Complete Percutaneous Revascularization for Multivessel Disease in Patients With Impaired Left Ventricular Function

Pre- and Post-Procedural Evaluation by Cardiac Magnetic Resonance Imaging

Patient population

Patients with multivessel coronary artery disease and LV wall motion abnormalities who were referred for PCI—on the basis of the discretion of the physician using the information of patient history, risk factors, and additional noninvasive stress testing if performed–were prospectively approached for enrolment in this study. Inclusion criteria were: 1) significant stenosis in at least 2 vessels; 2) sinus rhythm; and 3) abnormalities in wall motion on contrast ventriculography or echocardiography. Exclusion criteria were: 1) myocardial infarction within the last 3 months; 2) atrial fibrillation; 3) contraindications for magnetic resonance studies; 4) inability to give reliable informed consent; 5) known allergy to gadolinium-based contrast material; and 6) unstable coronary artery disease.

The institutional review board of the Erasmus Medical Center in Rotterdam approved the study, and all patients gave written informed consent.

Cardiac MRI protocol

A 1.5-T scanner with a dedicated 8-element phased-array receiver coil was used for imaging (Signa CV/i, GE Medical systems, Milwaukee, Wisconsin). Cine cardiac MRI was performed with a steady-state free-precession technique (FIESTA). Pulse sequence details have been published previously (8). To cover the entire ventricle, 10 to 12 short-axis slices were planned in the 4- and 2-chamber views (gap 2 mm). Dobutamine was infused at 5 and 10 μg/kg/min for 5 min at each dosage with an intravenous catheter, which was placed in the antecubital vein. Functional imaging was repeated during dobutamine infusion with the same long-axis imaging planes as at rest; for the short-axis only 3 slices were acquired. The 3 slices covered the basal, mid, and apical parts of the LV. During the test the patients were monitored with electrocardiographic leads for rhythm control, and blood pressure was measured at every 3-min interval. Criteria for ending the dobutamine-cardiac MRI examination were: 1) development of a new wall motion abnormality; 2) fall of systolic blood pressure of >40 mm Hg; 3) marked hypertension >240/120 mm Hg; 4) severe chest pain; 5) ventricular arrhythmias or new atrial arrhythmias; or 6) intolerable side effects of dobutamine.

Delayed enhancement (DE) cardiac MRI was performed 20 min after infusion of gadolinium-diethyltriaminepentaacetic acid (0.2 mmol/kg intravenously, Magnevist, Schering, Germany). A gated breath-hold T1-inversion recovery gradient-echo sequence was used as described previously (8). The slice locations of the delayed enhanced images were copied from the cine-images.

Definitions and data analysis

All conventional angiograms before PCI were evaluated by 2 observers, and lesions were scored visually (<50%, 50% to 99%, or 100%). A stenosis was considered significant if the diameter stenosis was >50%. Multivessel disease was defined as the presence of a significant lesion in at least 2 epicardial vessels in different perfusion territories. A chronic total occlusion (CTO) was classified as a complete occlusion for more than 3 months as obtained from either the clinical history of prolonged anginal chest pain or the date of the diagnostic angiogram before PCI. Revascularization was defined as complete when all significant stenoses defined on conventional angiogram were successfully treated. Revascularization was defined as incomplete when not all significant lesions but at least 1 was successfully treated. Revascularization was defined as unsuccessful when all significant lesions remained untreated. All cardiac magnetic resonance images were transferred to a Microsoft Windows-based personal computer for analysis with CAAS-MRV (version 3.2.1, Pie Medical Imaging, Maastricht, the Netherlands). This software uses the additional information of the long-axis to limit the extent of volumes at the base and apex of the heart. The EF was determined by subtracting end-systolic endocardial volume from the end-diastolic endocardial volume and dividing this number by the end-diastolic endocardial volume. Papillary muscles and trabeculations were considered as being part of the blood pool volume. A 17-segment model, excluding the apex, was used to analyze the myocardial wall in each patient. The LV segments were determined, according to the place of the stenosis and left or right dominance, as being perfused by a vessel with a significant lesion or a vessel with a nonsignificant lesion (9). Segmental wall-thickening was defined as a percentage increase of LV wall thickness during systole compared with diastole. We studied the effect of revascularization on global function and regional function. To study the effect of revascularization on regional myocardial function, segments in the perfusion territory of a significant lesion (related to anatomy on conventional angiogram) were analyzed. Myocardial segments were considered dysfunctional if wall thickening was <45% (10,11). Two viability indexes were evaluated before revascularization: 1) quantitative contractile reserve during dobutamine-cardiac MRI; and 2) transmural extent of infarction (TEI), which was calculated by dividing the hyper enhanced area by the total area in 16 segments and expressed as a percentage. The TEI was divided into 5 groups: 0%, 1% to 25%, 25% to 50%, 50% to 75%, and >75% infarct transmurality/segment, and segmental wall thickening was quantified for each group. A cutoff value of TEI <25% was used to predict functional recovery after revascularization (10,12,13). For quantitative contractile reserve during dobutamine-cardiac MRI a cutoff value of 7% was used (Kirschbaum MD, unpublished data that are under review, 2009). The percentage of dysfunctional but viable segments/patient was defined as the sum of all dysfunctional but viable segments divided by the total number of segments (n = 16). The angiograms and cardiac MRI data were analyzed in a random order with the investigator blinded to the clinical information and the previous results.

