Hibernating and Stunned Myocardium Imaging

Stunned myocardium is myocardium that suffers transient reversible myocardial contractile dysfunction that is caused by acute ischemia during which the blood supply is almost completely restored by reperfusion, with no metabolic deterioration. The term hibernating myocardium is also used to indicate chronic myocardial contractile dysfunction due to ischemia, in which there is reduced coronary blood flow at rest and increased myocardial demand results in impaired contractility. In hibernating myocardium, contractile function can be partially or totally restored by improving coronary blood flow or by reducing oxygen demand of the myocardium. ^{[1, 2, 3, 4]}

Myocardial ischemia is a clinical syndrome manifesting a variety of tissue effects and global cardiac effects that impair cardiac function. When ischemia is severe and prolonged, it causes myocyte death and results in loss of contractile function and tissue infarction. In cases of less severe ischemia, some myocytes remain viable but have depressed contractile function. Heyndrickx et al described a phenomenon of prolonged depression of regional function after a reversible episode of ischemia in dogs ^[5] ; this later came to be called myocardial stunning (see the image below). ^{[6, 7, 8, 9, 10, 11]}

Heyndrickx et al observed that after 5 minutes of occlusion in the left anterior descending coronary artery, surface electrocardiogram (ECG) findings and regional contraction (with reperfusion) rapidly normalized. When the hyperemic response subsided, regional contractile function was still depressed, and regional contractility recovered only after several hours. Recovery of myocardial contractile function after spontaneous restoration of flow may be protracted similarly after angioplasty or revascularization surgery. ^[5]

When ischemia is prolonged, myocytes have depressed contractile function but remain viable. This concept of an adaptive process that shuts down the contractile process and decreases myocardial oxygen demand in the presence of chronically or intermittently reduced blood flow has generated considerable interest in clinical and experimental settings.

The concomitant presence of myocardial necrosis with myocardial ischemia, stunning, or hibernation may complicate appraisal of left ventricular (LV) function and patient management. Several imaging modalities have been proposed for accurate assessment of myocardial necrosis, viability, stunning, and hibernation, with mixed results. ^[1]

Diamond et al found that resting wall motion abnormalities in patients with coronary artery diseases (CADs) improve after administration of an inotropic agent (dobutamine or epinephrine) or after coronary revascularization in some vascular territories with depressed contractile function, and that such territories eventually improve after revascularization. This finding shows that ischemic but noninfarcted myocardium can exist in a state of hibernation without cell death.

Rahimtoola suggested that hibernating myocardium is characterized by a state of persistently impaired myocardial and LV function at rest due to reduced coronary blood flow that can be partially or completely restored to normal by improving blood flow or by reducing oxygen demand (see the image below). ^[12]

Clinically, discerning the etiology of depressed myocardial contractile function is difficult, whether due to stunned myocardium, silent ischemia, or hibernating myocardium. Finding all 3 entities in the same patient with chronic myocardial dysfunction is not uncommon (see the image above). The critical difference is that blood flow is normal or near normal with stunning myocardium but is reduced in the other 2 conditions. Some authors have suggested that stunning myocardium, silent ischemia, and hibernating myocardium are processes by which the myocardium adapts to reduced myocardial oxygen supply to maintain cellular integrity. However, this theory has not been confirmed by animal and human experiments.

Mechanisms for myocardial stunning

Two major hypotheses have been proposed for myocardial stunning: (1) an oxygen-free radical hypothesis and (2) a calcium overload hypothesis. ^{[13, 14, 15, 16]} Postischemic dysfunction may be due to cytotoxic oxygen-derived free radicals (ie, hydroxyl radicals, superoxide anions) that are thought to be generated during occlusion or upon reperfusion. Such radicals cause lipid peroxidation, altering their function and structure.

Normal cardiac contraction depends on maintenance of calcium cycling and homeostasis across the mitochondrial membrane and the sarcoplasmic reticulum during each cardiac cycle. Brief ischemia followed by reperfusion damages Ca²⁺ pump and ion channels of the sarcoplasmic reticulum. This results in the electromechanical uncoupling of energy generation from contraction that characterizes myocardial stunning. Calcium accumulates in the cell at the time of reperfusion; this is followed by partial failure of normal beat-to-beat calcium cycling, which may occur at the level of the sarcoplasmic reticulum. This mechanism is proposed to account for contractile dysfunction. Structurally, myocytes in stunned myocardium appear normal when examined by light microscopy.

