CLINICAL NUCLEAR CARDIOLOGY CASE HISTORY AND QUESTIONS
MYOCARDIAL VIABILITY
Clinical history
A 75 year old hypertensive female with angina pectoris presented in July 1997 with unstable angina and CHF.
Labs
- The resting ECG showed anterolateral T-wave abnormalities (see Figure 1).
Figure 1 (Click to enlarge)
- A cardiac catheterization showed a 90% mid LAD stenosis with dyskinetic anterior and apical walls. As well, there was a 70% stenosis in a large OM branch of the left circumflex (see Figure 2 and video clip 1).
Figure 2 (click to enlarge)
The LVEF was estimated to be 30-35%.
The patient underwent an IV Dipyridamole TL-201 stress test with limited exercise. She developed dyspnea, hypotension, and 1.5 mm horizontal ST depression in CC5. The scintigraphic findings are given in Figure 3.
Figure 3 (click to enlarge)
The patient went on to have a 2 vessel CABG operation. See the echocardiogram (figure 4) for the degree of LV function recovery.
Questions
1. What clinical clues suggest that this patient has substantial dysfunctional-viable myocardium?
2. Detail the scintigraphic findings.
3. Do you predict an improvement in regional and/or global left ventricular function with successful revascularization of the LAD? Support your prediction.
4. Define myocardial hibernation and stunning.
5. What is the rationale for myocardial viability testing in patients with
coronary disease and severely reduced left ventricular systolic
function?
6. Detail the techniques for myocardial viability testing with Thallium - 201. Include in your discussion:
- (a) the stress - redistribution re-injection technique
- (b) the rest redistribution technique
- (c) definition of significant myocardial viability of a dysfunctional myocardial segment
- (d) conditions in which stress-redistribution re-injection is favored over rest - redistribution and vice versa
- (e) what is the accuracy of thallium - 201 imaging in predicting recovery of dysfunctional myocardial segments after revascularization
- (f) what is the data supporting the clinical utility of revascularizing dysfunctional viable myocardium once identified by TL-201 scintigraphy.
7. Detail the techniques for myocardial viability testing with TC-99m sestamibi. Include in your discussion (a) a description of the basic stress - rest 2 day protocol and rest-stress 1 day protocol (b) a description of the gated -SPECT protocol including acquisition parameters, theory behind myocardial thickening assessment, quantification of global and regional wall motion and regional wall thickening (c) clinical utility of gated SPECT in providing supplementary information about myocardial viability (d) definition of significant myocardial viability of a dysfunctional myocardial segment utilizing sestamibi (e) accuracy of sestamibi in predicting recovery of dysfunctional myocardial segments after revascularization .
8. Discuss the utility of positron imaging with F-18 deoxyglucose for detection of myocardial viability: (a) biochemical rationale for using this agent to detect hibernating myocardium (b) protocol for F-18 deoxyglucose myocardial imaging (c) definition of significant myocardial viability of a dysfunctional myocardial segment (d) accuracy of F-18 deoxyglucose PET imaging in predicting recovery of dysfunctional myocardial segments with revascularization (e) data supporting the utility of levascularizing dysfunctional viable myocardium identified by F-18 deoxyglucose imaging.
9. Compare the relative accuracies of TL-201, Sestamibi, FDG and low-dose dobutamine echocardiography in predicting the recovery of dysfunctional myocardium with revascularization. In your discussion, describe the low dose dobutamine echocardiography protocol, its strengths and weaknesses.
Answers
1. Chronic stable angina, unstable angina prior to presentation, the absence of a previous or present MI and the absence of Q waves on the electrocardiogram are clues for the presence of myocardial viability.
2. There is a severe defect involving the anterior, apical and apical inferior wall with partial reversibility on delayed imaging after re-injection. There is also a moderately severe defect involving the lateral wall with nearly complete reversibility on delayed imaging after re-injection. There is transient cavity dilatation.
Conclusion: A moderate degree of reversible ischemia involving a moderately large part of the LAD territory probably superimposed on a prior anteroapical infarction. Also, severe reversible ischemia involving a moderately large part of the left circumflex vascular territory.
