Abstract: Background. Percutaneous recanalization of chronic total coronary occlusion (CTO) tends to show a positive effect on left ventricular remodeling and ejection fraction (LVEF). Coronary flow velocity reserve (CFVR) is an important diagnostic index of the functional capacity of coronary arteries. The aim of this study was to evaluate, by non-invasive CFVR, whether the blood flow of donor artery reverts to normal after CTO percutaneous coronary intervention (PCI). Also, we assessed the effects of CTO recanalization on global cardiac functions by using myocardial performance index (MPI). Methods. We evaluated 25 patients (mean age, 57.5 ± 14.1 years) who underwent CTO-PCI of the right coronary artery, whose collaterals were provided by the left anterior descending (LAD) artery. The coronary flow velocities in the distal LAD were measured using transthoracic echocardiography (TTE) before, 24 hours after, and within 3 months of PCI. Both two-dimensional and tissue Doppler (tD) echocardiography were used to calculate MPI. Results. CFVR at month 3 was significantly increased compared to the basal and early CFVR (1.8 ± 0.3 vs 2.3 ± 0.3 [P<.001] and 1.8 ± 0.2 vs 2.3 ± 0.3 [P<.001], respectively). MPI at month 3 was significantly decreased compared to the basal and early MPI (0.61 ± 0.09 vs 0.53 ± 0.07 [P<.001] and 0.60 ± 0.08 vs 0.53 ± 0.07 [P<.001], respectively). Also, tD-MPI within 3 months was significantly decreased (0.58 ± 0.9 vs 0.53 ± 0.8 [P=.01] and 0.57 ± 0.07 vs 0.53 ± 0.8 [P<.001], respectively, for tD-MPI septal and 0.59 ± 0.08 vs 0.51 ± 0.07 [P<.001] and 0.58 ± 0.08 vs 0.51 ± 0.07 [P<.001], respectively, for tD-MPI lateral). Conclusion. Successful recanalization of CTO results in increased CFVR-indicated blood flow in the donor artery and MPI-indicated global cardiac functions.
J INVASIVE CARDIOL 2015;27(6):E75-E81
Key words: chronic coronary total occlusion, coronary flow velocity reserve, myocardial performance index
The incidence of chronic total occlusion (CTO) among patients with a clinical indication for diagnostic coronary angiography is nearly 20%.1 In the earlier studies, procedural success rates of percutaneous coronary intervention (PCI) of CTO have ranged from 51%-74%.2,3 However, procedural success rates have improved with the development of novel equipment and techniques.4 CTO recanalization can reduce ischemic burden as well as electrical instability, and tends to show a positive effect on left ventricular (LV) remodeling and ejection fraction (LVEF).5 Nevertheless, its effects on global cardiac functions are yet to be fully understood. The myocardial performance index (MPI) has been widely used to quantitatively assess myocardial performance.6,7 It is likely to be more effective for analysis of global cardiac function than systolic and diastolic measures alone.8,9 Also, increased MPI was shown to be an independent predictor for cardiac outcomes in coronary artery disease.10
In patients with a CTO, flow of the donor artery takes on great significance; with recanalization of the CTO, collateral resistance increases and blood flow is favored in the donor myocardium.11 In some case reports, it has been demonstrated that successful CTO-PCI has reverted an ischemic donor fractional flow reserve (FFR) to normal.12,13 Coronary flow velocity reserve (CFVR), defined as the ratio of hyperemic to baseline coronary blood flow, has been considered an important non-invasive diagnostic index of the functional capacity of coronary arteries.14 The diagnostic accuracy of CFVR has been shown to be high (sensitivity of 86% and specificity of 70%) in predicting significant stenosis of the left anterior descending (LAD) artery with a cutoff value of <2.0.15 However, to the best of our knowledge, little information is available regarding the changes in the CFVR in the donor artery providing collaterals distal to a CTO. The aim of this study was to evaluate, by non-invasive CFVR, whether the blood flow of the donor artery reverts to normal after successful CTO-PCI. Furthermore, we assessed the effects of CTO recanalization on global cardiac functions by using MPI.
