© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Coronary patency and its relation to contractile reserve in hibernating myocardium
aVeterans Affairs Western New York Health Care System, The University at Buffalo, Buffalo, NY, USA
bDepartment of Medicine, The University of Buffalo, Buffalo, NY, USA
cDepartment of Physiology/Biophysics, The University of Buffalo, Buffalo, NY, USA
jaf7{at}buffalo.edu
* Corresponding author. Biomedical Research Building, Room 347, Department of Medicine/Cardiology, University at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA. Tel.: +1-716-829-2663; fax: +1-716-829-2665
Received 26 September 2001; accepted 25 February 2002
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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Objectives: Recent clinical studies suggest that contractile reserve may occur in a minority of viable, chronically dysfunctional segments with reduced resting flow (hibernating myocardium). We hypothesized that epicardial artery patency might predict which segments have critically reduced subendocardial flow reserve and limited contractile reserve. Methods: Pigs were chronically instrumented with a fixed stenosis on the left anterior descending coronary artery (LAD) to produce hibernating myocardium. At least 3 months later, flow at rest and during adenosine vasodilation (microspheres), ventricular function and contractile reserve (contrast ventriculography), and 18F-2-deoxyglucose (FDG) deposition (ex vivo tissue counting) were quantified. Results: Hibernating myocardium (regional dysfunction with reduced resting perfusion) was present in animals with an occluded (n = 40) or patent (n = 19) LAD. Viability was confirmed by histology and FDG deposition. In collateral-dependent hibernating myocardium, subendocardial flow did not increase above baseline levels during epinephrine or adenosine stimulation, consistent with exhausted subendocardial flow reserve at rest. This was associated with limited contractile reserve and regionally increased FDG deposition. In contrast, subendocardial flow reserve was present in hibernating myocardium distal to a patent artery. Contractile reserve during epinephrine infusion in this group was significantly greater than in animals with an occluded artery. Conclusions: The physiology and metabolism of hibernating myocardium was dependent upon stenosis severity and its effects on subendocardial flow reserve. In collateral-dependent hibernating myocardium, contractile reserve was limited in the setting of exhausted subendocardial flow reserve, thus supporting the hypothesis that metabolic imaging may be preferable for determining viability distal to a complete occlusion.
KEYWORDS Hibernation; Collateral circulation; Regional blood flow; Contractile function; Inotropic agents
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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The assessment of contractile reserve during low dose dobutamine infusion has become an increasingly popular technique to determine viability in chronically dysfunctional myocardium [1]. Nevertheless, recent clinical studies have raised questions regarding the sensitivity of using contractile reserve to detect viability when resting flow is reduced as in hibernating myocardium [2,3]. For example, improvement in function during dobutamine echocardiography was present in only 32% [2] to 46% [3] of segments with reduced resting perfusion, but normal 18F-2-deoxyglucose (FDG) uptake.
Our previous observations in pigs with hibernating myocardium have suggested that limited contractile reserve might be the result of a critical limitation in subendocardial flow reserve [4–6]. This investigation tested the hypotheses that patency of the epicardial coronary artery might serve as a surrogate for segments with exhausted subendocardial flow reserve, and it is those viable, chronically dysfunctional regions that have limited contractile reserve. Accordingly, chronically instrumented pigs were grouped on the basis of coronary patency to evaluate differences in flow and flow reserve, function and contractile reserve, and FDG deposition.
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2 Methods |
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This investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). The initial instrumentation, experimental protocol, and results of individual groups of animals have been previously published in detail [4–6]. Seventy animals were instrumented in an identical fashion and housed under similar conditions. Animals were excluded if coronary angiography (n = 3) or microsphere flow measurements (n = 3) were unavailable, or if myocardial infarction involved >1% of the left ventricle (n = 5). Thus, this study consists of data from 59 animals.
