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(Circulation. 1996;94:3055-3061.)
© 1996 American Heart Association, Inc.

Articles

Hibernating Myocardium Has Reduced Blood Flow at Rest That Increases With Low-Dose Dobutamine

Shahbudin H. Rahimtoola, MB, FRCP, MACP

the Griffith Center and the Division of Cardiology, Department of Medicine, LAC+USC Medical Center, University of Southern California Medical Center, Los Angeles, Calif.

Key Words: blood flow • ischemia • revascularization • myocardial contraction • echocardiography • Editorials

	Introduction

Top Introduction Dobutamine Echocardiography Myocardial Blood Flow in... Impaired Wall Motion With... References

 
Hibernating myocardium^{1 2 3} was defined by Hearse⁴ as "exquisitely regulated tissue successfully adapting its activity to prevailing circumstances." Ross⁵ has described it as perfusion-contraction matching-which it is; however, in the normal heart and probably also in one with infarction and a high degree of interstitial fibrosis and of myocytes with myolysis or loss of sarcomeres, there is also a match between perfusion and contraction.^{6 7} Ross also suggested that "acute" experimental studies of hibernation be called short-term hibernation. In 1986, Braunwald and Rutherford⁸ endorsed the concept of HM, believed it was an appropriate use of the term, and confirmed its occurrence in patients. As a result, the subsequent decade has seen (1) a great deal of basic and clinical research in this area, (2) a reassessment of the definition of ischemia,⁴ (3) development and assessment of tests for diagnosis of HM, and (4) better treatment of patients.

However, much work still needs to be done. In the current issue of Circulation, the group from UCLA⁹ who have made major contributions to HM present data that contribute to an understanding of the response to dobutamine and document reduced resting MBF in HM. Their conclusion that functionally impaired though normally perfused myocardium frequently exists in patients with coronary artery disease is problematic.

	Dobutamine Echocardiography

Top Introduction Dobutamine Echocardiography Myocardial Blood Flow in... Impaired Wall Motion With... References

 
In the early 1970s, with use of inotropic agents (epinephrine, isoproterenol, and postextrasystolic potentiation) and contrast ventriculography, it was documented that resting wall motion abnormalities may improve^{10 11 12} and that this improvement was predictive of subsequent improvement with coronary bypass surgery.^{13 14 15}

The study of Sun and coworkers⁹ from UCLA, using the inotropic agent dobutamine and two-dimensional echocardiography, confirms that patients with perfusion-metabolism mismatch (HM) determined by PET have an inotropic and an attenuated coronary vasodilator reserve, a finding that has been documented in experimental and human studies.^{6 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42} They also document that MBF and exogenous glucose utilization are increased in HM during dobutamine infusion; this provides additional data that the observed improvement in wall motion with dobutamine represents a real improvement of function in these dysfunctional segments.

Dobutamine echocardiography for diagnosis of HM has a positive and negative predictive accuracy of 83% and 81%, respectively.⁴³ Two possible reasons the predictive accuracy is not perfect are that LV wall motion may not have been correctly evaluated and return of function after revascularization may not have been adequately or properly evaluated to correctly assess predictive accuracy. The lack of positive predictive accuracy in 15% could be explained by several factors: one is a tethering effect, that is, dobutamine increases contraction of normal myocardium that drags along the nonviable myocardium, which then appears to have increased contraction. Another explanation is that LV hypokinesis may result from subendocardial infarction that does not improve with dobutamine, but the adjacent normal mid- and epicardium has increased contraction, which is then interpreted as improved LV wall motion with dobutamine.^{37 40} This is also why it cannot be always assumed that all regions that are hypokinetic at rest will improve with revascularization. The lack of a negative predictive accuracy in 20% may be a result of many factors. These include (1) use of a higher dose of dobutamine may have shown an improvement of LV wall motion that was not seen with a lower dose, (2) MBF and coronary flow reserve may have been reduced to such a marked degree that the myocardium could not respond to dobutamine, and (3) myocardial changes that had occurred in HM may not allow for an adequate immediate response that could be clinically observed.^{7 42 44 45 46 47 48 49 50}

