Author + information
- Received May 28, 2015
- Revision received October 15, 2015
- Accepted October 22, 2015
- Published online May 1, 2016.
- Chiara Bucciarelli-Ducci, MD, PhDa,b,c,
- Dominique Auger, MD, PhDa,
- Carlo Di Mario, MD, PhDb,d,
- Didier Locca, MDa,
- Joanna Petryka, MDa,
- Rory O'Hanlon, MDa,
- Agata Grasso, MDa,
- Christine Wright, RNd,
- Karen Symmonds, RTa,
- Ricardo Wage, RTa,
- Eleni Asimacopoulos, MB, ChBa,
- Francesca Del Furia, MDd,
- Jonathan C. Lyne, MDa,d,
- Peter D. Gatehouse, PhDa,b,
- Kim M. Fox, MDb,d and
- Dudley J. Pennell, MDa,b,∗ ()
- aCardiovascular Magnetic Resonance Unit, Royal Brompton Hospital, London, United Kingdom
- bNational Heart and Lung Institute, Imperial College, London, United Kingdom
- cBristol Heart Institute, Bristol NIHR Cardiovascular Biomedical Research Unit, University of Bristol, Bristol, United Kingdom
- dDepartment of Cardiology, Royal Brompton Hospital, London, United Kingdom
- ↵∗Reprint requests and correspondence:
Prof. Dudley Pennell, CMR Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, United Kingdom.
Objectives This study explored whether cardiac magnetic resonance (CMR) could help select patients who could benefit from revascularization by identifying inducible myocardial ischemia and viability in the perfusion territory of the artery with chronic total occlusion (CTO).
Background The benefit of revascularization using percutaneous coronary intervention (PCI) in CTO is controversial. CMR offers incomparable left ventricular (LV) systolic function assessment in addition to potent ischemic burden quantification and reliable myocardial viability analysis. Whether CMR guided CTO revascularization would be helpful to such patients has not yet been explored fully.
Methods A prospective study of 50 consecutive CTO patients was conducted. Of 50 patients undergoing baseline stress CMR, 32 (64%) were selected for recanalization based on the presence of significant inducible perfusion deficit and myocardial viability within the CTO arterial territory. Patients were rescanned 3 months after successful CTO recanalization.
Results At baseline, myocardial perfusion reserve (MPR) in the CTO territory was significantly reduced compared with the remote region (1.8 ± 0.72 vs. 2.2 ± 0.7; p = 0.01). MPR in the CTO region improved significantly after PCI (to 2.3 ± 0.9; p = 0.02 vs. baseline) with complete or near-complete resolution of CTO related perfusion defect in 90% of patients. Remote territory MPR was unchanged after PCI (2.5 ± 1.2; p = NS vs. baseline). The LV ejection fraction increased from 63 ± 13% to 67 ± 12% (p < 0.0001) and end-systolic volume decreased from 65 ± 38 to 56 ± 38 ml (p < 0.001) 3 months after CTO PCI. Importantly, despite minimal post-procedural infarction due to distal embolization and side branch occlusion in 8 of 32 patients (25%), the total Seattle Angina Questionnaire score improved from a median of 54 (range 45 to 74) at baseline to 89 (range 77 to 98) after CTO recanalization (p < 0.0001).
Conclusions In this small group of patients showing CMR evidence of significant myocardial inducible perfusion defect and viability, CTO recanalization reduces ischemic burden, favors reverse remodeling, and ameliorates quality of life.
