Magnetic Resonance Imaging of Myocardial Viability

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CHAPTER 57 Magnetic Resonance Imaging of Myocardial Viability

Heart failure is a complex clinical syndrome with high hospitalization and mortality rates. The incidence of heart failure approaches 10 per 1000 in the population older than 65 years.¹ The most common etiology of heart failure in developed countries is coronary artery disease. In patients with left ventricular (LV) dysfunction, it is of great therapeutic and prognostic importance to differentiate irreversibly damaged scarred myocardium, dysfunctional but viable myocardium (hibernating or stunned), and LV dysfunction from causes not related to coronary artery disease. The assessment of myocardial viability is important to guide the management of patients with ischemic LV dysfunction when clinicians must weigh the risks and benefits of coronary revascularization in regard to the increased perioperative morbidity and mortality in this patient population.²^,³

The meta-analysis by Allman and colleagues ⁴ assessed the prognostic value of viability assessment across various nuclear and echocardiographic techniques. Determining the presence and extent of myocardial viability is crucial in guiding clinical decision making and influencing patient outcomes. Patients with significant viability assigned to be treated medically had higher rates of cardiac mortality (16% vs. 3.2 % per year) and nonfatal myocardial infarction (MI) (12.2% vs. 6 % per year) than patients who were assigned to undergo coronary revascularization. In patients without significant myocardial viability, there was no difference in annual mortality or nonfatal MI rates between coronary revascularization and medical therapy (7.7% vs. 6.2% and 10.2% vs. 8%).⁴ These findings underscore the importance of noninvasive assessment of viability in guiding appropriate treatment decision making.

VIABILITY DEFINITIONS

Dysfunctional but viable myocardium in patients with ischemic cardiomyopathy can be divided into two general categories: myocardial stunning and hibernation. These two processes likely coexist and lead to varying degrees of LV dysfunction depending on the severity of coronary stenosis, coronary vasomotor tone, hemodynamic states, and duration of ischemic episodes. Myocardial stunning is defined by nonpermanent contractile dysfunction resulting from transient ischemia without injury. Hibernation is a state of chronically impaired resting myocardial function resulting from reduced coronary blood flow.

Stunned and hibernating myocardium can benefit from restoration of blood supply. Rahimtoola ⁵ first reported the process of myocardial hibernation, and it was then observed that LV dysfunction resulting from myocardial hibernation is not an irreversible process. The process of myocardial hibernation is a dynamic process that involves a continuum of downregulation of myocyte metabolism, reduction in contractile elements, and dedifferentiation of myocardial cells with preserved cell membrane integrity. The following processes have been observed in hibernating myocardium: loss of sarcomeres, sarcoplasmic reticulum, and T tubules; intracellular buildup of glycogen; atrophic mitochondria; accumulation of extracellular matrix and fibrosis; and expression of fetal proteins.⁶

There are various noninvasive techniques to image myocardial viability. The traditional nuclear techniques include single photon emission computed tomography (SPECT) perfusion using thallium 201 or Tc 99m sestamibi or tetrofosmin radiotracers. The detection of viable myocardium with these radiotracers is based on the presence of intact cell membrane or intact mitochondria. ¹⁸FDG is used as a radiotracer in positron emission tomography (PET) or SPECT to detect preserved glucose metabolism in the myocytes. Echocardiography assesses myocardial contractile reserve with low-dose (5 to 15 µg/kg/min) dobutamine infusion. This chapter explores the role of MRI and CT in assessment of myocardial viability.

MAGNETIC RESONANCE IMAGING ASSESSMENT OF MYOCARDIAL VIABILITY

Several MRI techniques exist to assess myocardial viability. Common clinical techniques include assessment of LV end-diastolic wall thickness on resting cine MRI, myocardial contractile reserve and ischemia by dobutamine stress MRI (dobutamine MRI), and transmural extent of MI by contrast-enhanced myocardial delayed enhancement (MDE) imaging. Other MRI techniques, such as quantification of myocardial contractile reserve with MRI tagging ⁷^,⁸ and MR spectroscopy for assessment of high-energy phosphates metabolism (e.g., quantification of concentration and ratio of adenosine triphosphate and phosphocreatine using ³¹P spectroscopy within a small volume of myocardium), are currently not in wide clinical use and are beyond the scope of this chapter.⁹^,¹⁰

