Dobutamine stress echocardiography in the evaluation of hibernating myocardium

INTRODUCTION — Impaired left ventricular (LV) systolic function in patients with coronary heart disease is often a partially reversible process. As an example, left ventricular function may improve markedly, and even normalize, in subsets of patients following successful revascularization [1-3].

Since many studies have established a relation between LV systolic function and cardiovascular prognosis, it is reasonable to speculate that improved LV systolic function following revascularization would be associated with a favorable effect on outcome. The superiority of revascularization compared with medical management in selected patients with coronary disease and LV dysfunction is compatible with this hypothesis [4,5]. The myocardium that recovers function after revascularization has been called "hibernating." To the extent that improvement in regional or global LV systolic function is a significant goal in such patients, the ability to accurately assess regional myocardial viability in a dysfunctional territory prior to revascularization becomes an important component of the decision-making process (table 1 and algorithm 1 and algorithm 2). (See "Clinical syndromes of stunned or hibernating myocardium" and "Treatment of ischemic cardiomyopathy", section on 'Additional imaging'.)

Dobutamine stress echocardiography is an important noninvasive clinical tool for the detection of hibernating myocardium [6,7]. The role of dobutamine stress echocardiography in the evaluation of myocardial viability in the setting of hibernation will be reviewed here. The use of other modalities in conjunction with dobutamine stress, such as Doppler studies, the relative efficacy of other imaging modalities (eg, radionuclide imaging, magnetic resonance imaging) for the detection of hibernating myocardium, and protocols for dobutamine stress echocardiography are discussed separately. (See "Evaluation of hibernating myocardium" and "Overview of stress echocardiography", section on 'Dobutamine stress echocardiography'.)

DOBUTAMINE STRESS ECHOCARDIOGRAPHY — Pharmacologic stress echocardiography examines the "inotropic reserve" of dysfunctional but viable myocardium at rest by the administration of an inotropic agent, with dobutamine being the most frequently used agent. Viable myocardium shows improved global or regional contractile function (inotropic reserve), as assessed by simultaneous transthoracic echocardiography, in response to inotrope administration [8]. The prevalence of contractile reserve in patients with CHD and LV dysfunction is independent of the angiographic extent and severity of coronary artery disease, and the improvement in contractility in hypoperfused viable myocardium does not require an increase in regional myocardial perfusion [9,10].

A contractile response to dobutamine appears to require that at least 50 percent of the myocytes in a given segment are viable; the contractile response also correlates inversely with the extent of interstitial fibrosis on myocardial biopsy [11]. By comparison, radionuclide myocardial perfusion imaging identifies segments with fewer viable myocytes. In one series, for example, dobutamine stress echocardiography and thallium imaging showed equivalent sensitivity among segments with more than 75 percent viable myocytes (78 versus 87 percent) but dobutamine stress echocardiography was much less sensitive among segments with 25 to 50 percent viable myocytes (15 versus 82 percent) [12].

The predictive value of dobutamine stress echocardiography appears to be greatest when there is a biphasic response: improvement at low dose and worsening at high-dose dobutamine [13,14]. The initial improvement in wall motion reflects recruitment of contractile reserve during low-dose dobutamine, and hence reflects viability [15]. By comparison, higher doses lead to subendocardial ischemia and worsening of the wall motion abnormality, identifying stress-induced ischemia. Thus, testing at various doses appears to be important for the optimal assessment of myocardial hibernation by this technique.

The concurrent use of beta blockers at the time of the dobutamine stress echocardiogram can affect the response to dobutamine and reduce the number of viable segments detected [16]. If a study during beta blocker therapy shows only limited improvement in wall motion with low-dose dobutamine and no worsening with high dose, it suggests that the inotropic response was not adequate, and it may be useful to repeat the test after the dose of beta blocker has been reduced. (See "Overview of stress echocardiography", section on 'Dobutamine stress echocardiography'.)

Improvement in LV function after CABG — Dobutamine stress echocardiography can be used to identify hibernating myocardium prior to coronary artery bypass graft (CABG) surgery. Several studies have shown that it can be used to predict the likelihood of recovery after CABG [13,17,18]:

●Among 18 patients with coronary disease and LV systolic dysfunction who underwent two-dimensional echocardiography at rest and during dobutamine infusion, 61 percent of dysfunctional segments with inotropic reserve showed improved regional systolic function after CABG [17]. The positive and negative predictive accuracy of dobutamine infusion for predicting functional improvement of dysfunctional segments after CABG was 91 and 82 percent, respectively.

