What is Myocardial Viability?
Viable myocardium are myocardial segment(s) with reduced function that often appear dyssynergic on imaging studies. These dyssynergic or dysfunctional myocardial segments are capable of functional recovery, either spontaneously or after the offending insult - usually ischaemia - is removed by revascularisation.
In the context of myocardial viability, a number of terms have been used in different settings, giving rise to some confusion and ambiguity. Stunned myocardium refers to dysfunctional myocardial segments that subsequently recover spontaneously. This is seen when myocardial dysfunction occurs as a result of a significant but often transient insult. For this reason, myocardial dysfunction may persist for a variable period of time but eventually recovers spontaneously. Myocardial hibernation refers to persistent myocardial dysfunction due to ischaemia, the treatment of which eventually leads to restoration of function. Myocardial scars are myocardial segments that are non-viable and are not capable of significant functional recovery despite revascularisation. Viable myocardium is therefore dysfunctional but alive; myocardial scars are dysfunctional and non-viable; stunned myocardium is dysfunctional but non-ischaemic and capable of spontaneous recovery; while hibernating myocardium is dysfunctional and ischaemic and revascularisation will lead to recovery of function.
The above description may, in fact, be an oversimplification of the real-life situation. Not all myocardial scars are full thickness and the degree of transmurality of non-viable myocardium would determine the degree of functional recovery with revascularisation. Techniques that are very sensitive in detecting any degree of 'myocardial viability' may not translate into meaningful and detectable functional recovery after revascularisation if only small, partial thickness, viable segments are detected.
Functional recovery is the 'gold standard' of myocardial viability assessment. Of particular note, however, is that functional recovery may be defined differently in different studies. Assessment of functional recovery of individual myocardial segments is obviously different to using improvement in left ventricular (LV) ejection fraction as the outcome measure with revascularisation. Significant and measurable change in ejection fraction may only be observed if enough myocardial segments recover to effect such a change. Moreover, the minimal or optimal interval between revascularisation and subsequent assessment of functional recovery is unclear. Another complicating factor is the method and completeness of revascularisation, which will also significantly impact on the degree of functional recovery. Unfortunately, published studies examining the utilities of various methods for the detection of viable myocardium differ in all these important aspects and uniform consensus and properly conducted clinical trials are still lacking.
Why is Detection Important?
Impaired LV function is the main factor determining prognosis in a wide range of cardiovascular disorders. Patients with impaired LV function but with viable myocardium are at increased risk of death and adverse cardiovascular outcomes. The detection of viable myocardium in these patients is essential as successful revascularisation leads to an improvement in symptoms, LV function and a reduction in mortality.1-3 Furthermore, patients without significant myocardial viability may not benefit from revascularisation so the potential risks of any revascularisation procedures can therefore be avoided in these patients.4
A meta-analysis of 3,088 patients in 24 studies was carried out by Allman et al.4 Revascularisation of patients with LV dysfunction and viable myocardium, irrespective of the method of assessment, conveyed a significant survival advantage compared to those who received medical treatment alone (mortality 3.2 versus 16%, respectively). Furthermore, patients with the most severe LV dysfunction derived the greatest survival benefit from revascularisation, despite the associated increased risks of these procedures. Revascularisation of viable myocardium also led to a reduction in the composite endpoint of myocardial infarction, heart failure and unstable angina.4
Myocardial hibernation can therefore be seen as an 'unstable' state associated with increased risks of mortality and future cardiovascular events, whereby successful revascularisation leads to an improved outcome. Importantly, revascularisation of patients with LV dysfunction in the absence of viability resulted in no significant difference in outcomes compared with medical treatment alone.4 For these reasons, assessment for viable myocardium enables clinicians to identify patients who are most likely to benefit from revascularisation. They can also withhold such procedures from patients with myocardial scars so that these patients may be spared the associated risks.
Methods of Detection of Viable Myocardium
Myocardial viability may be assessed by various methods that test the integrity of a number of cellular mechanisms of the viable cardiac myocyte (see Table 1). These mechanisms include the determination of maintained cell membrane integrity, preserved metabolic machinery, recruitable inotropic reserve (or contractile reserve), coronary microvascular integrity and the absence of late enhancement.
Thallium single-photon emission computed tomography (SPECT) assesses cell membrane integrity. Technectium-99m-SPECT works via mitochondria-dependent energy processes to determine viability. It is also a marker cell membrane function. F-18 fluorodeoxyglucosepositron emission tomography (FDG-PET) evaluates cellular metabolic processes in viable and therefore metabolically active tissue.
Viable myocardium is capable of augmenting its function in the presence of inotropic stimulus - a property called contractile reserve or recruitable inotropic reserve. The improvement in function of viable myocardium can be visualised either with echocardiography or other imaging techniques, like magnetic resonance imaging (MRI).
