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Am J Physiol Heart Circ Physiol 292: H2791-H2797, 2007. First published January 19, 2007; doi:10.1152/ajpheart.01384.2006
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Determinants of contractile reserve in viable, chronically dysfunctional myocardium

Michael D. Banas,1,3,4 Sunil Baldwa,1,2,3,4 Gen Suzuki,3,4 John M. Canty, Jr.,1,3,4,5 and James A. Fallavollita1,3,4

1Veterans Affairs Western New York Health Care System, Buffalo; 2Canandaigua Veterans Affairs Medical Center, Canandaigua, New York; and 3Center for Research in Cardiovascular Medicine, 4Department of Medicine, and 5Department of Physiology and Biophysics, University at Buffalo, Buffalo, New York

Submitted 20 December 2006 ; accepted in final form 19 January 2007


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
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 REFERENCES
 
There is considerable variability in the sensitivity of inotropic reserve to identify viability in chronically dysfunctional myocardium. This is partially related to the underlying pathophysiology, with more frequent contractile reserve in chronically stunned (with normal resting perfusion) than hibernating myocardium (with reduced flow). This study was undertaken to determine the physiological responses to transient and graded stimulation in chronically stunned and hibernating myocardium to define the relative roles of acute catecholamine desensitization and biphasic responses. Pigs were chronically instrumented with a fixed left anterior descending artery stenosis that resulted in chronically stunned myocardium after 2 mo. One month later, hibernating myocardium was confirmed by regional dysfunction (wall thickening, 3.2 ± 0.3 vs. 5.5 ± 5 mm in remote, P = 0.01) with reduced resting flow (0.70 ± 0.07 vs. 0.92 ± 0.09 ml·min–1·g–1 in remote, P = 0.01) without infarction. Wall thickening in dysfunctional regions significantly increased during both graded and transient epinephrine stimulation in chronically stunned (from 3.6 ± 0.3 to 5.6 ± 0.5 and 4.9 ± 0.5 mm, respectively) and hibernating myocardium (from 3.3 ± 0.3 to 5.4 ± 0.6 and 5.0 ± 0.7 mm, respectively) and returned to baseline within 15 min. Although a biphasic response during graded stimulation was common, the subsequent decrement in function was small and similar in both groups (stunned, 0.7 ± 0.2 mm; hibernating, 1.1 ± 0.3 mm, P = 0.25). We conclude that 1) the extent of contractile reserve during beta-adrenergic stimulation is similar in chronically stunned and hibernating myocardium, 2) there are no significant differences between the responses to transient compared with graded catecholamine stimulation, and 3) submaximal catecholamine stimulation does not induce additional stunning in either chronically stunned or hibernating myocardium.

inotropic reserve; catecholamine; viability; stunned myocardium; hibernating myocardium

CLINICAL STUDIES HAVE SHOWN that there is considerable variability in the accuracy of contractile reserve during beta-adrenergic stimulation to predict myocardial viability. This appears to be at least partially related to the continuum of physiologies associated with viable myocardium, since most studies have shown a greater incidence of contractile reserve in chronically stunned myocardium with normal levels of resting flow compared with hibernating myocardium in which resting perfusion is reduced (4, 5). Among segments with hibernating myocardium, clinical evidence of contractile reserve may be absent in up to 50% (29). In a well-characterized porcine model of hibernating myocardium, our group (14) has previously shown that contractile reserve during beta-adrenergic stimulation is significantly blunted compared with the normally perfused remote myocardium. Furthermore, our work documented that this limited responsiveness was not due to the development of acute ischemia, because there was no regional lactate production or change in venous pH (14). Subsequent work by our group (21) has shown that despite normal levels of total beta-adrenergic receptors in hibernating myocardium, there is a reduction in high-affinity binding and regional desensitization of receptor signaling.

Our group also has previously demonstrated that pigs chronically instrumented with a proximal coronary stenosis systematically progress from chronically stunned myocardium (at 1 and 2 mo after instrumentation) to develop hibernating myocardium after 3 mo. By using serial studies in the same group of animals, the aims of the present study were to determine 1) whether transient beta-adrenergic stimulation elicits greater contractile reserve than a prolonged, graded stimulation protocol (24), 2) whether contractile reserve is different in chronically stunned versus hibernating myocardium, and 3) the relative frequency of a biphasic contractile response during graded catecholamine stimulation in chronically stunned and hibernating myocardium (29).


