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European Journal of Heart Failure 2003 5(3):217-227; doi:10.1016/S1388-9842(03)00008-4
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© 2003 European Society of Cardiology

The non-invasive assessment of hibernating myocardium in ischaemic cardiomyopathy—a myriad of techniques

Gavin I.W. Galasko and Avijit Lahiri*

Department of Cardiovascular Medicine, Northwick Park Hospital Watford Road, Harrow, Middlesex HA1 3UJ, UK

* Corresponding author. Tel.: +44-20-8869-2547/8; fax: +44-20-8864-0075. E-mail address: nph{at}cardiac-research.org


   Abstract
Top
 Abstract
1. Introduction
 2. Hibernating myocardium and...
 3. Traditional techniques to...
 4. Future techniques to...
 5. Revascularisation for...
 6. Conclusion
 References
 
Heart failure is placing an ever-increasing burden on society. Many subjects with heart failure and underlying coronary artery disease have a significant amount of akinetic but viable myocardium that is able to contract should myocardial perfusion improve (hibernating myocardium). Non-randomised studies have shown prognostic benefit in subjects with hibernating myocardium undergoing revascularisation. Several non-invasive techniques have been developed to assess the presence or absence of hibernating myocardium. This review will examine the epidemiology and underlying pathogenesis of hibernating myocardium; evaluate the non-invasive techniques for diagnosing hibernating myocardium, and look at therapeutic intervention in subjects with hibernating myocardium.

Key Words: Heart failure • Coronary artery disease • Hibernating myocardium • Non-invasive imaging

Received November 12, 2001; Revised July 17, 2002; Accepted September 25, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Hibernating myocardium and...
 3. Traditional techniques to...
 4. Future techniques to...
 5. Revascularisation for...
 6. Conclusion
 References
 
Heart failure is one of the commonest chronic disorders of the Western World with high associated morbidity and mortality and high and increasing prevalence and cost [1–13]. In the UK heart failure affects up to 2% of the population, accounts for over 5% of adult hospital admissions, and costs up to 2% of all National Health Service expenditure [5,7]. It affects a similar number in continental Europe [11,12] and the USA [13], with heart failure now estimated to affect over three million Americans [13], costing over ten billion dollars per year [14]. Mortality is high, even in the modern therapeutic era, with recent community-based 1-year and 5-year survival rates after the onset of heart failure 76 and 35%, respectively [15]. Many subjects with heart failure and underlying coronary artery disease, which occurs in up to 60–70% of cases [16,17], have an important amount of viable but dysfunctional myocardium, where akinetic or severely hypokinetic myocardium retains the ability to contract should perfusion improve [18,19]. This ‘re-awakening’ of acontractile myocardium after restoration of blood flow was noted as early as 1978 by Diamond et al. [20], who referred to such myocardium as ‘hibernating’, a term popularised later by Rahimtoola [21]. Coronary revascularisation in such subjects improves both cardiac function and prognosis, with subjects lacking sufficient hibernating myocardium showing deleterious outcome following surgery [22–31], although randomised data is still awaited. This has led to the development of several non-invasive techniques to diagnose viable or hibernating myocardium in subjects with ischaemic cardiomyopathy (heart failure as a result of left ventricular systolic dysfunction resulting from ischaemic heart disease), in an attempt to improve prognosis. This review will examine each technique in turn.


   2. Hibernating myocardium and stunning
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 Abstract
 1. Introduction
 2. Hibernating myocardium and...
3. Traditional techniques to...
 4. Future techniques to...
 5. Revascularisation for...
 6. Conclusion
 References
 
The mechanism of impaired myocardial function in subjects with ischaemic heart disease can range from reversible causes such as ischaemia, post-ischaemic stunning and hibernating myocardium, to irreversible myocardial fibrosis.

Myocardial stunning, first described by Heyndrickx et al. [32,33] is the process of transiently reduced myocardial contractility following a transient severe reduction or cessation of coronary blood flow. This dysfunction may persist for some time following the ischaemic event and restoration of normal coronary blood flow. Cellular mechanisms underlying stunning are thought to involve a number of factors including: altered energy utilisation by contractile proteins following a rapid decline in myocardial creatine phosphate stores and adenosine triphosphate (ATP); impaired sarcoplasmic reticulum function and calcium regulation; reduced myofilament responsiveness to calcium ion influx; production of cytotoxic oxygen-free radicals, and neutrophilic infiltration of previously ischaemic tissue with damage to the extracellular connective tissue matrix and further production of oxygen free radicals [34,35]. It has been hypothesised that myocardial stunning consists of two components: (1) a component that develops during ischaemia (ischaemic injury) which is not responsive to anti-oxidant therapy and (2) a component that develops after reperfusion (reperfusion injury) which can be mitigated by early antioxidant therapy [35].

