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Ann Thorac Surg 1996;61:1428-1434
© 1996 The Society of Thoracic Surgeons
Departments of Cardiac Surgery and Cardiology, Austin and Repatriation Medical Centre, Austin Campus, Melbourne, Australia
Accepted for publication January 24, 1996.
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Methods. We studied prospectively 57 patients with stable coronary artery disease and poor left ventricular function (left ventricular ejection fraction, 0.28 ± 0.04) who underwent coronary artery bypass grafting. Clinical variables were assessed as predictors of outcome in all patients, and preoperative stress thallium-201 scintigraphic data were analysed in 37 patients.
Results. The operative mortality was 1.7%. At 12 months after operation, 46 of the 49 survivors were angina-free and 35 had fewer heart failure symptoms, but postoperative left ventricular ejection fraction (0.30 ± 0.09) did not change significantly. Eighteen survivors had left ventricular ejection fraction improved by 0.05 or more (0.30 ± 0.03 preoperatively, 0.40 ± 0.05 postoperatively; p = 0.0001). The adjusted odds ratio of large reversible thallium-201 defects in predicting such outcome was 15 (95% confidence interval, 1.6 to 140), whereas other clinical variables had no predictive value. The transplantation-free 5-year survival was 73%.
Conclusions. In patients with poor left ventricular function, surgical revascularization can be performed safely, with good symptomatic relief and long-term survival. One-year survival and improvement in left ventricular function is better in patients with large reversible defects on preoperative stress thallium-201 scintigraphy.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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In patients with coronary artery disease and impaired left ventricular function, myocardial revascularization is often performed to ameliorate ischemic symptoms, to prevent future ischemic events, and to improve survival. However, the effects of revascularization on resting left ventricular function remain a subject of active investigation. In these patients, impairment of contractile function is the result of a continuum of pathologic processes ranging from total irreversible replacement of functioning myocardium by fibrous tissue as a result of infarction, to viable myocardium with reduced contractility secondary to ischemia. Myocardial ``stunning'' [1] can be described as a transient hypocontractile state after postischemic reperfusion in which viable myocytes regain contractile function spontaneously [2]. In contrast, ``hibernating'' myocardium contains viable myocytes with resting ischemia that remain hypocontractile unless the oxygen supply-demand imbalance can be reversed, usually by revascularization [3]. Patients with extensive areas of hibernating myocardium can be expected to derive the greatest benefits from revascularization in terms of improvement of left ventricular function, heart failure symptoms, and survival [4, 5].
Previous studies that have evaluated the impact of revascularization in patients with poor left ventricular function often included subjects with recent acute ischemic events and unstable symptoms, or did not clearly define the inclusion criteria [6–9]. Inclusion of patients with significant stunning may falsely attribute to revascularization any subsequent improvement that may have occurred spontaneously. Furthermore, most previous studies have been performed retrospectively and usually left ventricular function was not measured by a standard reproducible technique [7, 9–11].
The aim of this study was to examine prospectively the effects of coronary artery bypass grafting on resting left ventricular function and survival in a cohort of patients with clinically stable coronary artery disease and poor left ventricular function in whom the influence of myocardial stunning had been specifically minimized. Hence, postoperative changes in contractile function would likely be independent of resolution of myocardial stunning. In all patients, left ventricular function was measured by radionuclide ventriculography before and after revascularization. Also, an assessment was made of the predictive value of preoperative variables on improvement in left ventricular function and survival after operation.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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0.35 on radionuclide ventriculography) who were accepted for coronary artery bypass grafting were entered prospectively into the study after giving informed consent. Patients with unstable angina, myocardial infarction, and other significant ischemic events within 4 weeks of the study were specifically excluded. Those requiring repeat coronary artery bypass grafting or concomitant procedures (including valvular operation and aneurysmectomy) were also excluded. Patients with left main coronary artery stenosis of 50% or more of the luminal diameter were not included because of the risk involved in investigational stress testing. The protocol was approved by the Austin Hospital Ethics Committee for Human Research.
Coronary Revascularization
All patients underwent coronary artery bypass grafting under mild hypothermic (34°C) cardiopulmonary bypass using a membrane oxygenator. In all cases, distal anastomoses between the bypass grafts and native coronary arteries were performed under aortic cross-clamp on a heart arrested by blood cardioplegia infused at room temperature. In the initial part of the study, cardioplegic solution was infused into the aortic root antegradely. The proximal ends of vein grafts were then anastomosed to the aorta under a side-biting clamp. As retrograde coronary sinus cardioplegia became more popular, this technique was adopted in patients in the latter part of the study. These patients had proximal anastomoses completed during the single aortic cross-clamp period. Cardioplegic arrest and metabolic repletion of the arrested heart was maintained by regular infusions of blood cardioplegia every 15 to 20 minutes while the aorta was cross-clamped.
