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Collaterals and the recovery of left ventricular function after recanalization of a chronic total coronary occlusion
Interventional Cardiology
Collaterals and the recovery of left ventricular function after recanalization of a chronic total coronary occlusion Gerald S. Werner, MD, Ralf Surber, MD, Friedhelm Kuethe, MD, Ulf Emig, MD, Gero Schwarz, MD, Philipp Bahrmann, MD, and Hans R. Figulla, MD Jena, Germany
Background A good collateral function in patients with regional myocardial dysfunction may indicate viability with the potential for left ventricular (LV) recovery after revascularization of a chronic total coronary occlusion (CTO). Methods
A CTO (duration N 2 weeks) was successfully recanalized in 126 patients. During this procedure, the collateral function was assessed before the first balloon inflation by intracoronary Doppler and pressure wires. Collateral function indexes were calculated. Left ventricular function was assessed by the LV ejection fraction (LVEF) and the wall motion severity index (WMSI [SD/chords]). A repeat angiography was available in 119 patients after 4.9 F 1.4 m. An improvement of WMSI z1 SD/chord was considered significant.
Results
Left ventricular function was normal in 42%, regional dysfunction with LVEF z 0.60 was observed in 16%, and regional dysfunction with LVEF b 0.60 in 42%. The former had a better collateral function than patients with LV dysfunction. In 39% of patients with LV dysfunction, a significant myocardial recovery was observed at follow-up. The collateral function was similar in patients with and without recovery. However, patients with recovery had a lower peripheral resistance as an indicator of a better preserved microvascular integrity.
Conclusions Recovery of impaired LV function after revascularization of a CTO is not directly related to the quality of collateral function, as collateral development does not appear to require the presence of viable myocardium. However, a preserved microvascular integrity may be of relevance for myocardial recovery. (Am Heart J 2005;149:129-37.)
Despite the presence of coronary collaterals, most patients with a chronic total coronary occlusion (CTO) show various degrees of left ventricular (LV) dysfunction. The possible functional recovery and its beneficial effect on survival are the rationale for the often technically demanding attempt to recanalize a CTO.1-8 This recovery depends on the presence of hibernating myocardium, and of collaterals to provide a minimum metabolic supply.9,10 In the absence of collaterals, no viable myocardium can be expected,11,12 but there is dispute whether the extent of collaterals is directly related to viability and functional recovery.2,13,14 The collateral supply in
From the Clinic for Internal Medicine I, Friedrich-Schiller-University Jena, Jena, Germany. Submitted August 8, 2003; accepted April 19, 2004. Reprint requests: Gerald S. Werner, MD, Klinik fu¨r Innere Medizin I, Friedrich-SchillerUniversita ¨ t, Erlanger Allee 101, D-07740 Jena, Germany. E-mail: [email protected] 0002-8703/$ - see front matter n 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2004.04.042
these studies was assessed by angiography, which is only a semiquantitative evaluation of collaterals and inferior to the recently available invasive assessment of collateral function.15-17 Dysfunctional myocardium distal to a CTO can be the result of an acute myocardial infarction (MI) with irreversible myocardial damage and a variable border zone of hibernating and stunned myocardium. We could show by invasive assessment of collaterals that it takes about 3 m after an acute MI for collaterals to reach their full functional capacity.18,19 Dysfunctional hibernating myocardium can be also the result of an occlusion with already developed collaterals, which could prevent an acute MI but were not functionally competent to uphold full nutritional supply. On the basis of these different circumstances of collateral development, our hypotheses was that collateral function could be a predictor of myocardial recovery. Furthermore, we wanted to analyze in a consecutive, unselected dreal worldT cohort of patients with CTOs the potential of LV recovery after successful revascularization. The end point of our study was the recovery
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Figure 1
Examples of regional (1) and global (2) recovery of LV function after recanalization of a CTO. Case 1: Regional recovery in a 69 year old female with an occluded left anterior descending artery (prior MI 11 months before), single vessel disease. LVEF at baseline 0.65 with anterior WMSI 3.3. No restenosis 5 months after recanalization, LVEF 0.73, and normal WMSI. Case 2: Regional and global recovery in a 57 year old male with an occluded right coronary artery (prior MI 10 weeks before), single-vessel disease. At baseline LVEF 0.19, inferior WMSI 3.1; 5.5 months after recanalization LVEF 0.82, normalized WMSI despite a focal restenosis which has redilated.
of function after revascularization as the ultimate proof of the presence of viable myocardium.
Methods Patients The study group consisted of 126 consecutive patients with successful recanalization of a CTO out of a total of
168 patients in whom the procedure was attempted between August 1999 and February 2003. The inclusion criteria were (1) duration of the occlusion N2 weeks, (2) TIMI 0 coronary flow before percutaneous luminal coronary angioplasty (PTCA), (3) presence of spontaneously visible collaterals, and (4) passage of the occlusion with a probing catheter and recording of collateral function parameters without prior balloon dilatation. We excluded 2 patients with successful recanalization in whom Thrombolysis in
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Table I. Clinical characteristics of patients with successful recanalization of a CTO and either a normal, a regionally impaired, or a globally impaired LV function LV function Patients Age (y) Duration of occlusion (m) Duration N 3 m (%) Previous MI (%) Diabetes (%) Hypertension (%) CCS (1/2/3/4) NYHA (0/1/2/3/4) Number of diseased vessels (1/2/3) Occluded vessel (RCA/LCX/LAD) LVEF WMSI (SD/chord) Wall motion extent (chords)
Normal
Regional dysfunction
Global dysfunction
53 64.0 F 10.1 23 F 52 64 43 32 83 1/17/35/0 1/31/20/1/0 24/20/9 31/3/19 0.74 F 0.10 0.61 F 0.67 2.2 F 3.2
20 65.0 F 10.2 8 F 20 45 70* 25 80 2/10/7/1 1/8/9/2/0 7/11/2 14/2/4 0.67 F 0.06y 2.63 F 0.39z 15.9 F 6.4z
53 62.9 F 9.7 18 F 39 43* 85z 33 63* 2/27/23/0* 0/11/21/20/0z§ 23/18/12 27/1/25 0.41 F 0.12zO 3.07 F 0.67z§ 22.5 F 10.0zO
CCS, Canadian Cardiovascular Society angina score; NYHA, New York Heart Association heart failure score; LCX, left circumflex coronary artery; LAD, left anterior descending coronary artery. *Comparison with normal LV function, P b .05. yComparison with normal LV function, P b .01. zComparison with normal LV function, P b .001. §Comparison with regional dysfunction group, P b .05. OComparison with regional dysfunction group, P b .001.