A word of caution is appropriate with regard to the clinical use of dobutamine echocardiography to diagnose HM. Note that one explanation for the increased exogenous glucose utilization in the study of Sun et al⁹ could have been the production of ischemia caused by a 1-hour infusion of dobutamine for the ¹⁸F-deoxyglucose study. In 1976, Willerson et al⁵¹ showed that dobutamine in a dose of 20 µg/kg per minute increased regional MBF to all areas of the heart in anesthetized dogs with acute myocardial ischemia and also increased epicardial ST-segmental elevation indicating myocardial injury, effects that were not seen in doses of 4 µg/kg per minute. In experimental studies of short-term hibernation,⁵ inotropic stimulation with dobutamine and with atrial pacing has been shown to upset the balance between MBF supply and need, thereby producing ischemia^{16 17 18 51 52 53} or even infarction^{18 51 52 53} (Fig 1). This deleterious effect (infarction) appears to be related to the severity of the reduced MBF at rest and the severity and duration of inotropic stimulation. In the early 1970s, inotropic stimulation with isoproterenol and epinephrine was shown to produce deterioration of resting abnormalities of wall motion function in some patients.^{10 11 12} In experimental animals^{18 51 52 53} and in patients,^{27 28} dobutamine may produce deterioration of contraction in dysfunctional segments either initially, which may be the result of production of ischemia in hibernating or in normally contracting myocardium, or after a period of improvement of function; the latter may be more specific for the diagnosis of HM than is only an improvement of function.^{27 28} There is a tendency to use increasingly larger doses of dobutamine to show improvement and/or deterioration of segmental LV wall motion function, which is appropriate if adequate care is taken to perform the procedure. In all patients undergoing dobutamine echocardiography, the incidence of myocardial infarction was 0.1%⁵⁴ and of sustained ventricular tachycardia and of ventricular fibrillation resulting from acute ischemia, 0.4% and 0.2%, respectively^{54 55} ; Nagueh and Zoghbi⁵⁵ reported being aware of two deaths that occurred at another institution. The incidence may be higher in those with HM because by definition these patients have LV dysfunction at rest and coronary artery disease. I have been made aware of five patients at three medical centers in whom myocardial infarction occurred with dobutamine echocardiography. Thus, it would seem clinically prudent that when dobutamine echocardiography is being performed for diagnosis of HM that an appropriately experienced and skilled physician observe LV wall motion function and (1) the dobutamine is discontinued as soon as possible after a diagnosis of deterioration of LV wall motion function is made with reasonable confidence and (2) if the induced ischemia (ECG changes and/or deterioration of LV function) is not promptly relieved by discontinuing the dobutamine, then the patient should receive appropriate therapy.

View larger version (94K): [in this window] [in a new window]   Figure 1. In an experimental study of short-term hibernation,18 dobutamine infusion resulted in myocardial infarction (right) when subendocardial blood flow was further reduced from 0.17 mL/min per gram (left) to 0.11 mL/min per gram (right). With and Without indicate with and without infarction. Reproduced with kind permission of Professor Gerd Heusch, Essen, Germany.

	Myocardial Blood Flow in Hibernating Myocardium

Top Introduction Dobutamine Echocardiography Myocardial Blood Flow in... Impaired Wall Motion With... References

 
Measurement of MBF by PET using ¹⁵O-water has several limitations.^{56 57 58} One is that this technique measures blood flow per gram of "perfused tissue,"^{56 57} which means that ". . . the value measured is independent of the actual amount of perfused myocardium in that territory,"⁵⁷ which explains why it is not accurate in predicting the functional outcome after revascularization.⁵⁷ Another is the greater method-related heterogeneity due to the short physical half-life of ¹⁵O-water, which causes a rapid decline in count rates and thus leads to considerable statistical noise.⁵⁸ This limits the accuracy of measurement of regional MBF by ¹⁵O-water.^{58 13}N-ammonia is the preferable tracer to use for measurement of regional MBF by PET, and Sun et al⁹ did use it.

Sun et al⁹ state "blood flow did not differ between normal volunteers, normal remote, abnormal remote regions, and mismatches" and conclude that "blood flow-metabolism mismatch patterns are not consistently associated with a fixed downregulation of MBF." Is this a correct interpretation of their data?