The appearance of glycogen vacuoles adjacent to mitochondria and of myofibrillary loss is noted in most cases of hibernating myocardium examined by electron microscopy. Several controversies regarding these histologic changes are ongoing. ^{[17, 18]}

Progression from chronic repetitive stunning to hibernation—a continuum

Several animal models have been proposed to demonstrate the physiologic significance of coronary stenosis, in which regulation of flow and downregulation of metabolism lead to hibernating myocardium. The key determinant of this adaptive process is a reduction in the coronary perfusion reserve, which results from critical coronary stenosis. Conti reported that the production of an acute and critical reduction in coronary flow reserve (CFR) in chronically instrumented pigs led to accelerated progression of chronic stunning proceeding to hibernation in less than 2 weeks. ^{[19, 20, 21, 22, 23, 24]}

The time frame for the transition from stunning to hibernation can be fairly short and is directly related to the degree of flow impairment in a stenotic coronary artery that supplies the dysfunctional segment. As the ischemic threshold is decreased with a reduction in CFR, repetitive stunning results in delayed recovery of function that becomes longer than the interval between ischemic episodes. The image below shows a schematic diagram of the potential mechanism of myocardial stunning. ^{[13, 14, 15]}

Several other groups have reported impaired coronary vasodilator reserve in chronically dysfunctional myocardium. Investigators have shown that in patients with coronary artery disease (CAD), flow reserve is decreased as the degree of stenosis is increased, and flow reserve is absent when stenoses account for 80% of luminal diameter. Progression of coronary stenosis to a critical limit and loss of CFR mean that subendocardial flow cannot accommodate the increasing demand, predisposing the myocardium to hibernation. Borderline impairment with frequent intermittent ischemia when demand is increased may suffice to cause hibernation. Certainly, chronic resting ischemia may cause hibernation.

For patients with severe CAD, limited flow reserve leads to development of myocardial ischemia even with a small increase in oxygen demand, as occurs with ordinary daily activities and exercise. Thus, intermittent episodes of ischemia and, consequently, postischemic stunning (which should occur frequently in patients with severe CAD) might play a role in the development of chronic reversible LV dysfunction. No available animal models can support this finding, however. Differentiating between subendocardial ischemia and hibernating myocardium can be difficult.

Collectively, these findings indicate that chronic repetitive ischemia that progresses to hibernating myocardium is associated with regional downregulation of the sarcoplasmic reticulum, with changes in calcium regulation and gene expression. These changes are accompanied by modest increases in myocyte apoptosis and a reduction in regional myocyte nuclear density. These same structural and functional findings occur in patients with dilated cardiomyopathy of ischemic origin.

Severe CAD involves a combination of repetitive episodes of stunning superimposed on chronic hibernation with repetitive thrombosis and clot lysis. Over time, this combination results in adaptive downregulation of the contractile machinery to salvage cell integrity (see the image above, panel D). The degree of regional LV dysfunction depends on the severity and the repetitive nature of ischemic episodes. This variability results in a continuum from healthy cardiac tissue with normal contractile function to tissue affected by ischemic episodes, to chronically ischemic tissue, and ultimately to infarcted tissue. Thus, reversible dysfunction of myocardium represents a range of tissue responses to repetitively inadequate supply, intermediate between preserved normal function and infarction.

Endocardial electromechanical mapping is a new modality that can be used to diagnose stunned myocardium by assessing the amplitude of endocardial electrical signals. ^[2]  Appraisal of myocardial necrosis and residual viability remains a cornerstone of the modern management of patients with CAD. Current imaging modalities (echocardiography, positron emission tomography [PET], single photon emission computed tomography [SPECT], and cardiac magnetic resonance [CMR]) are widely used. ^[1]

Hibernating myocardium is characterized by the following:

• Episodic and/or chronically reduced blood flow, which is directly responsible for decreased myocardial contractile function

• Tissue ischemia and resultant remodeling without necrosis, which cause prioritization of the metabolic process in the myocardial cell relative to contractile function

• Residual contractile reserve in response to inotropic stimulation (in at least half of clinical cases)

• Recovery of contractile function after successful revascularization

Hibernating myocardium is suspected in all patients with CAD and with moderate to severe chronic LV dysfunction. As many as 50% of patients with previous infarction may have areas of hibernating tissue mixed with scar tissue, even in the presence of Q waves on electrocardiography. Extent and severity of ventricular dysfunction can vary considerably. Hibernating myocardium may be limited to a discrete portion of ventricle with normal systolic function, or it may involve global impairment of LV function and may result in the clinical syndrome of heart failure. Thus, a clinical dilemma exists regarding attempted coronary artery bypass grafting (CABG) to restore global ventricular function versus orthotopic cardiac transplantation in high-risk patients. ^{[25, 26, 27, 28]}

Pathophysiologic mechanism of hibernating myocardium

Prolonged ischemia and myocardial infarction are followed by a series of dynamic processes that determine the fate of affected myocardium toward recovery or necrosis. Metabolic adaptations are believed to play a vital role in recovery of salvageable myocardium in the context of stunned and hibernating myocardium. ^[29]