We prospectively included 29 patients with right coronary artery (RCA) CTO in this single-center study; due to a failed intervention in 4 patients, the final group consisted of 25 patients (20 men, 5 women; mean age, 57.5 ± 14.1 years). All patients had ischemia on myocardial perfusion imaging and underwent successful CTO-PCI of the RCA, with collaterals provided by the LAD. After taking detailed medical history and complete physical examination, each participant was questioned for major cardiovascular risk factors such as age, sex, diabetes mellitus (DM), smoking status, and hypertension (HT). In addition, systolic blood pressure (SBP), diastolic blood pressure (DBP), and initial heart rate were recorded. All patients underwent electrocardiography (ECG) and transthoracic echocardiography (TTE). The study was conducted according to the recommendations set forth by the Declaration of Helsinki on Biomedical Research Involving Human Subjects. The Institutional Ethics Committee approved the study protocol and each participant provided written informed consent.
Coronary CTOs were defined as angiographic evidence of a total occlusion with Thrombolysis in Myocardial Infarction (TIMI) grade 0 or 1 and estimated duration of at least 3 months. Estimation of occlusion duration was based on the first onset of angina pectoris, a history of myocardial infarction in the target vessel territory, or comparison with a previous angiogram. Technical success was defined as successful CTO recanalization with achievement of <50% residual diameter stenosis within the treated segment and restoration of TIMI grade-3 antegrade flow.
Echocardiography. Standard two-dimensional pulsed-wave Doppler and tissue-Doppler (tD) echocardiographic (TDE) examinations were performed using commercially available equipment (Vivid-7, GE Vingmed) with a 2.5-3.5 MHz transducer. Simultaneous ECG recordings were also obtained. One echocardiographer who was blinded to the patients’ clinical and laboratory data interpreted each echocardiographic examination independently. All patients were examined at rest in the left lateral decubitus position. M-mode echocardiograms were recorded from the parasternal window at rest to determine left ventricle dimensions. LVEF was determined using the Simpson’s method, according to the suggestions of the American Society of Echocardiography.16
Mitral pulsed-wave Doppler measurements were obtained with the transducer in the apical four-chamber view. Three consecutive beats were measured and averaged for each parameter. Doppler time intervals were measured from mitral inflow and left ventricular outflow Doppler tracings, as described by Tei and colleagues.6 The isovolumetric relaxation time (IVRT) was measured from closure of the aortic valve to opening of the mitral valve. The isovolumetric contraction time (IVCT) was measured from closure of the mitral valve to opening of the aortic valve. Ejection time (ET) was measured from the opening to the closure of the aortic valve on the LV outflow velocity profile. MPI was equal to the sum of the IVRT and IVCT divided by the ET.
After proper acquisition adjustments were made, left ventricle TDE evaluation was performed in apical four-chamber position by placing the pulse-wave Doppler beam on the part of the mitral annulus that is close to the left ventricle posterior wall and interventricular septum. Special attention was paid during recordings to place the Doppler beam right in the myocardium, not the endocardium or epicardium. Measurements were made for three consecutive heartbeats in all positions, and their average was taken. Doppler measurements were made at a recording rate of 100 mm/s. The MPI obtained by TDE was defined as the sum of the IVRT and IVCT divided by ET. All patients underwent TTE before (basal), 24 hours after (early), and at 3 months after (late) after successful PCI. All echocardiograms, as well as CFVR measurements, were recorded and interpreted online on hard disks for offline analysis by another observer blinded to patient data. Intraobserver and interobserver variability of CFVR and other echocardiographic data were evaluated from 8 randomly selected patients with RCA-CTO and calculated as the absolute difference divided by the average of the two observations. Mean intraobserver and interobserver variability was 4.3 ± 3.6% and 4.5 ± 4.1%, respectively.