Table II. Collateral hemodynamics in patients with a CTO and either a normal, a regionally impaired, or a globally impaired LV function LV function Patients Rentrop grade (2 or 3) Heart rate (beat/min) Mean aortic pressure (mm Hg) LV end-diastolic pressure (mm Hg) APV (cm/s) Collateral pressure index Collateral flow velocity index Collateral resistance index (mm Hg/cm per second) Peripheral resistance index (mm Hg/cm per second)
Normal
Regional dysfunction
Global dysfunction
53 5/48 67 F 12 101 F 20 12.6 F 7.0 12.4 F 6.1 0.41 F 0.12 0.47 F 0.28 6.6 F 5.1 4.9 F 2.7
20 4/16 68 F 14 101 F 14 19.6 F 8.1y 11.6 F 6.9 0.38 F 0.12 0.48 F 0.34 6.9 F 3.6 4.7 F 2.6
53 16/37 70 F 12 101 F 17 15.6 F 9.7 9.5 F 5.1* 0.38 F 0.12 0.39 F 0.26 9.4 F 7.8* 5.9 F 4.5
*Comparison with normal LV function, P b .05. yComparison with normal LV function, P b .01.
Myocardial Infarction flow grade ( TIMI ) 3 flow could not be restored. One hundred three of 126 patients had been included in previous studies on collateral physiology from our laboratory.18-20 The study had been approved by the institutional review board. All patients were scheduled for a repeat angiography after 4 to 6 m. During follow-up, 2 patients died, 2 patients had a subacute stent thrombosis, and 3 declined a repeat angiography, the remaining 119 patients underwent an angiography at follow-up.
Angioplasty procedure The recanalization was performed via the femoral approach using 6 or 7F guiding catheters. All patients received a bolus of 10,000 IU of heparin, they were on aspirin (100 mg), and
received clopidogrel (75 mg) for 4 weeks. Stents were implanted in all occlusions to cover the lesion site, with multiple stents in 59.5% of lesions (1.9 F 0.9 stents per lesion). The stents were implanted with a balloon/artery ratio z1.1. All patients were monitored continuously by electrocardiogram (EKG) for 24 hours, and troponin I (TnI) and creatinine kinase (CK) were measured between 12 and 24 hours after the procedure.
Assessment of collateral function before recanalization The recanalization was done as previously described.18,21 After the lesion was crossed by a guide wire, an exchange catheter or a low profile over-the-wire balloon catheter was passed distal to the occlusion. All subsequent measurements were done before the occlusion site was dilated by a
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132 Werner et al
Figure 2
Figure 3
Impact of recanalization of a CTO on LV function. Patients are categorized according to LVEF and WMSI at baseline. The numbers in boxes represent the patients in these categories before recanalization and at follow-up, the arrows and numbers indicate the patients with changes of LV function; No fup = patients without follow-up.
balloon. The guide wire was exchanged for a Doppler wire (FloWire, Endosonics Corporation, Rancho Cordova, Calif). The wire position was documented on cinefilm. A potential problem of the basal collateral flow recording could be an unaccounted contribution of antegrade flow along the exchange catheter within the occlusive lesion. This could be ruled out in all patients by lack of contrast passage during proximal contrast injection into the recanalized artery although the exchange catheter was in place. The continuously recorded Doppler signal of collateral flow did not change during this injection. All Doppler signals were measured manually as described previously.21 Depending on the relative position of the Doppler wire to the collateral inflow, the detected flow could be antegrade, retrograde, or bidirectional; therefore, the absolute values were used for further computation. A collateral flow index was obtained as the ratio of average peak velocity (APVD) distal to the occlusion and antegrade APV recorded after completion of the percutaneous coronary intervention (PCI) at the same wire position.22 Afterwards, the Doppler wire was exchanged for a pressure wire (PressureWire, RADI Medical Systems, Uppsala, Sweden). From the ratio of the mean distal coronary pressure ( P D) and the mean aortic pressure ( P Ao), a collateral pressure index was calculated.16,22 To assess the resistance of the collateral pathway, an index R Coll = ( P Ao P D)/APVD was calculated. A peripheral vascular resistance index to assess the microvasculature of the myocardium supplied by the occluded artery was calculated as R P = P D/APVD.18,23
Changes of LVEF and WMSI after recanalization of CTOs grouped according to the LV function at baseline. Note that WMSI has a negative prefix but is shown on an upward scale. Data are mean F SD. * P b .001 for change during follow-up.
Quantitative coronary angiography Coronary angiograms at baseline and at follow-up were analyzed using the CAAS II system (QCA 4.0, Pie Medical Imaging Maastricht, The Netherlands). A restenosis was defined as N50% diameter stenosis at follow-up.
Quantitative left ventriculography Biplane LV angiograms were obtained in all patients at the time of the baseline diagnostic angiography and repeated at follow-up. The LV function was analyzed using a standard software program (LVA 4.0, PieMedical Imaging). The centerline method was used to assess regional LV function in the territory of the recanalized artery by the regional wall motion severity index (WMSI [SD/chord]) and the extent of wall motion abnormalities (number of chords)24 (Figure 1).