At operation, the patients received from one to six coronary bypass grafts (mode of three). Fifty-four patients (95%) had at least one internal mammary artery used as a conduit, 8 of whom received bilateral internal mammary arterial grafts. The aortic cross-clamp time and cardiopulmonary bypass time were 61 ± 19 and 97 ± 27 minutes, respectively.
Clinical Assessment and Outcome
Before the operation, angina and heart failure symptoms were graded using the Canadian Cardiovascular Association and New York Heart Association classifications. Pathologic Q waves on surface electrocardiogram (in at least two leads of the same coronary vascular distribution) and the cardiothoracic ratio on chest roentgenogram were also recorded. All surviving patients were reviewed at 1 month and 12 months postoperatively. Angina and heart failure symptoms were reassessed by an independent physician with no knowledge of the preoperative clinical status and other investigational findings, using the same classifications. Subsequently, the patients had yearly telephone interviews by an experienced research assistant who documented predetermined end points including death and cardiac transplantation.
To evaluate the results of revascularization objectively, patients were divided into two categories. The first category, a favorable outcome, was defined as survival for at least 12 months after operation with an increase in LVEF of 0.05 or greater when comparing preoperative and postoperative radionuclide ventriculography. The second category, a poor outcome, included those patients who either died of a cardiac cause or underwent cardiac transplantation during the first 12 months after operation, or survived this period but showed insignificant improvement (<0.05), no change, or a decrease in LVEF.
Thallium-201 Scintigraphy
Fifty-one of the 57 patients underwent stress thallium-201 single-photon emission computed tomography (SPECT) before coronary artery bypass grafting. To provide uniform reporting, two independent nuclear medicine physicians reassessed all available studies. Only 37 of these were able to be recalled for analysis. Twenty-nine of these patients had exercise stress: 19 underwent the Bruce treadmill exercise protocol and 10 performed a symptom-limited bicycle exercise protocol. Eight patients underwent a pharmacologic stress protocol using dipyridamole (0.56 mg/kg). Thirty-two of the 37 patients who had thallium-201 SPECT received a reinjection of thallium-201 at rest before redistribution imaging (this study commenced before the reinjection protocol for severe defects became routine in our institutions). Three patients had redistribution imaging performed after an interval of approximately 24 hours to detect regions with late thallium-201 uptake.
To determine the presence and extent of any ischemic, viable myocardium, the left ventricle was divided into 19 segments (Fig 1
). The relative uptake of thallium-201 in each segment at stress and after redistribution was assessed visually and classified as normal, mildly, moderately, or severely reduced, given scores of 1, 2, 3, or 4, respectively. A left ventricular segment was described as showing a reversible perfusion defect when its thallium-201 uptake at stress was reduced and its uptake score at redistribution had improved by at least one grade. To evaluate the extent of such changes, the presence of redistribution in one to four left ventricular segments was classified as being of small to moderate size. Reversibility present in five or more segments was categorized as a large area. In contrast, a segment with no change in uptake score between stress and redistribution was described as a fixed perfusion defect. The intraobserver agreements in the detection of reversible changes in thallium-201 uptake within myocardial segments were 90% and 92%.
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Statistical Analysis
Data are expressed as mean ± 1 standard deviation where appropriate. Sensitivity, specificity, and positive and negative predictive accuracy were calculated using standard definitions. Paired Student's t test was used to test differences between mean values of continuous variables. Multivariate analysis of preoperative predictors of outcome was performed using logistic regression. Postoperative survival was calculated using the Kaplan-Meier method. A p value less than 0.05 was considered to represent statistical significance.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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. Their LVEF ranged from 0.17 to 0.35 (mean, 0.28 ± 0.04). Of the 37 patients who underwent thallium-21 SPECT, 6 had fixed perfusion defects only. The other 31 patients demonstrated some degree of reversibility, 13 of whom had small to moderate-sized defects whereas 18 had large defects.
