CLINICAL STUDIES
Dobutamine-atropine stress echocardiography for risk stratification in patients with chronic left ventricular dysfunction
Steven C. Smart, MD, FACCa,
Peter N. Dionisopoulos, MDa,
Thomas A. Knickelbine, MDa,
Timothy Schuchard, MDa and
Kiran B. Sagar, MD, FACCa
a Medical College of Wisconsin, Division of Cardiovascular Medicine, Milwaukee, Wisconsin, USA
Manuscript received December 19, 1997;
revised manuscript received August 27, 1998,
accepted October 2, 1998.
Reprint requests and correspondence: Dr. Steven C. Smart, Medical College of Wisconsin, Division of Cardiovascular Medicine, 9200 W. Wisconsin Ave. Milwaukee, Wisconsin
ssmart{at}post.its.mcw.edu
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Abstract
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Objective
To assess the prognostic value of sustained improvement, scar and inducible ischemia with or without viability in patients with chronic left ventricular dysfunction (LVD).
Background
Dobutamine-atropine stress echocardiography (DASE) accurately detects scar, reversible dysfunction and the extent of coronary artery disease in LVD.
Methods
Three hundred fifty consecutive patients (age 62 ± 13 years, mean ± SD, 215 men/135 women) with moderate to severe LVD (LVEF < 40%, mean 30 ± 8%) underwent DASE and were followed for  18 months. Dobutamine-atropine stress echocardiographic findings were classified according to sustained improvement in all vascular territories, scar, inducible ischemia (worsening wall motion at peak dose only or biphasic responses) and their extent.
Results
Sustained improvement occurred in 83 patients (24%), scar alone in 99 (28%) and inducible ischemia in 168 (48%, with biphasic responses in 104). Ischemia was induced in all vascular territories in 26 patients. Patients with sustained improvement or scar alone were treated medically, whereas 46% (78/168) with inducible ischemia were revascularized (coronary bypass surgery, n = 67 or angioplasty, n = 11). There were 76 hard events including cardiac death in 59, nonfatal myocardial infarction in 11, and resuscitated sudden death in 6. Hard events were rare in sustained improvement (5%, 4/83), uncommon in scar (13%, 13/99) and common (p < 0.01) in medically treated patients with inducible ischemia (59%, 53/90). Cardiac deaths were especially common (p < 0.01) in patients with biphasic responses (55%, 28/51). Inducible ischemia independently predicted hard events ( 2 = 75.35, p < 0.001) along with reduced LVEF at peak dose (2 = 8.38, p = 0.004). Hard cardiac events were uncommon (8%, 6/78, p < 0.001) in patients with inducible ischemia who underwent early revascularization.
Conclusions
Inducible ischemia during DASE was the major determinant of outcome in LVD and independent of clinical data and left ventricular function. Improved wall thickening alone and scar alone predicted good outcome. Survival of patients with inducible ischemia was better after revascularization.
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Abbreviations and Acronyms
| | BPM | = beats per minute | | CAD | = coronary artery disease | | DASE | = dobutamine-atropine stress echocardiography | | LVD | = chronic left ventricular dysfunction | | LVEF | = left ventricular ejection fraction | | PET | = positron emission tomography |
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Chronic left ventricular dysfunction (LVD) is a major cause of morbidity and mortality (1–3). Left ventricular ejection fraction (LVEF) and age are predictive of outcome, but risk stratification is optimized by evaluation for coronary artery disease (CAD) and the mechanism of ventricular dysfunction (1–7). Nuclear medicine imaging, especially positron emission tomography (PET), has shown that viable myocardium jeopardized by CAD predicted adverse outcome and the benefits of revascularization, but it is expensive and not widely available (8–13).
Dobutamine-atropine stress echocardiography (DASE) is being increasingly used to evaluate patients with LVD for myocardial viability and ischemia (14–22) and distinguish nonischemic from ischemic cardiomyopathies. Inducible ischemia with or without improvement at low dose (biphasic responses) is specific and sensitive for CAD in these patients (17,19,21). Biphasic responses are also predictive of recovery with revascularization (19,20). Akinesis or dyskinesis unresponsive to dobutamine is indicative of myocardial scar (15,19). Sustained improvement in all vascular territories noninvasively differentiates nonischemic from ischemic cardiomyopathies (17,22).
