Dobutamine Echocardiography in Myocardial Hibernation
Optimal Dose and Accuracy in Predicting Recovery of Ventricular Function After Coronary Angioplasty
Background Myocardial hibernation is a condition of chronic left ventricular dysfunction associated with severe coronary artery disease whereby significant recovery of function occurs after revascularization. Identification of hibernating myocardium has important prognostic and therapeutic implications. The presence of contractile reserve as assessed by dobutamine echocardiography may be promising in the detection of hibernation. We designed a prospective study to evaluate the accuracy and optimal dose of dobutamine echocardiography for predicting recovery of ventricular function after angioplasty in patients with stable coronary artery disease and ventricular dysfunction.
Methods and Results Twenty patients with stable coronary artery disease and segmental ventricular dysfunction scheduled for coronary angioplasty underwent dobutamine echocardiography before revascularization using incremental doses of 2.5, 5, 7.5, 10, 20, 30, and 40 μg/kg per minute every 3 minutes. Digital images of all eight stages were displayed simultaneously (two quad screens side by side) and interpreted using a 16-segment ventricular model and a 6-grade scoring system. Serial resting echocardiograms before, early (<1 week), and late (≥6 weeks) after angioplasty were digitized and randomized in a quad-screen format for the assessment of recovery of function. Wall motion score index in the revascularized regions decreased from 2.86±0.76 before angioplasty to 2.12±1.03 late after angioplasty (P<.05). Of 320 ventricular segments, 148 had abnormal wall motion at baseline and 114 were revascularized. Recovery of function (≥2 grades) occurred in 25% of revascularized segments early and in 33% late after angioplasty. Of the 34 abnormal segments not revascularized, recovery of function occurred in only 1. During dobutamine echocardiography, abnormal segments exhibited one of four responses: biphasic (improvement at low dose and worsening at high dose) in 28% of segments, sustained improvement (persistent improvement till peak dose) in 18%, worsening in 15%, and no change in 39%. A biphasic response had the highest predictive value (72%) for recovery of function followed by worsening only (35%), while the lowest was seen with a “no change” or sustained improvement response (13% and 15%). Combining biphasic and worsening responses resulted in a sensitivity of 74% and specificity of 73% for assessment of recovery of individual segments and 90% and 60%, respectively, for functional recovery of individual patients (n=10). In segments with a biphasic response, the low dose at which improvement in wall motion was most prevalent (84%) was 7.5 μg/kg per minute and increased to 94% when the 5 and 7.5 μg/kg per minute doses were displayed. The reworsening phase of the biphasic response was usually seen with doses ≥20 μg/kg per minute but was also observed as early as the 7.5 μg/kg per minute dose.
Conclusions The wall motion response during dobutamine echocardiography is useful in the prediction of recovery of ventricular function after revascularization in patients with stable coronary artery disease and ventricular dysfunction. The administration of low as well as high doses of dobutamine is needed for optimal evaluation.
It has been recognized recently that, in patients with coronary artery disease, segmental left ventricular dysfunction may not necessarily represent irreversibly necrosed myocardium.1 2 3 Noncontractile yet viable myocardium may be seen in two syndromes: myocardial stunning and myocardial hibernation. Myocardial stunning results from transient coronary occlusion followed by reperfusion. Ventricular dysfunction persists longer than the duration of occlusion and eventually recovers without intervention.2 Myocardial hibernation, on the other hand, refers to chronic ventricular dysfunction associated with severe coronary artery disease with complete or partial recovery of contractile function occurring after revascularization.3 4
Differentiation of necrosed from viable myocardium has important clinical implications. Identification of hibernating myocardium may allow selection of patients with coronary artery disease whose ventricular function may be improved by revascularization.5 6 7 Inotropic stimulation using dobutamine echocardiography (DE) has been shown to differentiate stunned from infarcted myocardium.8 9 Whether DE can identify hibernating myocardium is unclear at present. Furthermore, the optimal dose of dobutamine needed for the assessment of myocardial viability in this setting is presently unknown. We therefore designed a prospective study to evaluate first, the accuracy of dobutamine echocardiography in the detection of myocardial hibernation in patients with stable coronary artery disease and regional dysfunction undergoing revascularization with percutaneous transluminal coronary angioplasty (PTCA), and second, to evaluate the optimal dose of dobutamine in the detection of myocardial hibernation. Furthermore, the time course of recovery of ventricular function after PTCA was evaluated.