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Experimental procedures conformed to institutional guidelines for the care and use of animals in research, and were approved by the University Institutional Animal Care and Use Committee. Pigs (n = 15, weight = 8.0 ± 0.4 kg) were chronically instrumented with a fixed, 1.5-mm (inner diameter) Delrin stenosis on the proximal left anterior descending artery (LAD). At the time of instrumentation this stenosis caused no reduction in resting flow or flow reserve, but the physiological significance of the stenosis increased with animal growth. Previous studies have shown that 1 and 2 mo after instrumentation, there is regional dysfunctional myocardium with normal resting flow, consistent with chronically stunned myocardium (9, 11). However, by 3 mo after instrumentation, there was a critical reduction in flow reserve and resting flow became depressed, consistent with hibernating myocardium (10, 15, 23).

To determine differences in contractile reserve in chronically stunned compared with hibernating myocardium, we studied pigs ~2 mo (62 ± 1 days, weight = 44 ± 1 kg) and 3 mo (94 ± 2 days, weight = 68 ± 3 kg) after instrumentation. A previous study in different groups of animals with hibernating myocardium had suggested that the contractile response was greater with transient compared with graded epinephrine stimulation (24), so paired protocols at each time point were performed 4 ± 1 days apart in random order. Animals were initially sedated with a mixture of Telazol (tiletamine and zolazepam)-xylazine, and after peripheral vascular access was obtained, anesthesia was maintained with a continuous infusion of propofol (5–10 mg·kg–1·h–1). Blood pressure was noninvasively obtained with an automated cuff (Dinamap; Critikon). Heart rate and oxygen saturation were continuously monitored. Animals were intubated and given supplemental oxygen.

Assessment of regional ventricular function. Regional left ventricular (LV) function was assessed by transthoracic echocardiography through a right parasternal window with the animals on their left side (24), using a 2.5-MHz phased-array transducer (GE Vingmed System V; GE Healthcare) (6, 16). Mid-LV short-axis two-dimensional echocardiographic views were obtained, and two to four cycle loops were recorded. Anteroseptal and posterior wall thickness were determined using anatomic M-mode (GE Healthcare) (6). As recommended by the American Society of Echocardiography (30), end diastole was defined as the onset of the QRS complex and end systole was the point of minimum chamber diameter. Regional function was assessed with myocardial wall thickening (end-systolic thickness – end-diastolic thickness) (24). Fractional shortening, an assessment of global function, was defined as [100 x (LV end-diastolic dimension) – (LV end-systolic dimension)]/(LV end-diastolic dimension) (24).

For the transient stimulation protocol, a single stage of stimulation was produced with a dose of epinephrine (0.35 ± 0.01 µg·kg–1·min–1) that would increase heart rate by ~40 beats/min (34). For the graded simulation protocol, epinephrine was incrementally infused in four equal stages to a similar peak epinephrine dose (nominal doses of 0.0875, 0.175, 0.2625, and 0.35 µg·kg–1·min–1) (14). Each stage was maintained for ~10 min to allow heart rate to stabilize before echocardiograms were obtained (24). To assess the recovery of regional function and the possible induction of additional stunning following inotropic stimulation in viable dysfunctional myocardium, we assessed function after transient stimulation every 15 min for 1 h.

Regional perfusion and myocardial sampling. Myocardial perfusion and coronary flow reserve were assessed in 12 animals 95 ± 2 days after instrumentation in the closed-chest, propofol-anesthetized state (6). The remaining three animals died prematurely either as a result of spontaneous sudden death (n = 2) (6) or as a complication of a study (n = 1). Myocardial flow was quantified with fluorescently labeled microspheres injected at rest and during adenosine vasodilation (0.9 mg/kg iv) with phenylephrine coinfused to maintain systolic pressure (6). After all studies were completed, animals were euthanized under general anesthesia. The heart was serially sectioned, and samples from the LAD-perfused region and remote, normally perfused myocardium were analyzed to determine regional perfusion (6). Additional sections were stained with triphenyltetrazolium chloride (TTC) to exclude myocardial infarction (8, 14).

Data analysis. Data are reported as means ± SE. Regional wall thickening was quantified by two independent observers, one of whom was blinded to all study information. Discrepancies in baseline wall thickening of >1 mm were adjudicated with a third observer, and the values in closest agreement were averaged. The changes in wall thickening during each stimulation protocol were assessed with a two-way (myocardial region and protocol stage) analysis of variance (ANOVA; SigmaStat 3.00, SPSS). When significant differences were present, the Holm-Sidak test was used for post hoc comparisons versus baseline. Changes in hemodynamic parameters during a protocol were assessed with one-way ANOVA. Differences in baseline or peak stimulation parameters between myocardial regions or stimulation protocols were compared with paired t-tests. A value of P ≤0.05 was considered statistically significant.