Multiple cellular and animal models have been proposed, but most fall short of reproducing the clinical syndrome of hibernating myocardium. Arani et al infused soluble hydrogen gas in patients with collateral-dependent myocardium and complete occlusion of the left anterior descending artery with a distal collateral supply from the right coronary artery. Study findings suggest that coronary flow per unit weight is not maintained at usual basal values in densely collateralized myocardium that is totally collateral dependent. Reduction in flow presumably is associated with a marked reduction in local arterial pressure. ^[30]

The "smart heart" theory has postulated that reduced myocardial blood flow (MBF) at rest is responsible for myocytes switching to a state of hibernation; other theories suggest that reduced myocardial flow reserve (MFR) may be the cause. Benz and associates reported that In patients with ischemic cardiomyopathy, impaired MFR is associated with stunning and hibernation. These states of dysfunctional but viable myocardium show lower rest MBF compared with remote myocardium. At the end of the continuum, rest MBF is lowest in scar tissue, and this is linked to increased rates of tracer washout. ^[31]

Myocardial perfusion imaging is used to estimate MBF and metabolic activity. Several factors limit the use of thallium- and technetium-based agents to accurately quantify MBF. Positron emission tomography overcomes important limitations by providing attenuation correction, enabling quantification of the concentration of radiotracer in the organ of interest. Initial PET studies revealed that hibernating segments correspond to areas with qualitatively reduced perfusion, as assessed with ¹³N-labeled ammonia in the presence of preserved fluorodeoxyglucose (FDG) uptake. This resulted in the concept of perfusion and metabolism mismatch, in which flow is reduced but metabolic integrity is retained.

Investigators have concluded that in dysfunctional segments with a perfusion-metabolism mismatch, MBF is higher than in dysfunctional, nonviable segments but lower than in remote, normally contracting myocardium. Review of several studies has shown that in most cases, baseline blood flow to hibernating myocardium is within the range of values measured in the myocardium of healthy volunteers via PET. This discrepancy may be explained by insufficient accuracy of the PET measurement. Using a kinetic model with measurement of freely diffusible tracer in tissue provides a more accurate assessment of flow.

The H₂,¹⁵O technique provides flow per gram of perfused tissue. Because uptake of H₂,¹⁵O in scar tissue is negligible as compared to that in healthy myocardium, this value predominantly reflects flow to residual healthy myocardium in a myocardial region consisting of a mixture of viable and necrotic tissue. Ammonia N-13 (¹³NH₃) is used to measure the average flow per unit mass of tissue, as with the microsphere technique. Several studies of H₂ and ¹⁵O have revealed that MBF in dysfunctional segments was comparable to that in healthy segments.

In some cases, regional differences in flow are sustained, in part by higher perfusion in remote myocardium. Elevated perfusion may be triggered as a consequence of higher oxygen consumption. Compensatory changes in flow distribution may be responsible for an apparent reduction of tracer content in dysfunctional regions, which can be erroneously interpreted as an absolute flow reduction in the same segment. ^{[32, 33, 34, 35]}

Pathologic findings

Histologic specimens obtained at the time of surgery have revealed the following profound structural changes in dysfunctional but viable myocardium:

• Progressive loss of contractile protein (sarcomere) occurs without loss of cell volume. Depletion of sarcomeres is most prominent near the perinuclear region but may extend to the entire cell.

• Numerous small mitochondria can be found in areas adjacent to the glycogen-rich perinuclear zone.

• Nuclear heterochromatin is evenly distributed in the nucleoplasm.

• Substantial loss of sarcoplasmic reticulum occurs. The sarcoplasmic reticulum loses T-tubules and becomes disorganized.

• Primitive cytoskeleton proteins, including titin and cardiotin, have increased expression in hibernating myocyte cells.

Expression of primitive proteins suggests the occurrence of dedifferentiation of myocytes. ^{[17, 36, 37]}

A direct correlation exists between severity of these ultrastructural changes and the time course of functional recovery after revascularization. Cell dedifferentiation is reversible after restoration of blood flow with revascularization. Whether cell death occurs by means of apoptosis or necrosis is not known. Further investigation is needed.

Hibernating myocardium is suspected in all patients with CAD and chronic LV dysfunction ranging from regional dysfunction to ischemic cardiomyopathy. Extent and severity of LV dysfunction are not directly related to extent and severity of CAD. For many patients, preexisting collateral vessels and newly developed vessels in the coronary circulation can result in preservation of normal LV function despite the presence of CAD.