Patients with coronary artery disease and resting regional left ventricular dysfunction, who were scheduled to undergo PTCA, were screened for enrollment in the study. The investigational protocol was approved by the Institutional Review Boards of Baylor College of Medicine and The Methodist Hospital. Inclusion criteria were age >18 years, presence of significant coronary artery disease defined as a ≥70% stenosis of at least one major epicardial coronary artery, and evidence of resting regional left ventricular dysfunction, defined as any wall motion abnormality present on prior contrast ventriculography or echocardiography. Patients were already scheduled to undergo PTCA, and the echocardiographic studies did not influence the decision to perform or not to perform the angioplasty. The persistence of wall motion abnormality, initially identified at a mean of 10±21 days before enrollment, was confirmed with a screening echocardiogram on the day of the study.
Exclusion criteria included patients with unstable angina, recent myocardial infarction (<6 weeks), PTCA of a coronary artery bypass graft, any contraindication to perform DE, or the inability to obtain informed consent.
Each patient underwent a dobutamine echocardiogram within 24 hours before PTCA. To assess the recovery of ventricular function and its time course after revascularization, follow-up resting two-dimensional echocardiograms were performed early (<1 week) and late (6 to 8 weeks) after angioplasty. The dobu- tamine echocardiogram was performed using a standard protocol. First, a resting echocardiogram was performed with the patient lying in left lateral recumbent position. Echocardiographic imaging was then performed during the intravenous infusion of dobu- tamine starting at a dose of 2.5 μg/kg per minute, which was increased every 3 minutes to 5, 7.5, 10, 20, 30, and 40 μg/kg per minute. Images were obtained from the standard parasternal long-axis and short-axis views as well as the apical four- and two-chamber views, with particular attention to optimization of regional function. During the infusion, a 12-lead ECG and blood pressure were monitored every minute. The test was terminated prematurely if any of the following occurred: 85% of predicted maximal heart rate, severe angina, systolic blood pressure <85 or >220 mm Hg, ≥2 mm ST depression or significant arrhythmia (≥6 beats supraventricular tachycardia or ≥3 beats ventricular tachycardia).
All studies were performed on a Hewlett-Packard Sonos 1000 or 1500 ultrasound system equipped with a 2.5-MHz transducer and were recorded on half-inch VHS tape. During the study, images were digitized on-line at each of the eight stages of the test (rest and each dobutamine dose) from the four views, using a NovaMicrosonics digitizing system (model 886/AT). The generated cineloops were then stored on floppy disks for later review.
Echocardiographic Image Processing and Analysis
For analysis of wall motion, the left ventricle was divided into 16 segments as previously described.10 These consisted of the anterior, septum, inferior, posterior, and lateral walls, each subdivided into a basal, mid, and distal portion in addition to the ventricular apex. Wall motion was assessed visually, using both endocardial motion and wall thickening,10 and was semiquantitated using a 6-grade scoring system as follows: hyperkinesia, 0; normal, 1; mild hypokinesia, 2; hypokinesia, 3; akinesia, 4; and dyskinesia, 5.
The dobutamine echocardiographic studies were interpreted at random using all eight digital images from each view displayed on two monitors placed side by side to allow simultaneous review of all eight stages of the test. All studies were read by one experienced investigator, blinded to clinical information and results of serial resting echocardiograms. A wall motion score was assigned to each of the 16 segments at every stage of the test.