●Among 61 patients who underwent serial dobutamine stress echocardiography and radionuclide ventriculography prior to CABG, a biphasic response (improvement at low dose and worsening at high dose dobutamine) was highly predictive of recovery, especially in segments with the most severe wall motion abnormalities at baseline [13]. Other patterns of dobutamine responsiveness were predictors of non-recovery.

●In a series of 133 patients, those with the largest amount of dysfunctional but viable myocardium, defined as ≥6 segments improving with low-dose dobutamine, had the greatest functional improvement in left ventricular ejection fraction after surgical revascularization and a lower rate of cardiac events during a 20-month follow-up [18].

While a biphasic response to dobutamine is predictive of mechanical recovery after CABG, the amount of dysfunctional but viable myocardium may be a better predictor of long term outcome. This was suggested by a study of 95 patients in whom multiple indices of viability were measured by dobutamine stress echocardiography prior to CABG [19]. After a five year follow-up, the amount of dysfunctional but viable myocardium, as assessed by wall motion score during low dose dobutamine, was the most important independent predictor of survival (hazard ratio 6.7, 95% CI 2.8-15.8). A biphasic response to dobutamine, while significant on multivariable analysis, was less important.

The predictive value of dobutamine stress echocardiography is similar to that of positron emission tomography (PET) scanning (figure 1) [20]. The accuracy is less, however, when there is a totally occluded coronary artery [21]. (See "Evaluation of hibernating myocardium", section on 'Efficacy of imaging tests'.)

Improvement in LV systolic function after percutaneous revascularization — The accuracy of dobutamine stress echocardiography for predicting recovery of LV function after percutaneous revascularization in patients with stable coronary disease and LV dysfunction has also been evaluated.

●In a study of 20 patients undergoing dobutamine stress echocardiography, the accurate prediction of recoverability of contractile function depended upon the type of wall motion response observed during dobutamine [14].The greatest improvement in LV systolic function was seen in patients with a biphasic response to dobutamine, with less improvement in patients with either no change or sustained improvement after dobutamine.

●The administration of nitroglycerin may improve the accuracy of dobutamine stress echocardiography in detecting viable myocardium. In an animal model, nitroglycerin enhanced the improvement with low dose dobutamine but did not prevent high dose dobutamine from inducing ischemia in hibernating myocardium [22]. The clinical efficacy of nitroglycerin-dobutamine echocardiography was evaluated in a study of 32 patients in whom 309 of 512 myocardial segments were akinetic or dyskinetic [23]. In terms of improved contractility after revascularization, nitroglycerin-dobutamine echocardiography had a lower sensitivity than rest-redistribution thallium and myocardial contrast echocardiography (63 versus 95 and 87 percent, respectively), but was the most specific (83 versus 37 and 48 percent). Nitroglycerin alone increased regional thickening in 20 percent of viable akinetic segments, suggesting that it may be a useful addition to dobutamine stimulation.

Improvement in survival after revascularization — Patients with left ventricular systolic dysfunction who demonstrate myocardial viability with dobutamine stress echocardiography have a better outcome with revascularization than with medical therapy [15,24,25].

●In a study of 318 patients with coronary heart disease and a left ventricular ejection fraction ≤35 percent, those with myocardial viability (as determined by dobutamine stress echocardiography) had a lower mortality at 18 months when treated with coronary artery bypass graft (CABG) surgery compared with those with viability who were treated medically or those without viability who underwent CABG (6 versus 20 and 17 percent, respectively) [24].

●The results of dobutamine stress echocardiography can also predict long-term outcome [15,25]. In a study of 87 patients with heart failure due to an ischemic cardiomyopathy who were followed for 40 months, cardiac mortality in patients with at least 5 (out of 12) segments showing myocardial viability who underwent CABG was 3 percent, with associated improvement in functional class and left ventricular ejection fraction [25]. In contrast, cardiac mortality was 31, 50, and 44 percent in those with myocardial viability in at least 5 segments who were treated medically and in those with less than 5 segments showing myocardial viability who underwent revascularization or medical therapy, respectively.