   RESULTS
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DISCUSSION
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Development of hibernating myocardium in chronically instrumented pigs. Table 1 and Fig. 1 confirm the development of hibernating myocardium in chronically instrumented pigs 3 mo after initial instrumentation (6, 14, 15, 24). Myocardial wall thickening was reduced by 41% in the hibernating LAD region compared with the normally perfused remote region. This was associated with reductions in subendocardial and full-thickness resting perfusion and severe reductions in regional flow reserve in hibernating myocardium (Table 1). There was a critical reduction in subendocardial flow reserve, with flow during adenosine vasodilation (0.61 ± 0.16 ml·min–1·g–1) unable to increase over resting levels (0.75 ± 0.09 ml·min–1·g–1, P = 0.54). These abnormalities in function and perfusion were not the result of myocardial infarction, because fibrosis involved <1% of LV mass by TTC staining in each animal. Although this model of hibernating myocardium is associated with a small regional increase in connective tissue staining (~2%) (13), a similar change is present in animals with chronically stunned myocardium (9).


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  		Table 1. Function, perfusion, and flow reserve in hibernating myocardium

 

Figure 1
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  		Fig. 1. Regional function during inotropic stimulation in chronically stunned and hibernating myocardium. Regional function in the left anterior descending artery (LAD)-perfused region was reduced compared with the normally perfused remote myocardium (ANOVA, P < 0.001 during each protocol). In chronically stunned myocardium (2 mo), graded epinephrine infusion (E1–E4), resulted in significant functional improvement in both regions during the latter stages, although the peak function (Pk) did not always occur at the maximum dose of epinephrine (E4). In the transient stimulation protocol, the same peak dose of epinephrine (E4) also increased function in both regions. After both stimulation protocols, function returned to baseline (BL) within 15 min (recovery, or R15). Functional improvements were similar in pigs with hibernating myocardium (3 mo), and in neither group was there evidence for additional stunning following epinephrine stimulation. There were no significant differences in function between protocols at comparable time points. The periods of epinephrine stimulation are demarcated by the shaded background. *P < 0.05 vs. BL.

 
Transient versus graded epinephrine stimulation in chronically stunned myocardium. Myocardial dysfunction under baseline conditions was present in the LAD region of chronically instrumented animals 2 mo after instrumentation (Fig. 1), and function in the LAD region remained significantly reduced compared with the remote region during epinephrine stimulation (ANOVA, P < 0.001 for each protocol). The functional responses to both transient and graded epinephrine stimulation are shown in Fig. 1, top. Both the transient and graded stimulation protocols resulted in significant increases in function in the LAD-perfused region (Fig. 1, top left) as well as remote myocardium (Fig. 1, top right). There were no differences in LAD region function between the two protocols at comparable time points; however, as indicated by ANOVA, function in remote myocardium tended to be higher during the graded stimulation protocol (P = 0.04). At the maximum dose of epinephrine, both protocols resulted in similar improvements in regional function in both regions, and global function increased to a similar extent (Table 2). However, the peak improvement in regional function during the graded protocol frequently occurred at a submaximal epinephrine dose (peak LAD function at stage 2.8 ± 0.3). The peak improvement in remote region function during graded stimulation occurred at stage 3.0 ± 0.3 (P = 0.72 vs. LAD). There was no evidence of additional stunning following either stimulation protocol, because wall thickening returned to baseline within 15 min. The hemodynamic parameters associated with these protocols are shown in Fig. 2, left. There were no differences in hemodynamic parameters between the protocols at comparable time points (baseline, maximum epinephrine, and 15 min of recovery). Epinephrine stimulation resulted in a small decrease in LV diastolic dimension and an increase in LAD region diastolic wall thickness (Table 2).


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  		Table 2. Diastolic dimensions and left ventricular fractional shortening

 

Figure 2
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  		Fig. 2. Hemodynamic parameters during epinephrine stimulation. As expected, intravenous epinephrine (E1–E4) resulted in significant increases in heart rate over BL in both the graded and transient stimulation protocols. The hemodynamic values at peak LAD region function during epinephrine stimulation are also shown. There was a trend for systolic blood pressure to modestly decrease during each protocol. There were no significant differences in heart rate or systolic blood pressure between the protocols at comparable time points. The periods of epinephrine stimulation are demarcated by the shaded background. *P < 0.05 vs. BL.