For the interpretation of changes in resting ventricular function, cineloops from each view of the three resting studies (before PTCA and the two follow-up studies) were generated for each patient. These were displayed in a quad-screen format in random order and interpreted by one investigator, blinded to clinical information and timing of the studies. Recovery of individual segmental dysfunction was defined as an improvement in resting wall motion score of ≥2 grades after PTCA. This was based on a previous analysis of intraobserver variability in interpretation of regional function from our laboratory in which, using the above scoring system, reproducibility of grading wall motion of 232 segments in 16 patients was 84% for exact interpretation. Differences in interpretation by 1 grade of wall motion was seen in 15.5% and in 2 grades in 0.43%. For individual patients, recovery of function was defined as an improvement in wall motion of ≥2 grades in at least two contiguous ventricular segments.
To assess changes in ventricular function in vascular territories, the 16 ventricular segments were grouped into two vascular regions: the left anterior descending coronary artery territory comprising the apical, anterior, and septal segments (n=7), while the other 9 segments formed the combined right and circumflex coronary territory. A wall motion score index (WMSI) was derived for the entire left ventricle and for each vascular territory using the sum of individual scores divided by the respective number of segments.
All angiograms were analyzed by one of the investigators blinded to the echocardiographic data. The severity of coronary stenosis was determined by calipers and expressed as percent of luminal diameter reduction. The presence or absence of collaterals to the angioplasty vessel was determined visually. Significant coronary disease was defined as ≥70% stenosis of at least one epicardial artery.
Resting regional and global wall motion score indices and changes in heart rate, blood pressure, and double product during dobutamine infusion were compared using ANOVA. If the F value was significant, a Newman-Keuls multiple comparison test was performed. Percent vessel stenosis before and after PTCA were compared using the Student’s t test. A χ2 test was used to study differences in the echocardiographic and angiographic features of segments with different responses during DE. All values are expressed as mean±SD. Statistical significance was set at a value of P<.05.
A total of 20 patients were enrolled in the study between September 1992 and November 1993. These included 17 men and 3 women with a mean age of 60.3±11.4 years. A history of remote myocardial infarction (mean of 28.3 months before study) was present in 11 patients. A history of stable angina was obtained in 11 patients (55%). All individuals were on antianginal medications including 8 on β-blockers. None of the patients had unstable angina or recent myocardial infarction. The reason for performing PTCA was stable exertional angina in 9 patients, ischemic response on exercise or pharmacological stress testing in 7, congestive heart failure in 2, coronary restenosis in 1, and preoperative preparation for noncardiac surgery in 1. In the 7 patients referred for PTCA due to detection of ischemia, the decision to perform PTCA was based on a stress test other than DE, performed before enrollment in the study. Twelve patients had single-vessel, 6 had two-vessel, and 2 had multivessel disease. In 5 patients, collaterals to the PTCA vessel were identified on angiography.
Coronary angioplasty was successful in 18 of the 20 patients, with a reduction in mean coronary stenosis from 88.7±8.2% to 21.8±10.6% (P=.0001). In these patients, a total of 19 vessels were dilated including 7 right, 6 circumflex, and 6 left anterior descending coronary arteries. In 2 patients, PTCA was unsuccessful, and revascularization was achieved with coronary artery bypass surgery. A saphenous vein graft was placed to the right coronary artery in one patient, while the other received grafts to both right and left anterior descending coronary arteries. None of the patients, including the two in whom PTCA was unsuccessful, had unstable angina or myocardial infarction after the procedure.
For purposes of analysis, each patient was considered to have two vascular territories, left and combined right and circumflex. Thus, out of 40 vascular territories, 28 were supplied by stenotic vessels, of which 22 were revascularized.