One or more arteries with chronic total occlusion (CTO) are identified in approximately one-third of diagnostic coronary angiograms in patients with known or suspected coronary artery disease (1,2). The benefits of PCI of a CTO are controversial for 3 main reasons: first, PCI of a CTO is technically challenging for the interventional cardiologist, with a lower success rate than achieved in other coronary lesions; second, OAT (Occluded Artery Trial) demonstrated a lack of benefit of PCI versus medical therapy in patients with an occluded infarct-related artery (3). However, these results cannot be widely applied to patients with CTO (occlusion duration of ≥3 months) because the OAT patient cohort presented with an occluded infarct-related coronary artery 3 to 28 days after acute myocardial infarction (MI), and PCI was not guided by the presence of residual myocardial viability and ischemia; third, the procedure can last several hours with significant radiation exposure, contrast dose, and cost. Selection criteria aimed at identifying patients who can benefit from PCI of CTO have not yet been proposed. Cardiac magnetic resonance (CMR) is a high-resolution noninvasive imaging technique that can assess regional and global left ventricular (LV) function, and detect the presence and the extent of infarction and ischemic burden (4). We therefore hypothesized that CMR could help in selecting patients suitable for CTO PCI.
Study design and population
This single-center, prospective study included patients with a CTO considered suitable for recanalization after coronary angiography. CTO was defined as the presence of Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 within the occluded artery with an estimated occlusion duration of ≥3 months, as suggested in the EuroCTO Club consensus document (5). CMR was performed 1 month before intervention and 3 months after recanalization. The CMR criteria for proceeding to revascularization were: 1) a majority of the segments in the CTO territory had <75% transmural extent of infarction by late gadolinium enhancement (LGE); and 2) an inducible perfusion defect was present in the CTO territory. Myocardial segments were assigned to coronary arteries as described in the American Heart Association (AHA) 17 segment model, with 7 segments for the left anterior descending artery, 5 for the right coronary artery, and 5 for the left circumflex artery (6). If the left circumflex artery was dominant, 2 inferior segments were reassigned from the right coronary artery to the left circumflex artery. Of the 52 patients initially recruited, 32 completed the study. The patient flow in the study is summarized in Figure 1. Exclusion criteria were: 1) significant other cardiac disease; 2) estimated glomerular filtration rate of <30 ml/min; 3) contraindications to CMR (e.g., claustrophobia, pacemaker, implantable cardioverter defibrillator, cerebral clips); and 4) contraindication to adenosine (e.g., severe asthma, greater than first-degree heart block). All participants gave written informed consent and the study was approved by the local ethics committee.
Cardiac magnetic resonance
CMR was performed in a 1.5-T scanner (Avanto, Siemens, Erlangen, Germany) with a dedicated cardiac 8-channel phased array receiver surface coil. Cine images were obtained with a steady-state free-precession sequence in 2 long-axis and multiple contiguous short-axis views encompassing the LV from base to apex. Typical image parameters were: echo time, 1.6 ms; repetition time, 3.2 ms; time per cine frame, 51 ms; α, 60°; matrix, 256 × 256; slice thickness, 8 mm; and gap, 2 mm. First-pass stress perfusion imaging was performed using a 3-slice (basal, mid-cavity, and apical views) hybrid-EPI sequence with T-SENSE (repetition time, 5.8 ms; inversion time, 110 to 140 ms; field of view, 360 × 270 mm; voxel size, 2.8 × 2.8 × 10 mm) over 50 consecutive cardiac cycles. The images were acquired after 4 min of 140 μg/kg/min adenosine infusion and after the injection of 0.1 mmol/kg of gadopentetic acid. LGE images were acquired 10 to 15 min after gadolinium injection in long- and short-axis planes, using a segmented inversion recovery gradient echo sequence (repetition time, 600 ms; echo time, 3.8 ms; α, 25°, slice thickness, 8 mm; gap, 2 mm; typical pixel size, 1.7 × 1.4 mm) (7). The inversion time was progressively optimized and adjusted to adequately null normal myocardium (typical values 320 to 440 ms). Cine and LGE images were acquired at the same long and short axis slice position. Finally, first-pass rest perfusion images were acquired >20 min after stress perfusion imaging.