Myocardial contrast echocardiography (MCE) evaluates myocardial microvascular integrity. Viable myocardium has preserved microvascular integrity. Intravenously injected bubble contrast agents lead to contrast enhancement of dyssynergic but viable myocardial segments that can be detected with echocardiography. Non-viable myocardium does not show significant enhancement with bubble contrast due to disruption of the coronary microvasculature.
MRI uses indirect fibrosis imaging to examine the spatial extent of late gadolinium enhancement to identify and characterise the distribution of myocardial scarring. Since gadolinium is an extracellular interstitial agent and myocardial necrosis is associated with cell membrane rupture and interstitial oedema, there is increased gadolinium concentration within infarcted tissues in the acute setting. The disrupted microvascular integrity in chronic myocardial scars leads to delayed contrast wash-out resulting in delayed enhancement. Myocardial viability may therefore be assessed using different techniques. The remainder of this article will focus on the evaluation of myocardial viability using contrast and stress echocardiography.
The resting echocardiogram is useful for assessing myocardial viability. Myocardial wall thickness and the presence of post-systolic shortening at dyssynergic segments have been found to be useful parameters in identifying viable myocardium.
Myocardial necrosis is associated with wall thinning on echocardiography in chronic transmural infarction. The end-diastolic wall thickness (EDWT), measured from the leading endocardial edge to leading epicardial edge, is an important parameter of myocardial viability with comparable accuracy to thallium rest-redistribution SPECT.5 An EDWT ≤0.6cm is associated with akinesia or even dyskinesia, irreversible injury (negative predictive value 93%), no demonstrable contractile reserve in response to dobutamine,5,6 and indicates lack of potential for functional recovery. A preserved EDWT >0.6cm does not, however, always indicate myocardial viability.5
Pulse wave tissue Doppler imaging on resting echocardiography and during dobutamine stress echocardiography (DSE), is also useful to identify dyssynergic but viable myocardium. In normal myocardium at the onset of isovolumic relaxation, after aortic valve closure, a brief motion of the cardiac base away from the cardiac apex during myocardial relaxation is detectable using pulsed-waved tissue Doppler. The motion usually terminates before mitral valve opening (see Figure 1).
In dyssynergic but viable segments, a motion of the cardiac base towards the apex may be seen in the opposite direction during isovolumic relaxation phase (see Figure 1) indicating post-systolic shortening. Furthermore, during myocardial ischaemia systolic wall thickening decreases and post-systolic wall thickening develops. The amplitude of wall excursion and thickening is reduced and the time to maximum amplitude occurs in early diastole, rather than during systolic ejection.
The extent of post-systolic thickening during ischaemia correlates with the recovery of contractile function during reperfusion.7,8 A post-systolic thickening velocity of >2cm/second and a velocity higher than peak systolic thickening velocity has been shown to have an 82% sensitivity and 81% specificity in diagnosing peri-infarct ischaemia or viability after acute myocardial infarction.9
DSE is not only an established technique for the detection of coronary artery disease in patients who cannot exercise, it is also a valuable tool in the assessment of contractile reserve to identify myocardial viability. DSE involves the graded infusion of dobutamine while wall motion and myocardial thickening are evaluated. Its use in identifying viable myocardium is based on the demonstration of contractile reserve. Dyssynergic but viable myocardium will augment its contractility in response to beta-adrenergic stimulation, whereas nonviable myocardium will not.10-13
Dyssynergic but viable myocardium may respond to dobutamine infusion in one of two ways depending on whether the segments are ischaemic or not. For viable but non-ischaemic myocardial segments, an improvement in contractility is observed during low-dose dobutamine and the improvement is sustained during high-dose dobutamine. This pattern of response is usually observed in stunned myocardium. For hibernating myocardium (viable but ischaemic), a biphasic response where there is augmentation of contractility at low dose followed by deterioration at higher doses is seen. This biphasic response to increasing doses of dobutamine infusion is characteristic and diagnostic of viable myocardium. The various responses on DSE are illustrated in Table 2.