Changes in Resting Ventricular Function After PTCA
Serial resting echocardiograms were performed a mean of 2.4±2.9 days (early follow-up) and 7±2 weeks (late follow-up) after angioplasty. A significant improvement in segmental ventricular function was observed after revascularization (Fig 1⇓). Although global WMSI decreased from 2.02±0.92 before angioplasty to 1.83±0.83 at early follow-up, with a further decrease to 1.76±0.81 at late follow-up, these changes did not reach statistical significance. However, a significant improvement in regional function was seen in revascularized territories. In the 22 vascular regions revascularized, the regional WMSI fell from 2.86±0.76 to 2.34±0.97 early and to 2.12±1.03 late after PTCA (Fig 1⇓). The majority of improvement in WMSI (70%) occurred early after revascularization. On the other hand, there was no significant change in regional WMSI in the six nonrevascularized regions (Fig 1⇓).
Of a total of 320 ventricular segments, 318 were adequately visualized for wall motion assessment. Abnormal resting wall motion was seen in 148 segments, of which 114 were revascularized (Fig 2⇓). Significant recovery of resting function (≥2 grades) was seen in 28 segments (25%) early and in a total of 38 segments (33%) late after PTCA. In contrast, of the 34 abnormal segments in the distribution of nonrevascularized territories, significant recovery was seen in only 1 (P<.001) and occurred at late follow-up. Individual changes in wall motion in the revascularized regions from baseline to late follow-up after PTCA are shown in Fig 3⇓. The number of normal segments increased from 70 to 104 segments. Twenty-four of 49 hypokinetic and 8 of 46 akinetic segments showed normal wall motion after revascularization. Wall motion in an additional 6 segments improved from akinetic to mildly hypokinetic. There were only 3 dyskinetic segments among those revascularized, none of which showed recovery of function. A worsening of wall motion score by 1 grade was seen in 7 segments. None of the segments worsened by >1 grade.
Patient-by-patient analysis (n=20) revealed that recovery of function late after PTCA was seen in at least 1 segment in 12 patients (60%) and in ≥2 contiguous segments in 10 patients (50%).
Results of Dobutamine Echocardiography
During DE, 15 of 20 (75%) patients received the maximal 40 μg/kg per minute dose of dobutamine. In 5 cases, the test was terminated prematurely at a mean dose of 28±4.5 μg/kg per minute (range, 20 to 30). The reasons for termination were: reaching >85% predicted maximal heart rate in 3 patients, angina in 1, and hypotension in another. Changes in heart rate and double product during dobutamine infusion are shown in Fig 4⇓. Compared with resting values, significant changes in hemodynamics were not observed until the dobutamine dose exceeded 10 μg/kg per minute.
During the dobutamine infusion, ventricular segments with abnormal resting function exhibited one of four responses: (1) biphasic response: improvement in wall motion at low doses with worsening at higher doses of dobutamine; (2) sustained improvement: improvement in wall motion at low doses that persisted or further improved until peak dose; (3) worsening: further deterioration of resting wall motion during DE without any improvement; and (4) no change: no change in wall motion during DE.
Of the 114 abnormal ventricular segments that were revascularized, 32 (28%) exhibited a biphasic response, 20 (18%) showed sustained improvement, 17 (15%) showed worsening, and 45 (39%) had no change in wall motion during dobutamine. Baseline characteristics and the magnitude of changes in wall motion during dobu- tamine for the segments exhibiting the above responses are detailed below.
Of the 32 segments that exhibited a biphasic response, 17 were hypokinetic, 13 akinetic, and 2 mildly hypokinetic at baseline. During low-dose dobutamine, the majority (62%) improved by 1 grade, while 38% of segments improved by ≥2 grades before reworsening at higher dobutamine doses. The maximal initial improvement in wall motion was seen at doses ranging from 2.5 to 30 μg/kg per minute but was most prevalent (84%) at 7.5 μg/kg per minute (Fig 5⇓). Renewed worsening of wall motion during the biphasic response was seen as early as the 7.5 μg/kg per minute dobutamine dose, but the majority of segments (82%) worsened at ≥20 μg/kg per minute (Fig 5⇓). There was no single low dose of dobu- tamine that allowed detection of the improvement phase of all segments exhibiting a biphasic response (Fig 5⇓). The best combination of two low doses for this purpose was that of 5 and 7.5 μg/kg per minute, allowing detection of wall motion improvement in 94% of biphasic segments. Combining doses of 5, 7.5, and 10 μg/kg per minute allowed detection of the improvement phase in all individual segments.