3. The final anteroapical uptake on delayed imaging is under 50% of maximal TL-201 uptake. Nevertheless, the major redistribution between stress and delayed imaging in this territory does predict that the corresponding dysfunctional myocardium will recover with LAD revascularization.
4. Stunning: A process of myocardial injury in which blood flow is restored to previously ischemic myocardium. It represents blood-flow contraction mismatch, in that blood flow is restored, yet contractile dysfunction is present and may persist for several days to weeks before function returns spontaneously to normal.
Hibernating: Chronic reversible left ventricular dysfunction due to coronary heart disease which responds positively to inotropes. Resting coronary blood flow need not be reduced. However, there must be a reduction in coronary flow reserve in order for there to be repeated bout of ischemia and stunning resulting in hibernating myocardium.
5. The aim is to identify those patients in whom revascularization is likely to improve functional class, augment regional and global LVEF and increase survival. The identification of large areas of dysfunctional but viable myocardium predicts these beneficial effects. Conversely, the presence of predominant myocardial scarring predicts increased operative mortality and the absence of these salutary effects.
6. The initial uptake, or extraction, of thallium in cardiac myocytes is directly proportional to regional blood flow. Thallium is retained in the myocyte so long as sarcolemnal integrity and metabolic function remain intact. Over the ensuing hours, a process of exchange of thallium between the viable cells and the intravascular space goes on. Initially, hypoperfused areas have slower clearance of thallium compared to initially normal perfused areas. This results in the phenomenon of redistribution. Redistribution is defined as improvement or normalization of ischemic thallium perfusion defects with time. The presence of redistribution is a marker for myocardial ischemia and viability. On stress-redistribution imaging, fixed thallium defects were formerly equated with myocardial scarring. However many of these "irreversible" defects did show improvement after revascularization. Thus, in patients with LV dysfunction, stress-redistribution thallium scintigraphy frequently underestimates the presence of viable myocardium and the potential for recovery.
- a) The re-injection of a small dose of thallium immediately after redistribution imaging increases the intravascular concentration of thallium to allow more exchange between the myocyte and the intravascular space and provide uptake into regions with more severely reduced blood flow. Approximately 25 – 50% of irreversible thallium defects on stress – 4 hour redistribution imaging show reversibility after reinjection. The large majority of these regions with enhanced uptake after re-injection show improved testing LV function with revascularization. If one chooses to omit the 4 hour redistribution image and only image after re-injection, one must be aware that 10% of defects which would have shown redistribution on conventional delayed imaging fail to do so on re-injection imaging. This is caused by a low differential uptake of reinjected tracer in that segment. Differential uptake is defined as the magnitude of regional TL-201 uptake relative to a normal reference region. Presumably a very tight stenosis or occlusion severely limits the uptake of the thallium re-injected at rest to the corresponding segment resulting in an apparent worsening in the defect appearance. For this reason, one cannot simply do a stress and reinjection image in all cases. If a region doesn’t demonstrate significant viability after stress-reinjection, a delayed (24 hour) redistribution should be performed to determine whether the viability of the region is unmasked.
- b) The rest redistribution technique involves the administration of thallium under basal resting conditions with imaging 10-15 minutes after an then again 3-4 hours later. This protocol also provides strong information on myocardial viability.
- c) Myocardial viability of a dysfunction myocardial segment is defined quantitatively as greater than 50% of peak segmental myocardial thallium – 201 uptake. However, it must be recognized that thallium –201 % myocardial uptake is really a continuum . The greater the % myocardium uptake above 50 – 60%, the greater the positive predictive value for recovery of function. The lower the % myocardial uptake below 40% the higher the negative predictive value for regional recovery of function. It should also be accepted that clear-cut redistribution on a stress-redistribution-reinjection protocol (or a rest redistribution protocol) is another manner for viability even if the final % myocardial uptake fails to exceed 50%. This is because severe ischemia and/or low thallium blood levels can impair the redistribution process enough to prevent the final % myocardial uptake to rise above 50%.
