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J Am Coll Cardiol, 2003; 42:219-225, doi:10.1016/S0735-1097(03)00624-7 © 2003 by the American College of Cardiology Foundation |
* Clinic for Internal Medicine III, Friedrich-Schiller-University, Jena, Germany
Manuscript received December 19, 2002; revised manuscript received March 19, 2003, accepted April 3, 2003.
* Reprint requests and correspondence: Dr. Gerald S. Werner, Klinik für Innere Medizin III, Friedrich-Schiller-Universität, Erlanger Allee 101 D-07740, Jena, Germany.
gerald.werner{at}med.uni-jena.de
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BACKGROUND: Collaterals may have an adverse effect on TVF.
METHODS: In 111 consecutive patients, a CTO (duration >2 weeks) was successfully recanalized with stent implantation. Collateral function was assessed by intracoronary Doppler flow velocity and pressure recordings distal to the occlusion. Baseline collateral function was determined before the first balloon inflation, and recruitable collateral function after stenting during a balloon reocclusion. Finally, the coronary flow velocity reserve (CFVR) and the fractional flow reserve (FFR) were measured.
RESULTS: Angiographic follow-up after 5 ± 1.4 months in 106 patients showed a reocclusion in 17% and a restenosis in 36%. The major determinants of TVF were the stent length (p < 0.01) and number of implanted stents (p < 0.01). No difference was observed in baseline or recruitable collateral function between patients with and without TVF; 52% of patients had a CFVR 
2.0, and only 18% a CFVR 2.5 after percutaneous transluminal coronary angioplasty, but neither cutoff-value predicted TVF. A low FFR discriminated patients with reocclusion (0.81 ± 0.07 vs. 0.86 ± 0.08, p < 0.05) but not with restenosis (0.87 ± 0.06).
CONCLUSIONS: This study showed that there is no relation between a well-developed collateral supply and the risk of TVF in recanalized CTOs. This was rather determined by the stented segment length. There was also no adverse effect of the frequently observed impaired CFVR on TVF, whereas a low FFR was associated with a higher risk of reocclusion.
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The relevance of procedural parameters such as stent length and the angiographic result had been shown to be major determinants of target vessel failure (TVF) in CTOs (23). However, the potential influence of collateral and coronary hemodynamics had not been assessed previously. This can be done through the application of microsensor wires to assess intracoronary flow and pressure before and during percutaneous transluminal coronary angioplasty (PTCA) (24). The present study should test the hypothesis of a possible confounding effect of collateral function and coronary hemodynamics on restenosis and reocclusion in a nonselected, prospective consecutive series of successfully recanalized CTOs.
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2.5 mm) scheduled for PTCA between January 1999 and April 2002 at the University Hospital at Jena, Germany, were included in this study if the duration of the occlusion was >2 weeks and if there were spontaneously visible collaterals. The duration of CTOs was 0.5 to 337 months (median 4 months). The indication for PTCA was either chest pain related to the CTO or persistent occlusion after a prior myocardial infarction (MI). Of 138 CTOs, 117 were successfully recanalized, and 111 could be studied according to the study protocol described below. Angiographic follow-up was available in 106 patients, who constitute the study group. The study was approved by the university’s ethics committee, and written informed consent obtained. Angioplasty procedure. The recanalization was done as previously described (25). All patients were being treated with aspirin (100 mg) and received clopidogrel (75 mg) for four weeks starting on the day of the procedure. After the lesion was crossed by a guidewire, an exchange catheter (Transit, Cordis, Miami, Florida) or a low profile over-the-wire balloon catheter (Bandit, Scimed, Boston Scientific Corporation, Natick, Massachusetts) was advanced distal to the occlusion. Then the guidewire was exchanged for a 0.014-inch Doppler guidewire (FloWire, Endosonics/Jomed, Rancho Cordova, California) to record Doppler flow velocity distal to the occlusion. Then the Doppler wire was exchanged for a 0.014-inch pressure wire (PressureWire, RADI Medical Systems AB, Uppsala, Sweden) to record coronary pressure distal to the occlusion (POccl).