A sustained improvement response during DE was seen in 20 segments, of which 12 were hypokinetic, 4 akinetic, and 4 mildly hypokinetic at baseline. Improvement in wall motion during DE started at ≤10 μg/kg per minute in 16 segments (80%). Maximal improvement in wall motion was 1 grade in 14 segments (70%) and ≥2 grades in 6 segments. Compared with segments exhibiting a biphasic response, echocardiographic and angiographic characteristics of segments with sustained improvement were similar (incidence of collaterals, prevalence of ≥2 adjacent segments with normal wall motion). Although a tendency for lower severity of coronary stenosis supplying segments with sustained improvement was seen (84% versus 91%), this did not reach statistical significance.
A “worsening only” response of wall motion during DE occurred in 17 segments. Baseline wall motion in these segments was mildly hypokinetic in 5, hypokinetic in 6, and akinetic in 6 segments. During DE, 11 segments worsened by 1 grade, while the rest showed worsening of 2 or more grades. Only 4 of the 17 segments (24%) worsened at low doses (≤10 μg/kg per minute). Segments with worsening response tended to be supplied by more severely stenosed coronary arteries (92% versus 88%). This difference, however, did not reach statistical significance.
There were 45 abnormal segments in PTCA regions that showed no change in wall motion during DE. Over half of these (57%) were either akinetic (n=23) or dyskinetic (n=3) at baseline, while 14 were hypokinetic and 5 were mildly hypokinetic. Only 7 of these 45 segments had 2 or more normal adjacent segments (P<.01 compared with segments with other responses). Collaterals were present in 11 of these segments (P=NS compared with other segments).
Patients were classified according to the type of response observed in the majority (≥50%) of abnormal segments. A biphasic response during DE was seen in 9 patients, sustained improvement in 5, worsening in 4, and no change in wall motion in 2 patients. The combination of 5 and 7.5 μg/kg per minute doses allowed detection of all patients with a biphasic response. A history of angina was present in 5 of the 9 patients with a biphasic response, 2 of 5 with sustained improvement, 2 of 4 with worsening, and in the 2 patients with no change in wall motion during DE. Patients who were given β-blockers and those who were not appeared to have similar types of response to DE. Of 8 patients on β-blockers, 4 showed a biphasic response, 2 sustained improvement, 1 worsening, and 1 no change in wall motion during DE.
Wall Motion Response During Dobutamine and Recovery of Ventricular Function
The prediction of recovery of function of individual segments at late follow-up, analyzed by the type of wall motion response during dobutamine, is shown in Fig 6⇓. A biphasic response best predicted recovery of resting function after revascularization. Of 32 segments with a biphasic response, 23 (72%) had recovery of contractile function at late follow-up. On the other hand, of segments exhibiting sustained improvement or no change, only 15% and 13% showed functional recovery, respectively. Interestingly, 35% of segments with a worsening response during dobutamine had recovery of resting function.
Although a biphasic response was highly predictive of recovery of function after angioplasty, it was seen in only 23 of 38 segments that recovered function, thus giving it a sensitivity of 60% (Fig 7⇓). Combining both biphasic and worsening responses resulted in a sensitivity and specificity of 74% and 73%, respectively, with a positive predictive value of 59% and negative predictive value of 86%.