Wall Thickness

In the presence of extensive chronic MI, wall thinning develops in the infarct zone because of infarct resorption and fibrotic contracture. Although autopsy studies have shown that wall thinning is frequently associated with transmural scar,¹¹^,¹² end-diastolic wall thickness (EDWT) measured in millimeters has limited prediction for functional recovery after revascularization, which serves as the most common surrogate reference method for myocardial viability. Baer and coworkers¹³ compared resting MRI with ¹⁸FDG-PET in 35 patients. Regions with EDWT less than 5.5 mm had significantly reduced ¹⁸FDG uptake compared with regions with thickness 5.5 mm or greater that had preserved ¹⁸FDG uptake. The same investigators also tested the predictive value of EDWT for functional recovery after revascularization. A EDWT cutoff of 5.5 mm had 94% sensitivity, but only 52% specificity for predicting segmental functional recovery after revascularization.¹⁴

The low specificity of LV wall thinning can be attributed to the fact that myocardial segments even with preserved wall thickness can have substantial transmural scar. In addition, EDWT is a structural variable that does not assess physiologic response of the myocardium, and there is a wide variation of EDWT among individuals and among different myocardial segments in the same individual.¹⁵ Kim and Shah¹⁵ showed that regional wall thinning may occur early after MI even in the absence of transmural necrosis, and that the thinned myocardium can still improve its contractile function.

Dobutamine Magnetic Resonance Imaging Contractile Reserve

Improvement in wall thickening or contractile reserve in response to inotropic challenge such as a low-dose dobutamine infusion (5 to 15 µg/kg/min) has been well validated for assessment of myocardial viability in echocardiography and MRI literature.^14,¹⁶^–²⁰ There are several advantages of MRI over the conventional echocardiography for detecting contractile reserve. Widely used cine steady-state free precession provides excellent spatial resolution and tissue contrast between the blood pool and LV myocardium. In contrast to echocardiography, which is limited by acoustic windows, MRI is able to provide multiplanar image acquisition for improved volumetric coverage of the heart. The quantification of LV volumes, mass, and ejection fraction with MRI does not require any geometric assumptions and is highly reproducible.²¹

Schmidt and colleagues ²² assessed resting EDWT (5.5 mm cutoff), dobutamine-induced wall thickening of greater than 2 mm, and presence of normalized ¹⁸FDG uptake greater than 50% on PET in 40 patients with chronic MI to predict segmental functional recovery. The sensitivity and specificity for segmental functional recovery were 100% and 53% for resting EDWT 5.5 mm or greater alone, 96% and 87% for dobutamine-induced contractile reserve, and 100% and 73% for preserved ¹⁸FDG (>50%) uptake. These findings indicate that dichotomizing a threshold value of resting EDWT or ¹⁸FDG uptake is less accurate than the physiologic assessment of low-dose dobutamine challenge. This point is supported further by a study reported by Wellnhofer and associates,²⁰ which showed higher specificity of dobutamine MRI compared with transmural extent of late hyperenhancement on MDE imaging to predict functional recovery, especially with 1% to 74% transmural extent of late hyperenhancement.

Contractile response during low-dose dobutamine challenge is specific, yet is only moderately sensitive in detecting segmental viability. Kaandorp and coworkers ²³ reported a weighted mean sensitivity and specificity for predicting functional recovery of 73% and 83% after pooling nine previously published dobutamine MRI studies. The relatively low sensitivity of dobutamine MRI can be attributed to the fact that in the presence of severe coronary stenosis, viable myocardial segments fail to show augmentation of segmental thickening because of rapid development of ischemia even with low dobutamine doses. We choose to infuse low-dose dobutamine using 5-minute per stage protocol. This prolonged infusion allows building up of the inotropic effects of the dobutamine, and the resultant display of augmentation of segmental thickening may enhance the sensitivity in detection of segmental viability.

Hyperenhancement on Myocardial Delayed Enhancement Imaging

The basis for development of MDE imaging was an observation that the differential between normal and infarcted myocardium can be accentuated by the use of gadolinium-chelate contrast agents on T1-weighted images.²⁴ Gadolinium shortens the T1 relaxation time of tissues with increased gadolinium content. Nevertheless, the limitation in image quality had restricted the clinical application of contrast-enhanced MRI until recent years. The proposed mechanism of hyperenhancement on MDE (also known as late gadolinium enhancement) is related to a relatively large molecular size of conventional extracellular gadolinium-chelate contrast agents that is made metabolically inert by the chelation and unable to cross the cell membrane of a normal myocyte. When the cell membrane is damaged (e.g., acute MI), or if there is an increase in the extracellular space between myocytes (e.g., acute interstitial edema or chronic fibrosis), there is accumulation of gadolinium-chelate contrast agent in the extracellular space, and its washout is delayed after the injection (Fig. 57-1).