Whilst stunning is typically a short-term process, myocardial hibernation is a chronic process with persistently impaired myocardial contractile function until blood-flow is re-established. Although there is currently some controversy as to whether underlying resting blood flow is reduced in hibernating myocardium as initially postulated [21,36–38], or whether resting blood flow is maintained with this phenomenon simply reflecting repeated stunning [39,40] and reduced coronary flow-reserve [41], repeated or continuous reduction in myocardial perfusion leads to a reversible down regulation of myocardial function as a result of intracellular structural and metabolic changes [34]. This leads to matching between the reduced perfusion and reduced energy demand preserving cellular viability. If the hypoperfusion is relieved, the myocardium regains normal contractility. Intracellular structural changes include myofibrillar and sarcoplasmic reticulum loss without cell volume reduction and glycogen accumulation. These changes differ markedly from those seen in permanently damaged atrophied or infarcted tissue where extensive cell volume loss occurs in association with cell membrane damage, cytoplasmic vacuolisation, mitochondrial swelling and lipid droplet accumulation [34]. Intracellular metabolic changes include a reduction in fatty acid beta-oxidation and an increase in anaerobic glycolysis, with glucose now becoming the major substrate for metabolism [42]. Mitochondrial function and oxygen metabolism is well preserved [43], however, a key distinguishing feature of cellular viability.

Myocardial hibernation is now thought to occur in up to 50% of all cases of ischaemic cardiomyopathy [44–46]. Auerbach et al. [44] and Al-Mohammed et al. [45], using positron emission tomography (PET), reported that 50 and 55% of patients with severe ischaemic cardiomyopathy, respectively, had evidence of significant hibernating myocardium. Similarly, a preliminary analysis of the baseline enrolment data of the CHRISTMAS trial, a randomised, placebo controlled, multicentre study of carvedilol in ischaemic cardiomyopathy with or without hibernation, reported that 58% of enrolled subjects had significant myocardial hibernation (≥2 segments in a 9 segment model) [46,47].

Although the terms hibernation and stunning represent uniquely different pathophysiological processes, in clinical practice the boundaries are less distinct. Indeed both may coexist in the same patient, even in the same myocardial region, with some myocardial regions that are hibernating at rest undergoing ischaemia during exercise leading to super-imposed post-ischaemic stunning further contributing to dysfunction.


   3. Traditional techniques to diagnose hibernating myocardium
Top
 Abstract
 1. Introduction
 2. Hibernating myocardium and...
 3. Traditional techniques to...
4. Future techniques to...
 5. Revascularisation for...
 6. Conclusion
 References
 
Several non-invasive techniques have been developed to identify hibernating myocardium. These include PET with fluorine-18 fluorodeoxyglucose (18F-FDG), traditionally the most sensitive and specific technique for predicting recovery of left ventricular function after coronary revascularisation, but with limited availability and high cost precluding widespread use; planar imaging or single photon emission computed tomography (SPECT) imaging with 201Tl using stress-redistribution-reinjection or rest-redistribution protocols, traditionally showing high sensitivity but low specificity for predicting left ventricular functional recovery; SPECT imaging with 99mTc-sestamibi or 99mTc-tetrofosmin, and assessment of inotropic reserve using dobutamine echocardiography, a highly operator dependant technique, that may lose sensitivity in cases of severe left ventricular dysfunction. For the radioisotope-based techniques, a separate assessment of left ventricular wall motion needs to be made either by echocardiography, magnetic resonance imaging or by gated SPECT imaging, to locate the non-functional segments requiring assessment of hibernation status. Potential future non-invasive techniques currently under evaluation include magnetic resonance imaging and fatty acid metabolic imaging.

