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Is viability still viable after the STICH trial?

Lauro Cortigiani , Riccardo Bigi , Rosa Sicari
DOI: http://dx.doi.org/10.1093/ejechocard/jer237 219-226 First published online: 12 November 2011

Abstract

Stunning and hibernation represent two different forms of tissue viability identifiable in acute coronary syndromes and chronic ischaemic cardiomyopathy, respectively. Functional recovery occurs spontaneously with myocardial stunning, while it generally follows revascularization in case of hibernating myocardium. Low-dose dobutamine stress echocardiography is an accurate modality for identifying myocardial stunning and provides important information on ventricular remodelling after both systemic thrombolysis and primary angioplasty. In patients with conservatively treated infarction, the prognostic significance of viability by dobutamine stress echocardiography correlates with residual pump function. Substantial contractile reserve is predictive of favourable outcome in patients with poor but not in those with preserved or slightly reduced left ventricular function. Non-invasive assessment of coronary flow reserve with transthoracic Doppler echocardiography of the left anterior descending coronary artery allows to distinguish between necrotic and stunned myocardium and predicts ventricular remodelling following primary angioplasty. Resting echocardiographic examination can provide information on hibernating myocardium. In particular, systolic thickening <7 mm, restrictive filling pattern, and high end-systolic volume are predictive of no viability. Compared with nuclear imaging, dobutamine stress echocardiography is more specific for predicting functional recovery, less expensive, more generally available and radiation-free. A large body of evidence collected over the years demonstrates the favourable prognostic impact of revascularizing extensive myocardial territories which are found viable at dobutamine stress echocardiography in patients with ischaemic cardiomyopathy. The prognostic implications of viability-guided revascularization have been clearly established in both diabetic and non-diabetic patients. However, the prognostic value of myocardial viability has been questioned by the results of the STICH trial that did not demonstrate any advantage of survival in the patients with a large extent of myocardial viability undergoing revascularization. Is the end of a paradigm that deeply influenced clinical practice so far or just a neutral result that can be ignored due to the several limitations of study design? In the present review, we will address the main advantages and limitations of ultrasounds for the evaluation of myocardial viability and try to demonstrate that viability is still viable.

  • Myocardial viability
  • Revascularization
  • Prognosis

Regional left ventricular (LV) dysfunction in patients with coronary artery disease is an irreversible phenomenon in the presence of scarred tissue, but it could be reversible in case of stunned or hibernated myocardium. Though profoundly different in terms of pathophysiology and clinical course, myocardial stunning and hibernation share similar prognostic implications which are generally related to the degree of LV dysfunction. Owing to the exponential increase in mortality, the identification of viable myocardium becomes of critical importance in patients with the LV ejection fraction <40% (Figure 1)1,2 who may significantly benefit from any improvement of contractility.

Figure 1

Hyperbolic curves relating mortality and radionuclide (left panel) and echocardiographic (right panel) assessed left ventricular ejection fraction in patients recovering from an acute myocardial infarction. Below 40%, even small changes in ejection fraction determine marked increase in mortality. Modified from Refs.1,2

Myocardial stunning

Myocardial stunning is produced by acute ischaemia and can spontaneously recover within hours to several weeks.3 It is generally associated with normal or increased coronary blood flow and highly variable degree of stenosis of the culprit vessel.4 Acute coronary syndromes represent the clinical model of stunning. In the reperfusion era, variable amount of stunned tissue is generally detectable in more than half patients with acute myocardial infarction.5

Echocardiography provides a useful clinical tool for the diagnostic and prognostic assessment of myocardial stunning.

Dobutamine stress echocardiography

Echocardiographic examination in conjunction with low-dose dobutamine administration is an established technique for identifying the presence of stunned myocardium.6 After systemic thrombolysis, sensitivity and specificity of dobutamine echocardiography range from 72 to 86% and from 68 to 90%, respectively, to predict functional recovery.79 In addition, test result can predict LV remodelling1013 that is known to confer unfavourable prognosis following both conservative14 and invasive treatment15 of acute myocardial infarction. Absence of contractile reserve in patients undergoing thrombolysis is an independent marker of LV remodelling, while its presence is associated with preserved LV dimensions.1012 Similarly, patients with evidence of tissue viability undergoing primary angioplasty for anterior infarction show progressive increase in the ejection fraction and reduction in LV volumes during follow-up.13 Conversely, no functional improvement and progressive remodelling are observed in patients without tissue viability (Figure 2).13 Major determinant of LV remodelling in these patients is represented by the significant increase in LV end-diastolic pressure.16