When analyzed patient by patient, 8 of 9 patients with a biphasic response (89%) showed recovery of function in ≥2 contiguous segments. Recovery of function was seen in 1 of 4 patients with a worsening response, 1 of 2 patients with no change in wall motion during DE, and in none of the 5 with a sustained improvement response. The sensitivity of a biphasic response was 80% (8 of 10), with a specificity of 90%. Combining biphasic and worsening responses improved the sensitivity to 90%, with specificity of 60% (Fig 7⇑). History of exertional angina alone was only a fair predictor for recovery of ventricular function, with 4 of 11 patients (36%) having recovery of function after revascularization.
In the present study, significant improvement in ventricular function was observed in patients with stable coronary artery disease after revascularization with coronary angioplasty, the majority of which occurred early after revascularization. The prediction of recovery of function with dobutamine echocardiography depended on the type of wall motion response observed during dobutamine, the best being for a biphasic response and the worst for sustained improvement. Low doses as well as high doses of dobutamine are therefore needed for the optimal assessment of myocardial hibernation.
Most of myocardial energy is spent for maintenance of normal contractile function. In the absence of coronary artery disease, myocardial perfusion is closely matched to myocardial energy requirements. When coronary flow is acutely reduced, myocardial energy demands exceed supply, resulting in ischemia and contractile dysfunction.11 If this imbalance in energy supply and demand is not corrected, myocardial necrosis may occur.12 It is postulated that in some patients with coronary artery disease, the myocardium may respond to chronic hypoperfusion by downregulating contractile function, thereby reducing cardiac energy demands.13 Myocardial hibernation, a term originally coined by Rahimtoola,4 6 describes such a state in patients with chronic ischemic heart disease, whereby restoration of coronary flow allows recovery of ventricular contractile function. Although to date animal models for myocardial hibernation have been limited to short-term studies, this entity has been well documented clinically.3 14 15 16 Patients with myocardial hibernation appear to be at increased risk for future cardiac events, hence the importance of identification of such patients who may benefit from revascularization.5
In this study, we evaluated a patient population with stable coronary artery disease in whom reversible ventricular dysfunction is likely to represent hibernation. We considered recovery of segmental function to be significant only if wall motion improved by ≥2 grades, making such changes more likely to be clinically relevant. Recovery of function was seen in 33% of abnormal segments that were revascularized. The dependence of functional recovery on restoration of coronary blood flow is indicated by the lack of change in wall motion score of regions that were not revascularized. Wall motion improved in ≥1 segment in 60% of patients and in ≥2 segments in 50% of patients. This may not reflect a true incidence of hibernation, since consecutive patients were not enrolled and the study was limited to patients already scheduled to undergo angioplasty. Most of the recovery in the hibernating ventricular segments was seen at early follow-up (70%). This would suggest that hibernating myocardium has an intact contractile apparatus that is downregulated due to hypoperfusion and recovers quickly after revascularization. Early recovery of function after revascularization has been reported by others,17 although prolonged postischemic dysfunction in patients with myocardial hibernation also has been described.14 18
Dobutamine Echocardiography and Myocardial Hibernation
Contractile reserve of the stunned myocardium to inotropic stimulation has been well demonstrated in the experimental setting and more recently in patients with acute myocardial infarction undergoing thrombolysis.8 9 19 Evidence regarding contractile reserve of the hibernating myocardium is less clear. Few studies have used inotropic stimulation, postextrasystolic potentiation, or nitroglycerin administration to predict recovery of function after revascularization.20 21 22 23 24 Although there are no animal models of chronic hibernation, data on short-term hibernation indicate that hibernating myocardium retains contractile reserve, which may be elicited during dobutamine infusion. In a swine model of short-term hibernation, myocardial creatine phosphate levels initially declined, reflecting a loss of energy production.25 However, while the coronary stenosis was still maintained with depressed myocardial contractility, creatine phosphate levels increased back toward normal. Dobutamine infusion resulted in an improvement in contractility but redepletion of creatine phosphate stores. This suggests that although hibernating myocardium retains contractile reserve, the reserve is probably limited. Further inotropic stimulation leads to depletion of energy stores, resulting in ischemia.