 
Transient versus graded epinephrine stimulation in hibernating myocardium. Myocardial function assessed with wall thickening did not change in the LAD region from 2 to 3 mo after instrumentation, although there was an increase in diastolic wall thickness (Table 2) and function in the remote normally perfused myocardium tended to increase (Fig. 1). The results of both inotropic stimulation protocols in hibernating myocardium were remarkably similar to the data in chronically stunned myocardium (Fig. 1 and Table 2). Regional function (Fig. 1, bottom) and global function (Table 2) improved during each protocol at comparable hemodynamics (Fig. 2, right), but function in the LAD-perfused region remained significantly reduced compared with the normally perfused remote region. There were no differences in regional or global function between the two protocols. In hibernating myocardium (LAD region), the peak functional responses during the two protocols were more similar than the function at the maximum dose of epinephrine (Emax), but neither the difference nor change was statistically significant. During the graded stimulation protocol, the peak improvement in LAD function occurred at stage 2.3 ± 0.3 compared with stage 3.1 ± 0.4 in the normally perfused remote region (P = 0.19). Again, there was no evidence of additional stunning following either stimulation protocol.

Biphasic responses to graded stimulation in viable, chronically dysfunctional myocardium. As noted above, peak function frequently occurred during a submaximal dose of epinephrine in the graded stimulation protocol at both 2 mo (9 of 12) and 3 mo after instrumentation (8 of 9, P = 0.60 vs. 2 mo). This is consistent with a biphasic response (a fall in regional function from peak function to Emax) in the majority of the animals. However, as illustrated in Fig. 3, the reduction in function from peak response to Emax was usually small, and only rarely greater than one standard deviation of the baseline LAD wall thickening (>1.4 mm; 2 mo, 1 of 12; 3 mo, 3 of 9; P = 0.27) (24).


Figure 3
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  		Fig. 3. Decrement from peak function to peak epinephrine dose during graded stimulation. The absolute change in LAD wall thickening from peak function to the maximum dose of epinephrine (Emax) during the graded stimulation protocols are shown for each animal. Although peak function frequently occurred at a lower than maximal dose of epinephrine, the differences were small in both chronically stunned (2 mo) and hibernating myocardium (3 mo). If a significant change was defined as a difference of 1 standard deviation of the baseline function (1.4 mm, dashed line), a biphasic response was only present in 1 chronically stunned region and 3 hibernating regions (P = 0.27).

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
To our knowledge, this is the first systematic comparison of graded versus transient catecholamine stimulation protocols to assess inotropic reserve in both chronically stunned and hibernating myocardium. In contrast to most previous studies of contractile reserve, which have used a semiquantitative wall motion score, M-mode echocardiography was used to quantify regional wall thickening. Our results show that both graded and transient stimulation protocols can elicit significant and comparable improvements in regional function in animals with viable, chronically dysfunctional myocardium. Interestingly, the degree of contractile reserve was similar in chronically stunned and hibernating myocardium, and a biphasic response was common (but small in amplitude) at both time points.

Transient versus graded catecholamine stimulation in hibernating myocardium. On the basis of our previous study (24), we had hypothesized that a transient stimulation protocol might produce a greater contractile response than graded epinephrine infusion in pigs with hibernating myocardium (3 mo after instrumentation). In that study, separate groups of animals underwent graded and transient epinephrine stimulation to comparable increases in hemodynamic parameters. Although the difference between the groups was not statistically significant, there was an 80% greater increase wall thickening (peak function – baseline) during the transient protocol (1.8 ± 0.7 mm) compared with the graded epinephrine stimulation (1.0 ± 0.6 mm, P = 0.41) (24). This is in contrast to very similar increases in wall thickening in the present study (transient, 2.0 ± 0.6 mm; graded, 1.8 ± 0.3 mm; P = 0.67). The disparity between these two studies can be attributed to blunted contractile reserve during the graded epinephrine protocol of the earlier study (24). This finding is likely due to the isoflurane anesthesia that was unique to this group of animals and is consistent with the blunting of myocardial contractility in the presence of volatile anesthetics. Previous investigations have shown that propofol anesthesia maintains functional responses in normal and collateral-dependent myocardium similar to those occurring in conscious animals (25) and only affects beta-adrenergic responsiveness at high doses (35). Therefore, propofol should be the preferred anesthetic for studies of contractile reserve (as used in the present study and the transient stimulation group from the previous study) (25).