Table 1 summarises the overall mean sensitivity and specificity of established non-invasive techniques in predicting functional improvement following revascularisation, with data taken from 43 studies involving almost 1500 patients [48–50]. It can be seen that nitrate enhanced perfusion imaging with 99mTc-sestamibi or 201Tl agents improves sensitivity and specificity dramatically, with these techniques now as good as dobutamine echocardiography and PET imaging. It is not possible, however, to draw definitive conclusions as no statistical comparison is made.


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  		Table 1 Sensitivities and specificities for predicting functional recovery after revascularisation (hibernating myocardium) using established non-invasive techniques

 
3.1. PET imaging
The human heart produces and uses approximately 35 kg of ATP per day for metabolism [51]. Under basal conditions, the majority of this is produced by fatty acid beta-oxidation through the tricarboxylic acid cycle and the electron transport chain in an oxygen dependent manner [52,53]. Under conditions of chronic hypoperfusion where the oxygen supply is only just sufficient to allow maintained cellular viability with or without myocardial function, as in repeatedly stunned or hibernating myocardium, a major metabolic change occurs, with oxidative metabolism replaced by anaerobic glycolysis, with glucose now the major substrate for metabolism [54,55]. By imaging regional blood flow, generally using oxygen-15 labelled water (H215O) or nitrogen-13 labelled ammonia (13NH3) and glucose uptake and metabolism using the glucose analogue 18F-FDG by PET, those areas of dysfunctional myocardium that retain sufficient blood flow and metabolic activity to sustain myocyte viability and thus potential for improved function after revascularisation can be imaged. These areas include those with normal blood flow and normal 18F-FDG uptake, or those with reduced blood flow but preserved or increased 18F-FDG uptake (perfusion-metabolism mismatch). Those areas with a matched proportional reduction in blood flow and 18F-FDG uptake identifies irreversibly damaged myocardial dysfunction [56–58]. Recent technological advances in camera and collimator design have allowed the use of 18F-FDG imaging using the more widely available, and thus more cost-effective, SPECT technique, not only allowing simultaneous dual isotope studies but also the added benefits of wall motion and regional ejection fraction measurements via ECG-gating, although at a cost of reduced resolution as compared to 18F-FDG PET [59–63].

3.2. Thallium imaging
Thallium-201, the first radionuclide to be widely used as a myocardial perfusion agent, is considered the most physiological marker of tissue viability and thus hibernation in non-functioning segments, with its cellular retention dependant on an intact cell membrane and active transport into the cell via the Na/K ATPase pump [64,65]. Furthermore, although its initial myocardial uptake reflects myocardial perfusion, tracer begins to redistribute throughout the myocardium within 10–15 min of injection and is taken up by other metabolically active cardiomyocytes with intact cell membranes, including areas of hibernating myocardium, whatever their rest perfusion. Thus in a rest-redistribution study, where 201Tl is injected at rest, although the initial image taken within 5 min of injection is primarily a function of perfusion, redistribution leads to hibernating myocardium being imaged 4–24 h later. Unfortunately, many regions with significant myocardial hibernation do not receive sufficient tracer via redistribution and so falsely appear to have irreversible defects on the redistribution image, despite preserved metabolic activity. As a result of this observation, several protocols have now been established to further improve the ability of thallium imaging to differentiate myocardial hibernation from myocardial scar by allowing either: increased plasma thallium concentration, increased rest perfusion, or prolonged time for redistribution, thus allowing greater thallium uptake into viable tissues [66]. Such techniques include: late (24–72 h) redistribution imaging; stress-redistribution-reinjection thallium imaging, where imaging is repeated after an additional dose of thallium is given at rest 3–4 h after a stress image, and nitrate-enhanced rest-redistribution protocols, where thallium is injected at rest following the prior administration of sublingual nitrate medication [27,34,67,68]. Although both reversible and mild-to-moderate irreversible (fixed defects with greater than 50% of normal thallium uptake) thallium defects remain metabolically active as assessed by PET, Kitsiou et al. have shown that functional recovery is more likely in regions with reversible defects and at least moderate rest perfusion, as compared to regions with mild-to-moderate fixed thallium defects [69]. He et al. [67], in a randomised study of 96 subjects with fixed defects at the 4 h redistribution image following a 201Tl stress image, found that 33% of patients randomised to reinjection following placebo showed significant reversibility, compared with 58% of patients randomised to reinjection following glyceryl trinitrate (GTN) (P<0.05). The use of such techniques gives 201Tl imaging similar diagnostic power to PET imaging in detecting hibernating myocardium (Table 1).