Image analysis was performed by an experienced operator blinded to the clinical and angiographic data, using semiautomated software (CMRtools, Cardiovascular Imaging Solutions, London, United Kingdom). Quantitative LV volumes, left ventricular ejection fraction (LVEF), and LV mass were calculated from the short axis views excluding the papillary muscles. The images were assessed according to the AHA/American College of Cardiology 17-segment model (8). For each segment, wall motion was scored as 0 (normal), 1 (mildly hypokinetic), 2 (severely hypokinetic), 3 (akinetic), or 4 (dyskinetic). Infarcted myocardial mass was calculated from the LGE images. Myocardial regions were considered infarcted if the signal intensity was >5 standard deviations above that of the remote myocardium (8). Myocardial perfusion reserve (MPR) was calculated in all CTO and remote myocardial territories as previously described (9). In brief, MPR was derived from time–intensity curves during first pass stress perfusion imaging in each segment before CTO recanalization and at follow-up. Analysis was done according to Fermi deconvolution function for regional MPR (9). The extension of the inducible perfusion defect was also scored visually in all 17 myocardial segments, assigning to each segment 0 (normal), 1 (defect <25% wall thickness), 2 (defect 25% to 50%), 3 (defect 51% to 75%), or 4 (>75%).
In the majority of cases (>70%), patients were treated using a bilateral anterograde approach (right and left femoral artery puncture). This approach was attempted using microcatheters or over-the-wire balloon for support and wire exchange; wires used included the Miracle, Confianza and Fielder XT (Asahi Intecc, Nagoya, Japan). The retrograde coronary approach was mainly attempted in 25% of the patients after 1 or more unsuccessful anterograde attempts.
Seattle Angina Questionnaire
The Seattle Angina Questionnaire (SAQ) is a widely used questionnaire to assess health outcome measures in patients with coronary artery disease (10,11). In our study, we used the United Kingdom version of the SAQ which consists of 14 items that measure 3 different aspects of quality of life: a 7-item scale of physical limitations (how daily activities are limited by angina), a 4-item angina frequency and perception scale (frequency of symptoms and use of medications, and effect of angina on quality of life), and a 3-item treatment satisfaction scale (12). All items use 5-point descriptive scales and scores are calculated by summing all the single scores within each group and transforming them to on a scale of 0 to 100, where 0 is the worst and 100 is the best. The questionnaire was given to the patients at the time of their CMR scans (baseline and follow-up).
Continuous normal data are expressed as mean ± SD. Non-normally distributed data are expressed as median (interquartile range [IQR]). The chi-square test was used to compare categorical variables. Paired Student t or Wilcoxon tests were used to respectively compare parametric and nonparametric data at baseline and at follow-up. Differences were considered statistically significant with a 2-sided p value of ≤0.05. Statistical analyses were performed with SPSS software version 22.0 (IBM, Chicago, Illinois).
Clinical and angiographic data
Thirty-two patients completed the study (94% men; mean age 65 ± 9 years). Eighteen patients were excluded due to absent myocardial viability in a majority of segments (n = 6), absence of inducible myocardial ischemia (n = 7), failed PCI to CTO at the second attempt (n = 3), or lost to follow-up (n = 2) (Figure 1). Baseline characteristic are shown in Table 1. In study patients, there was a high incidence of cardiovascular risk factors. The majority of patients had previous MI (n = 21; 66%), previous PCI (n = 13; 41%), and multivessel disease (n = 21; 66%). Some patients had previous PCI to a CTO artery (n = 3; 9%). There was a low incidence of symptoms: the majority of patients had limited or no angina (Canadian Cardiovascular Society [CCS] classes I and II; n = 26; 81%) and New York Heart Association functional classes I and II (n = 21; 66%). Finally, there were no statistical differences in baseline characteristics between study patients and patients excluded from the trial.
The angiographic characteristics of the CTO study patients are summarized in Table 2. The majority of the vessels recanalized were right coronary artery (62%) with the remainder being left anterior descending artery (38%). Collaterals were present in 70% of the patients.
From baseline to follow-up, there was significant decreased of end-systolic volume (ESV) from 65 ± 38 ml to 56 ± 38 ml (p < 0.001) with no significant change in end-diastolic volume (166 ± 42 ml to 161 ± 42 ml; p = 0.18) (Figure 2). LVEF increased from 62 ± 13% to 67 ± 12% (p < 0.0001). Baseline regional wall motion was abnormal in 19 patients (58%) and improved after revascularization in 47% of patients. Mean visual wall motion score improved from 5.9 ± 9.5 to 4.5 ± 8.1 (p = 0.003).