Juvenile pigs were instrumented with a rigid Delrin stenosis (1.5–2.25 mm) around the proximal left anterior descending artery (LAD) to produce hibernating myocardium [4–6]. At least 3 months later, studies were conducted in the fasted, closed-chest anesthetized state as previously described [4–6]. Regional perfusion was measured with colored microspheres, followed by contrast ventriculography to assess myocardial function [4–6]. Anteroapical wall motion was quantified by a wall motion score (3, normal; 2, mild hypokinesis; 1, severe hypokinesis; 0, akinesis; dyskinesis was not observed in any study) [4,5]. Regional function was also assessed by the centerline analysis described by Sheehan et al. [7,8]. Ejection fraction was used to assess global function. Flow and function were then evaluated during a submaximal epinephrine infusion titrated to increase heart rate by 
40 bpm (0.20±0.02 µg/kg per min i.v.). Vasodilated flow was measured during adenosine infusion (0.9 mg/kg per min i.v.) with phenylephrine titrated to maintain arterial pressure (6.8±0.4 µg/kg per min i.v.). Angiography was performed to determine stenosis severity [4,5]. In pigs with an occluded LAD, collateral circulation was semi-quantitatively scored: 0, no collaterals; 1, faint opacification of the LAD; 2, delayed but complete opacification of the LAD; 3, rapid and complete filling of the LAD [4].
A subgroup of animals (n = 37) received 18F-2-deoxyglucose (FDG, 1–3 mCi i.v.) in the fasting state, as previously described [4,6]. After 45 min the heart was excised. A mid-ventricular ring was divided into 12 full-thickness wedges, and then subdivided into subendocardial, mid-myocardial and subepicardial layers. Samples were weighed and FDG activity was counted at 511 keV. FDG uptake was expressed as deposition (extractionxflow) by dividing sample activity by the integrated arterial activity [4,6]. These same samples were used for microsphere flow determinations, as previously described [4,6]. Connective tissue was quantified from trichrome stained samples from the LAD and normally perfused regions (n = 49 each) [4–6].
Data are presented as the mean±standard error. Flow and FDG in the LAD and normal remote regions represent weighted means for all samples within a given region [4–6,8]. The LAD and normally perfused regions were compared using paired t-tests. Differences between groups were assessed using unpaired t-tests. An analysis of variance was used for multiple comparisons (rest, epinephrine, adenosine) followed by a t-test with Bonferroni correction. P<0.05 was considered significant.
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3 Results |
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Pigs were divided on the basis of LAD patency. The 40 animals with complete LAD occlusion were studied 114±4 days after initial instrumentation when they weighed 88±3 kg. Collaterals from both the left (collateral score 2.4±0.1) and the right (collateral score 2.2±0.1) coronary arteries supplied perfusion to the distal LAD. In 19 animals the LAD was patent with an average diameter stenosis severity of 79±3%. These animals were studied 108±4 days after instrumentation (P, ns versus occluded), when they weighed 79±4 kg (P, ns versus occluded). Hematocrit and blood gases (averages values, Hct, 0.33±0.05; pH, 7.40±0.00; pCO2, 42.0±0.8; pO2, 491±12) and initial hemodynamic parameters (Table 1) were no different between groups.
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3.1 Resting flow and function in hibernating myocardium
Under baseline conditions, both groups demonstrated severe anteroapical hypokinesis by wall motion score (1.0±0.1 in occluded versus 1.3±0.2 in patent, P, ns) and centerline score (–2.1±0.1 in occluded versus –1.7±0.2 in patent, P, ns), with slightly reduced left ventricular ejection fraction (0.47±0.01 in occluded versus 0.53±0.03 in patent, P, ns). In each group, regional dysfunction was associated with significant reductions in subendocardial (occluded, 0.86±0.04 vs. 1.02±0.04 ml/min per g, P<0.01; patent, 0.87±0.06 vs. 1.02±0.08 ml/min per g, P<0.05) and full-thickness resting perfusion (occluded, 0.89±0.03 vs. 0.94±0.03 ml/min per g, P<0.01; patent, 0.85±0.05 vs. 0.93±0.07 ml/min per g, P<0.05), consistent with hibernating myocardium. The LAD endo/epi flow ratio was significantly reduced in comparison to the normally perfused remote region only in the animals with an occluded artery (occluded, 1.00±0.04 vs. 1.26±0.04, P<0.05; patent, 1.13±0.06 vs. 1.22±0.04, P, ns).