Figure 2

Left ventricular ejection fraction, infarct-zone wall-motion score index, end-diastolic volume index, and end-systolic volume index in patients with a first acute myocardial infarction treated with primary coronary angioplasty separated on the basis of presence (blue lines) or absence (red lines) of infarct-zone viability at dobutamine stress echo. During follow-up, left ventricular ejection fraction increases, whereas infarct-zone wall-motion score index, left ventricular end-diastolic volume index, and left ventricular end-systolic volume index decrease in patients with infarct-zone viability. Modified from Refs.13

The prognostic value of tissue viability after conservatively treated myocardial infarction depends on LV function. Patients with LV dysfunction and extensive contractile reserve show excellent survival rate, that is significantly better when compared with those with limited or absent contractile reserve (Figure 3).17 On the other hand, viability has a neutral effect on survival in case of preserved or slightly reduced LV function. Nevertheless, it is associated with an increased incidence of non-fatal events, thus representing an unstable substrate for further ischaemic episodes (Figure 3).18 In particular, the so-called biphasic response to dobutamine stimulation (low-dose functional improvement followed by high-dose deterioration) is a strong predictor of unfavourable outcome19 as well as residual stenosis of the culprit vessel.20

Figure 3

On the left panel the survival curves in patients with post-infarction left ventricular dysfunction who were not revascularized separated on the basis of presence or absence of myocardial viability at dobutamine stress echo are reported. The extent of viable myocardium is expressed as improvement of wall motion score index from resting conditions to peak stress >0.25 or <0.25. Absence of viability is associated with greater (P< 0.05) risk of cardiac death. In addition, survival in patients with small extent of viability (ΔWMSI <0.25) is similar to that of patients without viability. Modified from Ref.17 On the right panel the survival rates free of spontaneously cardiac events (death, reinfarction, and unstable angina) in patients with post-infarction preserved left ventricular function separated on the basis of presence or absence of myocardial viability at dobutamine stress echo are reported. The presence of viable myocardium is associated with increased (P< 0.05) incidence of cardiac events. Modified from Ref.18

Contrast echocardiography

The use of contrast media allows echocardiographic assessment of microvascular perfusion and provides a useful tool for distinguishing stunned from necrotic myocardium.21,22 However, microvascular integrity is an essential prerequisite of the technique and represents its major limitation due to the negative effect on specificity.23,24 In a direct comparison with dobutamine stress echo immediately after primary angioplasty, intracoronary contrast echo showed very similar sensitivity but markedly lower specificity (18 vs. 90%) for predicting functional recovery.23 Analogous results were obtained with intravenous contrast administration some days after the acute event, once reactive hyperaemia was no longer present.24

Transthoracic Doppler echocardiography

Transthoracic Doppler echocardiography of the left anterior descending coronary artery allows the identification of viable myocardium25 and predicts ventricular remodelling after primary angioplasty.26 Patients with functional recovery before hospital discharge show an increased coronary flow reserve at 24 h compared with immediate evaluation after revascularization, while no change is observed in those with no functional recovery.25 Moreover, coronary flow reserve measured immediately and 24 h after revascularization significantly correlates with regional wall motion score index at hospital discharge.25 At 6-month follow-up, patients with reduced coronary reserve show lesser increase in the ejection fraction and lesser decrease in both wall motion score and end-diastolic LV volume in comparison with those with preserved coronary flow reserve.26,27

Relevant information can also be obtained from serial analysis of coronary flow at rest. Persistence of systolic flow reversal at 48 h following primary angioplasty is a specific marker of irreversible dysfunction, while no or short-lasting systolic flow reversal is predictive of functional recovery 3 weeks after revascularization.28 Though long-term data on non-invasive assessment are still lacking, the invasively assessed coronary flow velocity pattern is an accurate predictor of in-hospital survival and congestive heart failure after acute myocardial infarction.29

Myocardial hibernation

Hibernation is characterized by chronically reduced contractile function following regional hypoperfusion in a myocardial territory served by a critically stenotic vessel.30 Myocardial revascularization is the only way to improve contractile function in these conditions. The ischaemic cardiomyopathy represents the clinical model of hibernating myocardium.