In the present study, we evaluated the type of response of the dysfunctional myocardium to low and high doses of dobutamine. Significant differences among responses were observed in the prediction of recovery of function after revascularization, the highest being for a biphasic response. The observed initial improvement in wall motion probably represents recruitment of contractile reserve during low-dose dobutamine. As the dobutamine dose is increased, ischemia ensues, resulting in renewed worsening of wall motion. This is the first description of a biphasic response specific for identifying reversible dysfunction in patients with stable coronary artery disease. A similar observation was recently made by Smart et al19 in patients early after acute myocardial infarction receiving thrombolysis, a setting associated with myocardial stunning. The observed magnitude of improvement in wall motion at low dose was generally small (1 grade in 62% of segments); however, it was ≥2 grades in 38% of segments. Although a biphasic response was highly predictive of recovery of function, it occurred in only 60% of hibernating segments. Eighteen percent of hibernating segments showed only worsening of wall motion during dobutamine, compatible with ischemia. This probably indicates that some hibernating tissue is supplied by such critically stenosed arteries that no contractile reserve is present, and any increase in demand results in ischemia. Segments with worsening response tended to be supplied by more severely stenosed arteries, although the difference did not reach statistical significance. Studies in larger populations might further clarify this issue. Combining biphasic and worsening responses increased the sensitivity of DE to 74%. On the other hand, a sustained improvement in wall motion to dobutamine had a very low predictive value for recovery of function. The underlying reason for this type of response is unclear. Most segments with a sustained improvement response were hypokinetic at baseline. However, these segments did not differ from those exhibiting a biphasic response with respect to degree of coronary stenosis, presence of collaterals, or number of normal adjacent segments. Although the small number of observations may not allow for a conclusive explanation, these segments did not exhibit worsening wall motion and thus were probably not ischemic even at maximal stress. Chronic resting ischemia is therefore not the underlying mechanism for resting ventricular dysfunction, and revascularization in this situation would not be expected to improve the resting dysfunction. Conceivably, these segments may represent areas of subendocardial infarction with a residual stenosis that is not flow limiting and/or tethered myocardium. Further studies in a larger population are needed to further understand the underlying basis of this response.
Comparison With Previous Studies
Two recent studies using DE to assess myocardial hibernation have shown contractile reserve to be a marker of functional recovery after coronary artery bypass.23 24 Both studies used only low-dose dobutamine. Cigarroa et al24 reported an 82% predictive value of DE for recovery of function. Data on patients were reported, and analysis by segments was not performed. A sensitivity of 86% was reported by LaCanna et al23 using segmental analysis. The latter study may have been biased toward a positive result, since patients enrolled were those who had indication of viability by rest-redistribution thallium-201 scintigraphy, and this is reflected in the high proportion (60%) of segments showing recovery of function. There have been no previous studies evaluating the dose response of the hibernating myocardium to dobutamine. In the present study, the use of higher doses of dobutamine subgrouped segments with initial improvement into those exhibiting a biphasic response or a sustained improvement, responses that had contrasting predictive values for functional recovery after revascularization. Furthermore, the use of high-dose dobutamine identified a subset of hibernating segments that exhibited only an ischemic response, without contractile reserve. The importance of the use of high-dose dobutamine is illustrated by the fact that, if the analysis in this study was restricted to doses up to 10 μg/kg per minute, the sensitivity would have decreased to 68% for segmental analysis and 80% for patients with a further drop in specificity to 65% for segments and 40% for patients. Since a high-dose DE was not performed in the previous studies, it is not known whether a biphasic response would have been observed, accounting for the reported predictive value of low-dose dobutamine alone. Interestingly, even though doses of only 5 and 10 μg/kg per minute were used in one of the studies, some segments did show improvement in wall motion at 5 μg/kg per minute and deterioration at 10 μg/kg per minute.23
Although DE is useful in the assessment of myocardial hibernation, it can also underestimate viability in some cases. Thirteen percent of segments showing no change in wall motion in response to dobutamine had recovery of function after angioplasty. The majority of these segments were akinetic at rest, showing no change in wall motion during dobutamine. Whether the combination of dobutamine with nitroglycerin or ATP administration may improve detection of myocardial hibernation in these cases remains to be determined.