3.2 Contractile reserve and the flow-function relation
Inotropic stimulation increased heart rate, rate pressure product, and flow to the normally perfused remote regions to similar extents in each group (Table 1 and Fig. 1). In hibernating myocardium the flow responses were attenuated, and the changes in subendocardial flow were markedly different between the groups (Fig. 2). In hibernating myocardium supplied by a patent artery, subendocardial flow increased from 0.87±0.06 to 1.32±0.13 ml/min per g during epinephrine infusion (P<0.05; Figs. 1 and 2), but not to the same extent as the normally perfused remote region (1.64±0.13 ml/min per g, P = 0.08). In contrast, subendocardial flow in collateral-dependent hibernating myocardium decreased slightly from 0.86±0.04 to 0.71±0.06 ml/min per g (P, ns; Figs. 1 and 2). Greater impairment in flow reserve in the occluded group was also evident in the more severely reduced LAD endo/epi flow ratio during epinephrine infusion (0.64±0.05) as compared to the patent group (1.02±0.07, P<0.001, Fig. 2).
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The disparate effects of inotropic stimulation on subendocardial perfusion resulted in dramatic differences in contractile reserve. In the majority of animals with collateral-dependent hibernating myocardium there was minimal improvement in regional function (Fig. 3) with wall motion score increasing from 1.0±0.1 to 1.2±0.1 (P<0.01) and centerline score improving from –2.1±0.1 to –1.5±0.1 (P<0.01). Global function modestly improved with ejection fraction increasing from 0.47±0.01 to 0.51±0.04 (P<0.05). However in animals with a patent LAD, contractile reserve was more consistently present (Fig. 3). Wall motion score increased from 1.3±0.2 to 2.4±0.2 (P<0.01 versus rest and occluded), centerline score improved from –1.7±0.2 to –0.7±0.2 (P<0.01 versus rest and occluded) and ejection fraction increased from 0.53±0.03 to 0.67±0.04 (P<0.01 versus rest and occluded). When assessed as a change from baseline, the patent artery group demonstrated significantly greater in improvement wall motion score (1.0±0.1 vs. 0.3±0.1, P<0.01) and ejection fraction (0.14±0.03 vs. 0.04±0.02, P<0.05).
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The relation between flow and function at rest and the alterations in this relationship during inotropic stimulation are illustrated in Fig. 4. Under resting conditions, the relationships between function and both absolute and relative (LAD/Normal) flow were similar in each group of animals. Despite an improvement in function in both groups during epinephrine stimulation, absolute flow only increased in hibernating myocardium supplied by a patent artery, and relative flow did not increase in either group. In fact, there was a significant fall in subendocardial perfusion to collateral-dependent hibernating myocardium relative to the normally perfused remote region. Unfortunately, the quantitative relation between relative flow and radial wall motion during acute ischemia has not been defined. Therefore, it is impossible to use this data to determine whether hibernating myocardium represents a ‘matched’ reduction in flow and function. Nevertheless, the fact that both groups demonstrated an upward shift in the relations during inotropic stimulation suggests some component of regional dysfunction is due stunning superimposed on hibernating myocardium [9].
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3.3 Metabolic and histological viability
In collateral-dependent hibernating myocardium (n = 24), FDG accumulation was 1.8-fold higher than the normally perfused, remote region (Fig. 5). FDG deposition was significantly increased in each layer, and there was a pronounced transmural gradient with the greatest relative increase in the subendocardium (LAD/normal=2.3). In contrast, there was only a small insignificant regional increase in FDG deposition in hibernating myocardium with a patent LAD (n = 13) in comparison to the normal region (Fig. 5). Full-thickness FDG deposition was similar in the normally perfused regions of each group (0.016±0.003 in patent versus 0.013±0.001 ml/g per min in occluded, P, ns), and the difference between the hibernating regions was not significant (0.019±0.003 in patent versus 0.024±0.003 ml/g per min in occluded, P, ns).
