gender, incidence of hypertension, diabetes, obesity, prior myocardial infarction, or history of smoking. U s e o f a s p i r i n , a n t i p l a t e l e t a g e n t s , ~ - b l o c k e r s , calcium antagonists, long-acting nitrates, and antihyperlipidemic drugs were similar between the two groups. Although a greater number of group N patients were receiving angiotensin-converting enzyme inhibitors compared with group R patients, the d i f f e r e n c e w a s n o t s i g n i f i c a n t . T h e r e w e r e no s i g n i f icant differences in levels of fibrinogen or lipid fractions. The distribution of the apo E isoform was simi l a r i n b o t h g r o u p s . F i g . 1 s h o w s t h e c u m u l a t i v e dist r i b u t i o n c u r v e s o f L p ( a ) i n g r o u p s R a n d N. T h e m e d i a n l e v e l o f s e r u m L p ( a ) w a s 34.9 m g / d l ( r a n g e 1.0 to 111.0) i n g r o u p R c o m p a r e d w i t h 19.4 m g / d l ( r a n g e 1.7 to 55.6) i n g r o u p N (p < 0.01). P l a s m a g l u -

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10G

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60

200

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Fig. 1. Cumulative distribution curves of lipoprotein (a) in patients with or without restenosis. Lp(a) level was higher in group R than those in group N (median; range: 34.9 mg/dl; 1.0 to 111.4 mg/dl vs 19.4 mg/dl; 1.7 to 55.6 mg/ dl, p < 0.01). Solid circles show Lp(a) levels in group R patients; open circles, group N.

cose concentrations and serum insulin levels were measured in 18 patients in group R and 39 patients in group N. Plasma glucose levels before and after the glucose challenge test were similar in both groups, but serum insulin levels tended to be higher in group R than in group N (Fig. 2). Angiographic findings (Table II). The distribution of the vascular lesion and its morphologic characteristics were similar in both groups. There was no statistical difference between groups in the RD or the MLD before PTCA. The MLD after PTCA tended to be smaller in group R t h a n in group N. The incidence of angiographic dissection tended to be higher in group R than in group N. The restenosis rate was significantly higher in patients with Lp(a) levels ->30 mg/dl t h a n in those with Lp(a) levels <30 mg/dl (62% vs 22%;p < 0.01; Fig. 3). A multiple logistic regression analysis model identified the serum Lp(a) level as a significant predictor of restenosis (Table III). DISCUSSION

This study demonstrated a highly significant relation between a high level of Lp(a) and an increased rate ofrestenosis after PTCA. There are three possible mechanisms for a relation between Lp(a) and restenosis. (1) It has been suggested t h a t Lp(a) competitively inhibits plasminogen binding to the surfaces of endothelial cells and reduces the activity of fibrin-dependent tissue-type plasminogen activator

0

0

30

60

120

(min.)

Fig. 2. Plasma glucose and serum insulin levels before and after oral challenge with 75 gm glucose monohydrate. Upper panel, Plasma glucose levels. Hatched bars, Plasma glucose in group R patients (n = 18); open bars, those in group N (n = 39). Lower panel, Serum insulin levels. Hatched bars, Serum insulin in group R patients; open bars, that in group N patients. Plasma glucose levels are expressed as mean _+SD. Serum insulin levels are expressed as the median value.

(t-PA)J ° (2) Alternatively, serum Lp(a) may promote an atherothrombosis by increasing in plasminogen activator inhibitor (PM-1) protein, activity, and messenger RNA (mRNA) expression in h u m a n endothelial cells. 9 Elevated PAI-1 activity in the presence of coronary arterial wall injury may be an important factor in the development of acute coronary syndrome. 21 However, although a decreased PAI-1 activity after PTCA is associated with a reduced risk of restenosis, 22 the relation between an increase in circulating PAl- 1 activity and restenosis after PTCA is unclear. To assess the effect of inhibition of fibrinolysis on restenosis, it would be necessary to evaluate the relation between Lp(a) and PAL1. We did not measure PAL1 activity in this study. (3) Because the proliferation of h u m a n smooth muscle cells in culture is accelerated by Lp(a) and apo(a), 23 Lp(a) may contribute to the growth of the arterial atherosclerotic lesions by promoting the proliferation of vascular smooth muscle cells by an inhibition of transforming growth factor p (TGF-p). 24 Lp(a) may play a role in the proliferation of vascular smooth muscle cells after a balloon injury in vivo. Hearn et al. 11reported that restenosis rate ofLp(a) <18 mg/dl was 58.5% and t h a t of >18 mg/dl was 89.3%. The rate of restenosis in both groups was higher t h a n our data, because their population included the patients who underwent a multivessel

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p
Table

I]. Angiographic and procedual characteristics

(%) 80

Group R (n =24)

Group N (n = 47)

12 (50%) 5 (21%) 7 (29%)

31 (66%) 10 (21%) 6 (13%)

-

62%

60 40

1171

22%

20

Fig. 3. Incidence ofrestenosis in groups with high and low levels of lipoprotein (a) [Lp(a)]. Hatched bar, Restenosis rate of patients with Lp(a) ->30 mg/dl (n = 21); open bar, that with Lp(a) <30 mg/dl (n = 50).

