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J Am Coll Cardiol, 1999; 33:1848-1854 © 1999 by the American College of Cardiology Foundation |
a Department of Cardiovascular Medicine, Northwick Park and St. Mark’s Hospitals and Institute of Medical Research, Harrow, United Kingdom
* Cardiovascular Division, University of Virginia, Charlottesville, Virginia, USA
Manuscript received July 31, 1998; revised manuscript received January 25, 1999, accepted February 15, 1999.
Reprint requests and correspondence: Dr. Avijit Lahiri, Department of Cardiology, Northwick Park Hospital, Harrow, Middlesex HA1 3UJ, United Kingdom
nphcardicac{at}compuserve.com
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Abstract |
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This study was conducted to evaluate the effect of revascularization on survival in patients with congestive heart failure (CHF) due to ischemic left ventricular (LV) systolic dysfunction based on the presence of myocardial viability (MV).
BACKGROUND
There are insufficient data regarding the survival benefit of revascularization in patients with CHF due to ischemic LV systolic dysfunction.
METHODS
Follow-up was obtained in 87 consecutive patients with CHF due to ischemic LV systolic dysfunction (New York Heart Association [NYHA] class II-IV; LV ejection fraction <0.35) who underwent low-dose dobutamine echocardiography (DE). MV within each of 12 myocardial segments representing the LV was defined as having either: 1) normal function or mild dyssynergy at rest; 2) severe resting dyssynergy that improved on DE, or 3) worsening of function on DE except in the case of akinesia.
RESULTS
At a mean follow-up of 40 ± 17 months, 37 patients had received revascularization on the basis of clinical grounds, and there were 22 (25%) cardiac-related deaths. Multivariate Cox regression analysis revealed that when patients with at least five segments showing MV underwent revascularization, mortality was reduced by an average of 93% (confidence interval of 22% to 99%), which was associated with improvement in NYHA class as well as LV ejection fraction. Patients with less than five segments showing MV who underwent revascularization (and thus, showing mostly scar), and those with at least 5 segments demonstrating MV who were treated medically, had a much higher mortality.
CONCLUSIONS
Revascularization produces a clear survival benefit in patients with CHF due to ischemic LV systolic dysfunction who have a significant region of the LV demonstrating MV. These data may have wide-ranging implications in the management of patients with coronary artery disease whose main clinical presentation is CHF.
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It is now recognized that revascularization provides both symptomatic relief and mortality benefit in patients with angina and ischemic LV systolic dysfunction (3–7). Ischemia in these patients can be documented on exercise electrocardiogram (ECG) (8,9). Most patients with CHF, however, are unable to exercise to work loads that can manifest ischemia on the ECG. Baseline abnormalities on the ECG also preclude interpretation of minor exercise-induced changes in many instances. Thus, recognition of viable but potentially ischemic myocardium is problematic in this cohort of patients. Without evidence for ischemia, physicians are reluctant to consider revascularization as an option, because LV systolic dysfunction in these patients is presumed to be due to multiple infarctions.
Echocardiography is a reliable clinical means for assessing regional LV function. If regional LV function is normal or only mildly reduced, myocardial viability (MV) is known to be present (10). When resting regional LV function is severely reduced, however, it is not possible to differentiate MV from scar. The response of severely dysfunctional myocardium to dobutamine has been shown to predict MV in patients post–myocardial infarction (10–13), and those with chronic ischemic LV dysfunction (14–18). The purpose of our study was to assess the interaction between the amount of MV (defined by regional LV function at rest and during dobutamine) and revascularization in terms of its effect on long-term outcome in patients with chronic CAD whose main clinical presentation is CHF. The hypothesis tested was that revascularization would not only improve symptoms and regional LV function, but would also provide a survival benefit if sufficient MV was present. Conversely, providing revascularization to a severely dysfunctional LV that did not have enough MV would not be beneficial.
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Methods |
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0.35, and 3) clinical evidence of CAD (usually prior infarction, and in some cases documented ischemia on exercise testing). Patients with significant valvular disease, unstable angina, myocardial infarction within three months, sustained ventricular tachycardia or atrial fibrillation were excluded from the study. All patients underwent clinical assessment, rest echocardiography, low-dose dobutamine echocardiography (DE), coronary angiography and prospective follow-up. Echocardiography. Echocardiographic images were acquired in the standard parasternal long and short axis as well as apical four- and two-chamber views. LV ejection fraction at rest was estimated from the apical views using the modified Simpson’s method previously validated in our laboratory (19). Dobutamine was infused intravenously starting at 5 µg/kg/min, and increased to 10 and then 15 µg/kg/min, with each dose maintained for 5 min (13). Although imaging was performed continuously, data were acquired only at baseline and during the last minute of each dobutamine dose.