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In animals with a patent epicardial artery (n = 14), there was no regional difference in connective tissue staining, with 4.3±0.5% in the LAD region versus 3.7±0.4% in the normal region (P, ns). In contrast, animals with an occluded LAD (n = 35) had a small increase in connective tissue staining in the hibernating region (7.2±0.5%) in comparison to remote, normal myocardium (4.0±0.3%, P<0.001). Most of the regional difference was due to a generalized increase in the normal collagen network.
3.4 Vasodilated flow and coronary steal
During adenosine vasodilation hemodynamics were similar to resting conditions, and there were no differences between the groups (Table 1). Blood flow increased to the same extent in the normally perfused remote regions of the two groups of animals (Fig. 1), but vasodilated flow in hibernating myocardium was markedly attenuated. In hibernating myocardium supplied by a patent epicardial artery, subendocardial flow increased only 70% over resting levels from 0.87±0.06 to 1.50±0.16 ml/min per g (P<0.01). In contrast, subendocardial flow did not change in collateral-dependent hibernating myocardium (0.86±0.04 to 0.82±0.09 ml/min per g, P, ns), consistent with exhausted subendocardial flow reserve at rest. Although the LAD endo/epi flow ratios were abnormal in both groups, there was a more severe reduction in collateral-dependent regions (0.40±0.04) as compared to those supplied by a patent artery (0.64±0.06, P<0.001).
During adenosine vasodilation it was not uncommon for subendocardial perfusion to fall below resting values, consistent with a transmural coronary steal. This occurred in 60% of collateral-dependent regions and 22% of the patent group (Fishers exact test, P = 0.01). As illustrated in Fig. 6, subendocardial FDG uptake was inversely correlated with regional adenosine flow (upper graph, r2=0.46, P<0.01) and flow reserve (lower graph, r2=0.42, P<0.01). The regions demonstrating a transmural steal (subendocardial flow reserve <1) had the greatest increase in relative FDG uptake. Interestingly, there was no significant relationship between function during inotropic stimulation and adenosine flow reserve (r2=0.07, P, ns), and only a modest correlation with absolute adenosine flow (r2=0.13, P<0.05).
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4 Discussion |
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To our knowledge, this is the first demonstration that the physiology and metabolism of hibernating myocardium is related to epicardial stenosis severity and its relation to subendocardial flow reserve. Regardless of whether the epicardial artery was patent or occluded, there was hibernating myocardium characterized by regional dysfunction with reduced resting perfusion. Viability in both circumstances was confirmed by FDG uptake and histology. In collateral-dependent hibernating myocardium, subendocardial flow reserve was exhausted at rest and there was only a limited increase in regional function during inotropic stimulation. In contrast, when a patent epicardial artery supplied hibernating myocardium, subendocardial flow had the ability to increase above baseline levels and contractile reserve was more consistently present. Thus, these data suggest that viability can be maintained with lower than normal resting perfusion; however, contractile reserve in this setting is dependent upon the ability to recruit subendocardial flow. This supports the hypothesis that hibernating myocardium represents an intrinsic myocardial adaptation to repetitive episodes of ischemia [10].
4.1 Intrinsic down regulation of resting perfusion in hibernating myocardium
Viable, chronically dysfunctional myocardium can have normal levels of resting perfusion (chronically stunned myocardium) or resting flow can be reduced (hibernating myocardium). However, it was previously unclear whether the reduced flow in hibernating myocardium was the result of an adaptive down regulation of oxygen demand [10] or a primary limitation in regional perfusion [11–13]. Previous studies in chronically instrumented animals have shown that regional dysfunction precedes the reduction in resting flow, consistent with a transition from chronically stunned to hibernating myocardium [4,8,14]. In addition, we have recently shown that although hibernating myocardium has reduced oxygen consumption at rest, significant increases in oxygen consumption can occur with pacing or catecholamine stimulation [15]. Thus, we have hypothesized that reduced resting flow is an intrinsic myocardial adaptation to prevent recurrent episodes of ischemia by providing at least a modest amount of flow reserve.