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Table III. Clinical and angiographic characteristics of patients with improved or unchanged regional wall motion after successful recanalization of a CTO
Patients Age (y) Duration N3 m (%) Previous MI (%) Diabetes (%) Hypertension (%) Incidence of reocclusion Postprocedure CK/ TnI increase (%) Number of diseased vessels (1/2/3) Occluded vessel (RCA/LCX/LAD) Residual stenosis (%) Stent length (mm) Minimum luminal diameter (mm) Baseline CCS (0-4) Follow-up CCS (0-4) Baseline NYHA (0-4) Follow-up NYHA (0-4) Baseline LVEF Follow-up LVEF Baseline WMSI (SD/chord) Follow-up WMSI (SD/chord) Baseline WM extent (chords) Follow-up WM extent (chords)
Regional function improved
Regional function unchanged
26 60.6 F 9.0 46 77 31 69 4 13
41 64.0 F 9.9 49 85 27 68 17 4
8/15/3
20/11/10*
19/2/5
19/1/21*
16 F 10 25 F 12 2.3 F 0.6
14 F 10 24 F 15 2.2 F 0.4
0/1/11/13/1 2/15/7/2/0b 1/9/13/3/0 4/17/5/0/0b 0.51 F 0.14 0.72 F 0.09b 3.01 F 0.56 0.76 F 0.82b 17.8 F 6.7 2.6 F 4.5b
0/3/24/14/0 6/20/12/3/0b 0/9/17/15/0 6/8/20/7/0yO 0.47 F 0.17 0.52 F 0.16bz 2.89 F 0.67 2.71 F 0.80z§ 22.2 F 10.7* 19.5 F 12.1z
RCA, Right coronary artery; LCX, left circumflex coronary artery; LAD, left anterior descending coronary artery. *Comparison between groups, P b .05. yComparison between groups, P b .01. zComparison between groups, P b .001. §Changes from baseline to follow-up within groups, P b .05. OChanges from baseline to follow-up within groups, P b .01. bChanges from baseline to follow-up within groups, P b .001.
Definition of study groups Patients with an LV ejection fraction (LVEF) z 0.60 and a WMSI z 2 were considered to have well-preserved LV function in the presence of a CTO. Patients with an LVEF z 0.60 and a WMSI b 2 had isolated regional dysfunction, and patients with both LVEF b 0.60 and a WMSI b 2 had global dysfunction. For the follow-up analysis, patients with regional and global LV dysfunction were combined and subdivided according to the change of WMSI: an improvement of z1 was considered a significant change.
Statistics Data are given as the mean value F SD. Changes between baseline and follow-up measurements were evaluated by a paired t test. Student unpaired t test or Fisher exact test, when appropriate, was used to analyze differences between groups. Differences of parameters within groups during follow-up were assessed by repeated measures analysis of variance. A probability level of P b .05 was considered significant. The calculations were done on a personal
Table IV. Collateral hemodynamics in patients with improved or unchanged regional wall motion after successful recanalization of a CTO Regional function improved Patients Rentrop grade (2 or 3) Heart rate (1/min) Mean aortic pressure (mm Hg) LV end-diastolic pressure (mm Hg) APV (cm/s) Collateral pressure index Collateral flow velocity index Collateral resistance index (mm Hg/cm per second) Peripheral resistance index (mm Hg/cm per second)
Regional function unchanged
26 8/18 69 F 13 105 F 15 17.5 F 9.0 10.0 F 5.0 0.34 F 0.12 0.40 F 0.24 8.4 F 4.6
41 10/31 70 F 13 99 F 16 16.2 F 9.9 10.1 F 6.2 0.41 F 0.11* 0.37 F 0.39 9.0 F 8.4
4.5 F 2.7
6.7 F 4.9*
*Comparison between groups, P b .05.
computer using SPSS for Windows (Version 10, SPSS Inc, Chicago, Ill).
Results Clinical data and LV function before recanalization Of the 126 patients initially entered in this study, 53 (42%) had a normal (WMSI = 0, n = 26) or slightly impaired regional function (WMSI N 2, n = 27), 20 patients (16%) had a severe regional dysfunction (WMSI b 2) with a normal LVEF (z0.60), and 53 patients (42%) had a depressed global and regional LV function (Table I). Patients with normal LV had less often a history of MI, and more often an occlusion z3 m. Clinical symptoms of heart failure were more pronounced in patients with global LV dysfunction, whereas angina was more severe with normal LV function. The collateral function was better in patients with normal LV function as compared to those with globally impaired LV function (Table II). However, there was no significant difference between patients with normal and regionally impaired LV function, but the latter had a higher LV end-diastolic volume with possible adverse influence on collateral perfusion. Clinical and angiographic follow-up The mean follow-up period was 4.9 F 1.4 m. Of the 119 patients with angiographic follow-up, a reocclusion was observed in 20 patients (17%) and a restenosis defined as N50% diameter stenosis in 42 patients (35%). A target lesion revascularization was done in 49%. In the whole group, LVEF improved by about 10% during follow-up from 0.60 F 0.19 to 0.67 F 0.16 ( P b .001) and WMSI from 1.92 F 1.32 to 1.30 F 1.28 ( P b .001). The changes in LV function during follow-up are
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Figure 4
largest improvement of LVEF by 25% was observed in patients with global LV dysfunction at the time of recanalization (Figure 3). In some of these patients, a reversal of LV remodeling affecting remote regions was observed (Figure 1).
Comparison of patients with and without recovery of LV function Among patients with follow-up angiography, 67 had an initially impaired regional and/or global LV dysfunction. Of these, 26 (39%) showed a significant improvement of regional function (WMSI increase z1), whereas 41 (61%) showed no change. Patients with less extensive coronary artery disease and a right coronary artery occlusion recovered more often than patients with a LAD occlusion, whereas history of diabetes, hypertension, prior MI, and occlusion duration did not influence LV recovery (Table III). Even in patients without significant regional LV recovery, clinical symptoms improved slightly, and LVEF increased by about 10%. Late occlusions were more frequent in patients without improvement as compared to those with improvement, but the overall target vessel failure was similar in both groups. Procedural characteristics were similar in both groups. Furthermore, only patients with TIMI 3 flow were included in this follow-up study. A postprocedural increase of CK and/or TnI above the upper limit of normal was observed in 11 of 126 patients (8.7%). This had no adverse effect on LV recovery (Table III). There was no difference in Doppler parameters of collateral function between patients with and without LV recovery (Table IV). The pressure-derived collateral index was lower in patients with recovery as compared to those without recovery due to a lower P D (Figure 4). However, this did not indicate an impaired collateral function, as the R Coll was similar in both groups. It was probably due to a difference in microvascular integrity, as the R P was higher in patients without LV recovery. A subanalysis on the basis of the history of prior Q wave MI showed a trend that 35 patients with MI and no recovery had the highest R P (6.5 F 5.5 mm Hg/cm per second), whereas 6 patients without MI and with recovery had the lowest R P (3.4 F 2.0 mm Hg/cm per second, P = .13). Collateral pressure index (A), collateral resistance index (B) and peripheral vascular resistance index (C) in patients with impaired regional function with and without recovery during follow-up.