To answer this question, one needs to address the issue of the correct reference to which MBF in HM should be compared. Sun et al⁹ compared it with healthy volunteers who were 37±18 years of age, whereas the patients in their study were much older (63±9 years). In a previous study of healthy volunteers from the same laboratory,⁵⁹ those 31±9 years of age had a significantly lower MBF than those 64±9 years of age (76±17 versus 92±25 mL/min per 100 g; P<.05), a difference that was partly accounted for by a difference in rate-pressure product. Thus, comparison of MBF in older patients with HM to that in younger healthy people may be inappropriate. MBF measurement by PET has several limitations.^{57 58 59 60 61 62} For example, MBF measurement by PET assumes that the LV wall thickness is 1.0 cm²,^{9 59} which may not be true for older healthy volunteers, all people, or all patients. Also, MBF in "normal subjects" by PET with the use of ¹³N-ammonia shows a very large range of values for the normal range (±2 SD of the mean ranges from 40 to 150 mL/min per 100 g) (Fig 2); therefore, in any given patient, transmural MBF could be reduced by 50%, and the MBF would still be in the normal range.

View larger version (39K): [in this window] [in a new window]   Figure 2. Myocardial blood flow (mean±2 SD) in "normal subjects" determined by PET with the use of 13N-ammonia. Eight studies are shown and arranged by increasing age of the study subjects (mean±SD) from left to right. Numbers of subjects in each study are listed (n). Studies 1 through 8 are from cited References 72, 73, 59, 74, 75, 41, 76, and 59, respectively.

Normal MBF is determined by myocardial oxygen needs (MVO₂). Major determinants of MVO₂ include heart rate, myocardial tension (LV volume, mass, and pressure), and myocardial contractility. Rate-pressure product does not give a complete assessment of MVO₂ needs and thus of what the normal MBF should be in an individual patient. Therefore, it seems reasonable that MBF in regions of HM should be compared with remote regions of normal MBF and normal function in the same patients, particularly if the MBF in HM is in the "normal range."

In the study of Sun et al,⁹ MBF at baseline in normal remote regions was available in only 5 of the 10 patients with mismatch. In these 5 patients, MBF was lower in mismatch regions versus that in normal remote regions (59±25 versus 81±26 mL/min per 100 g, P=.004), that is, those with normal function and normal MBF at rest (Fig 3). Note that MBF in mismatch regions was lower in each patient and that there was also a wide range of MBF in mismatch as well as in normal remote regions. Thus, the study of Sun et al⁹ actually showed that MBF is reduced at rest in regions of perfusion-metabolism mismatch (HM). Furthermore, all patients in the study of Sun et al⁹ had multivessel coronary artery disease (50% had three-vessel disease), and thus, the normal remote regions may have been supplied by obstructive coronary artery disease. The wide range of MBF in mismatch regions as well as in the normal remote regions (Fig 3) emphasizes the importance of comparing paired values from the same patients because in some instances, comparison between groups of patients or with normal volunteers could potentially give misleading information about MBF in HM.

View larger version (18K): [in this window] [in a new window]   Figure 3. Myocardial blood flow from the data of Sun et al (cited Reference 9). Values in normal remote and mismatch are from five patients in whom values were available in the same patients (normal remote regions, 81±26; mismatch regions, 59±25; mean±SD; P=.004 by paired t test). (Statistical calculations courtesy of Sharon Orrange, MHS).

Sun et al⁹ state ". . . relative blood flow in mismatches (as a percentage of blood flow in the normal remote regions in the same patients; n=5) averaged 72±11% at baseline (P<.005)." Can a 28% reduction in transmural MBF result in a reduction of myocardial contraction? Gallagher and coworkers⁶³ have shown in animal experiments that there is a linear relation between reductions in subendocardial blood flow and myocardial contraction. Vatner⁶⁴ measured subendocardial blood flow in animals and stated that "When blood flow fell by only 10% to 20%, regional function was severely impaired" and there was a ". . . sensitive coupling between blood flow and function in conscious dogs with acute myocardial ischemia." PET measures transmural MBF and at the present time cannot determine subendocardial blood flow in humans because it lacks sufficient spatial resolution. In animals, when transmural MBF falls by 22%, subendocardial blood flow falls by 38% to 48%^{63 65} (Fig 4). Thus, a 28% lower transmural MBF in mismatch regions in the Sun et al study can be expected to result in a reduced contraction in the mismatch regions.