The identification of myocardial hibernation allows to plan targeted revascularization procedures and, therefore, represents a major clinical goal. However, due to the exponential increase in ischaemic heart failure during the last decades, it has huge practical implications.31 Indeed, the ischaemic origin accounts for ∼70% of >20 000 patients enrolled in major clinical trials on heart failure.32

The echocardiographic evaluation of contractile response to inotropic stimulation, as with low-dose dobutamine test, or the assessment of myocyte integrity and metabolism using nuclear scan and positron emission tomography, respectively, are employed to identify hibernating myocardium. Moreover, standard echocardiographic examination also provides useful information on tissue viability.

Standard echocardiography

Different echocardiographic measurements proved to be useful markers of tissue viability. Systolic wall thickness >7 mm is >90% sensitive and 50% specific for predicting functional recovery following revascularization.33

On the other hand, the restrictive LV filling pattern is highly sensitive to rule out the presence of viable myocardium, as demonstrated by the strict correlation between E-wave deceleration time and number of viable segments identified by dobutamine echocardiography.34 LV filling pattern also provides information on functional recovery following revascularization; in particular, the majority of patients with an E-wave deceleration time <140 ms shows just minor or no recovery at all.34

Finally, ventricular remodelling negatively affects the presence of viable myocardium. LV end-systolic volume of patients with increased ejection fraction following revascularization is significantly lower than in those with unchanged ejection fraction.35

Dobutamine stress echocardiography

By far, the widest experience is available with low-dose dobutamine stress echocardiography,36 the preferred stressor for assessing myocardial viability. The protocol in most stress echocardiography laboratories uses dobutamine infusion at two low-dose stages (5 and 10 µg kg−1 min−1), with each stage lasting 3 min. Some advocate using an even lower starting dose of 2.5 µg kg−1 min−1 since in patients with critical coronary stenosis, myocardial ischaemia may be precipitated even with doses as low as 5 µg kg−1 min−1. The benefit of proceeding to higher doses of dobutamine, even if contractile reserve is demonstrated at lower doses, is to observe a ‘biphasic response’. It is not surprising that the biphasic response has the best predictive value of all the possible responses to dobutamine in determining improvement in LV function following revascularization. In a recent study, <15% of myocardial segments demonstrating either no change or sustained improvement with low- and high-dose dobutamine had functional recovery with revascularization, while 72% of segments with a biphasic response recovered function.37

Nuclear techniques

Nuclear medicine has been for a long time the only available technique for the assessment of myocardial viability. The viable myocardial cell maintains biochemical and metabolic activities that are critical for cell survival and are highly useful markers for the clinical identification of viability using nuclear techniques.38 The viable cells have a residual coronary flow, which can be visualized with a flow tracer such as technetium sestamibi (gamma emitting and therefore detectable by a gamma camera) or rubidium (positron emitting and therefore detectable by positron emission tomography). The viable cell has membrane integrity and intact function of ionic pumps and is therefore capable of taking up 201-thallium, a potassium analog, and storing it intracellularly. The viable cell can also metabolize glucose, which can be traced with fluorodeoxyglucose, a positron-emitting glucose analog. It competes intracellularly for phosphorylation by means of cellular exokinase. Phosphorylated fluorodeoxyglucose cannot be further metabolized and remains trapped with the cell as a viability marker.

Magnetic resonance imaging

Cardiovascular magnetic resonance with a delayed gadolinium enhancement technique39 directly visualizes myocardial scar as hyper-enhanced areas in T1-weighted images. The imaging study is performed at rest (no stress required) and after several minutes from contrast medium injection, since the redistribution phase of the tissue (and not the first pass effect of the vessels) is the diagnostic target.39 The transmural extent of scar tissue is an important predictor of the lack of contractile improvement after revascularization.39