Contractile reserve in viable, chronically dysfunctional myocardium. Although the presence of contractile reserve is commonly used to identify viable myocardium, previous studies have clearly shown that it is not universally present in viable, dysfunctional myocardium compared with recovery of function after revascularization or metabolic viability assessed with positron emission tomography (PET) (27, 29). For example, Melon et al. (27) have shown that among 142 dysfunctional segments that were viable by PET (normal resting perfusion or preserved [18F]fluoro-2-deoxyglucose uptake), only 77 (54%) had an improvement in regional wall motion by dobutamine echocardiography. Our assessment of contractile reserve in chronically instrumented pigs supports this clinical observation. Using a semiquantitative wall motion score in pigs with viable myocardium with reduced resting perfusion (hibernating myocardium), our group observed that only 25 of 44 (57%) animals showed a change in regional wall motion (12). However, in animals with a patent coronary artery, wall motion improved in 11 of 12 (92%, P = 0.01 vs. pigs with an occluded artery). This occurred despite the fact that resting perfusion was reduced to a similar extent in both groups of animals (12). We suggested that the greater contractile reserve in hibernating myocardium perfused through a patent artery was the result of greater subendocardial flow during inotropic stimulation and pharmacological vasodilation (12), as has been shown in patients with coronary artery disease (22, 33).

Regional wall motion score is a relatively insensitive assessment of regional function that could underestimate the degree of contractile reserve in viable, dysfunctional myocardium. Consistent with this hypothesis, our group has shown that M-mode echocardiographic quantification of wall thickening (24) and subendocardial segment shortening with sonomicrometry (14) can increase the proportion of animals that demonstrate an improvement in regional function, although even with these approaches, functional improvement could not always be documented in histologically viable myocardium. Similarly, in patients with coronary artery disease, wall thickening measurements with magnetic resonance imaging during dobutamine infusion have shown improved (but not perfect) sensitivity compared with dobutamine echocardiography (28).

Does viable dysfunctional myocardium develop ischemia during inotropic stimulation? An alternate explanation for the absence of contractile reserve in some segments of viable, dysfunctional myocardium is the development of acute ischemia with the exhaustion of subendocardial flow reserve and energy stores (1), as occurs in animal models of prolonged moderate ischemia or "short-term hibernation" (32). This mechanism has also been attributed to the biphasic response to graded inotropic stimulation in which an improvement in regional function is followed by functional deterioration at higher doses (1, 7). Although a biphasic response has been felt to be pathognomonic for hibernating myocardium (1), correlation with regional perfusion is limited to the study of Sawada et al. (29) in which 88% of segments demonstrating a biphasic response had normal levels of resting flow (chronically stunned myocardium). There are no criteria for defining a biphasic response by wall thickening; however, the majority of animals in the present study had small decrements in regional function at higher levels of inotropic stimulation (Fig. 3), with no differences between stunned and hibernating myocardium.

In pigs with hibernating myocardium, our group has shown that although subendocardial flow reserve is exhausted at rest, modest increases in demand and regional function are associated with increases in regional oxygen consumption (14). Furthermore, we have found no metabolic evidence of regional ischemia, with progressive increases in regional lactate consumption and normal levels of venous pH over the same range of epinephrine stimulation that was produced in the present study (14). The absence of acute ischemia is further supported by the lack of additional myocardial stunning following inotropic stimulation. In all four protocols presented in this study, regional wall thickening returned to baseline function within 15 min after the discontinuation of epinephrine.

In the clinical literature, there are conflicting data regarding the extent to which inotropic stimulation can induce acute ischemia in chronically dysfunctional myocardium. Consistent with our porcine data, Lee et al. (22) have shown that even in the absence of contractile reserve (which might suggest the development of ischemia), there is an increase in regional oxygen consumption during dobutamine stimulation. In contrast, Indolfi et al. (20) have shown that intracoronary dobutamine always caused a reduction in arterial-venous lactate differences, associated with regional lactate production in four of nine patients. However, with persistent stimulation, there was stabilization or improvement in arterial-venous lactate differences in all but one patient (20).

These clinical and basic studies support the contention that the development of hibernating myocardium involves intrinsic adaptations that not only downregulate resting flow and oxygen consumption but also blunt the response to inotropic stimulation to limit the development of acute ischemia (4, 14). This hypothesis is supported by the alterations in beta-adrenergic signaling identified using tissue from pigs with hibernating myocardium (21). Baseline cAMP production in hibernating myocardium was normal, but the response to isoproterenol stimulation was blunted and associated with an increase in the ratio of inhibitory to stimulatory G proteins (21). Despite normal beta-adrenergic receptor density and subtype distribution, there was a reduction in high-affinity binding sites (21), which would be consistent with regional desensitization. Before this study, we hypothesized that transient stimulation might result in greater contractile reserve by limiting any acute desensitization of beta-receptors compared with a longer, graded infusion. However, the fact that both protocols resulted in similar improvements in regional function in hibernating myocardium is inconsistent with such a mechanism but, rather, suggests a chronic downregulation.