Hibernating myocardium is viable, and this viability can be assessed by a variety of imaging techniques that depict either the presence of myocardial tissue that contracts if stimulated appropriately or the persistence of metabolic activity within the region of dysfunctional myocardium. These modalities can be used to distinguish between myocardium with potential for improved function and myocardium with irreversible damage that does not improve after revascularization. Functional recovery after revascularization appears to vary greatly among studies, ranging from 24 to 84%. Specific findings with various methods are used to determine potential outcomes of revascularization procedures. Several groups have published data regarding predictions of recovery of myocardial dysfunction after revascularization. ^[38]

Current approaches for identifying viability in hibernating myocardium

The following can be used in assessment of perfusion, membrane integrity, and metabolism ^{[39, 40, 41]} :

• Regional perfusion testing: ²⁰¹Tl scintigraphy, ^99mTc-sestamibi (MIBI), ^99mTc-tetrafosmin ^{[42, 43]}

• PET: ⁸²Rb, ¹³NH₃, ¹⁸FDG, ¹⁴C-acetate

• MRI for assessment of regional perfusion and wall function

The following can be used in assessment of regional function:

• Nitroglycerin administration

• Post-extrasystolic potentiation (PESP)

• Low-dose catecholamine administration

• Echocardiography

• Exercise testing

Nuclear imaging to detect hibernating myocardium relies on demonstration of membrane integrity and/or metabolic activity within the hibernating myocardium. Myocardial retention of the potassium analog ²⁰¹Tl can be detected via SPECT. In healthy myocardium, thallium uptake initially is high but decreases rapidly within hours.

Normal thallium uptake levels with exercise and thallium defects that redistribute on images obtained after a 3-4 hour delay are accurate predictors of viable myocardium. However, absence or lack of thallium uptake does not necessarily indicate myocardial scarring, because severely ischemic but viable myocardium, as well as a mixture of scar and viable myocardium, may produce an "irreversible defect."

Gibson and associates found that 45% of segments with irreversible defects had improved thallium uptake after CABG. ^[44] About 25% of preoperatively akinetic and dyskinetic segments (as demonstrated by ²⁰¹Tl defects) showed improved perfusion. This finding contrasts with the finding of 75% postoperative improvement in healthy and hypokinetic segments.

Segments that are likely to improve have thallium activity that is more than 50% of the activity of healthy myocardium. Thus, standard redistribution images obtained after 3-4 hours may not help in differentiating hibernating myocardium from scarred myocardium. From 45 to 75% of persistent early defects exhibit normal perfusion after revascularization.

Reinjection or a 24-hour thallium protocol may reduce the false assessment of irreversible defects. From 31 to 52% of defects show improved ²⁰¹Tl uptake after tracer reinjection following stress using a smaller dose of ²⁰¹Tl (1 mCi). Some investigators recommend repeating images 24 hours after injection. However, a small number of segments (3-4%) show some degree of reversibility ^[45] (see the image below).

PET imaging

Positron emission tomography (PET) is often considered the gold standard for detection of viable myocardium. Early studies attempted to identify whether thallium using the standard stress-redistribution protocol overestimates the infarct and/or scar tissue. Study findings clearly indicate that oxidative metabolism is preserved in ischemic and hibernating myocardium, in which regional substrate utilization shifts from free fatty acids to glucose. ^{[46, 47, 48]}

Production of the glucose protein transporter (GLUT) protein is increased, as demonstrated by Schwaiger et al, as is expression of myocardial glucose transporter messenger RNA protein in patients with advanced CAD. ^[44] In turn, glucose utilization is influenced by several factors, including coronary perfusion, cardiac work, and insulin and hormonal effects. FDG is a glucose analog that is intracellularly phosphorylated to FDG-6-phosphate in the myocardium. Increased uptake of ¹⁸FDG in relation to perfusion or flow-metabolism mismatch is indicative of hibernating myocardium, whereas matched defects are indicative of scar tissue; values between these represent healthy myocardial tissue mixed with fibrosis. ^[49]

Preoperative measurement of regional flow and uptake of ¹⁸FDG can be used to accurately predict functional recovery after revascularization in patients with depressed ventricular function. The predictive accuracy achieved with PET images is comparable to that seen with thallium images, with a positive predictive value (PPV) of 80-87% and a negative predictive value (NPV) of 82-100%. When quantitative analysis is performed, thallium images obtained by the stress-redistribution-reinjection protocol are comparable to standard PET metabolic images, as confirmed by Tamaki et al. ^{[33, 34]}  Table 1 shows potential relationships between these measurements.

Table 1. Potential Relationship Between Regional Wall Motion, Blood Flow, and FDG Uptake (Open Table in a new window)

Three patterns of myocardial viability may occur with a PET perfusion-metabolism mismatch protocol. The perfusion-metabolism match pattern shows concordantly reduced, absent, or regional myocardial perfusion and FDG uptake. If severe, this implies transmural infarction and irreversible LV function. A pattern in which mild to moderate flow is matched to metabolism suggests the presence of both viable and nonviable tissue in a given region of myocardium. On the other hand, when regional myocardial FDG uptake is disproportionately enhanced compared to blood flow, the pattern is termed perfusion-metabolism mismatch. This pattern closely resembles that of hibernating myocardium.