procedure. The difference of ranges of Lp(a) may reflect racial differences. Otherwise, Tenda et al. 12 reported that the patients with a serum levels of Lp(a) of >30 mg/dl seemed to carry a high risk of restenosis, as they did in our data. The ranges of lipid values in those two studies were not different from ours. Other studies 13, 14 suggested that restenosis is related to a low level of HDL cholesterol and not to the Lp(a) level. Shah and Amin ]3 studied 68 patients, including unstable angina and postinfarction angina cases. In that study, all asymptomatic patients underwent SPECT2°IT1 scintigraphy but not coronary angiography; therefore, a restenosis may have been missed in some subjects. Otherwise, Cooke et al. 14 revealed that the elevated levels of Lp(a) were not associated with restenosis, but median levels of Lp(a) in patients with restenosis tended to be higher t h a n the levels in those without restenosis. Those two studies did not assess restenosis by quantitatively analyzing coronary angiograms. We determined the percentage diameter by the MLD value at the site of obstruction with the corresponding value of the RD. Levels of total cholesterol, triglycerides, HDL cholesterol, apolipoproteins, and fibrinogen were not significantly related to restenosis in our study. Myler et al. 25 reported t h a t a history of hypercholesterolemia (->300 mg/dl) was a risk factor for restenosis, but Shah and Amin 13 suggested that only a low level of HDL cholesterol was related to restenosis. Austin et al. 26 found no association between restenosis and levels of total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, or apolipoproteins. Several studies have evaluated the relation of ar-

Location of dilated lesion LAD LCX RCA Lesion type* Type A Type B Type C RD (mm) MLD before PTCA (mm) DS before PTCA (%) B/C ratio MLD after PTCA (mm) DS after PTCA (%) Intimal dissection after PTCA MLD at follow-up (mm) DS at follow-up (%)

12 (50%) 9 (39%) 3 (11%) 2.78 ± 0.63 0.71 _+ 0.34 73.7 + 13.8 1.1 _+ 0.2 1.79 _+ 0.35 28.2 ± 14.4 6 (26%) 0.66 ± 0.40 73.6 _+ 15.0

19 (40%) 27 (57%) 1 (3%) 2.72 ± 0.56 0.79 -+ 0.42 71.8 ± 11.7 1.1 ± 0.2 1.90 ± 0.41 25.6 ± 13.4 7 (15%) 1.76 ± 0.45t 29.8 ± 12.6t

LAD, Left anterior discending artery; LCX, left circumflex artery; RCA, right coronary artery; RD, reference diameter; MLD, minimal lumen diameter; PTCA, percutaneous transluminal coronary angioplasty; DS, diameter of stenosis; B/C ratio, balloon]coronary artery diameter ratio; *American Heart Association/American College of Cardiology task force classification. 17 ~p < 0.01.

]]]. Multiple logistic regression analysis of risk factors for restenosis after PTCA Table

Variable

p Value

Lp(a) Apo E-IV Total cholesterol HDL cholesterol Type C lesion* MLD before PTCA MLD after PTCA

<0.001 NS NS NS NS NS NS

Lp(a), Lipoprotein (a); HDL, high-density lipoprotein; MLD, minimal lumen diameter; PTCA, percutaneous transluminal coronary angioplasty. *American Heart Association/American College of Cardiology task force classification. 17

teriosclerotic cardiovascular disease to insulin. 27, 28 Banskota et al. 29 showed that insulin induces the growth of h u m a n vascular smooth muscle cells. However, the relation between restenosis and hyperinsulinemia has not been clarified. We found t h a t the serum insulin levels before and after a glucose challenge test tended to be higher in patients with restenosis than in those without restenosis. Although several investigations a°, 31 suggested a relation between diabetes and restenosis, others did not.32, 33 A p o E protein polymorphism has profound effects on lipid metabolism. Population studies show

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that subjects with the E4 allele have higher levels of LDL than those with the E3 allele. 34 von Bockxmeer et al. 35 reported that apo E4 homozygosity was a determinant of restenosis. Our data showed the incidence of the E4 allele to be 17% in the restenotic group and 9% in the nonrestenotic group, not significantly different. There were inadequate data in our study to make a meaningful contribution to this debate. In this study, we evaluated patients who had undergone single-vessel procedures. The rate of restenosis is reportedly higher in patients who undergo multivessel procedures than in those who undergo a single-vessel procedure. 36 We excluded from evaluation a patient with unstable angina and recent myocardial infarction because of the reported transient increase in the serum level of Lp(a) during acute coronary syndrome. 37 Risk factors for restenosis after PTCA are thought to be multifactorial; therefore, other factors may exist in addition to Lp(a). We also detected the apo E isoform, which was not identified as a risk factor for restenosis. In conclusion, we demonstrated a highly significant relation between a high level of Lp(a) and the rate of restenosis after PTCA. Restenosis developed in 62% of patients with Lp(a) ->30 mg/dl compared with 22% of patients with Lp(a) <30 mg/dl. Thus an elevated serum level of Lp(a) is an independent predictor of restenosis after PTCA. This work was supported in part by Tsuchiya General Hospital, Hiroshima: Y. Hayashi, MD; Y. Oka, MD; Y. Maeda, MD; K. Nakaoka, MD; T. Sakuma, MD; K Ono, MD; J. Oiwa, MD; and Kure Kyosai Hospital, Kure: M. Ito, MD; Y. Shimosaki, MD; T. Masuoka, MD; and A. Shimohara, MD. We thank Professor Wilfred Y. Fujimoto at the University of Washington for his helpful comments. REFERENCES

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