CFVR measurements. Visualization of the distal LAD was performed with a modified, foreshortened, two-chamber view obtained by sliding the transducer on the upper part, and medially from an apical two-chamber view. Coronary flow in the distal LAD was examined by color Doppler flow mapping over the epicardial part of the anterior wall, with the color Doppler velocity range set in the range of 10-20 cm/s. The left ventricle was imaged on the long-axis cross-section, and the ultrasound beam was then inclined laterally. The spectral Doppler signals of the distal LAD displayed the characteristic biphasic flow pattern, with a diastolic dominant flow and a smaller systolic component. Peak systolic velocity and peak diastolic velocity were measured at baseline and under hyperemic conditions that were obtained with intravenous infusion of adenosine (140 µg • kg-1 • min-1) over 3-6 minutes. An average peak diastolic velocity was calculated from more than three cardiac cycles, and blood pressure and heart rate were also measured for the same cycles. CFVR was calculated as the ratio of hyperemic to baseline peak diastolic velocities.17 The coronary flow velocities in the distal LAD were measured using transthoracic Doppler echocardiography at rest and during hyperemia induced by intravenous infusion of adenosine at 3 time periods: before PCI (basal), 24 hours after PCI (early), and within 3 months of successful PCI (late).
Statistical analysis. The analyses were performed using SPSS software (Statistical Package for the Social Sciences, version 20.0; SSPS, Inc). Continuous variables were expressed as mean values ± standard deviation, and categorical variables as percentages. Analysis of normality was performed with the Kolmogorov-Smirnov test. Statistical comparisons between CFVR, MPI, and echocardiographic variables at different time points were examined using paired t-test. Statistical significance was defined as P<.05.
Indication for coronary angiography in all patients and subsequent CTO-PCI was severe stable angina despite maximal anti-angina therapy and ischemia on myocardial perfusion imaging. The baseline clinical, laboratory, and angiographic characteristics of the study population are listed in Tables 1 and 2. Overall, most patients were men (80%), with mean age of 57.5 ± 14.1 years. More than 1/3 (40%) had a family history of coronary artery disease (CAD), 28% had diabetes, 64% had hypertension, and 48% had a history of hyperlipidemia. The RCA was the target vessel in all patients. Eight percent of patients had at least one previous failed attempt for CTO recanalization. Most PCIs (88%) were performed using an antegrade approach. The overall technical success rate was 86%. The average stent length was 61.1 ± 27.6 mm and drug-eluting stents were used in all patients. A procedural complication occurred in 3 patients (12%). One patient had intracranial bleeding. Two patients had coronary artery dissection (1 Ellis type-C dissection and 1 Ellis type-E dissection). Both were treated successfully with stent implantation and no collateral damage occurred.
Echocardiographic findings. Echocardiographic findings are presented in Table 3. There was no difference between basal, early, and late LVEF values (53.5 ± 10.2%, 53.3 ± 9.5%, 53.3 ± 11.2%, respectively). The MPI at month 3 (0.53 ± 0.07) was significantly decreased compared to the basal (0.61 ± 0.09; P<.001 vs 3 months) and early (0.60 ± 0.08; P<.001 vs 3 months). On the other hand, there was no significant difference between basal and early MPI values (0.61 ± 0.09 vs 0.60 ± 0.08, respectively; P=.84). Also, septal tD MPI within 3 months (0.53 ± 0.8) was significantly decreased compared with basal (0.58 ± 0.9; P=.01 vs 3 months) and early (0.57 ± 0.07; P<.001 vs 3 months). Moreover, similar decrease in lateral tD MPI within 3 months (0.51 ± 0.07) was observed compared to basal (0.59 ± 0.08; P<.001 vs 3 months) and early (0.58 ± 0.08; P<.001 vs 3 months) (Figure 1).
Analysis of CFVR measurements. The coronary Doppler velocities, CFVR, heart rate, and blood pressure at rest and during hyperemia are listed in Table 3. The parameters of the velocity profiles in the distal LAD were measured at 3 time periods: before (basal), 24 hours after (early), and within 3 months (late) of successful PCI. During adenosine infusion, no significant electrocardiographic changes or major adverse effects were observed. The CFVR at month 3 (2.3 ± 0.3) was significantly increased compared to the basal (1.8 ± 0.3; P<.001 vs 3 months) and early CFVR (1.8 ± 0.2; P<.001 vs 3 months). On the other hand, there was no significant difference between basal and early CFVR (1.8 ± 0.3 vs 1.8 ± 0.2, respectively; P=.89) (Figures 2 and 3).