After the Doppler and pressure recordings, the occlusion was dilated and treated by stent implantation. The stent expansion was optimized according to angiographic criteria with a balloon-to-artery ratio of at least 1.1.
Protocol for intracoronary doppler and pressure recordings of collateral flow. The angiographic anatomy distal to the occlusion was visualized by a contrast injection through the exchange catheter to aid the positioning of the sensor wires. The Doppler wire was advanced 1 to 2 cm distal to the occlusion in a segment without a focal stenosis to a position where a clearly defined and stable velocity signal could be recorded. These Doppler recordings of baseline collateral flow were done before the first balloon inflation. The absence of antegrade flow was ascertained by lack of distal opacification after proximal contrast injection and no interference with the distal Doppler signal. All Doppler flow signals were measured manually as described before (25,26). Depending on the relative position of the Doppler wire to the collateral inflow, the detected flow could be antegrade, retrograde, or bidirectional, and, therefore, the absolute values were used for further computation of the average peak velocity (APV).
For the pressure recording, care was taken to position the transducer at the same spot where the Doppler wire tip had been located. The mean pressure of POccl and the aortic pressure (PAo), which was obtained through the fluid filled 6F or 7F guiding catheter, were used for further computation. A collateral pressure index (CPI) was calculated (27). The formula includes the central venous pressure (CVP): 
. In most patients CVP was not measured directly and substituted in the formula by 10 mm Hg. This was based on 24 patients with invasive measurement of CVP of 10 ± 3 mm Hg, which did not change significantly during balloon reocclusion.
In 85 patients, recruitable collateral function was reassessed at the end of the PTCA during a balloon inflation, with the last balloon used for the stent expansion. The identical location of the Doppler wire for all recordings was ascertained by fluoroscopy on two orthogonal planes with only minimal variations allowed to optimize the Doppler signal. Likewise, the pressure recording was repeated during a balloon reocclusion.
Functional assessment by doppler and pressure recordings after recanalization. After the PTCA, the Doppler wire was positioned distal to the stented site with a distance to side branches of at least 5 mm. At this position the antegrade APV was recorded. When the Doppler signal was stable, 20 to 40 µg of adenosine were injected rapidly, intracoronary, and the maximum increase of flow velocity was recorded to calculate the coronary flow velocity reserve (CFVR) as the ratio of hyperemic and baseline antegrade APV. The adenosine injection was repeated three times and averaged for further analysis.
Finally, the pressure wire was used to calculate the fractional flow reserve (FFR) at the end of the PTCA (28). The wire was positioned about 1 cm distal to the stented lesion. Intracoronary distal pressure (PD) and PAo were recorded on an identical scale at a speed of 10 mm/s. Particular care was taken to avoid artifacts by the guiding catheter, the pressure transducer position, and the selective intracoronary injection of 20 to 40 µg of adenosine (29). A simplified formula for myocardial 
was used (30). The measurement of FFR was repeated three times and averaged for further analysis.
Quantitative coronary angiography. The collateral supply was graded according to Rentrop et al. (31). Pre-interventional angiograms showed either collateral flow grade 2 (partial epicardial filling of the occluded artery) or 3 (complete epicardial filling of the occluded artery). The LV function at baseline and at follow-up was analyzed using a standard software program (LVA 4.0, PieMedical Imaging, Maastricht, the Netherlands). The centerline method was used to assess regional LV function in the territory of the recanalized artery by the regional wall motion severity index (SD/chord) (32).
The final result of stent implantation (reference diameter, minimum lumen diameter [MLD], residual stenosis, and lesion length) was assessed by quantitative angiography using the smallest diameter from two orthogonal planes (QCA 4.0, PieMedical Imaging, Maastricht, the Netherlands). Quantitative angiography was repeated at follow-up, and a restenosis was defined as an MLD in the recanalized artery of <50% of the reference diameter.