Follow-up CMR was performed in 8 of 18 patients that were excluded initially from the study. In this specific group of patients, there were no significant changes in LV volumes or LVEF at follow-up.
Presence and extent of myocardial ischemia
The presence of reversible perfusion defect was identified in all 32 patients, and was limited to the subendocardium in 12 patients (37%), transmural or near transmural in 4 (13%), and peri-infarct ischemia in the subepicardial viable rim was detected in 16 (50%) (Figure 3). A complete or near-complete resolution of ischemia after PCI was seen in 90% of patients (Figure 4). Mean visual perfusion score improved from 10.9 ± 7.1 to 1.6 ± 3.4 (p < 0.0001).
Myocardial perfusion reserve
At baseline, MPR in the CTO territory was reduced compared with remote territory (1.8 ± 0.7 vs. 2.2 ± 0.7; p = 0.01) (Figure 5), improved significantly after recanalization (2.3 ± 0.9; p = 0.02 vs. baseline), and was similar to the remote territory (2.5 ± 1.2; p = 0.21). There were no differences of MPR in the remote territory before and after PCI.
Presence and extent of MI
In the study cohort at baseline (n = 32), 12 (38%) had no MI, 15 (47%) had subendocardial infarct (<50% transmurality), and in 5 (16%) patients, MI was 50% to 75% transmural but with peri-infarct ischemia. The mean MI size was 11.5 ± 9.3 g.
After CTO PCI, new but limited post-procedural MI was identified in 8 of 32 patients (25%). In particular, septal branch perforation occurred in 3 patients with a median size of new myocardial damage of 0.23 g (IQR: 0.022 to 1.21 g). Distal embolization occurred in 2 patients with a median size of myocardial damage size of 0.42 g (IQR: 0.23 to 0.49 g). Side branch impairment occurred in 3 patients with a median myocardial damage size of 10.6 g (IQR: 5.32 to 10.6 g).
The total SAQ score significantly improved from a median of 54 (IQR: 45 to 74) to 89 (IQR: 77 to 98) after recanalization (p < 0.0001). The SAQ individual subgroup components also improved: physical limitation from 61 (IQR: 46 to 75) to 89 (IQR: 71 to 95; p < 0.0001), treatment satisfaction from 83 (IQR: 58 to 100) to 100 (IQR: 92 to 100; p = 0.001), and frequency and perception from 30 (IQR: 23 to 53) to 83 (IQR: 58 to 100; p < 0.0001) (Figure 6).
The main findings of this study are that: 1) CMR may help to identify patients who are more likely to benefit from CTO PCI by demonstrating pre-procedural myocardial viability and inducible perfusion defect in the CTO territory; 2) CTO recanalization may reduce ischemic burden and improves LV systolic function in these patients; and 3) successful revascularization in these patients could improve quality of life. To our knowledge, this is the first study that prospectively assesses the potential role of CMR in guiding the selection of patients for CTO for revascularization.
CTO recanalization and improvement of LV function
Changes in LV volumes, function, and wall motion after successful recanalization of CTO have been demonstrated in small series with mixed results. Sirnes et al. (13) described improvement in ejection fraction (EF) and regional radial shortening from baseline to 6 months assessed by LV angiography. EF improvement using LV angiography was also reported by the TOSCA (Total Occlusion Study of Canada) investigators; this was, however, confined to patients with recent occlusions (<6 weeks), compared with those with longer duration of occlusion (>6 weeks) (14). More recently, a significant decrease in ESV and end-diastolic volume, without significant change in EF, was reported using cine CMR after revascularization in CTO patients (15,16). Fiocchi et al. (17) used low-dose dobutamine CMR to predict functional recovery, and found improved EF and systolic wall thickening at 6 months after recanalization. Pavlovic et al. (18) demonstrated a significant reduction in end-diastolic volume using gated single-photon emission computed tomography, but no improvement in ESV or EF. The discrepancy in LV functional recovery after recanalization reported in these studies could relate to small sample size (usually 20 patients) and the different imaging techniques applied. We studied a larger cohort of patients with >3 months CTO using CMR as a gold standard imaging technique. The present study demonstrates a significant LVEF and LV end-systolic volume improvement in patients who showed CMR evidence of myocardial inducible perfusion deficit and significant viability in the CTO territory. Consequently, CMR viability assessment before a CTO PCI procedure may help to select patients who will most likely experience significant reverse remodeling at follow-up. Whether such improvement in LVEF and LV end-systolic volume is linked with an improved long-term clinical outcome after CTO PCI remains unclear.