summarized in Figure 2 with the patients grouped according to their regional and/or global LV function. There was one patient with new regional dysfunction who had developed a reocclusion at follow-up. The
Discussion This study showed that considerable recovery of LV function after recanalization of a consecutive cohort of patients with CTO can be expected, but this is independent of invasively determined parameters of collateral function. Obviously, coronary collateral development is not closely linked to myocardial viability but is rather the result of the recruitment of preexistent interarterial connections. On the other hand, we found
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evidence that regional LV recovery requires a preserved microcirculation.
Recovery of LV function after recanalization of a CTO Recovery of LV function in chronically ischemic myocardium depends on the presence of hibernating or stunned but viable myocardium.25 Left ventricular recovery starts within 1 to 4 weeks after revascularization and is usually complete within 3 m.26-28 Although these studies were done after surgical revascularization, they are probably applicable also to percutaneous revascularization. We observed an overall increase of LVEF of 10% during follow-up. The most pronounced increase occurred in patients with severely depressed LV function, in accordance with previous studies.5,6 We also confirmed that the history of MI, the duration of the occlusion, and the incidence of the nonocclusive restenosis had no influence on LV recovery, whereas reocclusion had an adverse influence on LV recovery.2-5 Collaterals and recovery of LV function There are conflicting reports on the influence of collaterals on the preservation of LV function and its relation to LV recovery.9,11,29-31 Studies using the angiographic grading observed no relation of LV recovery with collaterals,2,13,14 a weak relation,6 or a close relation.12,32 Quantitative studies using nuclear imaging showed that myocardial perfusion at rest was similar in normal and dysfunctional segments without correlation to LV recovery.33,34 The main problem of these studies is the semiquantitative angiographic grading of collaterals. The invasive assessment using Doppler and pressure microsensors is superior to the angiographic assessment.15-17,31 In a selected group of patients with normal LV function and no prior MI, collateral function indexes on the basis of distal coronary flow velocity or pressure may be exchangeable,22 but in patients with CTOs, there is no close correlation between pressure and flow velocity recordings.18 In CTOs with frequently impaired LV function and prior MI, the best approach to describe collateral function is to obtain both pressure and flow velocity recordings and calculate indexes of collateral and peripheral vascular resistance. We found no difference in collateral function in patients whose impaired regional LV function showed a significant recovery as compared to those without recovery. It appears that the presence of myocardium with preserved potential for functional recovery, that is, preserved viability, is not mandatory for the development of coronary collaterals in patients with severe LV dysfunction. These collaterals develop as a result of a pressure gradient across the occlusion that recruit preformed interarterial connections.35-37 The presence of these preformed interarterial connections was
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recently shown in about 20% of a study population without coronary artery disease,38 and is also confirmed by the recruitability of collaterals in 20% of patients with long-term patency of CTOs.20
Peripheral resistance and LV recovery Recent findings by myocardial contrast echocardiography suggest that an intact microvasculature has a favorable effect on the functional recovery of myocardium.39 The R P is a measure of microvascular resistance in the myocardium distal to a CTO.23 In the presence of a comparable collateral supply, R P was lower in patients with subsequent LV recovery due to a lower peripheral pressure. One may speculate that a higher pressure and resistance were caused by more fibrous tissue and/or a rarefied microvasculature in the scarred myocardium of patients without LV recovery. Consequently, patients with recovery would have a better preserved microvasculature and an R P similar to that in patients with CTO and normal LV function. Indeed, we observed the highest R P in patients with prior Q wave MI and no recovery, and the lowest in patients without MI and subsequent recovery. Limitations The present study is one of the largest to address the influence of collaterals on LV recovery in a consecutive patient cohort, and it is the first to use an invasive assessment of collateral function. Even with inherent limitations of this invasive method,18,19,21 it is superior to the angiographic quantification of collaterals.40 In contrast to some of the previous studies using angiography, we included only patients with angiographically visible collaterals of grades 2 and 3. We did not address the influence of angiographically poorly visible or undetectable collaterals, which is of relevance when studying patients immediately after an acute MI.41,42 The scope of this study were patients with CTOs as a well-defined model for chronic myocardial ischemia. The identification of hibernating dysfunctional myocardium is the goal of noninvasive techniques that achieve a positive predictive accuracy of around 70%.43 In the present study, we did not attempt to compare methods for the detection of hibernating myocardium with invasive measures of collateral function. Instead, we used functional recovery as the ultimate gold standard and clinical end point for our analysis. Clinical implications The recanalization of a CTO carries the potential for a considerable improvement or even normalization of severely depressed LV function. The selection for a revascularization should not be on the basis of the quality of collateral supply, as this is not closely related to LV recovery.
