Author + information
- Received May 1, 1996
- Revision received October 31, 1996
- Accepted November 12, 1996
- Published online March 1, 1997.
- Masatoshi Fujita, MDA,*,
- Izuru Nakae, MDB,
- Tetsuro Fudo, MDB,
- Terumitsu Tanaka, MDB,
- Tomoyuki Iwase, MDB,
- Shun-ichi Tamaki, MDB,
- Ryuji Nohara, MDC and
- Shigetake Sasayama, MD, FACCC
- ↵*Dr. Masatoshi Fujita, College of Medical Technology, Kyoto University, 53 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-01, Japan.
Objectives. The purpose of the present study was to evaluate whether severe restenosis after percutaneous transluminal coronary angioplasty (PTCA) promotes collateral development and whether successful dilation regresses collateral vessels.
Background. It is well known that in the presence of severe coronary stenosis, native collateral arterioles mature to small coronary arteries with several layers of smooth muscle cells. However, it remains unclear whether well developed collateral vessels regress after removal of coronary stenosis.
Methods. The study group comprised 41 patients who underwent elective PTCA for effort angina due to single-vessel disease, followed by repeat PTCA to treat restenosis. We classified the patients into three groups depending on the change in baseline Thrombolysis in Myocardial Infarction (TIMI) flow grade of the ischemia-related artery at initial and repeat PTCA, and we compared the extent of ST segment elevation at 1 min of the first balloon inflation between the two procedures. The average interval from initial to repeat PTCA was 125 days.
Results. The three patient groups comprised group A, 12 patients with decreased flow grade because of severe coronary restenosis; group B, 12 patients with increased flow grade who had severe initial stenosis and relatively mild restenosis; and group C, 17 patients with unchanged flow grade. In the presence of comparable rate-pressure products at initial and repeat PTCA, patients in group A had significantly greater ST segment elevation (p < 0.01) at initial than at repeat PTCA (mean ± SD 0.42 ± 0.31 vs. 0.13 ± 0.22 mV). In group B, ST segment elevation was significantly less at initial than at repeat PTCA (0.13 ± 0.25 vs. 0.19 ± 0.17 mV, p < 0.05), and in group C, it was comparable at the two procedures (0.37 ± 0.32 vs. 0.35 ± 0.33 mV, p = 0.50).
Conclusions. These findings indicate that severe restenosis after PTCA promotes collateral development and that successful dilation regresses collateral vessels during a relatively short period of time.
(J Am Coll Cardiol 1997;29:544–8)
A growing body of evidence () demonstrates that well developed collateral circulation plays an important protective role in patients with coronary artery disease. Collateral function is assessed accurately in the presence of a pressure gradient across the collateral network (). Percutaneous transluminal coronary angioplasty (PTCA) serves as a useful model in the study of the collateral circulation ([3–5]). This model may also make it possible to evaluate collateral regression as well as collateral development. To our knowledge, there is no report on the fate of collateral circulation after successful PTCA. We assumed that the extent of ST segment elevation during PTCA balloon inflation might reflect collateral circulation in the presence of comparable rate-pressure products. Measurements made at 1 min of the first balloon inflation were repeated at an interval of 2 to 6 months. The purpose of our study was to evaluate whether severe restenosis after PTCA promotes collateral development and whether successful dilation regresses collateral vessels during a relatively short period of time.
1.1 Study patients.
The study group comprised 41 consecutive patients (31 men and 10 women with a mean age ± SD of 66 ± 8 years (range 50 to 78)) who underwent elective PTCA for effort angina due to single-vessel coronary artery disease (right coronary artery in 18 patients, left anterior descending coronary artery in 23) followed by repeat PTCA for restenosis of the dilated coronary artery. We excluded patients with a previous myocardial infarction or any heart disease that would interfere with unequivocal interpretation of ST segment deviation in the 12-lead electrocardiogram (ECG).