- d) The major advantage of the stress-redistribution-reinjection protocol is that it answer the clinical question of myocardial ischemia and viability. The rest-redistribution technique pertains to the presence or absence of myocardial viability only. There also may be circumstances when the rest-redistribution study shows insignificant myocardial viability while the stress-redistribution-reinjection protocol brings it out. For example, if there is a critical stenosis limiting resting flow, there may be a moderately severe fixed defect in the rest-rest protocol suggesting non-viability. However, the stress-redistribution-reinjection protocol will rightly portray the presence of myocardial viability through the development of ischemia manifesting as a redistribution defect. Thus, the stress-redistribution-reinjection protocol should be favoured unless the patient is too unstable to have exercise or pharmacological stress.
- e) Both stress-redistribution-reinjection and rest-redistribution protocols have a limited positive predictive value for predicting regional recovery of myocardial function in the order of 65-70%. Both protocols, however, have relatively high sensitivities for detection of regional recovery of function (as high as 90%). One reason for relatively low positive predictive value is that when the subendocardium is scarred, an improvement in perfusion of the subepicardium might not translate into an improvement in regional function. This is likely due to a teetering effect of improvement in global LVEF, the percentage of the total myocardium mass demonstrated to have underperfused but viable myocardium must exceed about 40%.
- f) Besides predicting recovery of regional function, thallium-201 myocardial scintigraphy can predict which patients with dysfunctional myocardium will do poorly with continued medical management and which patients are likely to do poorly with surgical management. There is suggestive (non-randomized evidence that patients with myocardial viability do better with surgical rather than medical therapy. Patients without significant residual myocardial viability tend to fare worse with surgical than with medical management.
7. The stress-rest 2-day protocol involves a 20-22 mCi injection of Tc-sestamibi following stress. Images are taken 30-60 minutes later. Twenty-four (24) hours later, another injection is given at rest followed by images 90 minutes later.
The stress-rest 1-day protocol involves a 8-10 mCi injection followed by images 90 min. later. Three (3) hours later, the patient is stressed, and a 22-3- mCI injection is given followed by another set of images.
When comparing sestamibi to thallium-201 images in chronically dysfunctional myocardium, the former appears to show a disadvantage due to more fixed defects than the latter. However, with quantitation of imaging and the acceptance of mild to moderate fixed defects as viable and more severe fixed defects as nonviable, the concordance between the two techniques is over 90%. Two studies showed that resting sestamibi uptake 1 hour after injection correlated very highly with redistribution TL-201 activity. Using a % of peak myocardial uptake of 50-60%, the positive predictive value for regional recovery of function is about 70% and the negative predictive value is 80 – 90%. There is suggestive evidence that nitrate administration prior to resting sestamibi injection does enhance the sensitivity of sestamibi imaging for the detection of reversible regional dysfunction. To date, no studies have been performed to assess the value of sestamibi imaging in predicting which patients with resting left ventricular dysfunction will have a better outcome with revascularization as opposed to medical therapy. It is hoped that like with PET and Th-201, evidence translate into higher event free survival with revascularization over medical therapy.
8. Utility of positron imaging with F-18 deoxyglucose for detection of myocardial viability.
- a. F-18 FDG is a metabolic marker for glucose uptake that competes with glucose for hexokinase and tracks transmembrane exchange for glucose. After phosphorylation by hexokinase into FDG-6 –phosphate, it cannot be metabolized any further. Thus, myocardial uptake with F-18-FDG reflects the overall rate of transmembrane exchange and phosphorylation of glucose. Because dephosphorylation rate of glucose is slow, F-18-FDG becomes essentially trapped in the myocardium, and measurement of uptake reflects regional glucose flux. In turn, this measure is a reflection of cell viability. In the fasting state under resting conditions, free fatty acids are the predominant source of energy and glucose follows in second place. During conditions of ischemia, the myocyte switches to glucose as its predominant source of energy. This forms the basis for the assessment of myocardial viability using 18FDG PET. Chronically dysfunctional but viable myocardium may contain truly hibernating or repeatedly stunned myocardium, or both. The concept of myocardial hibernation postulates down regulation of myocardial metabolism and function to match chronically reduced blood flow. 18FDG PET imaging should be able to identify these ischemic but viable regions by showing enhanced 18FDG uptake relative to flow. Also, in stunned myocardium, post-ischemic glucose utilization is enhanced. 18FDG PET should therefore reveal viable myocardium in chronic dysfunctional wall segment regardless of whether hibernation or stunning is responsible for the wall motion abnormality.