Images were analyzed in a quad-screen cine-loop format (14) by two experienced observers blinded to all other clinical information. Systolic wall thickening (SWT) was graded in each of 12 myocardial segments (Fig. 1) as: 1 = normal; 2 = mild hypokinesia; 3 = severe hypokinesia; and 4 = akinesia (20) using a consensus opinion. SWT index was calculated by summing the grades of all segments that were visualized and dividing this sum by the number of segments visualized. The segments ascribed to each of the three vascular vascular territories are mentioned in the legend to Figure 1.
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1 grade when systolic function was severely reduced (grade 3 [14]); or, 3) worsening of systolic function on DE (indicating inducible ischemia, and thus also MV [18]), except when akinesia (grade = 4) was present at rest (10).
Coronary angiography.
CAD was defined as 50% luminal diameter narrowing of a major epicardial coronary artery or its major branch. Each patient was classified as having one-, two- or three-vessel disease. In addition, a coronary jeopardy score was calculated based on dividing the coronary tree into six segments and giving each segment with a 75% stenosis, or any segment distal to such a stenosis, a score of 2. In patients with a left dominant system, the right coronary artery was assigned no score. The maximal possible score in any patient was 12 (21).
Follow-up. All patients underwent clinical assessment at a mean of 21 months after entering the study. Survival status was determined at a mean of 40 months by contacting the patient or next of kin. The cause of death was established by review of hospital records or from the patient’s physician. Cardiac deaths were defined as those resulting from acute myocardial infarction, refractory CHF or occurring suddenly and not being attributed to other known causes.
Statistical methods. Continuous variables are expressed as mean ± 1 SD, and categorical variables are expressed as proportions. Survival data were assessed by Cox proportional hazard models (22) to estimate the interaction of revascularization with the extent of MV as well as with other potential prognostic factors, and to characterize the effects of these interactions on mortality. Univariate Cox regression analysis was initially performed using clinical, echocardiographic and angiographic variables. Multivariate Cox regression analysis was then performed by entering into the model variables that had a p value of <0.10 on univariate analysis. All variables with a p value of <0.05 were allowed to remain in the final model.
A receiver-operator characteristics curve was plotted to define the sensitivity and specificity of different cutoff points for the number of viable segments that needed to be revascularized to show survival benefit (23). Patients were then classified into groups based on the best cutoff point and the type of treatment offered (revascularization vs. medical management). Baseline clinical characteristics (including medical therapy), and echocardiographic as well as angiographic data, were compared between these groups using analysis of variance or Fisher exact test. Kaplan-Meier life table analysis was performed to assess event-free survival (24), which was compared between the four groups using the Mantel-Cox test. A p value of <0.05 (two-sided) was considered significant.
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Results |
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3), which was consistent with the low resting LV ejection fraction in these patients. Less than half of the dysfunctional segments in these patients showed improvement on DE. Most segments showed no response (improvement or worsening) to DE. Despite severe LV dysfunction, however, on an average more than half of the segments showed MV based on the combined assessment of resting and dobutamine-induced wall thickening.
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At a mean follow-up of 40 ± 17 months, there were 22 (25%) cardiac-related deaths: 5 from acute myocardial infarction, 14 from progressive CHF and 3 occurred suddenly. On Cox regression, the univariate predictors of survival were the number of segments demonstrating MV, number of viable segments in the right and left circumflex coronary territories, occurrence of revascularization and the interaction between MV and the occurrence of revascularization when the number of segments showing MV was at least five (Table 2). The last variable was the most important independent predictor of survival on multivariate Cox regression analysis. The only additional variable that was predictive of survival on multivariate analysis was the baseline NYHA class (Table 2).
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5 of the 12 myocardial segments) and type of treatment offered (revascularization vs. medical management): Group 1 (n = 31) had MV and underwent revascularization; Group 2 (n = 32) had MV but were managed medically; Group 3 (n = 6) had no MV but underwent revascularization; and Group 4 (n = 18) had no MV and were treated medically. There were no differences in any of the variables between the four groups at the time of entry into the study (Table 3).
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Discussion |
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The problem of CHF. There are ample data to support the use of revascularization in patients with CAD and LV systolic dysfunction who have angina. Such patients show marked symptomatic relief as well as significant improvement in long-term survival (3–6,25,26), and their regional LV systolic function generally improves (4–6). The systolic dysfunction can occur from either chronic reduction in resting myocardial blood flow or repetitive ischemia, or both (27). In either case, successful revascularization removes the cause of dysfunction.
Many patients with CAD present with symptoms other than angina. At times it is dyspnea on exertion from transient LV systolic dysfunction caused by exercise-induced ischemia. More often, the dyspnea is associated with chronic LV systolic dysfunction and CHF, with angina not being a major symptom. With people living longer lives, and the prevalence of CAD being higher in them, the incidence of chronic ischemic LV dysfunction is increasing rapidly, so that the epidemiology of CHF has changed in recent years from causes other than CAD to predominantly CAD (1,2).