1.2 Experimental protocol.
All medications were withheld for at least 24 h before the study. A 10,000-U intravenous bolus of heparin was administered after access was obtained. Selective coronary angiography was performed to evaluate the extent of coronary stenosis and collateral circulation. A regular guide wire and balloon catheter were then advanced, and the balloon was positioned into the stenosis as usual. All inflations lasted 2 min, and a standard 12-lead ECG was continuously recorded during all inflations, allowing detection of ischemia. The diameter of the coronary arteries was measured with a caliper on adequately magnified 35-mm cine frames at end-diastole. Significant coronary stenosis was defined as ≥75% narrowing of a major coronary artery branch. Written informed consent was obtained from each patient.
1.3 Grading of coronary perfusion.
The degree of perfusion of the ischemia-related coronary artery was graded on a scale of 0 to 3 with use of the Thrombolysis in Myocardial Infarction (TIMI) classification (): 0 = there is no anterograde flow beyond the point of occlusion. 1 = the contrast material passes beyond the area of obstruction but “hangs up” and fails to opacify the entire coronary bed distal to the obstruction for the duration of the cineangiographic filming sequence. 2 = the contrast material passes across the obstruction and opacifies the coronary bed distal to the obstruction. However, the rate of entry of contrast material into the vessel distal to the obstruction or its rate of clearance from the distal bed (or both) is perceptibly slower than its entry into or clearance from comparable areas (for example, the opposite coronary artery or the coronary bed proximal to the obstruction). 3 = anterograde flow into the bed distal to the obstruction occurs as promptly as anterograde flow into the bed proximal to the obstruction, and clearance of contrast material from the involved bed is as rapid as clearance from an uninvolved bed in the same vessel or the opposite artery.
1.4 Grading of coronary collateral filling.
Collateral circulation was graded on a scale of 0 to 3 depending on the degree of opacification of the recipient vessel. The score (collateral index) was based on the injection that best opacified the recipient vessel: 0 = no filling; 1 = filling of side branches of the artery to be perfused by collateral vessels without visualization of the epicardial segment; 2 = partial filling of the epicardial segment by collateral vessels; and 3 = complete filling of the epicardial segment by collateral vessels (). Three observers assessed the coronary cineangiograms in blinded fashion and reached a consensus regarding the TIMI grade and collateral filling.
1.5 Data analysis.
At 1 min of the first balloon occlusion, ST segment shift was measured 80 ms after the J point on tracings recorded at a paper speed of 50 mm/s. The lead showing the maximal ST segment elevation was selected for comparison of the extent of ischemia between initial and repeat PTCA. Arterial pressure was simultaneously recorded during all inflations. Analysis of all data was performed by two independent observers who were not aware of the time of PTCA.
The patients were classified into three groups depending on the change in flow grade of the ischemia-related coronary artery: group A = 12 patients with decreased flow grade because of severe coronary restenosis; group B = 12 patients with increased flow grade who had severe initial stenosis and relatively mild restenosis; and group C = 17 patients with unchanged flow grade with a relatively mild culprit lesion at both initial and repeat PTCA.
1.7 Statistical analysis.
All data are expressed as mean value ± SD. Proportional data were analyzed by the chi-square test, with the Yates correction if one of the frequencies in the 2 × 2 contingency table was <5. The paired ttest was utilized for comparisons between the initial and repeat PTCA. Nonparametric comparisons were performed with the Wilcoxon signed-rank test. A p value < 0.05 was considered statistically significant.