CTO, myocardial viability, and ischemia
CMR can identify the presence and extent of viable but dysfunctional myocardium, and predict its recovery after successful revascularization (19). Furthermore, CMR is a strong radiation-free imaging modality with increased spatial resolution for ischemic burden assessment. In our study, we demonstrated that the majority of patients with CTO have limited or no MI, and therefore have the potential to exhibit LV function improvement after successful recanalization. Such findings had also been demonstrated in previous studies. Indeed, in selected patients with CTO of the left anterior descending artery, Bellenger et al. (20) demonstrated with dobutamine CMR that the extent of viable myocardium in the infarct zone is related to improvements in LV remodeling in patients undergoing late recanalization of an occluded infarct-related artery. In particular, they observed a significant relation between the number of viable myocardial segments in the infarct zone and the improvement in ESV and EF. Additional small studies have also reported that myocardial segmental wall thickening improved significantly in segments with no or subendocardial infarction, whereas no improvement was observed in segments with almost full-thickness myocardial scar (15,16).
The present study showed complete or almost complete resolution of perfusion defect (qualitative assessment), which was coupled with an increased MPR (quantitative assessment) after CTO PCI. Pavlovic et al. (18) previously demonstrated improved perfusion in the CTO territory 1 year after successful recanalization by 99mTc single-photon emission computed tomography. Importantly, Cheng et al. (21) described that PCI of CTO improved regional hyperemic myocardial blood flow assessed by CMR. That benefit persisted at 6 months’ follow-up and was also seen in a group of 17 patients undergoing standard PCI for a non-CTO coronary lesion. Furthermore, the Oxford group compared these interesting findings with the ones obtained in a control group of 6 patients with CTO who did not have CTO recanalization (21). Patients in the control group did not experience improvement in hyperemic myocardial blood flow or in regional wall motion contractility (21). In our study, patients were only considered candidates for CTO recanalization if both CMR myocardial viability and inducible myocardial perfusion defect had been identified in the CTO territory. The majority of patients (84%) in our cohort had no or limited MI; larger MI but with peri-infarct ischemia was demonstrated only in 16% of patients. The high prevalence of myocardial viability in the present cohort may be explained by the concomitant high prevalence of collateral circulation, which was found in 70% of patients. As shown by Habib et al. (22), infarct size can be reduced by up to 35% in the presence of collaterals. The development of collaterals triggered by myocardial ischemia may not have been completely protective in our study patients as significant perfusion defect in the CTO territory was present in all patients before CTO relief (23). We also demonstrated that, after successful recanalization, perfusion level was restored in the treated segments to a level similar to the remote myocardium. Such amelioration in myocardial perfusion may have led to the concomitant quality of life improvement witnessed in the present study.
CTO recanalization and quality of life
The effect of PCI on quality of life in patients with stable coronary artery disease has been investigated by the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial, demonstrating a marked improvement in health status in patients treated with PCI versus those treated with optimal medical therapy (24). This positive effect, however, disappeared at 36 months’ follow-up. Quality of life was also assessed by OAT trial investigators and found that CTO PCI was associated with a marginal and unsustained advantage in cardiac physical function at 4 months’ follow-up (25). Furthermore, no difference in the psychological well-being aspect of quality of life was found (25). Our study is the first to specifically assess quality of life with the SAQ and to provide CMR imaging to all patients before and after CTO revascularization. Interestingly, even in our population of patients with limited symptoms (mainly CCS angina classes I and II), but with CMR evidence of significant myocardial viability and perfusion deficit in the CTO territory, reduction of the ischemic burden led to a notable improvement in quality of life.