Statistics. Data are given as the mean value ± SD if not indicated otherwise. Group differences of continuous variables were evaluated by analysis of variance (ANOVA) and, in case of a significant result followed, by an LSD post-hoc test. Group differences of categorical variables were tested by a chi-squared test. A paired t test was used to compare changes of LV function during follow-up. A logistic regression analysis was done to assess determinants of TVF. A level of p < 0.05 was considered significant. All calculations were done with SPSS for Windows (Version 10.05, SPSS Inc., Chicago, Illinois).
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0.75 was observed in 44%, indicating the presence of microvascular disease. Both a reduced CVR and FFR was observed in 4% as evidence of diffuse atherosclerosis. Patients with microvascular disease had a TVF of 47%, which was even slightly but insignificantly lower than the TVF of 58% in patients with a CFR 2.0 and an FFR 0.75 (p = 0.51).
A high CFVR 2.5 was observed in only 18% of patients with a TVF of 56%, which was similar to the TVF of 51% in patients with a CFVR <2.5 (p = 0.93). There was also no difference in CFVR with respect to patients with reocclusion. In contrast, the FFR was significantly lower in patients with a reocclusion, but there was no difference between patients with and without restenosis (Fig. 4). An FFR 0.9 was observed in 41% of patients. These patients had a similar TVF of 55.6% but a lower reocclusion rate (5.6%) than patients with an FFR <0.9, a TVF of 53.8%, but a reocclusion rate of 21.2%. An FFR 0.95 was achieved in only 12.5% of patients, none of whom had a reocclusion, with a TVF of 36%, compared with 53% in patients with an FFR <0.95 (p = 0.25).
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Relation between LV function and TVF. The baseline global and regional LV function was not significantly different in patients with and without TVF. Despite the high rate of restenosis, both the LV ejection fraction and regional wall motion severity index improved similarly in patients with restenosis and without TVF. However, LV function did not improve in patients with reocclusion (Fig. 5).
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TVF in chronic occlusions. This study was done in an unselected cohort of consecutive patients with a successful recanalization of a CTO. Despite the routine use of stents, the TVF was high compared with some of the randomized studies in CTOs. However, most of these studies had applied exclusion criteria regarding reference vessel diameter (>2.5 mm), and technical feasibility, which resulted in the exclusion of more than 50% of the screened patients (8,9,11,33). One study with less restrictive inclusion criteria had similar recurrence rates (10). Furthermore, the length of the lesion was no exclusion criterion, and the number of stents used was consequently high. Lesions treated with a single stent had a lower TVF than those treated with multiple stents and were comparable to the results of the aforementioned randomized studies (8,9,33).
Collaterals and the risk of TVF. Previous reports suggested that well-preserved collaterals are one of the factors responsible for the high TVF in CTOs (17,18). This was explained by an increased distal coronary pressure and concurrent flow via persistent collaterals in analogy to observations after bypass surgery of a progress in lesion severity in the native bypass receiving coronary artery (34,35). With native collaterals, however, concurrent collateral flow is much lower than that provided by a bypass graft. Previous studies that suggested an adverse effect of collaterals on TVF used the angiographic appearance of collaterals as a criterion of collateral function, and they compared nonocclusive and occlusive lesions (17,18). There is no doubt that CTOs have a better collateral supply, which may serve as an explanation for the high TVF rate, but there are also considerable differences in the morphology of a CTO lesion with higher plaque load than a nonocclusive lesion, which may influence the risk of TVF (13–15).