Dobutamine echocardiography vs. nuclear techniques

In comparison to nuclear techniques, dobutamine stress echocardiography is less sensitive and more specific in predicting functional recovery following revascularization (Figure 4).36,4043 This clinical finding relies on the histopathological background that at least 50% viable myocytes are required in a given region for a contractile response to be elicited during dobutamine stimulation. Differently, even minor amount of tissue viability can be identified with nuclear scan44 resulting in higher rate of positive tests. Simultaneous dobutamine stress echocardiography and post-stress reinjection of 201Tl single-photon emission computed tomography were used to detect tissue viability in 38 patients with severe chronic LV dysfunction undergoing coronary bypass surgery. Persistence of tissue viability in akinetic or severely hypokinetic segments was identified in 19–61% of cases with dobutamine echocardiography and nuclear scan, respectively.42 The likelihood of functional recovery following revascularization is very low in patients with viable myocardium detected by nuclear scan but not with dobutamine echocardiography.45,46 Further advantages of echocardiography compared with nuclear imaging are represented by lower cost, easier availability, reduced testing time, and no use of ionizing radiation potentially related to biological damage.47 Nuclear imaging represents a valuable alternative to dobutamine stress echocardiography in case of inadequate acoustic window or in presence of complex ventricular arrhythmias. However, cardiac magnetic resonance is becoming a reasonable alternative due to its ability to measure both the extent of necrosis and myocardial contractile reserve after an inotropic challenge.48,49

Figure 4

Sensitivity and specificity of nuclear techniques and low-dose dobutamine stress echocardiography in predicting functional recovery after revascularization in patients with ischaemic left ventricular dysfunction. Dobutamine stress echocardiography has a better specificity and slightly lower sensitivity than nuclear techniques. FDG PET, fluorodeoxyglucose positron emission tomography; LD DOB, low-dose dobutamine. Modified from Ref.36

The prognostic impact of myocardial viability

Functional improvement following revascularization is closely related to the amount of dysfunctional but viable myocardium, being totally absent in case of no viability (Figure 5).50,51 This has major prognostic implications. A large body of evidence demonstrates an increased prognostic benefit in patients with ischaemic cardiomyopathy undergoing revascularization of a substantial amount of viable myocardium (at least four segments or 20% of the total left ventricle) compared with those undergoing revascularization of non-viable myocardium or medical therapy.5258 In the VIDA study, myocardial viability by low-dose dobutamine echocardiography was associated with 79% reduction in cardiac mortality among revascularized vs. conservatively treated patients with severe LV ischaemic dysfunction, while no benefit was found in case of no viability.57 These findings did not apply to patients with ventricular remodelling, as demonstrated by the poor outcome of patients with high end-systolic volume independently of the presence and amount of tissue viability (Figure 6).35 Owing to the increased cardiovascular risk5961 associated to diabetes mellitus even after revascularization,62,63 the prognostic role of myocardial viability in these patients represents a relevant clinical issue. Improvement in the ejection fraction following revascularization and prevention of ongoing LV remodelling was found in a small series of viable patients with ischaemic LV dysfunction that was similar in diabetics and non-diabetics.64 In addition, the outcome of viable diabetics undergoing revascularization was similar to that of non-viable non-diabetics. A study including 612 patients with ischaemic cardiomyopathy showed similar prognostic implications of viability-guided revascularization in diabetics and non-diabetics undergoing dobutamine echocardiography (24 and 22% 4-year survival rate, respectively).65 On the other hand, diabetes was an independent predictor of death among conservatively treated patients.65 Two meta-analysis on a total of 5305 patients with ischaemic LV dysfunction tested with dobutamine stress echocardiography or nuclear techniques confirmed the strong association between myocardial viability and improved survival after revascularization while absence of viability predicted similar outcomes, irrespective of treatment strategy (Figure 7).66,67 In addition, no measurable performance difference for predicting revascularization benefit between the two imaging techniques was reported.66 In contrast, in the STICH trial myocardial viability on dobutamine echo or perfusion scintigraphy failed to identify patients with a differential survival benefit from coronary surgery when compared with optimized medical therapy alone.68 However, several limitations should be acknowledged for the STICH trial with regard to study design, myocardial viability assessment and criteria, indication to viability testing. Ninety-nine sites in 22 countries enrolled 1221 patients on a time span of almost 10 years. However, the analyzable subset with myocardial viability was of only 601 patients. Myocardial viability, due to an insufficient enrolment rate, was not a selection criteria and was performed whenever possible at peripheral centres: this may have introduced a selection bias in the population. The results from echo and SPECT were lumped together, but interestingly enough the extent of myocardial viability was different for the two techniques. Even though on large populations the two techniques are comparable, they have significant different specificity, being echo more specific than perfusion techniques, 36,4043 therefore the number of false positive results may have diluted the favourable effect of viability. The long-time span of enrolment may have changed surgical techniques, but mostly medical therapy.69 This is a major issue, and the real novelty of the study, that has not been appropriately investigated. The less striking effect on mortality in the STICH when compared with previous studies may be attributed to the adherence to optimal medical therapy in severely dysfunctioning patients. The remarkable and protective effect of beta-blocking agents has been demonstrated in heart failure patients, showing contractile reserve at dobutamine stress echocardiography.70 STICH trial has been long awaited as the ultimate piece of information on myocardial viability, revascularization, and survival, unfortunately it was not.