View larger version (23K): [in this window] [in a new window]   Figure 4. Relationship of % reduction of subendocardial MBF to % reduction of transmural MBF in experimental animals. The data are from Pantely et al65 and calculated from that of Gallagher et al.63

The conclusion from the data of Sun et al⁹ that MBF at rest is reduced in HM in patients supports six^{6 7 41 66 68 69} other earlier studies in patients, five of which measured MBF by PET with the use of ¹³N-ammonia.^{6 7 41 66 68} (1) Vanoverschelde et al⁶⁶ reported on 17 patients who had no infarction, had a totally occluded artery that supplied an area of myocardium that was collateral-dependent for flow, and had resting wall motion abnormality. MBF in LV dysfunctional segments was significantly lower than in normally functioning LV segments in the same 17 patients (77.1±24.6 versus 95.5±26.7 mL/min per 100 g; P<.001; Table).^{66 67} The importance of comparing MBF in HM with that in normal areas in the same heart can be appreciated from this study.⁶⁷ MBF in normally functioning LV segments in these 17 patients was greater than that in another group of 9 patients with coronary artery disease and normal LV function (95.5±26 versus 82.7±18.0 mL/min per 100 g; P<.05).^{66 67} One reason for the increased MBF in the 17 patients with LV dysfunction was that these 17 patients had a 5.6% higher rate-pressure product and 21.7% larger LV volume than the 9 patients with normal LV function⁶⁷ and thus, their MVO₂ needs would be greater.

View this table: [in this window] [in a new window]   Table 1. Myocardial Blood Flow at Rest by PET With the Use of N13-Ammonia in Hibernating Myocardium

(2)In an earlier report from UCLA in 22 patients with recent myocardial infarction, Czernin et al⁶⁸ showed that MBF in mismatch regions was lower than in normal regions in the same patients (57±20 versus 83±20 mL/min per 100 g; P<.05). Of the 20 patients who had coronary arteriography, 10, 7, and 3 had one-, two-, and three-vessel disease, respectively.

(3)Marzullo et al⁶ studied 14 patients with previous myocardial infarction, infarct-related single-vessel coronary artery disease, and regional LV dysfunction. LV segments with impaired LV systolic pump function and metabolically viable myocardium had MBF that was >2 SD below the mean of normally contracting segments (42±12 versus 100±24 mL/min per 100 g).

(4)Sambuceti et al⁴¹ studied 19 patients without myocardial infarction, with totally occluded single-vessel coronary artery disease supplying myocardium that was dependent on collaterals for flow; 6 had wall motion abnormalities in the collateral-dependent myocardium. "All six with a wall motion abnormality showed flow values >2 SD below normal values."⁴¹

(5)Shivalkar and coworkers⁷ have shown that 18 of 50 patients undergoing coronary bypass surgery had reduced regional myocardial function (regional ejection fraction), reduced MBF, and normal metabolism (HM). The HM subgroup was the only subgroup that had improved regional ejection fraction after revascularization; MBF also increased after revascularization. Before revascularization, this subgroup had MBF that was 67±10% of control region. The mean 33% reduction in transmural MBF would be expected to result in reduction of subendocardial MBF of 55% to 60%^{63 65} (Fig 4). In these 18 patients, MBF in the HM was lower than in the control regions (63.8±12.8 versus 93.4±12.6; P<.005; personal communication, Prof W. Flameng).