Study Advantages and Limitations
Angioplasty was chosen as the revascularization procedure for several reasons. After coronary artery bypass, wall motion may be influenced by postoperative stunning or hyperdynamicity resulting from use of inotropes, anemia, or infection. In addition, infarction after bypass may be difficult to diagnose and can confound assessment of changes in wall motion. Furthermore, since septal motion becomes paradoxical after bypass surgery, it would be difficult to blind the reader to timing of the echocardiographic studies. PTCA is a well-established technique for myocardial revascularization with a high success rate. A limitation of using angioplasty as the revascularization modality is restenosis. We excluded patients undergoing PTCA of a bypass graft due to the higher rate of restenosis. All patients, except 2 who underwent bypass, had satisfactory angiographic results. No patient had recurrent angina or complications after the procedure. In this study, patients enrolled were nonconsecutive and already scheduled to undergo PTCA, the majority based on either clinical grounds or a positive stress test suggesting the presence of ischemia. However, DE was not used in the decision process. Further studies in larger populations are needed to assess the predictive value of DE in suspected myocardial hibernation.
Serial resting echocardiographic images were digitized in comparable views and randomized for interpretation. Although this format puts the echocardiographer at a disadvantage by not providing intermediate echocardiographic views and a large number of cardiac cycles for evaluation of regional function, it helps reduce bias in interpretation and ensures comparability of tomographic images. Although wall motion was not quantitated, the advantage of qualitative assessment of regional function, along with the derivation of a semiquantitative wall motion score, is the enhanced ability to assess wall motion by integrating information from multiple views. This lessens the problems of endocardial dropout and lateral resolution that may occur depending on the imaging window.
We excluded patients with unstable ischemic syndromes and studied only patients with stable significant coronary artery disease in whom reversible ventricular dysfunction is more likely to represent hibernation. The possibility of silent ischemia resulting in stunning cannot be excluded in the absence of perfusion data. However, the presence of wall motion abnormality on two separate studies before revascularization and the observation that recovery of function in serial studies was seen almost exclusively in revascularized segments strongly support hibernation rather than stunning as the underlying entity in our study group.
Clinical Implications: Optimal Dobutamine Dose and Quad-Screen Display
The finding that DE can predict recovery of function after revascularization has considerable implications for patient management and risk assessment. Our results suggest the need for both low and high doses of dobutamine for optimal assessment of myocardial viability in patients with stable coronary artery disease. Although no single low dose allowed detection of all segments exhibiting the improvement phase of the biphasic response, the best combination of two low doses to be displayed was that of 5 and 7.5 μg/kg per minute. Since current digital echocardiographic technology allows viewing a maximum of four simultaneous images (quad screen), a display of resting images as well as those of 5 and 7.5 μg/kg per minute and peak dobutamine doses on a quad screen would allow optimal assessment of myocardial hibernation.
Computational assistance was provided by the CLINFO Project, funded by grant PR-00350 from the Division of Research Resources, National Institutes of Health, Bethesda, Md. The authors thank Eula Landry for her assistance in the preparation of the manuscript.
The guest editor was Robert A. O’Rourke, MD, University of Texas Health Science Center, San Antonio, Tex.
Presented in part at the 66th Annual Scientific Session of the American Heart Association, November 1993, Atlanta, Ga.
- Received May 11, 1994.
- Accepted September 23, 1994.
- Copyright © 1995 by American Heart Association
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