Contractile reserve in chronically stunned and hibernating myocardium. Clinical studies have clearly shown that the presence of contractile reserve is highly specific for myocardial viability (2). However, the results of the present study are in agreement with previous reviews suggesting that responsiveness to catecholamines is not specific for the underlying pathophysiology of dysfunction (17, 18). Nevertheless, contractile reserve as assessed by wall motion score is more common in regions with normal resting perfusion (chronically stunned myocardium) than in regions with reduced resting flow (hibernating myocardium) (22, 29, 31). For example, Sawada et al. (29) detected improvement in wall motion among 61 of 108 (56%) dysfunctional segments with normal resting flow but in only 9 of 28 (32%) dysfunctional segments with reduced resting perfusion but metabolic viability (P = 0.03). Nevertheless, despite the differences in the prevalence of contractile reserve, the limited clinical data are conflicting with regard to the extent of functional improvement in chronically stunned and hibernating myocardium. Bountioukos et al. (3) found that baseline pulsed wave tissue Doppler velocity was similar in stunned and hibernating myocardium. However, during dobutamine infusion, the increase in tissue velocity was significantly greater in chronically stunned than in hibernating myocardium (3). In contrast, Mazzadi et al. (26) showed that baseline circumferential shortening by tagged magnetic resonance imaging was similar in dysfunctional segments with matched (chronically stunned myocardium) and mismatched (hibernating myocardium) metabolism and perfusion(26). In agreement with our results in chronically instrumented pigs, they found that dobutamine stimulation increased circumferential shortening to a similar extent in chronically stunned and hibernating myocardium (26).

Methodological limitations. Theses studies in chronically instrumented pigs were performed with epinephrine rather than dobutamine, which is the more commonly used catecholamine for clinical viability testing. Although we cannot confirm that the results would be the same with dobutamine, epinephrine produces a stress that is more physiologically consistent with exercise. Furthermore, we believed it was critical to produce the same level of stress that we have previously shown to be free of acute myocardial ischemia in this model (14). Nevertheless, Horn et al. (19) was one of the first to describe contractile reserve in dysfunctional segments of patients with coronary artery disease using "The Epinephrine Ventriculogram" in 1974.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by the Department of Veterans Affairs; National Heart, Lung, and Blood Institute Grants HL-055324, HL-061610, and HL-081722; the Albert and Elizabeth Rekate Fund; the Mae Stone Goode Trust; and the John R. Oishei Foundation.