(6)Arani et al⁶⁹ studied 7 patients, using the inert gas technique for measurement of MBF. They showed MBF in collateral-dependent segments of a totally occluded left anterior descending coronary artery with wall motion abnormalities had reduced MBF (>2 SD below the mean) compared with normal subjects with the same rate-pressure product (38±8 versus 70±13 mL/min per 100 g)^{69 70} and to total MBF (normal plus abnormal flow regions) in the same patients (38±8 versus 51±8; P=.02).⁶⁹

	Impaired Wall Motion With Normal Blood Flow

Top Introduction Dobutamine Echocardiography Myocardial Blood Flow in... Impaired Wall Motion With... References

 
In the study of Sun et al,⁹ 11 patients are said to have impaired LV wall motion but "apparently" normal MBF (called "abnormal remote") when MBF was compared with normal volunteers and with those with normal wall motion and normal MBF ("normal remote"). Comparison of MBF to normal volunteers poses some difficulties (vide supra).

Complex protocols are very difficult to perform in patients, and Sun et al⁹ are to be congratulated for doing them successfully. Nevertheless, when analyzing the data and before making conclusions, we must keep limitations of the study in mind. In the study of Sun et al,⁶ these include (1) LV wall motion was evaluated subjectively by any one of three different investigators. The interobserver and intraobserver variability in assessing LV wall motion is not given. (2) The delay between measurement of resting MBF and assessment of LV wall motion in 6 patients averaged 12 days and ranged up to 22 days and thus, at the time of assessment of LV wall motion, resting MBF could have been different from that reported in their study. (3) The data on ß-adrenergic blockers is given, but no mention is made about coronary vasodilators, such as, nitrates or Ca²⁺ channel–blocking agents. (4) Coronary arteriography was performed an average of 182 days before MBF studies and ranged up to 2 years before the PET studies. During the intervening period, 3 patients reported worsening of their symptoms. Thus, one cannot be sure of the extent and severity of coronary artery disease in the "abnormal remote" regions in all patients at the time of PET studies. (5) Of the 11 "abnormal remote" regions, 2 were supplied by vessels with 99% and 95% stenosis and 3 were supplied by vessels that were totally occluded; 7 of the 11 also had three-vessel disease. Coronary vasodilator reserve also was not normal in the "abnormal remote" region; with dobutamine, MBF increased by 68% in the normal remote regions and by only 31% in the abnormal remote regions. Thus, MBF may not have been normal in the regions labeled "abnormal remote," that is, those with abnormal LV function and "normal" MBF. (6) Of the 11 regions, 6 had no improvement with dobutamine, which suggests that the myocardium in the abnormal remote region may not have been viable in all patients. Thus, it is very difficult to come to any meaningful conclusion about the findings in this subgroup of patients. Therefore, it is questionable whether repetitive stunning or remodeled LV myocardium can be invoked as the cause of the findings; moreover, no data were presented for either occurrence in any of the 11 patients. Previously, Vanoverschelde et al⁶⁷ inappropriately suggested repetitive stunning as a cause of the observed LV dysfunction in their study; subsequently, they acknowledged that "we agree that we have not yet proven that repeated stunning actually occurred in these patients."⁷¹ These comments should not be assumed to indicate that such a subgroup of patients does not exist; these comments are meant to emphasize that the data presented do not allow such conclusions to be made. However, Sun and coworkers⁹ are to be commended for presenting complete data on each patient, because such a detailed presentation allows a critical review and proper evaluation of this complex issue.

Summary
The study of Sun and coworkers is important because (1) it provides additional data that HM has an inotropic and an attenuated coronary vasodilator reserve. They also provided data that support the conclusion that with dobutamine, the improvement of abnormal LV wall motion is real in many patients. (2) It emphasizes the possibility of a deleterious effect (infarction) of dobutamine in HM and thus the need for appropriate caution during its use. (3) It provides additional data that confirm that areas of perfusion-metabolism mismatch on PET imaging (HM) are associated with a reduced MBF at rest.

However, their conclusions about areas of LV dysfunction with "normal" MBF in coronary artery disease are problematic; therefore, one must be extremely cautious about these conclusions on the basis of the data that are presented.

	Selected Abbreviations and Acronyms

 

HM = hibernating myocardium LV = left ventricular MBF = myocardial blood flow PET = positron emission tomography

	Footnotes

 
Reprint requests to Shahbudin H. Rahimtoola, MD, Distinguished Professor, University of Southern California, 2025 Zonal Ave, Los Angeles, CA 90033.

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

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