Compared to thallium imaging, FDG-PET imaging provides better results for differentiation of viable myocardium from scarred myocardium. Brunken et al published data from a comparison of tomographic thallium images with PET images, in which 47% of irreversible thallium defects were identified as viable on PET images. ^[50]

Tamaki et al subsequently confirmed these findings in 2 comparative studies of SPECT and PET, in which 38-42% of irreversible thallium defects had enhanced FDG uptake suggestive of viable myocardium. ^{[33, 34]} Thus, conventional stress-redistribution ²⁰¹Tl imaging has low predictive value for identification of viable myocardium when compared to PET. Brunken et al found comparable results between resting thallium uptake and FDG-PET findings ^[50] (see the image below).

When these similarities are considered, either thallium protocol yields satisfactory information. Positron emission tomography does provide information about regional blood flow, and metabolic function is assessed independent of flow. Its higher cost and limited availability preclude its wide usage; however, approval of payment by the Health Care Financing Administration (HCFA) has rekindled interest in this imaging technique.

Hybrid positron emission tomography-magnetic resonance (PET-MR) enables comprehensive assessment of myocardial viability. Beitzke et al compared LV perfusion, hibernation, and scar burden to assess myocardial viability in ischemic heart disease. They reported that In patients with ischemic heart diseases, there was good correlation between PET and cardiac magnetic resonance (CMR) for LV scar extent using hybrid cardiac PET-MR. The authors suggested that cardiac PET-MR may be a suitable tool for comprehensive assessment of myocardial viability if used to predict response to cardiac reperfusion strategies. ^[51]

Thallium scintigraphy

Thallium scintigraphy involves stress early redistribution imaging, late redistribution imaging at 8-24 hours, reinjection imaging, and rest redistribution imaging. ^[52]

In hibernating myocardium, initial uptake is low but increases gradually; this phenomenon is related to ²⁰¹Tl redistribution. Regional thallium activity on early (at 3-4 hr) or late (at 8-72 hr) redistribution imaging obtained after stress has been used to identify the distribution of viable myocardial cells and the extent of myocardial fibrosis. Determining the severity of the defect in ²⁰¹Tl uptake after redistribution is important as well.

Several protocols, including reinjection, are used to assess myocardial function and viability. Yang et al and Kiat et al performed late imaging in 118 patients with CAD. ^{[53, 54]} In these studies, late distribution was observed in 53% of patients but was seen in only 22% of segments with 4-hour irreversible defect. A possible explanation for late redistribution may be that initial uptake of thallium during exercise is sufficiently reduced in certain ischemic myocardial regions, so that it continues to mimic the appearance of scarred myocardium on early 3-4 hour images. Therefore, if more time is allowed for redistribution, more viable segments are distinguished from scarred or fibrotic myocardium. Late thallium redistribution, when present, is an accurate indicator of viable myocardium. ^[55]

Kiat et al showed that 95% of segments with late redistribution improved with revascularization. ^[53] However, absence of thallium redistribution on late images remains an inaccurate marker for nonviability; 37% of segments that remained irreversible on images obtained at both 3-4 and 24 hours also improved after revascularization. This finding suggests that even after acquisition of late redistribution images, this measure continues to cause overestimation of the frequency and severity of myocardial scar tissue.

On the other hand, reinjection of additional thallium immediately after conventional 3-4 hour imaging significantly improves the detection of viable myocardium in 31-49% of regions that were interpreted as having an irreversible perfusion defect on conventional redistribution images. Available data suggest that thallium reinjection in otherwise irreversible defects can be used to predict improvement in regional function after revascularization, with a PPV of 80-87% and an NPV of 82-100%. Thus, thallium reinjection improves the detection of viable myocardium, as has been shown in several studies, even when regional quantitative analysis is used ^{[45, 56, 57, 58]} (see the image below).

Some laboratories started to use the stress-reinjection protocol instead of stress-redistribution reinjection and found that 25% of reversible segments were incorrectly identified as irreversible defects. This result was thought to be due to the phenomenon of differential uptake—low differential uptake of thallium after reinjection, which causes an appearance of persistent defect. Thus, data suggest that stress-redistribution reinjection or stress-reinjection-late redistribution (24 hr) techniques may yield comparable information for identifying most of the ischemic but viable myocardium.

Ragosta et al were the first to report that thallium perfusion defects may occur on resting images in patients with CAD in the absence of acute ischemic process or previous myocardial infarction. ^[59] Available data suggest that rest-redistribution thallium imaging depicts viable myocardium in most reversible regions but may cause underestimation of viable myocardium in as many as two thirds of irreversible regions.