There are many economic disincentives to CTO recanalization (26). These procedures are challenging technically and require a long learning curve, longer procedural times, and greater contrast volume use and radiation exposure, as well as more use of materials than conventional PCI. Our study suggests that improved patient selection for revascularization can be achieved by CMR. Such an approach may help allocating this precious resource to patients most likely to experience beneficial ischemic burden relief, LV systolic function and quality of life improvements after CTO PCI.
The first and main limitation of the present study is its design. Data from a pre-defined control group that would have not undergone any cardiac imaging before CTO recanalization and/or that would not have undergone recanalization despite showing significant inducible ischemia in the CTO territory would have provided further insights into the potential role of CMR in that specific population. Furthermore, our study was not designed to compare CTO patients’ long-term outcome with a control group. Whether CMR-guided CTO revascularization is linked with a more favorable outcome should be explored further in a randomized, controlled trial. The second limitation of this study is the lack of consensus for CTO definition as the age of CTO could not be determined with confidence in all patients. Finally, this is a single-center study and the rate of success in CTO recanalization with anterograde and retrograde approach reflects the experience of a single operator.
In this small group of patients showing CMR evidence of significant myocardial inducible perfusion defect and viability, CTO recanalization reduces ischemic burden, favors reverse remodeling, and ameliorates quality of life.
COMPETENCY IN MEDICAL KNOWLEDGE: Stress CMR with LGE is a noninvasive imaging technique that permits reliable ischemic burden and myocardial viability assessment. The use of CMR in subjects with ischemic heart disease and CTO may help to identify patients who could derive significant LV reverse remodeling, ischemic burden relief, and quality of life improvement after CTO recanalization.
TRANSLATIONAL OUTLOOK: The relatively small sample size and lack of control group remains a limitation. Whether CMR-guided CTO revascularization is linked with a more favorable outcome should be further explored in a randomized controlled trial.
This work was supported by the National Institutes of Health Research Cardiovascular Biomedical Research Unit, a collaboration between Royal Brompton Hospital and Imperial College London, UK.
Professor Pennell has received consulting fees from Siemens, AMAG, ApoPharma, Novartis, Bayer, and Shire; and has equity interest/stock in CVIS and Private CMR. Dr. Bucciarelli-Ducci is a consultant for Circle CVI. Dr. Lyne has received honoraria from Medtronic, St. Jude Medical, and Boston Scientific. Dr. Gatehouse has a departmental research agreement with Siemens. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- cardiac magnetic resonance
- chronic total occlusion
- ejection fraction
- end-systolic volume
- left ventricle/ventricular
- left ventricular ejection fraction
- myocardial infarction
- myocardial perfusion reserve
- percutaneous coronary intervention
- Seattle Angina Questionnaire
- Received May 28, 2015.
- Revision received October 15, 2015.
- Accepted October 22, 2015.
- American College of Cardiology Foundation
- Cerqueira M.D.,
- Weissman N.J.,
- Dilsizian V.,
- et al.
- Spertus J.A.,
- Winder J.A.,
- Dewhurst T.A.,
- et al.
- Sirnes P.A.,
- Myreng Y.,
- Molstad P.,
- Bonarjee V.,
- Golf S.
- Baks T.,
- van Geuns R.J.,
- Duncker D.J.,
- et al.
- Fiocchi F.,
- Sgura F.,
- Di Girolamo A.,
- et al.
- Bellenger N.G.,
- Yousef Z.,
- Rajappan K.,
- Marber M.S.,
- Pennell D.J.
- Cheng A.S.,
- Selvanayagam J.B.,
- Jerosch-Herold M.,
- et al.
- Habib G.B.,
- Heibig J.,
- Forman S.A.,
- et al.,
- The TIMI Investigators
- Werner G.S.
- Grantham J.A.,
- Marso S.P.,
- Spertus J.,
- House J.,
- Holmes D.R. Jr..,
- Rutherford B.D.