Therefore, we looked exclusively at CTOs with a wide variability of collateral supply to study the influence of concurrent flow via collaterals on the risk of restenosis and reocclusion as demonstrated by the invasive assessment of collateral flow and pressure. We assessed both baseline and recruitable collateral function, the latter being the relevant source of concurrent flow after recanalization. Despite the use of a physiologic measure of collateral supply, which is superior to angiographic methods for the assessment of collaterals (36,37), we observed no adverse effect of a well-developed collateral system on TVF in CTOs.
Collateral function after recanalization of CTOs. Collateral function is lost after recanalization of CTOs (25,26), which becomes clinically evident with an MI rate of up to 6% within six months after PTCA (8–11). As this rate is lower than the actual incidence of reocclusion, either some CTOs remain protected from ischemic events by a residual collateral function (38) or collaterals recover during a gradual reocclusion. In our study the high rate of reocclusion was not associated with MI, but with recurrence of clinical symptoms in half of the patients with reocclusion. This is indirect evidence that the reocclusion occurred gradually and allowed for recruitment of collaterals sufficient to prevent an MI (39).
Coronary flow reserve and FFR and the risk of TVF. In nonocclusive lesions an impaired CFVR after PTCA identified patients with a high TVF and adverse event rate during long-term follow-up, but it was unclear whether it was of similar relevance in CTOs (22,40). The incidence of microembolization during PTCA is a potential cause for this observation (41). However, we could recently demonstrate that the incidence of troponin and creatinine kinase increase after recanalization of a CTO was <10% and did not account for the impaired CFVR in almost half of all patients (42). The impaired CFRV was not associated with a higher risk of TVF in CTOs. Thus, criteria based on CVFR for the guidance of balloon angioplasty for nonocclusive lesions are not applicable to CTOs with routine stenting (22).
In contrast, the recording of the FFR provided information that could be relevant for the PTCA. A low FFR after recanalization was associated with a high risk of reocclusion. As a reocclusion impedes LV recovery, every effort should be made to reduce its incidence, and FFR might be a valuable tool for this purpose. In a recently reported large registry of nonocclusive lesions, an FFR 0.90 predicted a low incidence of major adverse cardiac events (43). In CTOs we achieved an FFR 0.90 in only 41% of patients, with no difference in TVF. However, an FFR 0.95 in 12.5% of patients tended to be associated with a lower TVF. Even though this was not a significant effect, it may indicate that a more "aggressive optimization" guided by FFR should be tried to further improve the outcome. Whether this is a feasible approach, given the often diffuse atherosclerosis of the occluded artery, remains to be proven by a future study.
Study limitations. Studies in CTOs often contain a limited number of patients because CTOs constitute <10% of all patients undergoing a PTCA and the primary success rate is about 70%. The present study represents a large single-center series of CTOs with the additional strength of a prospective and consecutive patient inclusion and a sole exclusion criteria of a reference diameter <2.5 mm. Despite the limited number of patients, the high percentage of TVF provides a statistical power for a meaningful analysis.
Limitations of the invasive assessment of collateral function in CTOs by Doppler and pressure wires had been discussed in detail before (25,26). In principal, vascular flow is assessed by Doppler velocimetry, not by volume flow measurement. Specific care was taken for exact positioning of the pressure and Doppler wire under fluoroscopic control using angiographic landmarks. Furthermore, the CPI, which as a pressure-derived index is less sensitive to the exact wire tip position, also showed no difference between patients with and without TVF, further corroborating the Doppler findings.
Clinical implications. The presence of well-developed collaterals and the high prevalence of a low CFVR after PTCA does not influence the risk of lesion recurrence after recanalization of CTOs and should not prevent us from attempting a recanalization. The improvement of LV function can be considerable despite the frequent incidence of restenosis, which might be targeted successfully by drug-eluting stents (44). Still, the incidence of reocclusion is a specific problem of CTOs that impedes LV recovery. Target vessel failure may be reduced by limiting the number of stents, and FFR might be useful for the guidance of the angioplasty to avoid reocclusions. Such an FFR-guided approach with the goal of limiting the number of stents should be tested prospectively.
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