2.1 Patient characteristics.
Clinical and coronary angiographic features of the study patients are summarized in Table 1. There were no differences in gender, age, PTCA site and interval to repeat PTCA among the three patient groups. The baseline TIMI flow grade of coronary arteries with culprit lesions was significantly decreased from 3 ± 0 at initial coronary angiography to 1.5 ± 0.9 at the time of repeat PTCA in group A (p < 0.01). In group B, the flow grade was significantly increased from 1.6 ± 0.8 to 3 ± 0 because of the milder restenosis of culprit lesions (p < 0.01). The flow grade was well maintained in group C on both the initial and the repeat study (2.9 ± 0.2 vs. 2.9 ± 0.2, Table 1, Fig. 1). Changes in the percent coronary stenosis of culprit lesions are depicted in Fig. 2. Before the initial PTCA, the extent of coronary stenosis was 90% in all 12 patients in group A and it deteriorated to 100% in 3 patients and to 99% in 9 on repeat study (p < 0.01). In contrast, in group B total or subtotal occlusion of PTCA sites was ameliorated to 90% stenosis in 11 and to 75% stenosis in the remaining patient (p < 0.01). In group C the extent of coronary stenosis remained unchanged in 12 of 17 patients and decreased from 90% to 75% in 5 (p < 0.05). Changes in the preocclusion collateral index to the area perfused by the artery with culprit lesions are shown in Fig. 3. The collateral index at initial coronary angiography was 0 in all 12 patients in group A but increased to 1.5 ± 1.0 on repeat angiography (p < 0.01). The collateral index decreased from 1.7 ± 1.2 to 0.8 ± 1.0 (p < 0.05) in group B and was unchanged in group C (0.3 ± 0.7 vs. 0.2 ± 0.5).
2.2 Myocardial ischemia during balloon inflation.
Rate-pressure products at 1 min of the first balloon inflation did not differ between initial and repeat PTCA in any group (Table 2). In group A, the extent of ST segment elevation at 1 min of the first balloon inflation was 0.42 ± 0.31 mV at initial PTCA but decreased significantly (p < 0.01) to 0.13 ± 0.22 mV at repeat PTCA (Fig. 4). In contrast, in group B, ST segment elevation of 0.13 ± 0.25 mV at initial PTCA increased significantly (p < 0.05) to 0.19 ± 0.17 mV at repeat PTCA (Fig. 4). In group C, the extent of ST segment elevation was comparable at initial and repeat PTCA (0.37 ± 0.32 vs. 0.35 ± 0.33 mV, p = 0.05, Fig. 4).
The salient findings of this study were twofold: 1) Severe coronary stenosis with filling delay is prerequisite for collateral growth, and 2) collateral vessels regress with sufficient coronary perfusion during a relatively short period of time.
3.1 Methodologic considerations.
In this study collateral function was assessed by measurement of the extent of ST segment elevation during coronary occlusion with a PTCA balloon. The severity of myocardial ischemia, which is reflected in the extent of ST segment elevation, is determined primarily by myocardial oxygen balance. In our patients, rate-pressure products were quite similar during the two coronary occlusions compared. Accordingly, blood supply through collateral channels appears to be reflected in the extent of ST segment elevation ().
It has recently been demonstrated () that myocardial ischemic preconditioning attenuates myocardial ischemia during the subsequent coronary occlusion. We therefore studied ST segment elevation during the first PTCA balloon occlusion. In addition, because myocardial ischemia increases progressively after coronary occlusion, we measured hemodynamic variables and ST segments at 1 min of coronary occlusion.
3.2 Collateral vessel development.
Although the precise mechanisms responsible for collateral vascular growth remain unclear, many investigators ([8, 9]) agree that myocardial ischemia is deeply related to the development of collateral vessels. Our data indicated that severe coronary restenosis with a filling delay of contrast medium causes functionally significant collateral development. However, in patients with TIMI grade 3 perfusion (group C) further collateral development was not observed even in patients who had coronary restenosis of >50% narrowing. These findings are at variance with earlier reports ([10, 11]) that coronary arteries with >70% lumen narrowing are frequently accompanied by recruitable collateral vessels. Because the process of coronary restenosis progresses gradually, the duration of significant coronary stenosis may have been relatively short in our patients.
3.3 Collateral vessel regression.
Even if well developed collateral vessels are present, collateral flow cannot be expected unless there are pressure gradients across the collateral network. Thus, collateral function must be evaluated in the presence of pressure gradients (). Therefore, absence of angiographic visualization of collateral vessels known to be present before successful revascularization might better be termed “disappearance” rather than “regression.”
Collateral regression may be “functional” or “anatomic,” or both. When collateral circulation regresses functionally after reperfusion of the recipient coronary artery, it takes several minutes before preexisting collateral channels open completely after coronary reocclusion (). This “functional” regression depends on the interval between coronary occlusions.