The findings of scar, sustained improvement at low and peak dose and inducible ischemia with or without viability (biphasic responses) during DASE may also be useful for predicting outcome in LVD. In the only prior study, both improved wall thickening and worsening wall motion predicted adverse outcome (18). The authors did not differentiate the relative roles of myocardial viability and ischemia in predicting outcome. These findings correlated with a low sensitivity (42%) of inducible ischemia for CAD (18).
The aims of the present study were to 1) determine the value of the findings of scar, sustained improvement, inducible ischemia (worsening at peak dose or biphasic responses) and their extent in predicting outcome in patients with LVD, and 2) assess the effect of revascularization of high risk patients. To investigate these aims, 350 consecutive patients with LVEFs <40% underwent DASE and were followed for 18 months.
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Methods
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Patient selection.
From December 1992 to December 1996, 350 consecutive patients with LVEFs <40% without recent (<3 months) myocardial infarction or critical aortic stenosis underwent DASE for the detection of CAD or myocardial viability at the Medical College of Wisconsin, Milwaukee, Wisconsin. All were >21 years of age and gave informed consent and were followed for at least eighteen months.
Dobutamine-atropine stress echocardiography.
DASE was performed with continuous 12 lead ECG monitoring (23). ß adrenergic antagonists were not stopped. The stages of dobutamine infusion were 5, 10, 20, 30 and 40 µg/kg/min. Intravenous atropine (0.2 to 0.4 mg every 2 min to a maximum of 2 mg) was infused to achieve target heart rates if: 1) heart rate was submaximal at a maximal dose of dobutamine, or 2) cyclic variability in heart rate >10 bpm, hyperdynamic wall motion (end systolic left ventricular diameter <1 cm), or mild to moderate nausea occurred at submaximal doses of dobutamine (23). Stage duration was 7.5 min at 5 and 10 µg/kg/min and 5 min thereafter. Blood pressure was measured at 5 min of each stage.
Endpoints were: maximum dose, heart rate 120 bpm for patients >65 yr of age and 135 bpm for patients  65 yr (24), limiting chest pain, headaches, severe nausea, vomiting, 2 mm of ST elevation or depression compared to baseline in 2 leads, hypotension (systolic blood pressure <90 mm Hg), hypertension (systolic blood pressure 240 mm Hg), ventricular tachycardia (4 complexes at cycle lengths <600 msec) or sustained supraventricular tachyarrhythmias. Esmolol (0.1 to 0.5 mg/kg IV every 2 min up to 1.5 mg/kg) and nitroglycerin (0.4 mg SL every 5 min up to 3 doses) were administered after stopping the infusion if chest pain was severe or did not resolve within 4 min (23). The 59 (17%) patients with submaximal heart rates were grouped with those with maximal rates.
Six echocardiographic views (parasternal long and short axis and apical 4 chamber, 2 chamber, long axis, and short axis) were videotaped at rest and each dose of dobutamine and atropine. Images were digitized on-line at four stages (rest, 5 µg/kg/min, 10 µg/kg/min peak dose) with a Cine View (Prizm Imaging, Louisville, Colorado) R-wave triggered acquisition system and stored in a quad screen, continuous loop format on 3.5-inch floppy discs (23).
Echocardiographic measurements.
Left ventricular septal and posterior wall thickness, diameter and fractional shortening were measured in the parasternal long axis view. Left ventricular volumes and LVEF were measured in the apical 4 chamber view by the modified Simpson’s rule. Intra and interobserver variability of echocardiographic measurements were previously assessed in a cohort of 100 patients (25). Chamber size and wall thickness were reproducible (0.1 cm) in 90% of studies. Left ventricular volumes and LVEF were reproducible (8%) in 85%.
Dobutamine stress echocardiogram analysis.
The dobutamine echocardiographic images were interpreted by two investigators without knowledge of the clinical, angiographic or follow-up data. The videotape recordings were made available to the interpreters but were not routinely reviewed. Intraobserver variability was assessed in 50 randomly selected patients.