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Effects of Operation on Clinical Status
Angina and heart failure symptoms at 1 and 12 months postoperatively are summarized in Figures 2 and 3. Firty-six patients were alive at 1-month follow-up, all of whom were free of angina. At 1 year, 46 of the 49 surviving patients (94%) remained angina free. Thirty-five of these survivors (71%) also reported amelioration of their heart failure symptoms. Twelve patients (24%) improved by one class and 23 (47%) improved by two or more classes according to the New York Heart Association classification.
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Using the previously defined objective criteria, 18 patients demonstrated favorable postoperative outcome (2 patients who did not undergo follow-up radionuclide ventriculography and 1 patient who died of malignancy were excluded). Their LVEF improved by 0.10 ± 0.04 (range, 0.05 to 0.21), rising from 0.30 ± 0.03 preoperatively to 0.40 ± 0.05 postoperatively (p = 0.0001). At 12 months after the operation, 17 of these patients were free of angina and 15 reported an improvement in heart failure symptoms by at least one New York Heart Association class. The 36 patients with poor postoperative outcome had a mean preoperative LVEF of 0.27 ± 0.04. Of these, 6 died within 12 months of operation and 1 underwent cardiac transplantation for refractory heart failure. The remaining 29 survivors failed to have an improvement in LVEF of 0.05 or more at 1 year. Six of these patients improved their LVEF by 0.01 to 0.04, 1 had no change, and in 22 LVEF decreased after operation. The LVEF of these 29 patients fell from 0.27 ± 0.04 preoperatively to 0.24 ± 0.05 postoperatively (p = 0.0004). Twenty-seven patients were angina-free at 1 year and 19 had improved heart failure symptoms. There were no significant differences in postoperative symptomatic improvement in the survivors between the two patient groups with different objective outcome on the basis of changes in LVEF.
Predictors of Postoperative Outcome
Excluding 1 patient who died of malignancy within 12 months of the operation and 2 patients who did not undergo repeat radionuclide ventriculography, 54 patients were included in an analysis of preoperative variables in the prediction of outcome after revascularization. Severe preoperative angina and heart failure symptoms (classes III and IV), age at operation, presence of pathologic Q waves on surface electrocardiogram, and cardiothoracic ratio on chest roentgenograms were examined in all patients. Findings of preoperative stress thallium-201 SPECT were available in 35 patients. In these patients, the presence of extensive reversible perfusion defects on SPECT (arbitrarily 
5 of 19 segments) was used as an indicator of clinically significant ischemic viable myocardium. Comparison of these variables in the two patient groups with different outcome is presented in Table 2. As shown, significantly more patients in the favorable outcome group had large reversible defects on thallium-201 SPECT. None of the other clinical variables were found to be significantly different in these two groups.
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The preoperative and postoperative LVEF of patients with and without large reversible defects on thallium-201 SPECT are illustrated in Figure 4. All 18 patients with large reversible defects survived for at least 12 months, with mean LVEF rising from 0.29 ± 0.04 preoperatively to 0.34 ± 0.08 at 12 months after operation (p = 0.01). Sixteen of these 18 patients noted an improvement in heart failure symptoms at 1 year postoperatively.
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Long-Term Survival During Follow-up
The follow-up period for patients in this study ranged from 13 to 72 months. During follow-up, 11 deaths were reported (two due to malignancy) and 1 patient underwent cardiac transplantation. The probability of survival free of transplantation is plotted in Figure 5. As shown, the probabilities of survival at 12 months, 3 years, and 5 years postoperatively were 86%, 80%, and 73%, respectively.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Improvement in angina and heart failure symptoms occurred in most patients in this study after revascularization, independent of objective outcome as assessed by postoperative changes in LVEF. This discrepancy between subjective and objective status has a number of possible explanations. Changes in LVEF may not reflect the postoperative improvement in coronary flow reserve in areas of viable myocardium with no resting ischemia. Hence, a patient with no significant postoperative improvement in LVEF can still potentially have improved heart failure symptoms and exercise tolerance due to resolution of ischemic left ventricular dysfunction induced by exercise and improvement in diastolic function. The New York Association classification of symptoms in patients with heart failure has been the subject of criticism in recent years [15]. It relies on subjective history taking and has been shown to have relatively poor reproducibility. After a coronary operation, a placebo effect can potentially influence the subjective ``clinical status'' of patients as assessed by this classification. More objective measurements of functional, hemodynamic, and neurohormonal status should be considered in future studies.