3.3. Technetium-99m imaging
Although 99mTc agents are better suited for gamma camera imaging than 201Tl, due to their higher energy photons and shorter half-life, producing higher quality images and better patient dosimetry, controversy exists over their accuracy in evaluating hibernating myocardium [70–72]. 99mTc uptake certainly implies cellular viability, as its retention in cardiomyocytes requires intact mitochondrial function and thus viable cells [73]. However, because 99mTc unlike 201Tl does not significantly redistribute following initial myocardial uptake, in cases of critical flow-limiting coronary artery stenosis at rest, insufficient tracer may reach viable but poorly perfused myocardium leading to an underestimation of the degree of viability.

To enhance resting myocardial blood flow, several investigators have used sublingual or intravenous administration of nitrate medication prior to several 99mTc-labelled agents including 99mTc-sestamibi [74–76], 99mTc-teboroxime [77] and 99mTc-tetrofosmin, showing increased rest perfusion [78–80]. By increasing basal flow and thus reducing the proportion of fixed perfusion defects, nitrate administration prior to rest imaging succeeds in improving the detection of viable myocardium to that approaching or even exceeding PET. Peix et al. [80], for example, found that in 50 patients with previous myocardial infarction, and thus likely left ventricular systolic dysfunction and hibernating myocardium, undergoing stress, rest and GTN rest 99mTc-tetrofosmin imaging, of the 186 segments with severe stress defects, 74 improved at rest, 41 (55%) only after administration of GTN. Most of the evidence for an increased detection of viable myocardium using nitrate-enhanced rest imaging has been seen with 99mTc sestamibi perfusion imaging [47], and this technique has been used in the diagnosis of hibernating myocardium in the ongoing CHRISTMAS study [46,47].

3.4. Mechanism of nitrate action
Nitrates, first used to treat angina pectoris in 1867 [81], with GTN first used in 1879 [82], were first conclusively shown to increase blood flow to regions of poorly perfused myocardium in patients with coronary artery disease in 1971 [83], and first shown to aid detection of viable myocardium in 1974 [84]. Since then, nitrates have been shown to increase perfusion and thus tracer delivery in poorly perfused but viable myocardium in a number of ways. Firstly, they act by vasodilating arteries, arterioles, veins and venules to reduce both cardiac preload and afterload [85–88], reducing oxygen demand and thus ischaemic burden. Secondly, their arterial vasodilating properties are most profound in the coronary circulation and again especially at sites of stenosis [86], directly improving flow. Thirdly, they improve collateral flow beyond such stenoses [67,89], and improve sub-endocardial perfusion by reducing left ventricular end-diastolic pressure and thus sub-endocardial compressive forces. Indeed, they have been shown to improve regional myocardial perfusion at rest [90,91] and during exercise [89,92] as well as global and regional left ventricular function [93,94]. Only during the mid-1990s, however, has this property of increasing myocardial blood flow to poorly perfused but viable myocardium been used to improve the sensitivity, specificity and diagnostic accuracy for myocardial perfusion imaging of both coronary artery disease per se as well as hibernating myocardium [67,68,74–76,78,79].

3.5. Dobutamine stress echocardiography
A characteristic feature of stunned and/or hibernating myocardium is the presence of residual inotropic reserve that may be elicited by catecholamine stimulation to produce improved myocardial wall thickening [95–97]. Furthermore, because of the reduced coronary flow-reserve typical of hibernating myocardium [41], on increasing the catecholamine stress, ischaemia often develops to produce reduced contractility and thus reduced wall thickening. Therefore during low dose catecholamine infusion a severely hypokinetic or akinetic but viable segment would show increased wall thickening on echocardiography, whilst at high dose this segment would become increasingly akinetic or dyskinetic (a biphasic response) [98]. Using low dose dobutamine stress echocardiography, Cigarroa et al. [99] showed that 9 of 11 subjects with contractile reserve showed improved systolic wall thickening after revascularisation, whereas 12 of 14 subjects without contractile reserve showed no improvement (P=0.003). Senior et al. [27], again using a low dose technique, went on to show a sensitivity and specificity of 87 and 82%, respectively, for this technique to detect ‘recoverable’ or viable segments following revascularisation in 22 patients with more severe ischaemic cardiomyopathy (mean left ventricular ejection fraction 25%). They showed a significant increase in mean left ventricular ejection fraction in those with improved contractility in at least two contiguous dysnergic segments (using a 13 segment model) from 27 to 38% (P<0.001) and showed no significant difference in predicting recovery of function and increased left ventricular ejection fraction to that of nitrate enhanced rest-redistribution 201Tl imaging performed at the same time. Several studies have confirmed these findings further [61,100–102], with some studies finding that the biphasic response or even a worsening response (a worsening of contraction without any initial improvement) to be the best predictors of recovery of function [102]. Senior et al. [103] have gone on to show that dobutamine stress echocardiography compares well with both nitrate-enhanced 99mTc-sestamibi and nitrate-enhanced 201Tl imaging in predicting outcome in subjects with ischaemic cardiomyopathy and heart failure undergoing surgical revascularisation.