The left ventricle was evaluated using the previously described scoring system (1 = normal, 2 = hypokinesis, 3 = akinesis and 4 = dyskinesis) and standard 16-segment model (23,26). Segments were assigned to the left anterior descending, left circumflex and right coronary arterial distributions according to the vascular distribution of segments (23). Normal was defined as normal wall thickening. Hypokinesis was defined as reduced wall thickening. Akinesis was defined as the absence of wall thickening. Dyskinesis was defined as paradoxical excursion away from the lumen and systolic wall thinning.
Global wall motion score index was calculated at each stage. Patients were classified according to three responses (23). Sustained improvement was defined as a sustained improvement in multiple dysfunctional segments in all vascular territories at low (5 and 10 µg/kg/min) and peak dose. Scar was akinesis or dyskinesis with or without wall thinning and increased echogenicity in 2 contiguous segments that did not change at low or peak dose (26–28). Inducible ischemia was defined as: 1) decreased wall thickening at peak dose after no change at low dose in 2 contiguous segments that were normal or hypokinetic at rest or 2) a biphasic response (i.e., improved wall thickening in 2 contiguous dysfunctional segments at low dose with worsening at peak dose). Akinetic segments that changed to dyskinesis or the reverse were considered unchanged (29). Multiple abnormalities were defined as scar or inducible ischemia in 2 vascular territories (23). Patients with combinations of findings were categorized hierarchically (inducible ischemia > scar > sustained improvement).
Follow-up data/definition of adverse outcome.
Patients were followed by patient interviews, hospital chart reviews and/or telephone interviews for a minimum of eighteen months or until a hard event occurred (26). Adverse outcomes were cardiac death, nonfatal myocardial infarction, resuscitated sudden death (ventricular tachycardia or fibrillation), late (>1 month after DASE) myocardial revascularization and congestive heart failure requiring hospitalization. Hard events were cardiac death (sudden death or death related to myocardial infarction, congestive heart failure or cardiac arrhythmias), nonfatal myocardial infarction (hospital admission for chest pain lasting >20 min, EKG changes and elevated creatine kinase or lactate dehydrogenase isoenzymes) and resuscitated sudden death (ventricular tachycardia or fibrillation).
Statistical analysis.
Stepwise multiple logistic regression analysis and the Cox proportional hazard model (True Epistat, Richardson, Texas) were used to identify independent predictors of hard cardiac events and their incremental prognostic value (30). Hard event-free survival was evaluated by Kaplan-Meier plots and differences evaluated by Mantel-Haentzel Chi-square analysis. Continuous data was expressed as mean ± standard deviation. Categorical variables were analyzed by the Chi-square or Fisher’s Exact Test. Repeated measures analysis of variance (ANOVA) and multi-way ANOVA were used to compare continuous data within and among groups. The Bonferroni t-test was used to identify differences in means. A two-tailed p < 0.05 was considered significant.
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Results
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Patient data.
The mean age was 61 ± 13 years. There were 215 men and 135 women. Indications for DASE were the detection of CAD in 261 patients and myocardial viability in 89. There was a prior myocardial infarction in 143 patients (41%), hypertension in 236 (67%), diabetes in 141 (40%), hypercholesterolemia in 106 (30%) and cigarette smoking in 172 (49%). ß-adrenergic blocking agents were used in 72 (21%) patients, ACE inhibitors in 177 (51%), nitrates in 170 (49%), diuretics in 197 (56%), and digoxin in 155 (44%).
Coronary angiography was performed in a subset of 186 (53%) patients. CAD (50% luminal diameter stenosis) was detected in 162 patients (87%) including three vessel disease in 80 patients, two vessel disease in 57 and single vessel disease in 25.
Outcome data.
There were 134 events (38%) during the follow-up period including 76 hard events (22%). The 76 hard events consisted of cardiac death in 59 patients, nonfatal myocardial infarction in 11 and resuscitated sudden death in 6. The other 58 events consisted of congestive heart failure in 38 patients and late myocardial revascularization in 20.
Dobutamine infusion data.