- b. To enhance 18FDG utilization and consequently visualization in the myocardium and oral glucose load or a euglycemic hyperinsulinemia pump technique is utilized. Next, 18FDG is injected intravenously 2 hours later. Myocardial blood flow is also examined by means of 13Nammonia or 15Owater or ribidium-82 or a single-photon emitting isotope (eg. Sestamibi).
- c. A myocardial region with normal 18FDG uptake and normal perfusion is classified as viable. A myocardial region is determined to have reversible left ventricular dysfunction and, hence, preserved viability when there is a mismatch between perfusion and FDG uptake. Patients who have this mismatch pattern will demonstrate a significant defect on the 13N-labeled ammonia perfusion scan but show normal or mildly decreased 18FDG uptake exceeding reduced perfusion (metabolism-perfusion mismatch). Regions with a concordant reduction in perfusion and FDG uptake (matched pattern) have predominantly myocardial scar as the cause of regional asynergy and are considered nonviable..
- d. The positive and negative accuracies for functional recovery are in the range of 80%. Of note, the intregration of all available information including PET, angiographic, and wall motion data, for the optimal selection of patients increases the accuracy of F-18-FDG to 88% positive predictive value and 86% negative predictive value (as shown by vom Dahl et al.)
- e. Studies by Tillisch et al. And Tamaki et al. Evaluated resting myocardial blood flow and metabolism before and after coronary revascularization. In these two (2) studies, pre-operative identification of enhanced F-18-FDG uptake relative to blood flow was associated with functional improvement in 78 to 85% or regions after revascularization. In patients demonstrating two (2) or more regions of flow-metabolism mismatch, LVEF improved from a mean of 30% before to 45% after bypass surgery. Di Carli et al. Showed that in patients with CAD and depressed LV function, the total extent of metabolism-perfusion mismatch correlated linearly with the percentage improvement in functional status after CABG surgery. Multiple studies have shown that patients with perfusion-metabolism mismatches have significantly lower cardiac mortality and coronary event rates when treated with surgical revascularization as opposed to with medical therapy. The overall conclusion is that 18FDG PET in combination with perfusion imaging is a powerful prognostic indicator in patients with CAD and LV dysfunction.
Dobutamine stress echocardiography for detection of myocardial hibernation is performed with a low dose (5-7.5mg/kg/min)- high dose (20-40 mg/kg/min) protocol. Atropine in doses of 0.25 mg to a total dose of 2 mg is administered intravenously as needed to augment the heart rate. Wall motion at rest, low dose and high dose dobutamine is scored 1 through 5, according to the 16 –segment model set by the American Society of Echocardiography.
Dysfunctional myocardium shows one of four characteristic responses to dobutamine: (1) a biphasic response, with augmentation of function at low dose followed by deterioration at higher doses. (2) a sustained response improvement at low dose that persisted or further improved at high dose. (3) no change. (4) worsening of function without contractile reserve. A biphasic response has the highest positive predictive value for recovery of function (72%) followed by worsening only (35%). Sustained improvement and the absence of augmentation of function with dobutamine showed poor predictive values of 15% and 13% respectively. Thus the presence of viability with ischemia appears to be the most predictive of functional recovery. The pattern of sustained improvement suggests the absence of ischemia even during stress. Therefore chronic resting ischemia or repetitive stress-induced ischemia are not the underlying mechanisms for resting dysfunction in pattern 2.
In general, measurement of contractile reserve with dobutamine stress echocardiography has less sensitivity but greater specificity than radionuclide perfusion imaging for predicting recovery of function after revascularization. The discrepancies between the two technologies are greatest when the amount of myocardial fibrosis is intermediate. Perhaps the end-point of improved post-revascularization resting contractile function is too restrictive. Other benefits besides improved resting function may be accompanied by revascularization including less ventricular remodeling less electrical instability and fewer coronary events.
Overall, the demonstration of substantial viable myocardium by dobutamine stress echocardiography, myocardial perfusion or metabolic imaging is a key prognostic factor in patients with CAD and resting LV dysfunction. The benefit from subsequent revascularization appears to be conclusive.