One potential drawback with this technique is an increased number of false negative results (reduced sensitivity) in subjects with severe left ventricular dysfunction [104,105], a putative mechanism for this being the loss of a critical amount of myofibrils preventing a contractile response to dobutamine, despite cellular viability. Indeed in an elegant study of 22 patients undergoing surgical revascularisation for ischaemic cardiomyopathy, all of whom undergoing transmural biopsies from hibernating segments, Pagano et al. [106] showed that whilst uptake of glucose by 18F-FDG PET was preserved in all hibernating segments biopsied (segments whose contractility improved following revascularisation), the inotropic contractile response to dobutamine was lost in those subjects with myocytes with the most extensive myofibrillar loss and greatest glycogen-rich stores. The sensitivity of dobutamine stress echocardiography may also be reduced in those with severe resting perfusion defects, with Bigi et al. [107] finding that only 25% of segments supplied by totally occluded coronary arteries show a positive response to dobutamine stress echo.


   4. Future techniques to diagnose hibernating myocardium
Top
 Abstract
 1. Introduction
 2. Hibernating myocardium and...
 3. Traditional techniques to...
 4. Future techniques to...
5. Revascularisation for...
 6. Conclusion
 References
 
4.1. Fatty acid imaging
As stated above, long-chain fatty acids are the principal energy source for the normal myocardium, being rapidly metabolised via beta-oxidation, to produce 60–80% of all myocardial ATP. In ischaemic conditions, although down-regulation of fatty acid metabolism and up-regulation of glucose metabolism occurs, some fatty acid metabolism remains. Thus, by comparing radiolabelled fatty acid uptake as a metabolic tracer of viable tissue with perfusion imaging, myocardial viability can be assessed.

Although not yet widely available for routine clinical practice, several studies have shown that perfusion-metabolism mismatch using labelled fatty acid tracers correlates well with other measures of viability including perfusion-metabolism mismatch using 18F-FDG PET, and contractile reserve by dobutamine echocardiography, dobutamine magnetic resonance imaging and dobutamine ECG-gated 201Tl perfusion imaging [108–111]. Furthermore, a number of studies have gone on to show improved regional contractility following revascularisation in subjects with akinetic or severely hypokinetic myocardial segments diagnosed as viable on fatty acid perfusion-metabolism mismatch [112–115]. In the largest of these studies, Verani et al. [114] evaluated the role of using the straight chain fatty acid 123I-iodophenylpentadecanoic acid (IPPA) in identifying viable, hibernating myocardium prior to revascularisation. 119 subjects with ischaemic cardiomyopathy (left ventricular ejection fraction <40%) already scheduled for coronary artery bypass grafting underwent IPPA tomography (rest and 30-min redistribution) and blood pool radionuclide angiography within 3 days of surgery. Radionuclide angiography was repeated 6–8 weeks following surgery. Using receiver-operating characteristic analyses they found that the best predictor of a 10% or greater increase in left ventricular ejection fraction following revascularisation was 7 or more viable segments on IPPA imaging (accuracy 72%) using a 10 segment model of the left ventricle. Furthermore, using multivariate regression analysis amongst clinical and scintigraphic variables, the single most important predictor for a 10% or greater increase in left ventricular ejection fraction following revascularisation was the number of IPPA-viable segments, adding significant incremental value to the best clinical predictor model. Similar results have been seen with the branch-chained fatty acid 123I-(piodophenyl)-3-methyl pentadecanoic acid (BMIPP). Hambye et al. [113] performed 99mTc-sestamibi and BMIPP SPECT rest imaging twice within 6 months in 20 patients with chronic ischaemic left ventricular dysfunction and infarction before and after either revascularisation or a decision of conservative management and results compared with dobutamine stress echocardiography. Metabolic-perfusion mismatch (reduced BMIPP uptake as compared to 99mTc-sestamibi rest uptake) gave a sensitivity of 93%, specificity of 60% and overall accuracy of 80% in predicting viability on DSE. At follow up 11 of the 15 viable patients as assessed on dobutamine stress echocardiography (73%) showed improvement in global left ventricular function, associated with a significant increase in both sestamibi and BMIPP uptake.