Biochemistry

Troponin T was measured 6 h after the procedure. If troponin T was above the upper limit of normal (0.02 μg/l) serial blood samples were taken every 6 h until maximum troponin T was identified. A diagnosis of an enzymatic periprocedural infarction was made according to the guidelines (European Society of Cardiology/American College of Cardiology/American Heart Association) if troponin T was >3× the upper limit of normal (14). Troponin T was quantified with Electro Chemi Luminescence Immuno Assay (ECLIA) on an Elecsys type 2010 (Roche Diagnostics, Almere, the Netherlands).

Statistical analysis

Continuous data are expressed as mean value ± 1 SD, whereas dichotomous data are expressed as numbers and percentages. Differences in baseline characteristics among patients undergoing complete, incomplete, or unsuccessful revascularization were evaluated with chi-square tests, Fisher exact tests, 1-way analysis of variance (ANOVA), or Kruskal-Wallis test where appropriate. The number of segments/patient perfused by a significant lesion was tested with 1-way ANOVA. Post hoc analysis was performed with Bonferroni correction. The changes in left ventricular ejection fraction (LVEF) and volumes within each group were tested with paired Student t test. The change in global functional parameters among groups was tested with ANOVA or the unpaired Student t test. The relationship between the amount of viability/patient and the change in LVEF was analyzed with linear regression analysis. We present the observed area under the receiver-operator characteristic curves (AUC) for both predictors. Differences in sensitivity and specificity between contrasting dobutamine-cardiac MRI and DE-cardiac MRI were evaluated by McNemar tests with exact methods. All tests were performed 2-sided, and a p value of <0.05 was considered statistically significant. All analyses were performed with SPSS version 15.0.1 (SPSS, Inc., Chicago, Illinois).

Patient population

Between June 2006 and January 2008, 118 patients who met the inclusion criteria were prospectively selected, of which 28 refused to participate. Of the 90 patients that were included, 71 completed the study protocol. Inclusion flow chart is presented in Figure 1. The mean time interval between baseline cardiac MRI and PCI was 36 ± 36 days; clinical evidence of myocardial infarction did not occur during this time interval. In 71 patients a second cardiac MRI scan was repeated at a mean of 7 ± 1 month after PCI. All treated patients received drug-eluting stents (DES). Baseline patient characteristics are presented in Table 1. Thirty-four patients underwent complete revascularization by PCI. The left anterior descending artery was treated in 34 patients, left circumflex artery was treated in 23 patients, right coronary artery was treated in 18 patients, the main stem was treated in 3 patients, first diagonal branch was treated in 6 patients, second diagonal branch was treated in 2 patients, and the marginal obtuses were treated in 3 patients. A total of 89 vessels and 94 lesions underwent PCI with DES implantation. An average of 1.9 DES/vessel and 4.1 DES/patient were implanted with an average stent length of 21.3 mm/patient. New York Heart Association (NYHA) functional classification improved from 2.6 ± 1.1 before revascularization to 1.1 ± 0.4 at 6-month follow-up.

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Flow Diagram of Patient Recruitment

Flow diagram of patient recruitment according to the Standards for Reporting of Diagnostic Accuracy statement. CMR = cardiac magnetic resonance imaging.

In patients with incomplete revascularization (n = 22), left anterior descending artery was treated in 8 patients, the first diagonal branch was treated in 1 patient, the left circumflex artery was treated in 4 patients, the marginal obtuses were treated in 1 patient, and the right coronary artery was treated in 10 patients. An average of 2.8 DES were implanted/vessel with an average stent length of 22.1 mm. The NYHA functional classification was 2.6 ± 0.7 before and changed to 1.4 ± 0.5 at 6-month follow-up. In 15 patients, PCI was not successful, mainly due to the presence of a chronic total coronary occlusion, and in some patients CABG was already rejected as a treatment option, due to comorbidity; these patients were only medically treated. The NYHA functional classification changed from 2.8 ± 0.8 at baseline and changed to 2.1 ± 1.1 at 6-month follow-up. Administration of low-dose dobutamine during cardiac MRI was well-tolerated by all patients; no serious side effects occurred. All patients with DE showed a distribution pattern extending from the endocardium, typical for ischemic heart disease.