Quantitative analysis improves the detection of viable myocardium. Findings from comparisons of stress-redistribution-reinjection and stress-reinjection–24-hour imaging may be used to assess the extent and severity of myocardial ischemia and viability. If the clinical question concerns viability, rest-redistribution or late-redistribution imaging is a good alternative in distinguishing viable from nonviable myocardium. Late redistribution of ²⁰¹Tl injected at rest occurs occasionally; only 3% of segments with initial thallium defects are considered viable, with late-redistribution images obtained 20-24 hours later. Late redistribution did not significantly improve the prediction of functional recovery after revascularization. Therefore, most clinically relevant information can be obtained via conventional rest-early redistribution imaging.

Dobutamine echocardiography

Several groups have investigated the role of dobutamine echocardiography in predicting outcomes after revascularization procedures for patients with severe chronic CAD and hibernating myocardium. ^{[17, 60, 61, 62, 63, 64, 65]} This noninvasive technique uses a progressively increasing dose of dobutamine, which first augments regional function and then induces ischemic wall motion abnormalities by increasing myocardial oxygen demand in the presence of coronary stenosis (see the image below).

However, the response to dobutamine is difficult to interpret because it is dependent on various factors such as extent of viable myocardium, severity of coronary stenosis responsible for the hibernating myocardium, and collateral circulation. Contractile response of viable myocardium to dobutamine is, again, dependent on several factors. ^{[13, 66, 67]}

Factors affecting contractile reserve in hibernating myocardium include the following:

• Amount of interstitial fibrosis (scar tissue) in the myocardium

• Sarcoplasmic reticulum function

• MBF at rest

• CFR

During dobutamine infusion, resting ventricle function shows one of the following responses ^{[62, 64]} :

• Biphasic response with improvement in wall motion at low doses and worsening at high doses (see the image below)

  Hibernating and stunned myocardium. Positron emission tomography depicts metabolic viability in myocardium with persistent 24-hour thallium-201 defects observed with single photon emission CT. (Adapted from Brunken et al. Circulation. 1992 Nov; 86[5]: 1357-69.)

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• Sustained improvement in wall motion at low doses, with further improvement at higher doses

• Worsening of resting wall motion without any improvement

• No change in wall motion during dobutamine echocardiography

Perrone-Filardi et al examined 18 patients with chronic CAD who were undergoing revascularization with 2-dimensional echocardiography and inotropic stimulation (dobutamine). During dobutamine infusion, none of the 79 hypoperfused dysfunctional segments showed further deterioration of function, whereas 46 (58%) dysfunctional segments functionally improved by at least 1 score grade. Functional improvement was observed in 35 hypokinetic segments that became normokinetic; of 11 akinetic segments, 4 became hypokinetic and 7 became normokinetic. The remaining 33 dysfunctional hypoperfused segments showed no functional recovery. Of 48 hypoperfused dysfunctional segments with improved function after revascularization, 42 (87%) also improved during dobutamine infusion, whereas 27 of 31 segments with unchanged function after revascularization did not improve during infusion. ^[63]

Sensitivity and specificity of the dobutamine infusion technique in identifying dysfunctional segments that are capable of recovering function after revascularization were 88% and 87%, respectively. Of 46 dysfunctional segments that improved during dobutamine infusion, 42 improved after revascularization, as opposed to 6 (18%) of 33 segments with no changes during infusion. Therefore, positive and negative accuracies in predicting functional improvement among dysfunctional hypoperfused segments after revascularization were 91% and 82%, respectively. Data suggest that most hypoperfused and dysfunctional segments are capable of improving function with inotropic stimulation. These myocardial segments have a functional and vasodilator reserve despite increased myocardial oxygen demand during inotropic stimulation. Notably, the dobutamine technique has lower sensitivity for predicting outcomes in segments that are akinetic preoperatively.

Afridi et al found similar results. They noted that the biphasic response during dobutamine infusion is a best predictor of improvement. Preinterventional identification of improved systolic wall thickening with inotropic stimulation (low-dose dobutamine) at echocardiography has been a preferred method. Viable myocardial segments thicken in response to dobutamine. With increasing doses of dobutamine, deterioration of functional wall thickening occurs, and akinesis and lack of synergy result in the so-called biphasic response, with a PPV of 83% and an NPV of 81%. The finding of a biphasic response had the highest predictive value for recovery. Researchers concluded that low- and high-dose dobutamine infusion are best in evaluating the need for optimal assessment of myocardial viability.

The major finding of all studies is that echocardiographic detection of contractile reserve during low-dose dobutamine infusion is a strong predictor of LV function after coronary revascularization. ^{[59, 60]}

Scognamiglio et al demonstrated that post-extrasystolic potentiation (PESP) is another sensitive method for predicting outcomes after revascularization. Specificities of the 2 methods are the same. PESP offers an advantage over dobutamine infusion in that it achieves maximal contractility without inducing ischemia. ^[68] . Table 2 shows the sensitivities and specificities of various techniques.