Figure 5

Effect of the extent of viable myocardium assessed during dobutamine stress echo on post-revascularization left ventricular ejection fraction in patients with ischaemic cardiomyopathy. The greater improvement in the ejection fraction is observed in patients with >6 dysfunctional but viable left ventricular segments. Conversely, no change in the ejection fraction is observed in patients without viability. Modified from Ref.51

Figure 6

Cardiac events (cardiac death, myocardial infarction, and hospitalization for heart failure) at 3-year follow-up for four different patient categories with ischaemic left ventricular dysfunction according to the presence of substantial viable myocardium (>4 segments) at dobutamine stress echo and the left ventricular end-systolic volume. Patients with small ESV (<130 mL) and viable myocardium have the best prognosis, whereas those with large end-systolic volume (>130 mL) and no viability have the worst prognosis. Modified from Ref.35

Figure 7

Results of two meta-analysis on 3088 and 2217 patients with ischaemic cardiomyopathy, respectively, assessing the effect of revascularization and medical therapy according to the presence or absence of viability at dobutamine stress echo or nuclear techniques. A 79.6 and 65.1% reduction in mortality for patients with viable myocardium treated by revascularization is shown. Conversely, no relevant prognostic difference between the two therapeutic strategies is reported for patients without viability. Modified from Refs.66,67

Conclusions

Myocardial viability remains one of the many parameters to be taken into consideration for the evaluation of patients with heart failure. Echocardiography is probably the best cost-effective tool for its assessment due to its high availability, low cost and lack of ionizing radiations. The lessons learned from clinical trials on imaging such as that given by the STICH is that we cannot rely on one single parameter and that optimal medical therapy in some subsets may be as effective as revascularization procedures. There is no convincing evidence that the assessment of myocardial viability should not be included in the work-up of the chronic dysfunctioning patient, at least not on the basis of the STICH trial.69 However, more studies are needed to determine the role of cardiac imaging in clinical decision-making. The available techniques are deeply influenced by the extent and severity of damage, and this is translated into variable diagnostic accuracy.71 New clinical scenarios in which myocardial contractility may play a significant role in risk stratification are to be investigated. In recent years, the documentation of viable myocardium during dobutamine stress echocardiography has also shown to predict responders to resynchronization therapy. In fact, patients with contractile reserve have a favourable clinical and reverse LV remodelling response to resynchronization therapy.72 Conversely, the electrocardiographic and echocardiographic dyssynchrony criteria are equally present in clinical and echocardiographic responders and non-responders (Figure 8).72 New imaging techniques are available such as cardiac magnetic resonance, but still we need the evidence for its clinical utility and more studies are warranted. The currently accepted appropriate (and less appropriate) indications for clinically driven testing of myocardial viability are to remain unchanged, at least for the time being.73

Figure 8

Percentages of responders to cardiac resynchronization therapy for four different patient categories according to the presence (+) or absence (−) of contractile reserve at dobutamine stress echo in combination with the presence (+) or absence (−) of baseline tissue Doppler criteria of intraventricular dyssynchrony. Myocardial contractile reserve is more often associated with response to therapy, whereas dyssynchrony criteria are equally distributed in the two groups. Modified from Ref.72

Conflict of interest: none declared.

Funding

Financial support for the present study was received from institutional funding of the CNR, Institute of Clinical Physiology, Pisa, Italy.

References

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