Myocardial injury by DE-cardiac MRI and serum markers

Delayed enhancement cardiac MRI before PCI showed pre-existing myocardial damage in 85% (29 of 34) of the patients that underwent complete revascularization, in 77% (17 of 22) of the patients with incomplete revascularization, and in 87% (13 of 15) of the patients with an unsuccessful revascularization (p = 0.97). Mean infarct mass at baseline was 24 ± 21 g in patients that underwent complete revascularization, 19 ± 22 g in patients with incomplete revascularization, and 25 ± 21 g in patients with unsuccessful revascularization (p = 0.70). The number of dysfunctional segments (TEI <25%) and dobutamine responsive segments/patient showed no significant difference for the 3 groups (Table 2).

Troponin levels after procedure were elevated in 10 patients that underwent complete revascularization in which new patterns of late enhancement appeared in 3 patients and in 5 patients that underwent incomplete revascularization; none of these patients developed new patterns of DE. For the 3 patients in the complete revascularization group that developed new patterns of DE, maximum troponin levels were 0.65, 0.43, and 0.06 μg/l, and corresponding new infarct masses on DE were 6.7, 9.4, and 2.0 g, respectively. In the 3 patients with new DE, the average myocardial infarct mass changed from 11 g to 19 g. The change in infarct mass in these 3 patients did not change the total infarct size in the complete revascularization group (23.6 ± 21.7 g to 23.9 ± 22.6 g). In patients without successful revascularization, troponin levels were elevated in 3 patients, and only 1 patient developed a new infarct pattern on DE-cardiac MRI. The new infarct mass was 2 g. Total infarct mass did not change in these patients (22.0 ± 22.2 g to 20.6 ± 22.3 g).

LV function and volumes

Pre-PCI cardiac function did not differ significantly among the 3 groups (46 ± 12% vs. 49 ± 11% vs. 49 ± 13%, p = 0.51). In patients with complete revascularization by PCI, mean EF improved significantly from 46 ± 12% before revascularization to 51 ± 13% (p < 0.0001) at 6-month follow-up. The EF did not change significantly in patients after incomplete (49 ± 11% to 49 ± 10%; p = 0.88) and without successful revascularization (49 ± 13% to 47 ± 13%; p = 0.11). More detailed information is presented in Table 3.

The improvement in EF and cardiac output in the group that underwent complete revascularization was significantly higher as compared with patients that underwent incomplete or unsuccessful revascularization (Table 4). In patients with complete revascularization the change in global parameters was not influenced by positive troponin level after PCI or whether a CTO was treated. There was a trend toward a greater improvement in EF in patients with a baseline infarct size <24 g versus patients with an infarct size of >24 g (5.4 ± 4.4% vs. 2.8 ± 5.1%; p = 0.10) (Table 4).

Global contractile function and the predictive value of cardiac MRI

The change in EF was linearly related to the extent of the LV that was dysfunctional but viable before PCI for TEI <25% (r = 0.64; p < 0.0001) (Fig. 2A) and for contractile reserve >7% (r = 0.67; p < 0.0001) (Fig. 2B).

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

Prediction of Change in Ejection Fraction

The change in left ventricular ejection fraction was related to the extent of dysfunctional but viable myocardium before revascularization with delayed enhancement cardiac magnetic resonance imaging (A) and with dobutamine cardiac magnetic resonance imaging (B). Solid circles = complete revascularization; open circles = incomplete revascularization. TEI = transmural extent of infarction.

According to the linear regression line for TEI, 4% improvement in EF corresponded to 25% of the LV that was dysfunctional but viable, which are 4 segments before revascularization. The AUC for DE-cardiac MRI to predict improvement in EF was 0.84 (95% confidence interval: 0.74 to 0.95; p < 0.0001). For dobutamine-cardiac MRI, 3 dysfunctional but viable segments/ventricle were required to achieve an improvement in EF >4%. The AUC for dobutamine-cardiac MRI to predict improvement in EF was 0.91 (95% confidence interval: 0.82 to 0.99; p < 0.0001). Dobutamine-cardiac MRI had a significant higher sensitivity (100% vs. 70%; p < 0.0001), and specificity was not different (75% vs. 77%; p = 0.80) as compared with DE-cardiac MRI. Sensitivity, specificity, positive predictive value, and negative predictive value for both viability parameters were presented in Table 5.

Regional contractile function

Segments were stratified according to the presence or absence of viability in the perfusion territory of vessels with significant lesions. Segmental wall thickening improved significantly in patients who underwent PCI if contractile reserve (positive change in segmental wall thickening >7%) was present or if TEI was <25%. Segmental wall thickening remained unchanged in patients with unsuccessful PCI regardless, if viable tissue was present (Fig. 3).