An intrinsic down regulation of resting flow would appear to be an attractive myocardial adaptation to limit acute episodes of ischemia [10,16], but among individual groups of chronically instrumented animals with hibernating myocardium we have never been able to document the presence of subendocardial flow reserve. However, in the present study both inotropic and vasodilatory stimuli were able to recruit subendocardial flow in the group of animals with a patent epicardial coronary artery. Thus, the regional reduction in resting flow indicative of hibernating myocardium was due to an intrinsic down regulation in demand, rather than the result of exhausted subendocardial flow reserve. Animals with hibernating myocardium and a patent epicardial artery also provide irrefutable evidence that regionally reduced resting perfusion in hibernating myocardium was not due to an admixture of fibrosis. Despite significant reductions in full-thickness resting flow, connective tissue staining by point counting of trichrome-stained samples was not increased relative to the remote, normally perfused region.
4.2 Exhausted subendocardial flow reserve in collateral-dependent hibernating myocardium
Despite the fact that there was regional dysfunction with reduced resting flow in both groups of animals, we found significant physiological, metabolic and structural differences in hibernating myocardium depending upon the patency of the epicardial coronary artery. The key physiological feature of collateral-dependent hibernating myocardium was exhausted subendocardial flow reserve at rest. Thus, inotropic stimulation was unable to recruit subendocardial flow, resulting in only a modest increase in regional function. Since regional function is critically dependent on subendocardial perfusion [17], it is in fact surprising that there was any demonstrable contractile reserve. However, in patients with recent myocardial infarction contractile reserve has been demonstrated without improvement in relative perfusion [18].
Limited contractile reserve in collateral-dependent hibernating myocardium is consistent with recent reports of patients with viable, dysfunctional myocardium with reduced resting flow [2,3]. In these clinical studies, improvement in function during dobutamine echocardiography was only present in 32% [2] to 46% [3] of segments with reduced resting perfusion, but normal FDG uptake. Although our data would suggest that limited contractile reserve in these patients was due to an inability to recruit subendocardial perfusion, proof of this in humans will have to await technological advances that will provide the spatial resolution necessary to accurately quantify subendocardial blood flow.
In contrast to regions with a patent epicardial coronary artery, collateral-dependent hibernating myocardium had regionally increased FDG deposition in the fasting state. Although FDG is an imperfect tracer of glucose uptake, this finding does support the hypothesis that there is altered myocardial metabolism in hibernating myocardium with an increased reliance on glucose. Interestingly, regionally increased FDG uptake does not appear to be an obligate finding in viable, chronically dysfunctional myocardium, but rather appears to reflect a critical limitation in subendocardial flow reserve. This conclusion is consistent with our previous observation in chronically stunned myocardium (with normal levels of resting perfusion) in which regional increases in FDG deposition in the fasting state occurred only in animals with the most severely impaired flow reserve [8].
In almost half of all regions with hibernating myocardium (48%), subendocardial flow during pharmacological vasodilation was lower than resting values. This occurred despite the fact that full-thickness flow increased in the vast majority of animals (86%). This response, consistent with a transmural coronary steal [19], was more common in collateral-dependent hibernating myocardium, and was similar to that described by Gallagher et al. during pharmacological vasodilation distal to an acute stenosis [20]. In their study, intracoronary adenosine in the setting of an acute critical stenosis increased subepicardial flow, but there was a significant fall in subendocardial perfusion. As a result, the endo/epi flow ratio fell from 1.28±0.07 to 0.55±0.07 (P<0.001) [20]. This was explained by persistent subepicardial vasodilator reserve despite maximal vasodilation in the subendocardium. A similar effect has been described with inotropic and physiological stimuli in the presence of a critical stenosis [19].
4.3 Variable contractile reserve in hibernating myocardium
Since collateral-dependent hibernating myocardium had critically limited subendocardial flow reserve, it was not surprising that there was only a modest improvement in regional function during inotropic stimulation. However, despite similar reductions in relative perfusion at rest, hibernating myocardium distal to a patent epicardial artery demonstrated more consistent improvement in regional function. Contractile reserve occurred in the setting of improvement in subendocardial perfusion and relative preservation of the endo/epi flow ratio. The functional response of this group is consistent with a recent report in pigs instrumented to produce a 90% stenosis on the left circumflex coronary artery [21]. Among viable segments with reduced resting perfusion, contractile reserve was present in 56%, which was not significantly different from viable dysfunctional segments with normal resting flow 64% [21].