FIGURE 57-1 Diagram of potential mechanisms for hyperenhancement on MDE MRI. The actual mechanisms for hyperenhancement on MDE imaging have yet to be determined. Differing theories have been proposed, however, for hyperenhancement that is noted clinically in acute versus chronic MI. A, In healthy myocardium, intact cell membranes preclude gadolinium-chelate contrast medium (Gd) from entering the otherwise tightly arranged myocytes, and Gd remains primarily extracellular in the interstitial space. Normally, there is no significant Gd retention on delayed imaging, and myocardial signal is typically homogeneously nulled on MDE imaging. B, With acute MI, myocyte cell membranes rupture, enabling the intracellular entry of Gd into the swollen myocytes, resulting in an increased concentration of Gd and hyperenhancement on MDE imaging. The concomitant edema and increase in interstitial space associated with acute MI may also contribute to the retention of interstitial Gd and hyperenhancement. C, With chronic MI, myocardial scarring occurs. Myocytes are replaced with collagen matrix and an increased interstitial space, which has been proposed as the underlying cause for an increased concentration of Gd and hyperenhancement on delayed imaging.

Areas of abnormal myocardium (e.g., infarcted, fibrotic, inflamed, or infiltrated myocardium) have elevated per-voxel gadolinium concentration and have a brighter signal (i.e., hyperenhancement) relative to normally enhancing myocardium, which appears nulled (i.e., dark) on the T1-weighted inversion recovery imaging sequence used for MDE imaging.²⁵ Using this technique in a clinical setting of coronary artery disease, dysfunctional myocardium with normal nulled signal intensity suggests myocardial stunning or hibernation. In acute or chronic MI, myocardial hyperenhancement characteristically involves the subendocardium or progresses to involve the entire transmural extent in myocardial segments subtended by a coronary arterial territory (Fig. 57-2). Apart from illustration of myocardial hyperenhancement consistent with MI, other specific patterns of hyperenhancement (mid-wall, epicardial, focal, or diffuse) can also provide potential differentiation of other etiologies of cardiomyopathy, such as myocarditis, nonischemic idiopathic dilated cardiomyopathy, cardiac sarcoidosis, cardiac amyloidosis, or endomyocardial fibrosis (Fig. 57-3).²⁶

FIGURE 57-2 Hyperenhancement on MDE using MRI in four different patients. A-C, Transmural hyperenhancement (arrows) represents significant MI with little viable myocardium (A, inferior wall MI; B, inferior and inferoseptal wall MI; C, apical MI). D, Less severe hyperenhancement (arrows) limited to the subendocardium (anteroseptal, anterior, and anterolateral MI)—that is, less than full thickness or transmural hyperenhancement—corresponds with residual viable myocardium in the affected regions that is represented by the proportion of normal (nonhyperenhancing) nulled or dark myocardium. Generally, the less transmurality of hyperenhancement (e.g. <25%) corresponds with higher likelihood for functional improvement after a myocardial revascularization procedure.

FIGURE 57-3 Patterns of hyperenhancement on MDE using MRI in four patients with nonischemic cardiomyopathy. A-D, Cardiac amyloidosis (A, diffuse subendocardial hyperenhancement [arrowheads]), hypertropic cardiomyopathy (B, mid-myocardial hyperenhancement [arrow]), myocarditis (C, subepicardial hyperenhancement [arrow]), and cardiac sarcoidosis (D, mid-myocardial hyperenhancement [arrows]). These patterns are distinct from the hyperenhancement of MI that is based primarily in the subendocardial region or subendocardium outward, a distribution consistent with the end-vessel territory of the coronary circulation.

Many animal and human studies have validated the use of this technique to detect the presence of or the extent of MI. Kim and colleagues ²⁷ used the inversion recovery MDE technique in 18 dogs with experimental MI and showed that MDE imaging accurately depicts the extent of histologically defined necrosis. The signal intensity of the infarcted myocardium was on average three to six times higher than the signal intensity of the normal myocardium during the acute and convalescence phases of infarction, allowing sensitive delineation of the transmural extent of myonecrosis. These authors also showed high agreement between the extent of scar tissue on MDE and histologic extent of necrosis across all time points during infarct healing (Fig. 57-4).²⁷

FIGURE 57-4 Comparison of ex vivo MR images with triphenyltetrazolium chloride–stained slices of the heart in an animal 3 days after infarct. Slices are arranged from base to apex starting at the top. On the right is a magnified view.

(From Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation 1999; 100:1992-2002.)

Kim and colleagues ²⁸ went on to study the use of gadolinium-enhanced MDE MRI in 50 patients with LV dysfunction before undergoing surgical or percutaneous revascularization. They showed that the likelihood of improvement in segmental myocardial contractility after revascularization decreased progressively with the increased transmural extent of the myocardial hyperenhancement on MDE (Fig. 57-5). The major advantage contrast-enhanced MDE MRI had over other imaging modalities is the ability to assess the presence of subendocardial micromyonecrosis and the transmural extent of MI because of the excellent spatial resolution of this technique (1 to 3 mm in-plane).