• Download figure
• Open in new tab
• Download powerpoint

Figure 3

Segmental Wall Thickening for Dysfunctional Segments in the Perfusion Territory of a Treated Versus a Nontreated Vessel in Viable Versus Nonviable Segments

Improvement in segmental wall thickening was related to the presence of viability with magnetic resonance imaging before percutaneous coronary intervention (PCI). Solid bars = before PCI; open bars = 6 months after revascularization. *p < 0.05 versus before PCI.

Overall LV function

The magnitude of change of EF of 4% in patients that underwent complete PCI in the present study was relatively small but in line with previously reported data about the effect of CABG on LV function where an increase in EF of 4% to 5% was also reported (18,19). Several established clinical therapies for ischemic heart failure with a demonstrated significant impact on prognosis, such as angiotensin-converting enzyme inhibitor or beta-blocker therapy, are associated with similar improvements in LVEF (20).

The EF did not change in patients with multivessel disease followed by incomplete PCI, although segments in the perfusion territory of the significant lesion in patients with incomplete PCI were dysfunctional and viable, but apparently remaining nontreated lesions subserving dysfunctional segments might have diluted any positive effect. Not unexpectedly, an unsuccessful attempt did not improve EF. The significant increase in EF in patients that underwent complete revascularization might be a reason for the beneficial effect of complete revascularization on survival (6,7).

The PCI procedure might be associated with peri-procedural myocardial infarction, which might offset the potential improvement of successful revascularization of dysfunctional but viable myocardial tissue. To account for this effect, we performed DE-cardiac MRI before and after the procedure to detect the occurrence of procedure-related myocardial infarctions. Only 3 patients with successful, complete PCI developed a peri-procedural infarction on DE-cardiac MRI; in 2 of these patients EF improved, and in the other patient EF remained the same. In the patient group with an unsuccessful attempt, 1 patient developed a peri-procedural myocardial infarction of 2 g, which is small because the mean infarct mass in these patients was 25 g. In patients with incomplete PCI no peri-procedural infarcts were detected. Therefore we can conclude that the lack of change in EF in these last 2 patient groups was not influenced by peri-procedural infarctions.

The improvement in EF in the present study was linearly related to the amount of dysfunctional but viable myocardium before revascularization (r = 0.64, p < 0.001 for DE-cardiac MRI; and r = 0.67, p < 0.001 for dobutamine), as was also shown by previously reported data by Kim et al. (12). They reported in a cohort of 41 patients undergoing revascularization by either PCI (n = 14) or CABG (n = 27) that an increasing extent of dysfunctional but viable myocardium before revascularization correlated with greater improvements in EF after revascularization (r = 0.70; p < 0.001).

Prediction of recovery of EF

Previous studies using echocardiography or nuclear imaging have shown that improvement of EF after revascularization can be predicted with a sensitivity of 57% to 84% and a specificity of 53% to 73% (21). In our study we demonstrated that the predictive power of dobutamine-cardiac MRI was higher, with a sensitivity of 100% and a specificity of 75%. However, the sensitivity with DE-cardiac MRI was lower (70%), and specificity was 77%. Several reasons might explain why dobutamine cardiac MRI had a higher diagnostic performance than DE-cardiac MRI. Dobutamine stress testing is a functional parameter; the positive inotropic effects of dobutamine are a measure of functionality that mimics the potential effects of revascularization by improving contractile function in hypoperfused myocardium even in the absence of an increase in blood flow (22–24).

Delayed enhancement cardiac MRI is an anatomic parameter that accurately delineates the extent of infarction that will not improve after revascularization (25) but does not provide information on the extent and the functional state of the surrounding viable myocardium. The TEI is a relative value that omits the thickness of a segment and might therefore miss important information that is relevant for accurate prediction of recovery of function after revascularization therapy (13).

Study limitations

The number of patients included in this study was relatively small; nevertheless, with cardiac MRI as the gold standard for the serial assessment of cardiac function (26,27), we were able to demonstrate a significant improvement in EF. Baseline EF tended to be lower for the group that underwent complete revascularization as compared with the other 2 groups, which in theory might have influenced outcome results positively, although our results for PCI are in line with results published for CABG (18,19).

The patients in the present study had a moderately reduced EF. The results might not be applicable to patients with a severely reduced EF, because in these patients more nonviable segments might be present; however, cardiac MRI is able to detect the presence of viability that is independent of the EF. Our results might have been compromised by the occurrence of in-stent restenosis, because we did not perform late invasive coronary angiography. However, the likelihood of in-stent restenosis is low after DES implantation, and the patients that underwent complete revascularization were all symptom-free at follow-up (28).