4.2. Magnetic resonance imaging
Cardiovascular magnetic resonance (CMR) is now an accepted gold standard for the non-invasive assessment of cardiac mass and structure [116]. More recently CMR techniques have been expanded to look at measures of myocardial perfusion and viability. Two techniques have now been developed to assess the presence or absence of hibernating myocardium. The first technique, similar to dobutamine stress echocardiography, is that of assessing changes in left ventricular wall motion in dysfunctional segments using cine CMR sequences with low and/or high dose dobutamine [117–120]. As with dobutamine stress echocardiography, during a low dose catecholamine infusion a severely hypokinetic or akinetic but viable segment would show increased wall thickening, whilst at high dose it would become increasingly akinetic or dyskinetic. Currently this technique is qualitative, although attempts at quantitation are being developed. Indeed, even without quantitation, one study comparing dobutamine transoesophageal echocardiography with cine MRI in assessing myocardial viability in dysfunctional segments in 43 patients with prior myocardial infarction found very similar results when compared to PET imaging as the gold standard [119]. Overall agreement between the two techniques was 91%, with sensitivities and specificities in detecting myocardial viability of 77 vs. 81% and 94 vs. 100%, respectively, as compared to the gold standard. They went on to show that myocardial viability as assessed by dobutamine MRI predicted left ventricular functional recovery after revascularisation with a sensitivity of 89% and specificity of 94%, as good as if not better than traditional techniques [120].

The second technique is that of using MRI contrast media to probe cellular membrane integrity and thus viability. Gadolinium based contrast agents are actively removed from intact myocytes, and taken up by damaged cells. Thus relative hyperenhancement will occur in permanently damaged myocardium. By using a combination of contrast CMR and cine CMR, myocardial scar (hyperenhanced with reduced contractile function), hibernating myocardium (not hyperenhanced with reduced contractile function) and normal myocardium (not hyperenhanced with normal contractile function) can be differentiated [121,122]. Using this technique, Kim et al. [122] found that contractility improved in 256 of 329 (78%) akinetic or severely hypokinetic segments with no or minimal hyperenhancement (<=25% of segment), but only 1 of 58 (2%) segments with greater than 75% hyperenhancement in 50 subjects with ischaemic left ventricular dysfunction undergoing surgical revascularisation.


   5. Revascularisation for hibernating myocardium
Top
 Abstract
 1. Introduction
 2. Hibernating myocardium and...
 3. Traditional techniques to...
 4. Future techniques to...
 5. Revascularisation for...
6. Conclusion
 References
 
Ragosta et al. [26] using 201Tl planar rest-redistribution imaging in 21 subjects with ischaemic cardiomyopathy (mean left ventricular ejection fraction 27%) prior to surgical revascularisation found that if 8 or more dysfunctional segments in a 15-segment model of the left ventricle had significant myocardial viability then left ventricular ejection fraction rose significantly following revascularisation (29–41%, P=0.002), whilst 7 or fewer viable, asynergic segments led to no significant change in ejection fraction (27–30%, P=NS). Pagley et al. [22] went on to show a survival benefit in these 21 plus a further 49 subjects where the degree of myocardial viability was greatest. They showed that those with a viability index (mean viability score per segment assessed, with 2 scored for normal viability, 1 scored for ‘mildly reduced viability’ and 0 for no viability in each of the 15 segments assessed) of >0.67 were significantly freer of cardiac death or transplantation than those with less viability (viability index <=0.67) at three years follow-up, with better in-hospital outcome. One criticism of this study, however, is that the vast majority of these patients had presented to hospital with unstable angina or myocardial infarction prior to assessment and revascularisation and so are not typical heart failure subjects.