Contractile reserve on low-dose DSE has been shown to be a reliable predictor of functional recovery, both early after infarction and in chronic ischaemic LV dysfunction with a sensitivity of 75-80% and specificity of 80-85%.14-16 The amount of myocardium identified as viable correlates with the degree of global and regional improvement after revascularisation. While individual studies examining the accuracy of low-dose DSE in identifying functional recovery after revascularisation were small, a meta-analysis by Bax and co-workers showed an overall sensitivity of 84% and specificity of 81%.17 The overall accuracy of low-dose DSE compared favourably with other techniques with similar sensitivities but the highest specificity.17
Low-dose DSE has been combined with measurement of EDWT at-rest echocardiography to evaluate myocardial viability. Although an EDWT of >0.6cm had a 94% sensitivity in predicting functional recovery two months after revascularisation, its specificity was only 48%. Combining an EDWT >0.6cm and any contractile reserve on low-dose DSE had a sensitivity of 88% and an improved specificity of 77% in predicting functional recovery after revascularisation.5
The response of post-systolic thickening velocity during low-dose DSE has also been shown to be useful in identifying viable myocardium. A doubling of post-systolic thickening velocity of the dyssynergic segments during low-dose DSE has been shown to be indicative of peri-infarct ischaemia or myocardial viability after acute myocardial infarction (see Figure 1).9
Combining these semi-quantitative techniques with low-dose DSE may help to overcome problems related to subjective visual assessment with DSE. It may also improve inter-observer variability and diagnostic accuracy.9,18
DSE, although a widely available and relatively low-cost approach for the detection of viability, is subjective and relies on semi-quantitative evaluation of endocardial excursion and wall thickening. Furthermore, the assessment of contractility in segments adjacent to infarct-related areas may be problematic. This is because endocardial excursion of the segments due to active contraction may be difficult to distinguish from tethering to adjacent segments. Newer techniques that measure myocardial deformation, such as strain and strain-rate imaging, may more reliably quantify this response, however, and help improve the inter-observer variability and diagnostic accuracy of DSE.
Strain and Strain-rate Echocardiography
Strain and strain rate are measures of myocardial deformation that reflect LV function. They are validated methods for the quantification of regional myocardial function.19,20 Strain is the deformation of an object relative to its original length. Strain rate, the gradient of velocities between two points in space, is the rate by which this deformation occurs. Strain and strain rate imaging can be derived either from colour tissue Doppler imaging or 2D speckle tracking.
Strain and strain rate imaging allow measurements that are site specific, not influenced by overall cardiac and respiratory motion. The measurements are independent of the passive tethering effects from adjacent segments that complicate the visual wall motion assessment of DSE and concomitant tissue Doppler velocity approaches to viability assessment.
While strain and strain rate imaging have been the focus of research efforts in identifying viable myocardium, there is no common consensus on the best parameters. A number of parameters have been used in different studies (see Figure 2). For strain imaging, end-systolic strain refers to the strain at aortic valve closure, which may be different to peak systolic strain if there is significant post-systolic thickening. Peak systolic strain may therefore occur during isovolumic relaxation or later, after the aortic valve closure. For strain rate imaging, the peak systolic strain rate is generally used.
Strain rate imaging in combination with low-dose dobutamine infusion has been used to identify viable myocardium. In a study of 37 patients with ischaemic cardiomyopathy,21 changes in peak systolic tissue velocities and peak strain rate were used to identify viable myocardium with FDG-PET as the gold standard. The increase in peak tissue Doppler velocities (cut-off value of 1.05cm/second) with dobutamine had suboptimal sensitivities and specificities of 69 and 64%, respectively. There was significant overlap between responses of viable and non-viable myocardial segments. This was perhaps not surprising as tissue Doppler velocities are angle-dependent and subject to tethering effects from adjacent segments. An increase of peak systolic strain rate of ÔëÑ0.23/second, however, had a significantly better sensitivity and specificity of 83% and 84%, respectively.21
In another study of 55 patients with ischaemic cardiomyopathy, wall motion scoring during low-dose DSE was compared with strain and strain rate imaging with functional recovery nine months after revascularisation as the gold standard. End-systolic strain, peak systolic strain rate and their increments alone were not significantly better than wall motion scoring in predicting functional recovery. Combining wall motion scoring with strain rate imaging parameters, however, significantly increased the sensitivity from 73 to 82% with similar specificity (see Figure 3).22
Myocardial Contrast Echocardiography
MCE is a well-established technique for LV chamber opacification. This technique involves the use of microbubbles of encapsulated high-molecular-weight gas with rheology similar to that of red blood cells. These microbubbles therefore act as an intravascular red blood cell tracer.
MCE has been used to evaluate myocardial blood flow. The two commonly used imaging protocols for MCE are low mechanical index continuous imaging and high mechanical index gated intermittent imaging (see Table 3).
Low mechanical index continuous imaging uses a mechanical index of 0.1-0.3 to allow continuous real-time imaging. Echocardiography contrast may either be given as a slow intravenous bolus or an infusion. A high mechanical index flash is then delivered to destroy the microbubbles in the myocardium so that myocardial blood flow can be measured from the rate of their reappearance. This is called destruction-replenishment imaging. Continuous imaging enables simultaneous analysis of LV systolic function and regional wall motion.