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39. Shimoni S, Frangogiannis NG, Aggeli CJ, et al. Microvascular structural correlates of myocardial contrast echocardiography in patients with coronary artery disease and left ventricular dysfunction. Implications for the assessment of myocardial hibernation. Circulation 2002;106:950 - 6. 40. Seiler C, Fleisch M, de Marchi SF, et al. Functional assessment of collaterals in human coronary circulation. Semin Interv Cardiol 1998;3:13 - 20. 41. Garot J, Scherrer-Crosbie M, Monin JL, et al. Effect of delayed percutaneous transluminal coronary angioplasty of occluded coronary arteries after acute myocardial infarction. Am J Cardiol 1996;77:915 - 21. 42. Barilla` F, De Vincentis G, Mangieri E, et al. Recovery of contractility of viable myocardium during inotropic stimulation is not dependent on an increase of myocardial blood flow in the absence of collateral filling. J Am Coll Cardiol 1999;33:697 - 704. 43. Schinkel AFL, Bax JJ, Geleijnse ML, et al. Noninvasive assessment of ischaemic heart disease: myocardial perfusion imaging or stress echocardiography? Eur Heart J 2003;24:789 - 800.
Collaterals and the recovery of left ventricular function after recanalization of a chronic total coronary occlusion Gerald S. Werner, MD, Ralf Surber, MD, Friedhelm Kuethe, MD, Ulf Emig, MD, Gero Schwarz, MD, Philipp Bahrmann, MD, and Hans R. Figulla, MD Jena, Germany
Background A good collateral function in patients with regional myocardial dysfunction may indicate viability with the potential for left ventricular (LV) recovery after revascularization of a chronic total coronary occlusion (CTO). Methods
A CTO (duration N 2 weeks) was successfully recanalized in 126 patients. During this procedure, the collateral function was assessed before the first balloon inflation by intracoronary Doppler and pressure wires. Collateral function indexes were calculated. Left ventricular function was assessed by the LV ejection fraction (LVEF) and the wall motion severity index (WMSI [SD/chords]). A repeat angiography was available in 119 patients after 4.9 F 1.4 m. An improvement of WMSI z1 SD/chord was considered significant.
Results
Left ventricular function was normal in 42%, regional dysfunction with LVEF z 0.60 was observed in 16%, and regional dysfunction with LVEF b 0.60 in 42%. The former had a better collateral function than patients with LV dysfunction. In 39% of patients with LV dysfunction, a significant myocardial recovery was observed at follow-up. The collateral function was similar in patients with and without recovery. However, patients with recovery had a lower peripheral resistance as an indicator of a better preserved microvascular integrity.
Conclusions Recovery of impaired LV function after revascularization of a CTO is not directly related to the quality of collateral function, as collateral development does not appear to require the presence of viable myocardium. However, a preserved microvascular integrity may be of relevance for myocardial recovery. (Am Heart J 2005;149:129-37.)
Despite the presence of coronary collaterals, most patients with a chronic total coronary occlusion (CTO) show various degrees of left ventricular (LV) dysfunction. The possible functional recovery and its beneficial effect on survival are the rationale for the often technically demanding attempt to recanalize a CTO.1-8 This recovery depends on the presence of hibernating myocardium, and of collaterals to provide a minimum metabolic supply.9,10 In the absence of collaterals, no viable myocardium can be expected,11,12 but there is dispute whether the extent of collaterals is directly related to viability and functional recovery.2,13,14 The collateral supply in
From the Clinic for Internal Medicine I, Friedrich-Schiller-University Jena, Jena, Germany. Submitted August 8, 2003; accepted April 19, 2004. Reprint requests: Gerald S. Werner, MD, Klinik fu¨r Innere Medizin I, Friedrich-SchillerUniversita ¨ t, Erlanger Allee 101, D-07740 Jena, Germany. E-mail: [email protected] 0002-8703/$ - see front matter n 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2004.04.042
these studies was assessed by angiography, which is only a semiquantitative evaluation of collaterals and inferior to the recently available invasive assessment of collateral function.15-17 Dysfunctional myocardium distal to a CTO can be the result of an acute myocardial infarction (MI) with irreversible myocardial damage and a variable border zone of hibernating and stunned myocardium. We could show by invasive assessment of collaterals that it takes about 3 m after an acute MI for collaterals to reach their full functional capacity.18,19 Dysfunctional hibernating myocardium can be also the result of an occlusion with already developed collaterals, which could prevent an acute MI but were not functionally competent to uphold full nutritional supply. On the basis of these different circumstances of collateral development, our hypotheses was that collateral function could be a predictor of myocardial recovery. Furthermore, we wanted to analyze in a consecutive, unselected dreal worldT cohort of patients with CTOs the potential of LV recovery after successful revascularization. The end point of our study was the recovery
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Figure 1
Examples of regional (1) and global (2) recovery of LV function after recanalization of a CTO. Case 1: Regional recovery in a 69 year old female with an occluded left anterior descending artery (prior MI 11 months before), single vessel disease. LVEF at baseline 0.65 with anterior WMSI 3.3. No restenosis 5 months after recanalization, LVEF 0.73, and normal WMSI. Case 2: Regional and global recovery in a 57 year old male with an occluded right coronary artery (prior MI 10 weeks before), single-vessel disease. At baseline LVEF 0.19, inferior WMSI 3.1; 5.5 months after recanalization LVEF 0.82, normalized WMSI despite a focal restenosis which has redilated.
of function after revascularization as the ultimate proof of the presence of viable myocardium.