Our study demonstrates that successful recanalization of CTO results in increased CFVR-indicated blood flow in the donor artery and MPI-indicated global cardiac functions while the LVEF values remain unchanged within 3 months.
CTOs are the most complex and challenging coronary lesions for PCI. Recently, the reported success rate of CTO-PCI has reached >80% due to the use of new sophisticated techniques and development of specialized devices.18,19 The overall technical success rate of the present study is 86% and similar to the rates reported in recent large United States and European CTO-PCI registries (85.5%-87.5%)4,20 and better than previous studies.3 This is likely because of application of novel crossing strategies (including the retrograde approach and dissection or reentry techniques), novel equipment (microcatheters, guidewires, over-the-wire balloons, and drug-eluting stents) and increasing operator experience. A major procedural complication occurred in 3 patients (12%). Likewise, the incidence of coronary dissection in our study (8%) agrees with the series reported by Mehran et al (4.3%-9.4%).21 No other in-hospital major complications occurred, such as cardiac tamponade, coronary perforation, emergent surgery, or death. There are several possible explanations for the absence of these fatal complications and death. First, patients in whom the retrograde approach was used tended to have greater incidence of complications;20,22 however, in our study, most PCIs (88%) were performed using an antegrade approach. Second, patients with failed CTO-PCI, who have been shown to have a significantly higher incidence of in-hospital major adverse cardiac events,23 were not included in our study.
To the best of our knowledge, our study is the first report to evaluate the changes in the CFVR in the donor artery before and after revascularization of CTO. The CFVR determined by TTE has been widely used for the detection of significant stenosis of the LAD.24 It is non-invasive, cost-effective, and easily reproducible; thus, physicians can use it for the daily assessment of patients with CTO as well as for follow-up after coronary angioplasty, evaluation of coronary bypass grafts, and evaluation of the coronary microcirculation. In a previous report, Pizzuto et al suggested that measurement of the CFVR in the distal LAD before and after successful stent implantation has the potential for the detection of in-stent restenosis.25 They also demonstrated that the CFVR recovered to normal range early after the procedure. In contrast to this study, we did not find a difference in the CFVR between basal and early period. Hemodynamics in CTO revascularization are different from non-CTO revascularization. In CTOs, differential resistances in the collateral and donor artery determine the coronary blood flow. After CTO recanalization, the collateral resistance starts to increase immediately, thus favoring blood flow to the donor territory during maximal hyperemia.26 A previous study demonstrated that although collateral resistance index increased immediately after recanalization of CTO, a major increase was reported in the follow-up period at 5 months.27 In our study, increase in CFVR was observed only within 3 months, while no change was recorded in the early period. A possible explanation for this coronary flow pattern may be that within recanalization, an immediate increase in collateral resistance causes regression of most visible collaterals in the early period, but the majority of the remaining non-visible collaterals gradually regress and may not fully disappear for several months. Therefore, coronary flow and CFR in the donor artery gradually increases as the collaterals regress.
In the present study, both basal and early CVFR were <2.0. After successful revascularization, CFVR significantly improved to >2.0. The cut-off value of 2.0 for CFVR is precise, with a high sensitivity (90%) and specificity (93%) for detecting significant coronary dysfunction.28 Furthermore, hyperemic peak diastolic flow velocity (PDFV) of the donor artery increases after successful revascularization as a consequence of increased blood flow in the donor artery. In several previous studies, it has been demonstrated that non-invasive measurement of CFVR in the distal LAD using TTE accurately reflects intracoronary measurements in different clinical settings.29,30 However, a direct comparison of invasive and non-invasive CFVR has never been performed for the donor artery, particularly in the setting of CTOs. In a recent study, Sachdeva et al reported that successful CTO-PCI reverted an ischemic donor fractional flow reserve (FFR) to normal.31 Similar to this report, our study confirms that recanalization of CTOs not only restores the blood flow in the occluded artery, but also increases the diminished blood flow in the donor artery that supplies collaterals to the CTO territory, resulting in the return of myocardial function.