Similar mortality benefits have been reported with all of the major imaging techniques for the detection of myocardial viability. In a meta-analysis of 24 viability studies (with viability determined by dobutamine echocardiography, thallium perfusion imaging, or positron emission tomography (PET) scanning) involving 3088 patients with coronary artery disease and left ventricular dysfunction, myocardial viability was present in 42 percent [26]. The patients with myocardial viability had an 80 percent reduction in annual mortality with revascularization (3.2 versus 16 percent with medical therapy). In contrast, there was no difference in annual mortality with revascularization in patients without myocardial viability (annual mortality 7.7 versus 6.2 percent with medical therapy).

A similar difference in mortality was noted in another review in which annual mortality was reduced after revascularization only in patients with myocardial viability (7 versus 20 percent with medical therapy) [27]. (See "Treatment of ischemic cardiomyopathy", section on 'Additional imaging'.)

Use after MI — Dobutamine stress echocardiography is also useful for establishing the presence of hibernating myocardium due to a residual stenosis following a myocardial infarction (MI). In one series of 232 patients undergoing a dobutamine-atropine stress echocardiography within one week after MI, the presence of either an ischemic or a biphasic response in two or more contiguous infarction zones was both sensitive (82 percent) and specific (80 percent) for a residual stenosis and had a predictive accuracy of 82 percent [28]. Sensitivity was greatest when a biphasic response was observed. In another study sustained improvement with high dose dobutamine was the most specific predictor (100 percent) for the absence of significant residual stenosis [29].

Dobutamine stress echocardiography is also of use for predicting recovery and the extent of irreversibly damaged myocardium after direct angioplasty in patients with an acute MI [30]. Its predictive value for improvement is higher for hypokinetic than akinetic segments. Recovery of rest regional LV contraction usually occurs quickly after revascularization, although one-quarter of patients require up to six weeks [31]. Patients who recover rest function after angioplasty show the most marked improvement with dobutamine; however, some improvement may be seen in those without recovery of rest function, particularly when there was evidence of ischemia before revascularization.

Although dobutamine stress echocardiography is useful for predicting recovery, dysfunctional but viable segments may show less improvement in basal contractility after revascularization than predicted. As an example, one study performed dobutamine stress echocardiography more than three months after CABG [32]. Most infarct zones which showed contractile reserve before surgery but which failed to recover after surgery had the same or greater contractile reserve with dobutamine; some contractile reserve was present even in those infarct zones that showed no reserve preoperatively [32].

Use in LV dysfunction after MI — Dobutamine stress echocardiography after an MI can identify residual, ischemic viable myocardium which can act as a substrate for further events.

●In one study of 138 patients with left ventricular (LV) dysfunction following MI, the presence of myocardial viability was the only independent predictor of recurrent ischemic events (20 versus 7 percent without viable myocardium) [33]. However, viability in the absence of underlying ischemia may be protective in patients with global LV dysfunction after MI in whom the recovery of LV function can offset the risk of ischemia.

●In another study evaluating 314 patients with moderate to severe resting LV dysfunction after an MI, the presence and extent of viability was associated with a lower mortality at 9 months (1.9 versus 5.5 percent for no viability) [34]. In patients with a greater number of segments showing improvement, there was a larger impact of viability on survival. In contrast, the presence of inducible ischemia was the best predictor of cardiac death.

Use in the elderly — Dobutamine stress echocardiography can be used safely in elderly patients to evaluate chest pain. In 550 octogenarians evaluated for chest pain, dobutamine stress echocardiography was safe, predicted the risk of cardiac events over the subsequent two years, and identified a subset at high risk of a cardiac event [35].

Comparison with perfusion imaging — Direct comparisons between nuclear imaging techniques and dobutamine stress echocardiography are limited. However, when used for the assessment of myocardial viability and hibernating myocardium, dobutamine stress echocardiography has both a high negative predictive value as well as a high positive predictive value. (See "Evaluation of hibernating myocardium", section on 'Pooled analysis of rMPI and DE studies'.)