Methods Patients The study group consisted of 126 consecutive patients with successful recanalization of a CTO out of a total of
168 patients in whom the procedure was attempted between August 1999 and February 2003. The inclusion criteria were (1) duration of the occlusion N2 weeks, (2) TIMI 0 coronary flow before percutaneous luminal coronary angioplasty (PTCA), (3) presence of spontaneously visible collaterals, and (4) passage of the occlusion with a probing catheter and recording of collateral function parameters without prior balloon dilatation. We excluded 2 patients with successful recanalization in whom Thrombolysis in
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Table I. Clinical characteristics of patients with successful recanalization of a CTO and either a normal, a regionally impaired, or a globally impaired LV function LV function Patients Age (y) Duration of occlusion (m) Duration N 3 m (%) Previous MI (%) Diabetes (%) Hypertension (%) CCS (1/2/3/4) NYHA (0/1/2/3/4) Number of diseased vessels (1/2/3) Occluded vessel (RCA/LCX/LAD) LVEF WMSI (SD/chord) Wall motion extent (chords)
Normal
Regional dysfunction
Global dysfunction
53 64.0 F 10.1 23 F 52 64 43 32 83 1/17/35/0 1/31/20/1/0 24/20/9 31/3/19 0.74 F 0.10 0.61 F 0.67 2.2 F 3.2
20 65.0 F 10.2 8 F 20 45 70* 25 80 2/10/7/1 1/8/9/2/0 7/11/2 14/2/4 0.67 F 0.06y 2.63 F 0.39z 15.9 F 6.4z
53 62.9 F 9.7 18 F 39 43* 85z 33 63* 2/27/23/0* 0/11/21/20/0z§ 23/18/12 27/1/25 0.41 F 0.12zO 3.07 F 0.67z§ 22.5 F 10.0zO
CCS, Canadian Cardiovascular Society angina score; NYHA, New York Heart Association heart failure score; LCX, left circumflex coronary artery; LAD, left anterior descending coronary artery. *Comparison with normal LV function, P b .05. yComparison with normal LV function, P b .01. zComparison with normal LV function, P b .001. §Comparison with regional dysfunction group, P b .05. OComparison with regional dysfunction group, P b .001.
Table II. Collateral hemodynamics in patients with a CTO and either a normal, a regionally impaired, or a globally impaired LV function LV function Patients Rentrop grade (2 or 3) Heart rate (beat/min) Mean aortic pressure (mm Hg) LV end-diastolic pressure (mm Hg) APV (cm/s) Collateral pressure index Collateral flow velocity index Collateral resistance index (mm Hg/cm per second) Peripheral resistance index (mm Hg/cm per second)
Normal
Regional dysfunction
Global dysfunction
53 5/48 67 F 12 101 F 20 12.6 F 7.0 12.4 F 6.1 0.41 F 0.12 0.47 F 0.28 6.6 F 5.1 4.9 F 2.7
20 4/16 68 F 14 101 F 14 19.6 F 8.1y 11.6 F 6.9 0.38 F 0.12 0.48 F 0.34 6.9 F 3.6 4.7 F 2.6
53 16/37 70 F 12 101 F 17 15.6 F 9.7 9.5 F 5.1* 0.38 F 0.12 0.39 F 0.26 9.4 F 7.8* 5.9 F 4.5
*Comparison with normal LV function, P b .05. yComparison with normal LV function, P b .01.
Myocardial Infarction flow grade ( TIMI ) 3 flow could not be restored. One hundred three of 126 patients had been included in previous studies on collateral physiology from our laboratory.18-20 The study had been approved by the institutional review board. All patients were scheduled for a repeat angiography after 4 to 6 m. During follow-up, 2 patients died, 2 patients had a subacute stent thrombosis, and 3 declined a repeat angiography, the remaining 119 patients underwent an angiography at follow-up.
Angioplasty procedure The recanalization was performed via the femoral approach using 6 or 7F guiding catheters. All patients received a bolus of 10,000 IU of heparin, they were on aspirin (100 mg), and
received clopidogrel (75 mg) for 4 weeks. Stents were implanted in all occlusions to cover the lesion site, with multiple stents in 59.5% of lesions (1.9 F 0.9 stents per lesion). The stents were implanted with a balloon/artery ratio z1.1. All patients were monitored continuously by electrocardiogram (EKG) for 24 hours, and troponin I (TnI) and creatinine kinase (CK) were measured between 12 and 24 hours after the procedure.
Assessment of collateral function before recanalization The recanalization was done as previously described.18,21 After the lesion was crossed by a guide wire, an exchange catheter or a low profile over-the-wire balloon catheter was passed distal to the occlusion. All subsequent measurements were done before the occlusion site was dilated by a
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132 Werner et al
Figure 2
Figure 3
Impact of recanalization of a CTO on LV function. Patients are categorized according to LVEF and WMSI at baseline. The numbers in boxes represent the patients in these categories before recanalization and at follow-up, the arrows and numbers indicate the patients with changes of LV function; No fup = patients without follow-up.
balloon. The guide wire was exchanged for a Doppler wire (FloWire, Endosonics Corporation, Rancho Cordova, Calif). The wire position was documented on cinefilm. A potential problem of the basal collateral flow recording could be an unaccounted contribution of antegrade flow along the exchange catheter within the occlusive lesion. This could be ruled out in all patients by lack of contrast passage during proximal contrast injection into the recanalized artery although the exchange catheter was in place. The continuously recorded Doppler signal of collateral flow did not change during this injection. All Doppler signals were measured manually as described previously.21 Depending on the relative position of the Doppler wire to the collateral inflow, the detected flow could be antegrade, retrograde, or bidirectional; therefore, the absolute values were used for further computation. A collateral flow index was obtained as the ratio of average peak velocity (APVD) distal to the occlusion and antegrade APV recorded after completion of the percutaneous coronary intervention (PCI) at the same wire position.22 Afterwards, the Doppler wire was exchanged for a pressure wire (PressureWire, RADI Medical Systems, Uppsala, Sweden). From the ratio of the mean distal coronary pressure ( P D) and the mean aortic pressure ( P Ao), a collateral pressure index was calculated.16,22 To assess the resistance of the collateral pathway, an index R Coll = ( P Ao P D)/APVD was calculated. A peripheral vascular resistance index to assess the microvasculature of the myocardium supplied by the occluded artery was calculated as R P = P D/APVD.18,23
Changes of LVEF and WMSI after recanalization of CTOs grouped according to the LV function at baseline. Note that WMSI has a negative prefix but is shown on an upward scale. Data are mean F SD. * P b .001 for change during follow-up.
Quantitative coronary angiography Coronary angiograms at baseline and at follow-up were analyzed using the CAAS II system (QCA 4.0, Pie Medical Imaging Maastricht, The Netherlands). A restenosis was defined as N50% diameter stenosis at follow-up.
Quantitative left ventriculography Biplane LV angiograms were obtained in all patients at the time of the baseline diagnostic angiography and repeated at follow-up. The LV function was analyzed using a standard software program (LVA 4.0, PieMedical Imaging). The centerline method was used to assess regional LV function in the territory of the recanalized artery by the regional wall motion severity index (WMSI [SD/chord]) and the extent of wall motion abnormalities (number of chords)24 (Figure 1).