The peak dose of dobutamine was 25 ± 9 µg/kg/min. Atropine was used in 193 patients (55%). The peak systolic blood pressure and heart rates were 139 ± 29 mm Hg and 126 ± 16 bpm, respectively. Endpoints for dobutamine-atropine infusion were: target heart rate in 291 patients (83%), maximum dose in 23 (7%), severe angina in 12 (3%), nonsustained ventricular tachycardia (6–11 beats) in 11 (3%), hypotension in 6 (2%), hypertension in 1 (0.3%), vomiting in 3 (1%) and >2 mm of ST segment elevation in 3 (1%). There were no severe complications: death, acute myocardial infarction, sustained ventricular tachycardia or ventricular fibrillation. Frequent PVCs occurred in 68 patients (19%), nonsustained VT in 28 (8%), ST elevation or depression in 67 (19%) and chest pain in 73 (21%). Atropine did not increase the incidence of tachyarrhythmias or side effects. No signs of atropine intoxication were noted.
Dobutamine echocardiographic data.
Resting wall motion score index was 2.19 ± 0.33. The mean resting LVEF was 30 ± 8%. Wall motion score index was 1.86 ± 0.41 at low dose and 2.02 ± 0.50 at peak dose. Mean LVEF was 34 ± 9% at low dose and 33 ± 10% at peak dose. Dobutamine stress echocardiography revealed sustained improvement in all vascular territories in 83 patients (24%), scar alone in 99 (28%) and inducible ischemia in 168 (48% with worsening at peak dose only in 60 and biphasic responses in 104). In patients with inducible ischemia, abnormalities involved one vascular territory in 77 (left anterior descending in 49, left circumflex in 7 and right coronary in 21), two vascular territories in 65 (left anterior descending and right coronary in 36, left anterior descending and left circumflex in 18 and left circumflex and right coronary in 11) and all three vascular territories in 26. Inter and intraobserver agreement regarding the interpretation of studies as sustained improvement, scar, biphasic responses or inducible ischemia at peak dose only were 92% (322/350) and 96% (48/50), respectively. Inter and intraobserver agreement regarding resting segmental scores were 88% (4921/5592) and 92% (716/778), respectively. Inter and intraobserver agreement regarding segmental responses during low and peak dose were 86% (4809/5592) and 91% (708/778), respectively.
Table 1 compares the patient data according to DASE findings. Clinical data were similar in all groups except for lower prevalence of prior myocardial infarction in patients with sustained improvement. Rest wall motion score index and ventricular volumes were similar in all groups. The number of akinetic and dyskinetic segments at rest was lower in patients with sustained improvement. The number of vascular territories involved in patients with scar was similar to the number of vascular territories involved in patients with inducible ischemia. Scar was present in one or more additional vascular territories in 65% (50/77) and 35% (23/65) with inducible ischemia in one and two vascular territories, respectively.
The dobutamine-atropine echocardiographic findings influenced the decision to perform coronary angiography. Angiography was done in 24% (20/83) of patients with sustained improvement, 37% (37/99) with scar alone and 77% (129/168, p < 0.001) with inducible ischemia.
In a subset of 186 patients that underwent angiography, inducible ischemia was predictive of the presence of CAD. Inducible ischemia occurred in 87% (69/80) of patients with three vessel disease, 74% (42/57) with two vessel disease, 60% (15/25) with single vessel disease but only 13% with no disease (3/24, p < 0.01 vs. patients with CAD). Scar alone did not correlate with the presence or absence of CAD (34/162 vs. 3/24 without CAD, p = NS), whereas sustained improvement correlated with the absence of CAD (18/24 vs. 2/162 with CAD, p < 0.01).
All patients with sustained improvement or scar only were treated medically, whereas 51% (78/154) of patients with inducible ischemia were revascularized within one month after DASE at the private cardiologist’s discretion (coronary artery bypass surgery in 67 and percutaneous transluminal coronary angioplasty in 11). Table 2 compares patients with inducible ischemia who were medically treated to those treated with revascularization. The decision to revascularize these patients was influenced by several factors. The majority of revascularized patients had lesions in the proximal or mid left anterior descending artery (p < 0.01 vs. medical treatment). Angina was more common (p < 0.05). There were fewer scarred segments, more viability at low dose and more extensive inducible ischemia in revascularized patients. All other clinical, echocardiographic and angiographic factors were similar in revascularized and medically treated patients.