In our model of hibernating myocardium, the development of reduced resting flow follows and is assumed to be secondary to the development of regional dysfunction [4,8]. An alternative approach used by other investigators has been to study animal models in which there was a primary reduction in resting flow. In these studies, a moderate reduction in resting perfusion produced a new steady-state matching between oxygen supply and oxygen demand, known as ‘short-term hibernation’ [22]. Although this physiology can be maintained for hours without producing infarction [22,23], there is controversy regarding viability after 24 h [24–26], questioning the clinical correlates of this model. Nevertheless, function in this model can acutely improve during inotropic stimulation. However, contractile reserve is at the expense of the development of regional lactate production consistent with acute ischemia [22,24], and persistent stimulation leads to necrosis [27]. Although regional metabolism was not measured in the present investigation, we have recently shown that epinephrine stimulation to 130 bpm resulted in an increase in oxygen consumption with no regional lactate production in pigs with hibernating myocardium [15]. Thus, these data suggest different mechanisms of adaptation in acute as compared to chronic coronary disease.
4.4 Methodological limitations
Contractile reserve was only determined at a single dose of epinephrine, and thus we may have underestimated inotropic responsiveness. However, our findings are consistent with clinical studies of patients with hibernating myocardium in which contractile reserve was uncommon even with graded dobutamine infusion [2,3]. In addition, we have recently shown limited improvement in regional wall thickening and segment shortening during graded epinephrine infusion in pigs with hibernating myocardium [15,28]. Finally, Sawada et al. have shown that a biphasic response to inotropic stimulation (improved function at low dose and deterioration at higher doses) was not characteristic of hibernating myocardium. They found that 15 of 17 segments (88%) with this response had normal resting blood flow consistent with chronically stunned myocardium. A biphasic response occurred in only one of 28 segments (4%) with a flow-metabolism mismatch (hibernating myocardium) [2].
In order to accurately quantify blood flow and FDG uptake across the myocardial wall, only a single study could be performed in each animal. Thus, it was impossible to determine the time course and progression of flow, contractile reserve and FDG uptake during the development of hibernating myocardium. Serial studies in individual animals will be necessary to clarify the temporal progression of physiological findings in viable, chronically dysfunctional myocardium. FDG deposition was quantified in fasting animals to take advantage of enhanced uptake in hibernating myocardium; however, this technique is less suitable for imaging since low glucose uptake limits visualization of normal myocardium.
Approximately two-thirds of pigs instrumented for these studies developed complete occlusion of the LAD and collateral-dependent myocardium. Due to the relatively limited number of animals with a patent epicardial artery, further sub-grouping based on stenosis severity was not attempted. Therefore, it remains unclear whether the physiological, metabolic and structural alterations found in animals with collateral-dependent myocardium might also occur distal to a severe epicardial stenosis (>90%), as has been recently described in pigs with a severe, but patent epicardial artery [21].
4.5 Summary/clinical implications
These data provide evidence that there are a range of physiological, metabolic and structural features that may be present in viable, chronically dysfunctional myocardium with reduced resting flow, thus extending the continuum of myocardial adaptations to repetitive episodes of ischemia [16]. The finding that subendocardial flow reserve was exhausted at rest in collateral-dependent hibernating myocardium may explain the limited contractile reserve in patients with viable myocardial segments with reduced resting perfusion [2,3]. Thus, these data support the contention that metabolic imaging may be preferable to assessment of contractile reserve for identifying viability in collateral-dependent myocardium. On the other hand, contractile reserve was more consistently present in viable chronically dysfunctional myocardium supplied by a patent artery, supporting the use of either technique to determine viability.
Time for primary reviews 30 days.
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We would like to thank Anne Coe, Deana Gretka, Susan Fopeano, and Amy Johnson for their technical assistance. Supported by the American Heart Association, Department of Veterans Affairs, the Albert and Elizabeth Rekate Fund, and NHLBI.
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