Senior et al. [27], using dobutamine echocardiography to diagnose the presence or absence of hibernating myocardium in 87 subjects with chronic stable ischaemic cardiomyopathy recruited from the out-patient setting, found similar improvements in left ventricular dysfunction and similar survival advantage when subjects with significant hibernating myocardium underwent revascularisation as compared to medical therapy of the time [31]. Those undergoing surgical revascularisation had a 40-month cardiac mortality of only 3%, compared with 31% for those with hibernating myocardium treated with medical therapy, 44% for those without hibernating myocardium treated with medical therapy and 50% for those without significant hibernating myocardium treated with revascularisation (P=0.01). Similar results have been found by other investigators using both dobutamine echocardiography [30] and PET in diagnosing viable myocardium [23–25]. A recent meta-analysis has examined 24 studies involving 3088 patients assessing the impact of revascularisation on the prognosis of patients with ischaemic left ventricular systolic dysfunction with or without hibernating myocardium [123]. It found an annual mortality rate of 3.2% for those with significant viable myocardium undergoing revascularisation, compared to 16% for those undergoing medical therapy (P<0.0001). For patients without significant viable myocardium, annual mortality was not significantly different by treatment method (7.7% with revascularisation vs. 6.2% for medical therapy, P=NS).

All of these studies, however, predated the widespread use of beta-blocker therapy in heart failure, a new therapy that may potentially improve outcome in those medically treated for hibernating myocardium. The carvedilol hibernation reversible ischaemia trial, marker of success (CHRISTMAS study) [46,47] is a double-blind randomised, placebo controlled study designed to assess this by looking at the effect of the beta-blocker carvedilol on left ventricular ejection fraction in subjects with ischaemic cardiomyopathy with or without significant hibernating myocardium. Hibernating myocardium is being assessed by use of a combination of resting echocardiography and resting nitrate enhanced 99mTc-sestamibi SPECT. Carvedilol is being used as the beta-blocker in this study, being the only beta-blocker thus far to show survival advantage in mild, moderate and severe heart failure [124,125], as well as preventing adverse remodelling following acute myocardial infarction [126], and causing regression of remodelling in chronic heart failure [127,128]. Other newer therapies may include new anti-ischaemic agents [129,130]. Belardinelli and Purcaro [129] showed that 2 months of oral treatment with the anti-ischaemic agent trimetazidine, a mitochondrial enzyme inhibitor, in a double-blind placebo-controlled study led to an improved contractile response of dysfunctional myocardium to dobutamine in subjects with ischaemic cardiomyopathy, as well as increasing overall ejection fraction. This suggests that it and other similar agents may also play important future roles in treating hibernating myocardium medically, acting in an analogous manner to revascularisation by reducing chronic ischaemia and/or stunning, restoring the energy/function imbalance [130].

However, none of the aforementioned imaging studies looking at revascularisation in subjects with congestive heart failure and significant hibernating myocardium were randomised in study design to aggressive medical therapy vs. revascularisation, allowing potential although unlikely bias. This is currently being assessed in the Heart—UK (Heart Revascularisation Trial—UK) study [131], where any validated non-invasive assessment of myocardial viability may be used for the diagnosis of viable myocardium prior to randomisation to either best medical therapy, including beta-blockade, or surgical revascularisation plus best medical therapy.


   6. Conclusion
Top
 Abstract
 1. Introduction
 2. Hibernating myocardium and...
 3. Traditional techniques to...
 4. Future techniques to...
 5. Revascularisation for...
 6. Conclusion
References
 
As congestive heart failure places an increasing burden on health care expenditure, improved therapies are required. Non-randomised studies have shown a clear survival advantage for those with ischaemic cardiomyopathy and significant hibernating myocardium when undergoing revascularisation surgery. This calls for an ever increasing role for the non-invasive assessment of myocardial viability in all cases of ischaemic cardiomyopathy fit for revascularisation, as well as completion of the first randomised trials of beta-blocker therapy in those with ischaemic cardiomyopathy with or without significant hibernating myocardium [46,47] and surgical vs. best medical therapy in those with significant hibernating myocardium [131].


   References
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 Abstract
 1. Introduction
 2. Hibernating myocardium and...
 3. Traditional techniques to...
 4. Future techniques to...
 5. Revascularisation for...
 6. Conclusion
 References
 

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