Univariate predictors of adverse outcome.
Table 3 compares clinical, resting and dobutamine-atropine echocardiographic data in medically treated patients with hard events, soft events and no events. Diabetes was more common in patients with soft events, but all other clinical and resting echocardiographic data were similar in patients with hard events, soft events and no events. Dobutamine echocardiographic data were also similar in patients with no events and soft events but were significantly different in patients with hard events. Wall motion score was higher and LVEF was lower in patients with hard events. The number of segments demonstrating sustained improvement was lower in patients with hard events. The number of scarred segments was similar in patients with and without events. Finally, inducible ischemia was more common (p < 0.01) and involved more segments and vascular territories (p < 0.01) in patients with hard events than those with soft events or no events. Left ventricular ejection fraction at peak dose was lower and decreased from low to peak dose in patients with hard events.
The incidence of soft events was similar in patients with sustained improvement (21%, 16/83), scar alone (16%, 16/99) and medically managed patients with inducible ischemia (12%, 9/90). Early revascularization of patients with inducible ischemia had a modest effect on the incidence of soft events (22%, 17/78). Heart failure was as common in medically managed as it was in revascularized patients (9%, 7/78, vs. 12%, 31/272, p = 0.69), but late revascularization was more common in revascularized patients (13%, 10/78, vs. 4%, 10/272, p < 0.01).
Figure 1 compares hard event rates according to sustained improvement, scar and inducible ischemia treated with medical therapy or early revascularization. Hard events were rare in patients with sustained improvement and similarly uncommon in those with scar alone (p = 0.1). In contrast, hard events were common (p < 0.0001 vs. nonischemic responses or scar alone) in medically managed patients with inducible ischemia. Hard events were as common in medically treated patients with biphasic responses as they were in patients with worsening at peak dose only, but were more often (p = 0.01) fatal in those with biphasic responses (28/31 vs. 12/23 in those with worsening at peak dose only). Finally, outcome was better in the subset of patients with inducible ischemia that were managed with early revascularization and similar to patients with sustained improvement.
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Figure 1 Bar graph of hard cardiac events according to DASE. Hard events were uncommon in patients with sustained improvement (Sustained Imp) and scar alone but were common (*, p < 0.01 vs. scar only or sustained improvement) in medically-treated patients with inducible ischemia. Hard events were uncommon ( , p < 0.01) in patients with inducible ischemia treated with revascularization.
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The extent of inducible ischemia was also predictive of hard events in medically treated patients. Inducible wall motion abnormalities in multiple vascular territories were more common in patients with hard events (30%, 21/70 vs. 10%, 21/202, p < 0.01) and especially those with fatal events (33%, 18/54 vs. 11%, 24/218, p < 0.01). Hard events occurred in 82% (9/11, p < 0.01 vs. no ischemia) of patients with ischemia in all three vascular territories, 39% (12/31, p < 0.01 vs. no ischemia and ischemia in three territories) in two territories, 67% (32/48, p < 0.01 vs. no ischemia) in one vascular territory and 9% (17/182) with no inducible ischemia. Fatal events occurred in 73% (8/11, p < 0.01 vs. no ischemia) of patients with ischemia in all three vascular territories, 32% (10/31, p < 0.01 vs. no ischemia and ischemia in three territories) in two territories, 46% (22/48, p < 0.01 vs. no ischemia) in one territory and 8% (14/182) with no inducible ischemia.
Multivariate analysis.
Table 4 presents the results of stepwise multiple logistic regression analysis to identify independent predictors of hard events and the additive predictive value of resting and DASE. The only independent predictors of hard cardiac events were inducible ischemia and LVEF at peak dose during DASE. All other clinical and echocardiographic determinants including resting LVEF, stroke volume, chamber diameter, age and history of myocardial infarction or heart failure were not independently predictive of hard events. Stepwise analysis revealed that: 1) clinical data were modestly predictive of hard events, 2) resting echocardiography did not improve the prediction of hard events, but 3) peak dose DASE markedly improved the accuracy by detecting inducible ischemia and reduced LVEF at peak dose.