Because improvement in LVEF was one of the predefined objective end points, radionuclide ventriculography was used as the standard technique for its measurement before and after revascularization. An increase in LVEF of 0.05 or more after operation was arbitrarily chosen to overcome any potential variation in its measurement and to represent an increment that may have an influence on long-term prognosis. In the present study, only 18 patients achieved such a favorable outcome. They represented the subgroup who derived an additional benefit of improved left ventricular function from revascularization. In contrast, 22 of 29 patients in the poor outcome category showed a decrease in LVEF postoperatively. The mean LVEF of these 47 survivors who underwent repeat radionuclide ventriculography did not improve significantly after operation. This indicates that improvement in left ventricular function is not a universal finding after revascularization. Instead, it depends on factors including the presence and extent of stunned and hibernating myocardium, the surgeon's ability to completely revascularize hibernating tissue, perioperative myocardial infarction, postoperative graft complications, and the presence of paradoxical motion in the interventricular septum after cardiopulmonary bypass [16]. This study is limited by a lack of angiographic follow-up on postoperative graft patency.
In this study, the presence of large reversible perfusion defects on preoperative stress thallium-201 SPECT was independently predictive of postoperative improvement in LVEF, whereas other clinical variables failed to show any predictive value. Patients with this finding also had more frequent improvement in heart failure symptoms at 1 year postoperatively. Although SPECT images were available for blinded reassessment in only 37 patients, we believe that data from the analysis can probably be generalized to the other patients in the study because of identical inclusion criteria and baseline data in those whose SPECT studies could not be reviewed. Other studies have shown that findings from preoperative positron emission tomography and low-dose dobutamine echocardiography are also predictive of postoperative outcome [5, 9, 17, 18], supporting the use of these imaging modalities before revascularization in patients with poor left ventricular function in whom prediction of recovery in left ventricular function may be clinically relevant. However, it should be noted that many patients who did not have large reversible thallium-201 defects reported improved angina and heart failure symptoms postoperatively. These patients also benefited from revascularization and thus should not be denied operation based on scintigraphic findings alone.
The reversible defects on stress thallium-201 SPECT represent regions of ischemic viable myocardium with relative hypoperfusion during stress that are capable of further thallium-201 uptake at rest during redistribution imaging [19]. The latter identifies intact cellular membrane function, which is a good marker of myocardial viability [20]. Without any documentation of the relative perfusion status at rest and correlation with regional contractile function, these areas cannot be assumed to be composed entirely of hibernating myocardium, although this is likely to be present. A number of recent studies have challenged the conventional concept of hibernation and instead postulated that myocardium that might be considered to be hibernating may, at least in some cases, be hypocontractile as a result of repetitive episodes of acute ischemia and reperfusion with a persistent stunning effect [21]. Perhaps the reversible thallium-201 defects seen in some patients in this study represented potential areas that were susceptible to myocardial stunning during subclinical ischemic events.
The operative mortality of 1.7% in the present study was low, and very few patients required interventional supportive measures in the early postoperative period. In addition to minimization of ischemic injury during the operation through meticulous surgical and anesthetic techniques, recent studies suggest that ischemic ``preconditioning'' may exert protective effects against subsequent ischemic injury [22]. Similarly, it is possible that the presence of hibernating myocardium may, at least in some cases, be protective against superimposed ischemic injury during cardiopulmonary bypass. In fact, the majority of patients in whom SPECT results were available for analysis in this study had some degree of reversibility, suggesting the presence of ischemic, viable myocardium.
The medium-term survival of the patient cohort compares favorably with those from other published series [7, 9–11], lending support to an aggressive approach to surgical revascularization of selected patients, even those with poor left ventricular function. Although historical comparison between patients in this study and those from other published nonsurgical series (medical management) is inappropriate because patients accepted for operation represent a highly selected cohort, it is interesting to note that patients with LVEF of 0.35 or less and heart failure symptoms in the Studies of Left Ventricular Dysfunction demonstrated a 4-year survival rate of 60% and 65% in the placebo arm and treatment arm (angiotensin-converting enzyme inhibitor), respectively [23].
In conclusion, in patients with coronary artery disease and poor left ventricular function in whom contribution by myocardial stunning has been minimized, revascularization by coronary artery bypass grafting can be performed safely with low operative mortality. In this study, improvement in angina and heart failure symptoms was seen in the majority of patients after operation, and the transplantation-free survival at 5 years was 73%. Twelve-month survival and improvement in resting left ventricular function was predicted independently by the presence of large areas of ischemic viable myocardium as indicated by reversible perfusion defects on preoperative stress thallium-201 scintigraphy.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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References |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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