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Table III. Clinical and angiographic characteristics of patients with improved or unchanged regional wall motion after successful recanalization of a CTO
Patients Age (y) Duration N3 m (%) Previous MI (%) Diabetes (%) Hypertension (%) Incidence of reocclusion Postprocedure CK/ TnI increase (%) Number of diseased vessels (1/2/3) Occluded vessel (RCA/LCX/LAD) Residual stenosis (%) Stent length (mm) Minimum luminal diameter (mm) Baseline CCS (0-4) Follow-up CCS (0-4) Baseline NYHA (0-4) Follow-up NYHA (0-4) Baseline LVEF Follow-up LVEF Baseline WMSI (SD/chord) Follow-up WMSI (SD/chord) Baseline WM extent (chords) Follow-up WM extent (chords)
Regional function improved
Regional function unchanged
26 60.6 F 9.0 46 77 31 69 4 13
41 64.0 F 9.9 49 85 27 68 17 4
8/15/3
20/11/10*
19/2/5
19/1/21*
16 F 10 25 F 12 2.3 F 0.6
14 F 10 24 F 15 2.2 F 0.4
0/1/11/13/1 2/15/7/2/0b 1/9/13/3/0 4/17/5/0/0b 0.51 F 0.14 0.72 F 0.09b 3.01 F 0.56 0.76 F 0.82b 17.8 F 6.7 2.6 F 4.5b
0/3/24/14/0 6/20/12/3/0b 0/9/17/15/0 6/8/20/7/0yO 0.47 F 0.17 0.52 F 0.16bz 2.89 F 0.67 2.71 F 0.80z§ 22.2 F 10.7* 19.5 F 12.1z
RCA, Right coronary artery; LCX, left circumflex coronary artery; LAD, left anterior descending coronary artery. *Comparison between groups, P b .05. yComparison between groups, P b .01. zComparison between groups, P b .001. §Changes from baseline to follow-up within groups, P b .05. OChanges from baseline to follow-up within groups, P b .01. bChanges from baseline to follow-up within groups, P b .001.
Definition of study groups Patients with an LV ejection fraction (LVEF) z 0.60 and a WMSI z 2 were considered to have well-preserved LV function in the presence of a CTO. Patients with an LVEF z 0.60 and a WMSI b 2 had isolated regional dysfunction, and patients with both LVEF b 0.60 and a WMSI b 2 had global dysfunction. For the follow-up analysis, patients with regional and global LV dysfunction were combined and subdivided according to the change of WMSI: an improvement of z1 was considered a significant change.
Statistics Data are given as the mean value F SD. Changes between baseline and follow-up measurements were evaluated by a paired t test. Student unpaired t test or Fisher exact test, when appropriate, was used to analyze differences between groups. Differences of parameters within groups during follow-up were assessed by repeated measures analysis of variance. A probability level of P b .05 was considered significant. The calculations were done on a personal
Table IV. Collateral hemodynamics in patients with improved or unchanged regional wall motion after successful recanalization of a CTO Regional function improved Patients Rentrop grade (2 or 3) Heart rate (1/min) Mean aortic pressure (mm Hg) LV end-diastolic pressure (mm Hg) APV (cm/s) Collateral pressure index Collateral flow velocity index Collateral resistance index (mm Hg/cm per second) Peripheral resistance index (mm Hg/cm per second)
Regional function unchanged
26 8/18 69 F 13 105 F 15 17.5 F 9.0 10.0 F 5.0 0.34 F 0.12 0.40 F 0.24 8.4 F 4.6
41 10/31 70 F 13 99 F 16 16.2 F 9.9 10.1 F 6.2 0.41 F 0.11* 0.37 F 0.39 9.0 F 8.4
4.5 F 2.7
6.7 F 4.9*
*Comparison between groups, P b .05.
computer using SPSS for Windows (Version 10, SPSS Inc, Chicago, Ill).
Results Clinical data and LV function before recanalization Of the 126 patients initially entered in this study, 53 (42%) had a normal (WMSI = 0, n = 26) or slightly impaired regional function (WMSI N 2, n = 27), 20 patients (16%) had a severe regional dysfunction (WMSI b 2) with a normal LVEF (z0.60), and 53 patients (42%) had a depressed global and regional LV function (Table I). Patients with normal LV had less often a history of MI, and more often an occlusion z3 m. Clinical symptoms of heart failure were more pronounced in patients with global LV dysfunction, whereas angina was more severe with normal LV function. The collateral function was better in patients with normal LV function as compared to those with globally impaired LV function (Table II). However, there was no significant difference between patients with normal and regionally impaired LV function, but the latter had a higher LV end-diastolic volume with possible adverse influence on collateral perfusion. Clinical and angiographic follow-up The mean follow-up period was 4.9 F 1.4 m. Of the 119 patients with angiographic follow-up, a reocclusion was observed in 20 patients (17%) and a restenosis defined as N50% diameter stenosis in 42 patients (35%). A target lesion revascularization was done in 49%. In the whole group, LVEF improved by about 10% during follow-up from 0.60 F 0.19 to 0.67 F 0.16 ( P b .001) and WMSI from 1.92 F 1.32 to 1.30 F 1.28 ( P b .001). The changes in LV function during follow-up are
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134 Werner et al
Figure 4
largest improvement of LVEF by 25% was observed in patients with global LV dysfunction at the time of recanalization (Figure 3). In some of these patients, a reversal of LV remodeling affecting remote regions was observed (Figure 1).