Admission (and readmission) for CHF is now the leading cause of hospitalization in the western hemisphere (28). Many of these patients have reversible ischemic LV dysfunction, and if revascularized, would show both symptomatic improvement and benefit from a longer life. The cost of revascularization may offset the cost of repeated hospitalizations and improve the quality of life. With modern surgery and other forms of revascularization, elderly patients are tolerating interventions much better (29). If surgery is not an option, aggressive medical therapy to alleviate ischemia and its sequelae, such as with carvedilol, may also provide survival benefit (30). The challenge is to recognize the presence of reversible LV systolic dysfunction in these patients.
Comparison with previous studies.
There are remarkable similarities between our results and those of Ragosta et al. (6) and Pagley et al. (7) using 201thallium imaging. Similar to us, they found only a minority of patients with chronic ischemic LV dysfunction lacking evidence for MV. Using a 15-segment model of the LV, they found that if 7 dyssynergic segments exhibited MV, LV ejection fraction was likely to improve after revascularization (6). Survival benefit was seen only in patients undergoing revascularization. Conversely, patients with sufficient MV who did not undergo revascularization had a poor outcome (7).
Dobutamine echocardiography has also been used to assess MV in chronic ischemic LV dysfunction. In all studies, patients with MV had poor outcome on medical therapy compared with revascularization (31–33). Williams et al., however, reported less events in medically treated patients with no MV compared with those with MV (31). The difference between their study and ours could be explained by the differences in the types of events. Whereas we considered only cardiac-related death as events, they included other soft points as well. Our results are very similar to those of Afridi and colleagues, who demonstrated improved survival in patients with CAD and severe LV dysfunction who had both MV and revascularization (32). Like us, they found lack of MV and revascularization to be associated with poor outcome. Like Afridi et al. and us, Meluzin et al. also showed that the beneficial effect of revascularization was related to the amount of MV (33).
The major difference between our study and all previous studies assessing the role of MV in LV dysfunction due to CAD is that although these studies also included patients with CHF, their major clinical presentation was angina. We specifically studied patients whose main presentation was CHF. Nonetheless, these studies combined with ours make a strong argument for assessing MV in patients with ischemic LV dysfunction irrespective of the presenting symptom. Such an approach can guide management.
For scoring regional LV function, we selected a model in which each myocardial segment is equivalent in weight (20). Thus, when half the segments are involved, half the LV myocardium is involved. The major difference between this and some other models is the segmentation of the apex. In our model, the apex is divided into two segments. Consequently, some adjustments need to be made when interpreting our results in the context of other segmentation schemes.
Study limitations. Similar to previous studies (5–7,31,33), this is a single-center study where selection bias is unavoidable. The patients were selected from an outpatient setting and may not be as sick as those who seek repeated hospitalizations for CHF. The number of patients in the group who underwent revascularization in the absence of MV is small. Also, the results may not be applicable to populations where multi-vessel disease is less frequent. A randomized design would undoubtedly be ideally suited for a study such as this, but it is difficult, if not impossible, to prospectively randomize patients with very poor LV systolic function for surgery versus medical management.
In our study, the results of DE were not divulged to the physician making the decision whether to revascularize or not. Although no differences were noted between patients undergoing revascularization and those receiving medical management, selection bias may have favored taking one group to surgery over another. Factors such as quality of vessels on angiography, pulmonary status and the reluctance to operate on patients with poor LV ejection fraction played a role in our study. A significant number of patients also did not receive surgery because of lack of funds.
We only used low-dose dobutamine in our study. We were, therefore, unable to study the value of the "biphasic" response on the prediction of survival. The "biphasic" response indicates the presence of a physiologically significant coronary stenosis proximal to viable myocardium (10), and revascularization of myocardium showing this response is highly predictive of functional recovery after revascularization (16). However, a "biphasic" response can only be seen in segments that first demonstrate an improvement in thickening, a criterion for MV in our study. Thus, segments likely to ultimately show a "biphasic" response were considered viable in our study. Segments likely to demonstrate ischemia on DE (worsening of function except in the presence of akinesia) were also considered viable.
Conclusions. Patients with CHF due to LV systolic dysfunction from CAD who have sufficient MV on echocardiography have a marked survival benefit from revascularization compared with those with MV who do not undergo revascularization or those without sufficient MV who undergo revascularization. This survival benefit is also associated with improvement in NYHA class and global systolic LV function. These data may have wide-ranging implications in the management of patients with ischemic LV systolic dysfunction whose main clinical presentation is CHF.
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Acknowledgments |
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Footnotes |
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