In several previous studies, the effect of revascularization of CTO on LVEF was investigated.32 Overall, the improvement on left ventricular function is not satisfactory and is likely to escape detection by crude measurements of global LVEF. In our study, we assessed both systolic and diastolic functions of the left ventricle using TDE in addition to conventional echocardiographic methods. Furthermore, all patients underwent MPI measurement before and after successful PCI, which is calculated by using data obtained from pulsed-wave Doppler and TDE, permitting refined assessment of left ventricular global functions. These new techniques are not affected by limiting variables of conventional methods, such as preload, afterload, heart rate, ventricular geometry, and blood pressure.33 MPI is likely to be more effective for analysis of global cardiac functions than systolic and diastolic measures alone. In the present study, overall mean LVEF remained unchanged within 3 months. However, on the other hand, MPI at month 3 was significantly decreased compared to the basal and early periods.
To the best of our knowledge, this is the first study to investigate the effects of successful CTO recanalization on cardiac functions by using MPI obtained from TDI. In our study, we also found that tD-MPI values for both septal and lateral segments were significantly decreased after successful revascularization within 3 months. In a previous study, Cheng et al demonstrated improvement in regional contractility as well as wall thickening confined to revascularized CTO segments and no change in overall LVEF after successful PCI for CTO.34 After CTO recanalization, blood flow in both occluded and donor artery increases. As a consequence, regional wall contractility in the territory subtended by the CTO and donor artery returns toward normal. These clear benefits after CTO-PCI may explain the improvement on global cardiac functions assessed by MPI and tD-MPI.
Study limitations. Several limitations of the present study should be mentioned. We have evaluated only patients with RCA-CTO and collaterals provided by LAD in this single-center study. The methodology used to assess non-invasive CFVR is applicable with a high success rate only in the LAD. Hence, our results cannot be generalized for other coronary arteries. We used TTE to measure CFVR of the donor artery instead of invasive methods such as FFR, which has been shown to have high specificity and sensitivity to correctly identify functional status of the coronary arteries. However, CFVR by TTE is non-invasive, cheaper, entails no radiation exposure, and is easily available at bedside. The sample size is relatively small; for this reason, our study does not allow definitive conclusions. However, our data suggest that CTO recanalization results in increased blood flow in the donor artery, as well as improvement in global cardiac functions. Levels of MPI, tD-MPI, and CFVR are affected by several medications, such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, statins, anti-aggregants, and β-receptor blockers. In our study, these medications may affect our results, but neither type of cardiovascular drugs nor their doses were changed after the revascularization procedure.
Our study confirms that CTO recanalization not only restores the blood flow in the occluded artery, but also increases the diminished blood flow in the donor artery, which supplies collaterals to the CTO territory, resulting in the return of global myocardial function.
Acknowledgment. We thank the cardiology fellows and nurses of the Adana Numune Training and Research Hospital, Department of Cardiology, for their contributions to this study.
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From 1Adana Numune Training and Research Hospital, Department of Cardiology, Adana, Turkey; 2Kafkas University School of Medicine, Department of Cardiology, Kars, Turkey; 3Yenimahalle State Hospital, Department of Cardiology, Ankara, Turkey; and 4Dicle University School of Medicine, Department of Cardiology, Diyarbakır, Turkey.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted April 28, 2014, provisional acceptance given May 5, 2014, final version accepted June 12, 2014.
Address for correspondence: Ahmet Oytun Baykan, Adana Numune Eğitim ve Araştırma Hastanesi, Seyhan Uygulama Merkezi, Kardiyoloji Kliniği, Süleyman Demirel Bulvarı, Çukurova, Adana, Turkey. Email: email@example.com