Comparison of patients with and without recovery of LV function Among patients with follow-up angiography, 67 had an initially impaired regional and/or global LV dysfunction. Of these, 26 (39%) showed a significant improvement of regional function (WMSI increase z1), whereas 41 (61%) showed no change. Patients with less extensive coronary artery disease and a right coronary artery occlusion recovered more often than patients with a LAD occlusion, whereas history of diabetes, hypertension, prior MI, and occlusion duration did not influence LV recovery (Table III). Even in patients without significant regional LV recovery, clinical symptoms improved slightly, and LVEF increased by about 10%. Late occlusions were more frequent in patients without improvement as compared to those with improvement, but the overall target vessel failure was similar in both groups. Procedural characteristics were similar in both groups. Furthermore, only patients with TIMI 3 flow were included in this follow-up study. A postprocedural increase of CK and/or TnI above the upper limit of normal was observed in 11 of 126 patients (8.7%). This had no adverse effect on LV recovery (Table III). There was no difference in Doppler parameters of collateral function between patients with and without LV recovery (Table IV). The pressure-derived collateral index was lower in patients with recovery as compared to those without recovery due to a lower P D (Figure 4). However, this did not indicate an impaired collateral function, as the R Coll was similar in both groups. It was probably due to a difference in microvascular integrity, as the R P was higher in patients without LV recovery. A subanalysis on the basis of the history of prior Q wave MI showed a trend that 35 patients with MI and no recovery had the highest R P (6.5 F 5.5 mm Hg/cm per second), whereas 6 patients without MI and with recovery had the lowest R P (3.4 F 2.0 mm Hg/cm per second, P = .13). Collateral pressure index (A), collateral resistance index (B) and peripheral vascular resistance index (C) in patients with impaired regional function with and without recovery during follow-up.
summarized in Figure 2 with the patients grouped according to their regional and/or global LV function. There was one patient with new regional dysfunction who had developed a reocclusion at follow-up. The
Discussion This study showed that considerable recovery of LV function after recanalization of a consecutive cohort of patients with CTO can be expected, but this is independent of invasively determined parameters of collateral function. Obviously, coronary collateral development is not closely linked to myocardial viability but is rather the result of the recruitment of preexistent interarterial connections. On the other hand, we found
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evidence that regional LV recovery requires a preserved microcirculation.
Recovery of LV function after recanalization of a CTO Recovery of LV function in chronically ischemic myocardium depends on the presence of hibernating or stunned but viable myocardium.25 Left ventricular recovery starts within 1 to 4 weeks after revascularization and is usually complete within 3 m.26-28 Although these studies were done after surgical revascularization, they are probably applicable also to percutaneous revascularization. We observed an overall increase of LVEF of 10% during follow-up. The most pronounced increase occurred in patients with severely depressed LV function, in accordance with previous studies.5,6 We also confirmed that the history of MI, the duration of the occlusion, and the incidence of the nonocclusive restenosis had no influence on LV recovery, whereas reocclusion had an adverse influence on LV recovery.2-5 Collaterals and recovery of LV function There are conflicting reports on the influence of collaterals on the preservation of LV function and its relation to LV recovery.9,11,29-31 Studies using the angiographic grading observed no relation of LV recovery with collaterals,2,13,14 a weak relation,6 or a close relation.12,32 Quantitative studies using nuclear imaging showed that myocardial perfusion at rest was similar in normal and dysfunctional segments without correlation to LV recovery.33,34 The main problem of these studies is the semiquantitative angiographic grading of collaterals. The invasive assessment using Doppler and pressure microsensors is superior to the angiographic assessment.15-17,31 In a selected group of patients with normal LV function and no prior MI, collateral function indexes on the basis of distal coronary flow velocity or pressure may be exchangeable,22 but in patients with CTOs, there is no close correlation between pressure and flow velocity recordings.18 In CTOs with frequently impaired LV function and prior MI, the best approach to describe collateral function is to obtain both pressure and flow velocity recordings and calculate indexes of collateral and peripheral vascular resistance. We found no difference in collateral function in patients whose impaired regional LV function showed a significant recovery as compared to those without recovery. It appears that the presence of myocardium with preserved potential for functional recovery, that is, preserved viability, is not mandatory for the development of coronary collaterals in patients with severe LV dysfunction. These collaterals develop as a result of a pressure gradient across the occlusion that recruit preformed interarterial connections.35-37 The presence of these preformed interarterial connections was
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recently shown in about 20% of a study population without coronary artery disease,38 and is also confirmed by the recruitability of collaterals in 20% of patients with long-term patency of CTOs.20
Peripheral resistance and LV recovery Recent findings by myocardial contrast echocardiography suggest that an intact microvasculature has a favorable effect on the functional recovery of myocardium.39 The R P is a measure of microvascular resistance in the myocardium distal to a CTO.23 In the presence of a comparable collateral supply, R P was lower in patients with subsequent LV recovery due to a lower peripheral pressure. One may speculate that a higher pressure and resistance were caused by more fibrous tissue and/or a rarefied microvasculature in the scarred myocardium of patients without LV recovery. Consequently, patients with recovery would have a better preserved microvasculature and an R P similar to that in patients with CTO and normal LV function. Indeed, we observed the highest R P in patients with prior Q wave MI and no recovery, and the lowest in patients without MI and subsequent recovery. Limitations The present study is one of the largest to address the influence of collaterals on LV recovery in a consecutive patient cohort, and it is the first to use an invasive assessment of collateral function. Even with inherent limitations of this invasive method,18,19,21 it is superior to the angiographic quantification of collaterals.40 In contrast to some of the previous studies using angiography, we included only patients with angiographically visible collaterals of grades 2 and 3. We did not address the influence of angiographically poorly visible or undetectable collaterals, which is of relevance when studying patients immediately after an acute MI.41,42 The scope of this study were patients with CTOs as a well-defined model for chronic myocardial ischemia. The identification of hibernating dysfunctional myocardium is the goal of noninvasive techniques that achieve a positive predictive accuracy of around 70%.43 In the present study, we did not attempt to compare methods for the detection of hibernating myocardium with invasive measures of collateral function. Instead, we used functional recovery as the ultimate gold standard and clinical end point for our analysis. Clinical implications The recanalization of a CTO carries the potential for a considerable improvement or even normalization of severely depressed LV function. The selection for a revascularization should not be on the basis of the quality of collateral supply, as this is not closely related to LV recovery.
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