Studies in dogs have demonstrated divergent results in anatomic regression of collateral vessels. Eckstein () reported that a significantly enhanced collateral function stimulated by severe anemia regressed with the correction of anemia. In contrast, Khouri et al. () observed no anatomic regression of well developed collateral vessels. When the coronary artery was reoccluded after 3 to 90 days of reperfusion, the intracoronary pressure at the distal site of the occluder and the retrograde flow increased progressively to the same level as during the coronary occlusion just before reperfusion. We have also shown () that the newly developed collateral vessels serve as significant blood-conveying conduits even after 15 weeks of reperfusion. The difference among reports may be at least partly due to the extent of collateral growth. The stimulus of anemia may be much weaker than that of coronary occlusion. Thus, it is likely that incompletely matured collateral vessels may be prone to undergo anatomic regression. Yamakado et al. () described a patient with acute myocardial infarction presumably due to the anatomic regression of previously well developed collateral channels; this regression was demonstrated angiographically within ∼1 month after successful PTCA.
3.4 Study limitations.
There are several limitations to our study. 1) Although we used ST segment shifts in the surface ECG to evaluate collateral function during coronary occlusion, the measurement of coronary artery wedge pressure ([10, 16]), which correlates well with collateral flow, appears to be more appropriate for the estimation of collateral circulation. 2) Collateral function may have regressed as a result of PTCA-induced damage to arteries receiving collateral circulation (). However, in our patients there was no large dissection responsible for decreasing collateral flow during initial and repeat PTCA. 3) Repeat PTCA was not conducted in patients without coronary restenosis (diameter narrowing ≤50%) because balloon injury might provoke restenosis. Evaluation of collateral function in these patients would have allowed comparison of collateral regression with that in our group B patients. 4) Because we evaluated collateral function at 1 min of balloon occlusion, we cannot easily determine whether lack of collateral flow at this time was due to anatomic or functional regression.
3.5 Clinical implications.
Our data show that collateral growth and regression are dependent on flow grade of the culprit lesion and are a dynamic process of collateral recruitment and vascular remodeling. Our findings also demonstrate that PTCA of a moderately severe recurrent lesion may be not as well tolerated as the initial intervention if the original lesion was total or subtotal. Because the severity of ischemic insult mainly depends on the extent of collateral perfusion to the area supplied by a completely occluded major coronary artery or coronary artery bypass graft, it is important to determine the presence or absence of collateral vessels. We believe that in the near future, complete understanding of the exact mechanisms of collateral growth and regression will help to establish a new therapeutic strategy for patients with coronary artery disease.
We thank Kumiko Tsuru and Yoko Yamamoto for the preparation of our manuscript.
☆ This study was supported by Grant-in-Aid for Scientific Research (C) 07670777 from the Ministry of Education, Science and Culture, Tokyo, Japan.
- percutaneous transluminal coronary angioplasty
- Thrombolysis in Myocardial Infarction
- Received May 1, 1996.
- Revision received October 31, 1996.
- Accepted November 12, 1996.
- The American College of Cardiology
- Sasayama S,
- Fujita M
- Rentrop KP,
- Cohen M,
- Blanke H,
- Phillips R
- Cohen M,
- Rentrop KP
- Deutsch E,
- Berger M,
- Kussmaul WG,
- Hirshfeld JW Jr.,
- Herrmann HC,
- Laskey WK
- Cribier A,
- Korsatz L,
- Koning R,
- et al.
- Fujita M,
- Ikemoto M,
- Kishishita M,
- et al.
- Chilian WM,
- Mass HJ,
- Williams SE,
- Layne SM,
- Smith EE,
- Scheel KW
- Cohen M,
- Sherman W,
- Rentrop KP,
- Gorlin R
- Fujita M,
- McKown DP,
- McKown MD,
- Franklin D
- Eckstein RW
- Khouri EM,
- Gregg DM,
- McGranahan GM Jr.