High mechanical index gated intermittent imaging uses a mechanical index of 0.8-1.0 for the detection of the ultrasound contrast agent in the myocardium. Imaging is gated to the ECG. Intermittent imaging allows time for the replenishment of contrast in the myocardium between imaging. This gated imaging method is more sensitive for the detection of contrast, although simultaneous assessment of function and flow is not possible.
Both acquisition modalities allow the assessment of the number of segments with enhancement, which is used as a semi-quantitative approach to identify viable myocardium. A quantitative approach has also been used where a time-intensity curve is generated within the myocardial region of interest. This curve generally adopts an inverse exponential curve (Figure 4). The rate of intensity increase reflects blood flow velocity, the peak intensity reflects total myocardial blood volume and their product is proportional to the myocardial blood flow.
The use of MCE for viability assessment is based on the principle that microvascular integrity is a fundamental prerequisite for myocardial viability.23 Myocardial contrast enhancement can be observed only if the coronary microvasculature is preserved and perfusion defects indicate a disrupted coronary microvasculature.
After acute myocardial infarction, microvascular blood flow correlates with recovery of function. Since the extent of perfusion defects on MCE have been shown to correlate with post-mortem histology, MCE can be used to visualise and quantify the amount of myocardium at risk during coronary occlusion. Studies comparing MCE with thallium and technetium sestamibi SPECT have shown good agreement for the detection and sizing of perfusion defects.24,25
Iliceto et al. compared MCE and DSE in identifying viable myocardium in 24 patients after acute myocardial infarction with functional recovery three months post-infarction as the gold standard.23 Enhancement of >50% with MCE at the dyssynergic segments was considered indicative of myocardial viability. While low-dose DSE had a sensitivity of 71% and specificity of 88%, MCE had a very high sensitivity of 100% with a very low specificity of 46%.23 MCE has also been used to assess viability in patients with chronic ischaemic LV dysfunction, with reported sensitivities ranging from 62-92% and specificities from 67-87%. When compared to thallium rest redistribution SPECT and DSE, MCE has high sensitivity for detecting hibernating myocardium but low specificity for predicting regional functional recovery.26,27
While individual studies examining MCE in identifying viable myocardium are small, the overall accuracy of resting MCE for such purposes based on 20 small studies similarly showed a high sensitivity of 85% but a low specificity of 70%.28 The possible mechanism underlying the low specificity for MCE in predicting functional recovery is that, although essential for myocardial viability, an intact coronary microvasculature alone may not be sufficient for functional recovery.
It has been suggested that low-dose DSE and MCE may serve complementary roles in identifying viable myocardium. A biphasic response during DSE is diagnostic of hibernating myocardium with high specificity and positive predictive value for functional recovery after revascularisation.29,30 An absence of contrast enhancement on MCE, however, has high negative predictive value and is predictive of LV remodelling on follow up.29,30
Ongoing advances in technology have led to contrast and stress echocardiography increasingly evolving as an invaluable clinical tool for the assessment of myocardial viability. The detection and recognition of dyssynergic but viable segments is critical for:
- risk stratification;
- predicting improvements in patient symptoms;
- selecting patients likely to benefit from revascularisation in terms of functional recovery of viable segments and improved survival outcomes; and
- predicting LV remodelling.
Rest echocardiography is useful in identifying viable myocardium. An EDWT of ≤0.6cm at the dyssynergic segments generally indicates non-viable myocardium. The presence of post-systolic thickening at these segments at rest suggests myocardial ischaemia or viable myocardium.
DSE is established as a useful tool to identify myocardial viability, with an overall accuracy comparable to thallium SPECT and FDG-PET imaging. In particular, a biphasic response to dobutamine infusion is diagnostic of hibernating myocardium and has a high predictive value for functional recovery after revascularisation.
The amount of viable myocardium identified on DSE correlates with improvements in regional and global function post revascularisation. Furthermore, with DSE, a doubling of post-systolic thickening velocities at dyssynergic segments by tissue Doppler imaging is also suggestive of myocardial viability.
Strain and strain rate imaging allow the objective assessment of regional myocardial function that is site-specific and not influenced by the passive tethering effects that complicate visual wall motion analysis. Used in combination with low-dose DSE, strain and strain rate parameters have been shown to improve the accuracy of wall motion analysis alone for the assessment of viability and prediction of functional recovery.
Contrast enhancement at dyssynergic segments on MCE indicates intact coronary microvasculature as an essential prerequisite for myocardial viability. The presence of microvascular integrity alone, however, is not sufficient to predict functional recovery. MCE is therefore generally a sensitive but not specific tool to predict functional recovery and is perhaps best used in combination with DSE. Absence of contrast enhancement at MCE is indicative of myocardial scarring and predictive of LV remodelling.
Due to its availability, safety, relatively low costs and high accuracy, rest and stress echocardiography are indispensable tools in the assessment of myocardial viability.