Comparison with CMR — Late gadolinium enhancement cardiovascular magnetic resonance imaging (CMR) can accurately discriminate nonviable from viable myocardial segments. However, the accuracy of low-dose dobutamine CMR and low-dose dobutamine echocardiography is not known as they have not been directly compared. However, in a comparative study using high-dose dobutamine stress echocardiography and dobutamine CMR, CMR had a higher sensitivity and specificity for detection of viable segments. This was primarily related to nonvisualization of segments on surface echocardiography. Comparison of late gadolinium enhancement CMR versus low dose dobutamine stress CMR suggests that low dose dobutamine CMR is superior, primarily related to improved accuracy for patients with intermediate late gadolinium enhancement pattern. (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Myocardial viability'.)

Role in idiopathic dilated cardiomyopathy — Dobutamine stress echocardiography can help in establishing the prognosis of patients with an idiopathic dilated cardiomyopathy, as an improvement in left ventricular contractility (ejection fraction or wall motion score) predicts a lower incidence of cardiac death or need for transplantation [36,37].

In one of the largest prospective studies, dobutamine stress echocardiography was performed using high-dose dobutamine (up to 40 µg/kg per min) in 184 patients with a left ventricular ejection fraction less than 30 percent [36]. After a 15-month follow-up, patients with a large inotropic response to dobutamine (defined as a change in wall motion score index ≥0.44) had a significantly better survival (94 versus 69 percent for a small or no response to dobutamine). A large change in wall motion score index was an independent predictor of outcome on multivariate analysis. (See "Predictors of survival in heart failure with reduced ejection fraction".)

ENOXIMONE STRESS ECHOCARDIOGRAPHY — Dobutamine stress echocardiography is widely used to assess myocardial viability, but the inotropic response to adrenergic stimulation may be attenuated in patients receiving a beta blocker. In addition, dobutamine may sometimes induce ischemia in patients with a critical coronary stenosis, which might mask hibernation by preventing the improvement in wall motion.

An alternative approach is the use of a phosphodiesterase inhibitor such as enoximone or milrinone, drugs which have been used for inotropic support in the treatment of heart failure. These drugs are relatively unaffected by concurrent use of a beta blocker. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)

The possible role of enoximone stress echocardiography was evaluated in one study of 45 patients with chronic coronary artery disease and left ventricular dysfunction who underwent echocardiography with both dobutamine and enoximone [38]. Both increased heart rate, but enoximone did not cause a change in systolic blood pressure. Concordant results were seen in 85 percent of affected segments, but enoximone had a higher sensitivity (88 versus 79 percent for dobutamine) and negative predictive value (90 versus 84 percent) in predicting functional recovery after revascularization. Specificity and positive predictive value were similar between enoximone and dobutamine.

While enoximone is not approved for use in the United States, the pharmacology of milrinone is very similar, and this agent could be considered for use as a pharmacologic stress agent in selected patients on beta blockers. Given the limited data, however, we feel that further investigations are required to validate this approach.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Heart failure in adults" and "Society guideline links: Chronic coronary syndrome" and "Society guideline links: Multimodality cardiovascular imaging appropriate use criteria" and "Society guideline links: Stress testing and cardiopulmonary exercise testing".)

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SUMMARY

●Dobutamine stress echocardiography is an important noninvasive clinical tool for the detection of viable "hibernating" myocardium, or myocardium that recovers systolic function after revascularization. Viable myocardium shows improved global (ejection fraction) or regional contractile function (inotropic reserve) in response to inotrope administration. (See 'Dobutamine stress echocardiography' above.)

●When performed on patients with ischemic heart disease and left ventricular dysfunction, dobutamine stress echocardiography predicts the likelihood of left ventricular functional recovery following both surgical and percutaneous revascularization. In addition, in patients with left ventricular dysfunction post-myocardial infarction who have not undergone revascularization, dobutamine stress echocardiography is useful for establishing the presence of hibernating myocardium due to a residual stenosis. (See 'Improvement in LV function after CABG' above and 'Improvement in LV systolic function after percutaneous revascularization' above and 'Use after MI' above.)

●Patients with left ventricular dysfunction who demonstrate myocardial viability with dobutamine stress echocardiography have a better survival with revascularization than with medical therapy. (See 'Improvement in survival after revascularization' above.)

●Direct comparisons between radionuclide imaging and cardiovascular magnetic resonance imaging techniques and dobutamine stress echocardiography in the same patients are limited. (See 'Comparison with perfusion imaging' above and "Evaluation of hibernating myocardium", section on 'Pooled analysis of rMPI and DE studies'.)