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Table 4 Computer Directed and Clinically Directed Stepwise Multiple Logistic Regression and Cox Proportion Hazard Analysis of Determinants of Hard Events in Medically Treated Patients
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Life table analysis.
Figure 2 is a Kaplan-Meier plot of hard event free survival in the dobutamine-atropine echocardiographic subsets. Patients with sustained improvement did very well with an 18 month hard event free survival of 95%. The hard event free survival of patients with scar alone was similarly good. In contrast, the survival of patients with inducible ischemia was much worse than patients with sustained improvement or scar alone. Hard events occurred throughout the 18 month follow-up period in the subset with biphasic responses but occurred late in those with worsening wall motion at peak dose only. Hard event free survival of patients with inducible ischemia was better in those treated with revascularization.
Figure 3 is a Kaplan-Meier plot of the survival (number alive) of the dobutamine-atropine stress echocardiographic subsets treated medically and with revascularization. Again, patients with sustained improvement and scar alone did similarly well. The survival of patients with inducible ischemia was much worse. The survival of patients with biphasic responses was worse than those with worsening at peak dose only. The survival of patients with inducible ischemia was better in those treated with early revascularization.
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Discussion
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Previous studies.
Chronic left ventricular dysfunction and heart failure are major causes of morbidity and mortality (1–6). Ischemic cardiomyopathies convey a much worse prognosis than nonischemic dysfunction (1–9). Coronary artery disease may cause LVD by infarction, remodeling, chronic hypoperfusion, and repetitive ischemia and reperfusion. Coronary revascularization may convey the greatest benefit when selectively used in high risk patients (5,6).
Noninvasive techniques may assist in patient management by detecting: 1) the mechanism of LVD, 2) viable myocardium, and 3) the extent and severity of CAD (16,31). Nuclear cardiologic studies have shown that viable myocardium in patients with CAD and LVD is predictive of adverse outcome (8–13). Positron emission tomography studies have shown that mildly hypoperfused or normally perfused myocardium with altered metabolism correlates with adverse outcome in patients with CAD and LVD and that these same patients have fewer events when revascularized (10–11). PET imaging is limited by its cost and availability. Iskandrian et al. have reported similar findings with rest-redistribution Tl-201 scintigraphy (8,9).
Dobutamine-atropine stress echocardiography is an alternative test to study patients with LVD and noninvasively differentiates ischemic from nonischemic cardiomyopathy by contractile response. Several studies have reported moderate concordance with PET and Tl-201 data (14–20). Dobutamine-atropine stress echocardiography is very sensitive and moderately specific for CAD in these patients (17,21,32). Scar can also be differentiated from reversible dysfunction (14,15,19,20). Wall thinning, increased echogenicity and fixed akinesis or dyskinesis identify scar and fixed dysfunction (26–28). Segments with biphasic responses commonly recover with revascularization alone with hypokinetic segments that worsen at peak dose (19,20). In contrast, sustained improvement at low and peak dose correlates with fixed dysfunction and differentiates nonischemic from ischemic dysfunction (17,19,20,22).
Dobutamine-atropine stress echocardiography has been shown to risk stratify patients with acute myocardial infarction, known or suspected CAD and those considered for noncardiac surgery (26,33–34). Only one previous study investigated the value of DASE in LVD (18). Williams et al. performed DASE in 136 patients with a mean LVEF of 30 ± 5%. The remaining 130 were followed for 16 ± 8 months. Twenty-two patients were revascularized early and 108 were treated medically. Cardiac events occurred in 24% (26/108) patients. Events occurred in 43% of patients with ischemia or viability but only in 8% of patients with scar. The predictive value was independent of clinical and resting echocardiographic data. The authors concluded that recurrent ischemia in viable myocardium mediated the recurrent events. The study did not differentiate the relative predictive values of myocardial viability and ischemia.
The present study.