Table 2. Sensitivity and Specificity of Different Methods in the Detection of Hibernating Myocardium in Different Studies (Open Table in a new window)

Role of technetium-99m

Tc-99m-MIBI is only minimally redistributed and is not taken up by necrotic myocardium. Also, ^99mTc has a shorter half-life (half-life, 6 hr) than thallium (half-life, 2.8 days). Therefore, some have suggested that use of ^99mTc-MIBI causes underestimation of viable myocardium. However, when resting myocardial perfusion scintigraphy with ^99mTc-MIBI is combined with preinjection administration of nitroglycerin, this may be as effective as redistribution with ²⁰¹Tl. ^{[65, 69, 70, 71, 72]}

Prediction of functional recovery is based on semiquantitative analysis of residual MIBI uptake in dysfunctional segments compared to remote areas of high uptake. Uptake of 50-60% is used as the threshold for viable tissue. Udelson et al compared regional activities of ²⁰¹Tl and ^99mTc-MIBI after resting injection. They found that quantitative analysis of regional activities of both ²⁰¹Tl and ^99mTc-MIBI after resting injections can be used to differentiate viable from nonviable myocardium and that these 2 agents are comparable in predicting recovery of wall motion abnormalities after revascularization. ^{[73, 74]}

Other studies have reported a much lower correlation between the presence of a severe technetium defect and FDG uptake. Addition of ECG gating and evaluation of regional wall thickening have also been suggested as techniques to enhance the detection of viable myocardium (see the image below). As a result, thallium is preferred to technetium for determining the viability of myocardium. ^[75]

Similarly, low-dose dobutamine infusion with ^99mTc-MIBI SPECT has been shown to provide better accuracy for predicting functional recovery than rest SPECT. Thus, an optimal viability SPECT protocol consists of rest-redistribution ²⁰¹Tl imaging followed by nitroglycerin-augmented low-dose dobutamine ^99mTc-MIBI gated SPECT.

In an effort to evaluate the influence of SPECT attenuation correction on quantification of hibernating myocardium derived from perfusion SPECT and ¹⁸F-FDG PET, investigators studied 20 patients who underwent rest ^99mTc-tetrofosmin perfusion SPECT/CT and ¹⁸F-FDG PET/CT. Perfusion images were reconstructed without attenuation correction (NC); with attenuation correction based on computed tomography (CT) from SPECT/CT (AC_SPECT); and with attenuation correction based on CT from PET/CT (AC_PET). Study authors concluded that AC of SPECT perfusion scans with an attenuation map derived from PET/CT scans is feasible. If AC is unavailable, perfusion scans should be compared with NC normative databases for assessing total perfusion deficit (TPD), hibernation, and mismatch. ^[76]

Assessment of regional perfusion with perfusion MRI

Because of the noninvasive nature of magnetic resonance imaging (MRI), cine MRI (cMRI) of the heart, when available, is an excellent method of assessing regional wall motion. Baer and coworkers reported findings in 35 patients with myocardial infarction and regional akinesis or dyskinesis who underwent rest and dobutamine MRI, as well as FDG analysis. In this study, quantitative and functional MRI parameters (end-diastolic wall thickness at rest and dobutamine-induced systolic wall thickening, respectively) were studied as markers of myocardial viability and were compared with corresponding ¹⁸FDG uptake, as assessed by PET. ^{[77, 78, 79]}

Comparison of segmental MRI and FDG-PET results revealed that dobutamine-induced wall thickening was a better predictor of residual metabolic activity (sensitivity, 81%; specificity, 95%; PPV, 96%) than end-diastolic wall thickness (sensitivity, 72%; specificity, 89%; PPV, 91%). When both parameters were taken into account, the overall sensitivity of MRI improved to 88% for metabolic activity assessed at FDG-PET, without a major decrease in specificity (87%) nor in PPV (92%).

Pearlman et al used a porcine model to measure wall motion and wall thickening during the cardiac cycle. They used a serial motion assessment by reference tracking system (SMART) to analyze cardiac motion. This system increased the contrast between ischemic and normal values for wall motion and thickening change. It is twice as sensitive in detecting abnormalities of wall motion and thickening and is thus useful in differentiating ischemic myocardium from normal myocardium. However, additional studies are needed to validate this system for clinical evaluation (see the image below).

Kim et al reported results of delayed gadolinium enhancement with gated MRI for the diagnosis of hibernating myocardium. PPV and NPV were 71% and 79%, respectively, for kinetic and dyskinetic segments, but otherwise 88% and 89%. ^[78]

Gadolinium-based contrast agents have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). This disease has occurred in patients with moderate to end-stage renal disease after they were given a gadolinium-based contrast agent to enhance MRI or magnetic resonance angiography (MRA) scans. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

Summary

Bax et al performed a meta-analysis of various perfusion imaging and echocardiographic techniques and their usefulness in prediction of myocardial viability (see the image below). Data revealed that sensitivity in predicting improved regional contractile function after revascularization was high for all techniques analyzed; however, specificity varied greatly and was lowest for ²⁰¹Tl stress-redistribution and ²⁰¹Tl rest-redistribution imaging. ^[38]  Specificity was highest for low-dose dobutamine echocardiography (LDDE). Other data suggested that dobutamine MRI with SMART (serial motion assessment reference tracking) tagging and/or point trajectory assessment is most accurate because it provides better endocardial definition, has higher resolution, and corrects for tethering. Negative predictive value was highest for MRI or FDG-PET.