   ACKNOWLEDGMENTS
 
We thank Deana Gretka and Elaine Granica for technical assistance with these studies. Anne Coe and Marsha Barber were instrumental in the completion of this manuscript.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. A. Fallavollita, Biomedical Research Bldg., Rm. 349, Dept. of Medicine/Cardiovascular Medicine, Univ. at Buffalo, 3435 Main St., Buffalo, NY 14214 (e-mail: jaf7{at}buffalo.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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  1. Afridi I, Kleiman NS, Raizner AE, Zoghbi WA. Dobutamine echocardiography in myocardial hibernation: optimal dose and accuracy in predicting recovery of ventricular function after coronary angioplasty. Circulation 91: 663–670, 1995.[Abstract/Free Full Text]
  2. Bax JJ, Wijns W, Cornel JH, Visser FC, Boersma E, Fioretti PM. Accuracy of currently available techniques for prediction of functional recovery after revascularization in patients with left ventricular dysfunction due to chronic coronary artery disease: comparison of pooled data. J Am Coll Cardiol 30: 1451–1460, 1997.[Abstract]
  3. Bountioukos M, Schinkel AF, Bax JJ, Rizzello V, Valkema R, Krenning BJ, Biagini E, Vourvouri EC, Roelandt JR, Poldermans D. Pulsed wave tissue Doppler imaging for the quantification of contractile reserve in stunned, hibernating, and scarred myocardium. Heart 90: 506–510, 2004.[Abstract/Free Full Text]
  4. Canty JM, Fallavollita JA. Hibernating myocardium. J Nucl Cardiol 12: 104–119, 2005.[CrossRef][Web of Science][Medline]
  5. Canty JM Jr, Fallavollita JA. Chronic hibernation and chronic stunning: a continuum. J Nucl Cardiol 7: 509–527, 2000.[CrossRef][Web of Science][Medline]
  6. Canty JM Jr, Suzuki G, Banas MD, Verheyen F, Borgers M, Fallavollita JA. Hibernating myocardium: chronically adapted to ischemia but vulnerable to sudden death. Circ Res 94: 1142–1149, 2004.[Abstract/Free Full Text]
  7. Cornel JH, Bax JJ, Elhendy A, Maat AP, Kimman GJ, Geleijnse ML, Rambaldi R, Boersma E, Fioretti PM. Biphasic response to dobutamine predicts improvement of global left ventricular function after surgical revascularization in patients with stable coronary artery disease: implications of time course of recovery on diagnostic accuracy. J Am Coll Cardiol 31: 1002–1010, 1998.[Abstract/Free Full Text]
  8. Fallavollita JA. Spatial heterogeneity in fasting and insulin-stimulated 18F-2-deoxyglucose uptake in pigs with hibernating myocardium. Circulation 102: 908–914, 2000.[Abstract/Free Full Text]
  9. Fallavollita JA, Canty JM Jr. Differential 18F-2-deoxyglucose uptake in viable dysfunctional myocardium with normal resting perfusion: evidence for chronic stunning in pigs. Circulation 99: 2798–2805, 1999.[Abstract/Free Full Text]
  10. Fallavollita JA, Jacob SC, Young RF, Canty JM Jr. Regional alterations in SR Ca2+ATPase, phospholamban, and HSP-70 expression in chronic hibernating myocardium. Am J Physiol Heart Circ Physiol 277: H1418–H1428, 1999.[Abstract/Free Full Text]
  11. Fallavollita JA, Lim H, Canty JM Jr. Myocyte apoptosis and reduced SR gene expression precede the transition from chronically stunned to hibernating myocardium. J Mol Cell Cardiol 33: 1937–1944, 2001.[CrossRef][Web of Science][Medline]
  12. Fallavollita JA, Logue M, Canty JM Jr. Coronary patency and its relation to contractile reserve in hibernating myocardium. Cardiovasc Res 55: 131–140, 2002.[Abstract/Free Full Text]
  13. Fallavollita JA, Logue M, Canty JM Jr. Stability of hibernating myocardium in pigs with a chronic left anterior descending coronary artery stenosis: absence of progressive fibrosis in the setting of stable reductions in flow, function and coronary flow reserve. J Am Coll Cardiol 37: 1989–1995, 2001.[Abstract/Free Full Text]
  14. Fallavollita JA, Malm BJ, Canty JM Jr. Hibernating myocardium retains metabolic and contractile reserve despite regional reductions in flow, function, and oxygen consumption at rest. Circ Res 92: 48–55, 2003.[Abstract/Free Full Text]
  15. Fallavollita JA, Perry BJ, Canty JM Jr. 18F-2-deoxyglucose deposition and regional flow in pigs with chronically dysfunctional myocardium: evidence for transmural variations in chronic hibernating myocardium. Circulation 95: 1900–1909, 1997.[Abstract/Free Full Text]
  16. Fallavollita JA, Riegel BJ, Suzuki G, Valeti U, Canty JM Jr. Mechanism of sudden cardiac death in pigs with viable chronically dysfunctional myocardium and ischemic cardiomyopathy. Am J Physiol Heart Circ Physiol 289: H2688–H2696, 2005.[Abstract/Free Full Text]