The present study documented the relative roles of inducible ischemia, improved wall motion and scar in recurrent cardiac events in patients with LVD. The study also provided evidence that revascularization may improve outcome of high risk patients. While it was not randomized, revascularization was only done in the high risk subset of patients with inducible ischemia. The extent of inducible ischemia was greatest in revascularized patients, but the hard cardiac event rate was reduced. Again, this study enrolled patients with LVD of various etiologies, typical of clinical practice. Multivariate analysis showed that the predictive value of DASE was independent of clinical data and resting echocardiography.
Dobutamine-atropine stress echocardiography only predicted hard events. All patients tolerated the infusion well. Heart failure was not predicted by any clinical, resting or stress echocardiographic finding. Late revascularization only correlated with the performance of early revascularization. Left ventricular dimensions were not predictive of outcome. Hard events were not predicted by clinical or resting echocardiographic findings. The critical finding of the study was that hard events were only predicted by inducible ischemia and reduced LVEF at peak dose. Sustained improvement alone, especially in all vascular territories, predicted good outcome. Scar without inducible ischemia also correlated with a low incidence of hard events. In contrast, hard events were common in patients with inducible ischemia with or without improvement at low dose (viability). Fatal events were most common in the subsets with biphasic responses or inducible ischemia in all vascular territories.
The higher sensitivity of inducible ischemia for coronary heart disease in the present study likely mediated the discrepancy in findings of the present study and that of Williams et al. (18). Inducible ischemia was more common in the present study (47% vs. 26%, p < 0.05 vs. Williams et al.). Angiography showed that viability without ischemia often occurred in patients with CAD in Williams’ study, but almost always occurred in patients without CAD in the present study. Both nonischemic cardiomyopathies and viable but chronically dysfunctional myocardium due to ischemic heart disease responds to inotropic stimulation, but only the latter will manifest induced ischemic dysfunction during stress.
The present study strongly supports the conclusion that recurrent ischemia in viable, dysfunctional myocardium mediated recurrent events in these patients. Further evidence is the low incidence of hard events in patients with inducible ischemia treated with revascularization. These data compare favorably with the revascularization data of prior PET studies showing that only patients with metabolically active, dysfunctional myocardium and CAD benefited from revascularization (8–13).
These data imply that patients with LVD should be evaluated for inducible ischemia. Dobutamine-atropine stress echocardiography is a safe and accurate method for identifying inducible ischemia and risk stratifying these patients (19,20). Selective use of revascularization in high risk patients identified by DASE improves patient outcome.
Limitations.
The present study was limited by nonrandomized surgical management. The decision for revascularization may have been influenced by uncontrollable biases. Despite these biases, the only difference in medically treated and revascularized subsets with inducible ischemia was a higher prevalence of angina and more extensive inducible ischemia. Thus, revascularized patients may have been at higher risk and biases likely did not account for the differences in survival. Another limitation was the limited coronary angiographic data so the outcome data could not be compared to angiography. Medical treatment was not standardized but was uniform and not a determinant of outcome. We acknowledge that some of the patients with scar alone or sustained improvement with submaximal peak heart rates may have demonstrated inducible ischemia at maximal heart rates. Likely, this would only have had a minor effect on the data because the number of patients with scar or sustained improvement and submaximal heart rates was small.
Conclusions and clinical implications.
Dobutamine-atropine stress echocardiography safely risk stratified patients with moderate to severe LVD. Results were highly predictive of nonfatal myocardial infarction and cardiac death. The major finding of the study was that inducible ischemia was the major determinant of hard events. Sustained improvement in multiple vascular territories and scar without ischemia predicted good outcome. Inducible ischemia and a low LVEF at peak dose were the only independent predictors of hard events. An important corollary was that biphasic responses were highly predictive of cardiac deaths. Dobutamine-atropine stress echocardiographic findings were independent of clinical data and LVEF. Finally, the nonrandomized data showing that outcome was better in patients with inducible ischemia treated with revascularization suggest that outcome may be significantly improved by selective use of revascularization in these high risk patients.
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Acknowledgments
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We thank Debra Bambolus, RN and Duane Eder for their technical support.
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Footnotes
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This study was supported in part by the Kyle Company, Mequon, Wisconsin.
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