Preliminary data suggest that SMART-MRI may be more accurate. Thus, available evidence supports the use of LDDE as the first technique of choice for predicting regional functional recovery in patients with chronic ischemic LV dysfunction. ^{[38, 80, 81, 82, 83]}

Receiver operating characteristics (ROCs) evaluate the performance of different tests in terms of trade-off between sensitivity and specificity. The most useful methods have high area under the curve for true-positive fraction (sensitivity) versus false-positive fraction (1-specificity) (eg, 0.90-1.0). ROC data have shown fairly good ability to identify salvageable myocardium via FDG PET, dobutamine echocardiography, and nitroglycerin-enhanced ^99mTc-MIBI imaging.

Patients with CAD are often referred for revascularization because of angina or chronic ventricular dysfunction with viable myocardium. The most important benefit of revascularization is improvement of the global ejection fraction. This improvement is directly related to the number of dysfunctional but viable segments and is more obvious when functional response to exercise or dobutamine infusion is evaluated after treatment. The magnitude of improvement in symptoms of heart failure and in exercise capacity is proportionate to the mass of revascularized myocardium noted to be viable before surgery.

Results of the Coronary Artery Surgery Study (CASS), in which bypass surgery was compared with medical treatment, indicate that patients with multivessel disease and poor ventricular function benefited most from surgery in terms of survival. Revascularization improves the prognosis of patients with hibernating myocardium. Therefore, identification of patients with hibernating myocardium is vital to overall treatment of patients with coronary artery disease.

Evaluation before revascularization in patients with LV dysfunction includes the following:

• Assess the presence of available target vessels for bypass or angioplasty.

• Consider other risk factors for death after bypass surgery (eg, age, sex, comorbid condition, prior surgery, valvular disease).

• Consider hemodynamic support during angioplasty (use of an intra-aortic balloon pump or percutaneous circulatory assistance).

• Evaluate the extent of viable myocardium in the distribution of target vessels.

• If severe heart failure is present, consider use of a device to assist LV or cardiac transplantation.

Myocardial hibernation is an important and reversible cause of myocardial dysfunction in ischemic heart failure, promoting myocyte survival over contractile function. ^[84]  Hibernating myocardium is characterized by reduced regional contractile function and blood flow. Myocardial hibernation can be clinically identified with imaging techniques, and the myocardium recovers after reperfusion or revascularization. ^[3]

Stunned myocardium is characterized by a long-lasting, yet fully reversible, contractile dysfunction following brief myocardial ischemic events. Myocardial stunning is observed clinically and must be recognized, but it is rarely hemodynamically compromising. ^[3]

Study results have led to a paradigm for development of chronically reduced regional flow in viable dysfunctional myocardium. In this paradigm, repetitive episodes of ischemia lead to chronic myocardial stunning, in which resting flow is normal. With time and progression in the physiologic significance of coronary stenosis, regional downregulation in flow and function occurs. The key determinant of this adaptive response is the extent to which coronary flow during maximal vasodilatation (the CFR) is reduced. Thus, this conceptual framework links chronic stunning and chronic hibernation on a continuum. ^{[79, 85]}

Considering the frequency of ischemia and the prevalence of hibernating myocardium, recognition of hibernation and how it affects treatment is important. The mortality rate is higher in patients with hibernating myocardium who do not undergo revascularization (see the image below).

Accurate identification of patients with reversible LV dysfunction is important in clinical decision making. In clinical practice, several strategies are used for patients with severe LV dysfunction. Current analysis shows that FDG-PET has the highest sensitivity, followed by other nuclear techniques, and dobutamine echocardiography has the lowest sensitivity, except for MIBI imaging. The highest NPV has been observed with FDG-PET, followed by dobutamine echocardiography and other nuclear imaging techniques. Specificity has been highest with dobutamine echocardiography, followed by FDG-PET. The highest PPV has been observed with dobutamine echocardiography, followed by FDG-PET. Although not widely available, cardiac MRI offers even greater promise of high accuracy in identifying salvageable myocardium in terms of impaired contractility that can respond to inotropic stimulation. ^[77]

Issues such as ischemic symptoms, suitability of the coronary anatomy, severity of LV dysfunction, and presence or absence of inducible ischemia are determined before clinical decisions are made. Overall, identification of hibernating myocardium and prudent use of revascularization procedures have improved treatment outcomes in patients with this condition.