  17. Heusch G. Hibernating myocardium. Physiol Rev 78: 1055–1085, 1998.[Abstract/Free Full Text]
  18. Heusch G, Schulz R, Rahimtoola SH. Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol 288: H984–H999, 2005.[Abstract/Free Full Text]
  19. Horn HR, Teichholz LE, Cohn PF, Herman MV, Gorlin R. Augmentation of left ventricular contraction pattern in coronary artery disease by an inotropic catecholamine. The epinephrine ventriculogram. Circulation 49: 1063–1071, 1974.[Abstract/Free Full Text]
  20. Indolfi C, Piscione F, Perrone-Filardi P, Prastaro M, Di Lorenzo E, Sacca L, Salvatore M, Condorelli M, Chiariello M. Inotropic stimulation by dobutamine increases left ventricular regional function at the expense of metabolism in hibernating myocardium. Am Heart J 132: 542–549, 1996.[CrossRef][Web of Science][Medline]
  21. Iyer V, Canty JM Jr. Regional desensitization of beta-adrenergic receptor signaling in swine with chronic hibernating myocardium. Circ Res 97: 789–795, 2005.[Abstract/Free Full Text]
  22. Lee HH, Davila-Roman VG, Ludbrook PA, Courtois M, Walsh JF, Delano DA, Rubin PJ, Gropler RJ. Dependency of contractile reserve on myocardial blood flow: implications for the assessment of myocardial viability with dobutamine stress echocardiography. Circulation 96: 2884–2891, 1997.[Abstract/Free Full Text]
  23. Lim H, Fallavollita JA, Hard R, Kerr CW, Canty JM Jr. Profound apoptosis-mediated regional myocyte loss and compensatory hypertrophy in pigs with hibernating myocardium. Circulation 100: 2380–2386, 1999.[Abstract/Free Full Text]
  24. Malm BJ, Suzuki G, Canty JM Jr, Fallavollita JA. Variability of contractile reserve in hibernating myocardium: dependence on the method of stimulation. Cardiovasc Res 56: 422–433, 2002.[Abstract/Free Full Text]
  25. Mayer N, Legat K, Weinstabl C, Zimpfer M. Effects of propofol on the function of normal, collateral-dependent, and ischemic myocardium. Anesth Analg 76: 33–39, 1993.[Abstract/Free Full Text]
  26. Mazzadi AN, Janier MF, Brossier B, Andre-Fouet X, McFadden E, Revel D, Croisille P. Dobutamine-tagged MRI for inotropic reserve assessment in severe CAD: relationship with PET findings. Am J Physiol Heart Circ Physiol 286: H1946–H1953, 2004.[Abstract/Free Full Text]
  27. Melon PG, de Landsheere CM, Degueldre C, Peters JL, Kulbertus HE, Pierard LA. Relation between contractile reserve and positron emission tomographic patterns of perfusion and glucose utilization in chronic ischemic left ventricular dysfunction: implications for identification of myocardial viability. J Am Coll Cardiol 30: 1651–1659, 1997.[Abstract]
  28. Nagel E, Lehmkuhl HB, Bocksch W, Klein C, Vogel U, Frantz E, Ellmer A, Dreysse S, Fleck E. Noninvasive diagnosis of ischemia-induced wall motion abnormalities with the use of high-dose dobutamine stress MRI: comparison with dobutamine stress echocardiography. Circulation 99: 763–770, 1999.[Abstract/Free Full Text]
  29. Sawada S, Elsner G, Segar DS, O'Shaughnessy M, Khouri S, Foltz J, Bourdillon PD, Bates JR, Fineberg N, Ryan T, Hutchins GD, Feigenbaum H. Evaluation of patterns of perfusion and metabolism in dobutamine-responsive myocardium. J Am Coll Cardiol 29: 55–61, 1997.[Abstract]
  30. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 2: 358–367, 1989.[Medline]
  31. Schinkel AF, Bax JJ, van Domburg R, Elhendy A, Valkema R, Vourvouri EC, Sozzi FB, Roelandt JR, Poldermans D. Dobutamine-induced contractile reserve in stunned, hibernating, and scarred myocardium in patients with ischemic cardiomyopathy. J Nucl Med 44: 127–133, 2003.[Abstract/Free Full Text]
  32. Schulz R, Guth BD, Pieper K, Martin C, Heusch G. Recruitment of an inotropic reserve in moderately ischemic myocardium at the expense of metabolic recovery: a model of short-term hibernation. Circ Res 70: 1282–1295, 1992.[Abstract/Free Full Text]
  33. Skopicki HA, Abraham SA, Weissman NJ, Mukerjee AK, Alpert NM, Fischman AJ, Picard MH, Gewirtz H. Factors influencing regional myocardial contractile response to inotropic stimulation. Analysis in humans with stable ischemic heart disease. Circulation 94: 643–650, 1996.[Abstract/Free Full Text]
  34. Suzuki G, Lee TC, Fallavollita JA, Canty JM Jr. Adenoviral gene transfer of FGF-5 to hibernating myocardium improves function and stimulates myocytes to hypertrophy and reenter the cell cycle. Circ Res 96: 767–775, 2005.[Abstract/Free Full Text]
  35. Zhou W, Fontenot HJ, Wang SN, Kennedy RH. Propofol-induced alterations in myocardial beta-adrenoceptor binding and responsiveness. Anesth Analg 89: 604–608, 1999.[Abstract/Free Full Text]



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