FIGURE 57-5 Relationship between the transmural extent of hyperenhancement on MDE imaging before revascularization and the likelihood of increased contractility after revascularization.

(From Kim RJ, Wu E, Rafael A, et al. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med 2000; 343:1445-1453.)

Ricciardi and associates ²⁹ studied a small group of patients without history of infarction who had elevated creatine kinase-MB enzyme after percutaneous coronary intervention. They found that MDE MRI detected discrete areas of myonecrosis that were not detected by cine wall motion imaging. Wagner and colleagues³⁰ compared the detection of MI by gadolinium-enhanced MDE MRI and SPECT in 12 dogs. Both imaging modalities detected all segments with greater than 75% transmural extent of MI. Gadolinium-enhanced MRI detected 92% of segments with less than 50% transmural infarction, whereas SPECT detected only 28% of those segments (Fig. 57-6).³⁰

FIGURE 57-6 Short-axis views from three dogs with subendocardial infarcts. From left to right, SPECT, MDE MRI, and histology with triphenyltetrazolium chloride staining.

(From Wagner A, Mahrholdt H, Holly TA, et al. Contrast-enhanced MRI and routine single photon emission computed tomography [SPECT] perfusion imaging for detection of subendocardial myocardial infarcts: an imaging study. Lancet 2003; 361:374-379.)

Klein and coworkers ³¹ directly compared MDE MRI with ¹⁸FDG-PET in 31 patients with severe LV dysfunction. They found that myocardial hyperenhancement on MDE imaging correlated well with areas of PET scar defined as matched decrease in perfusion and metabolism. Of segments defined as viable by PET, 11% showed some degree of subendocardial hyperenhancement, reflecting the stronger capability of MRI in detecting small subendocardial infarction than PET because of its higher spatial resolution.

COMPUTED TOMOGRAPHY FOR ASSESSMENT OF MYOCARDIAL VIABILITY

Multidetector CT is a noninvasive imaging technique primarily used for evaluation of coronary artery anatomy and coronary stenoses. Coronary multidetector CT provides a three-dimensional volumetric data set of the entire heart after injection of iodinated contrast medium, and the data can be reconstructed at multiple phases of the cardiac cycle, able to provide additional functional information, such as LV volumes, mass, and ejection fraction. In small pilot clinical studies, comparison with MRI showed a good correlation in measuring LV volumes and global LV ejection fraction.³²^,³³

Another emerging application of multidetector CT is evaluation of myocardial perfusion and viability. Similar to MRI, multidetector CT images are acquired during administration of an intravenous bolus of contrast agent. Similar to MRI first-pass perfusion technique, the hypoperfused areas on dynamic contrast-enhanced multidetector CT have lower attenuation compared with normally perfused myocardial segments.³⁴ Nieman and associates³⁵ investigated the ability of multidetector CT to differentiate recent and chronic MI based on CT attenuation measured in Hounsfield units (HU). Significantly lower CT attenuation values on the CT perfusion images were found in patients with long-standing MI (−13 ± 37 HU) than in patients with acute MI (26 ± 26 HU) or normal controls (73 ± 14 HU).

Using MDE multidetector CT in animal models of acute and chronic MI, Lardo and coworkers ³⁶ could identify the infarct size and its transmural extent when compared with histology (Fig. 57-7). The peak hyperenhancement of infarcted regions occurred approximately 5 minutes after contrast injection (see Fig. 57-7A1-A3). Acute and chronic infarcts by multidetector CT were characterized by hyperenhancement on MDE imaging, whereas regions of microvascular obstruction were characterized by hypoenhancement. Lessick and colleagues³⁷ evaluated sensitivity of myocardial early perfusion defects and late enhancement with multidetector CT in 26 patients with acute MI to predict myocardial functional recovery. They concluded that in segments abnormal at baseline, the lack of functional recovery was related to the presence and size of the defect on early perfusion and late enhancement.

FIGURE 57-7 A, Typical contrast-enhanced multidetector CT myocardial images: A1, at baseline (preinfarct) obtained 5 minutes after contrast agent administration; A2, postinfarct during first-pass contrast agent injection; and A3, postinfarct 5 minutes after contrast agent injection. The infarcted region is represented by subendocardial anterior hyperenhancing region (arrows). B, Multidetector CT and histopathologic staining comparison of infarct morphology: B1, reconstructed short-axis multidetector CT slice 5 minutes after contrast agent injection showing a large anterolateral infarct (hyperenhancing region) with discrete endocardial regions of microvascular obstruction (arrows); B2, triphenyltetrazolium chloride–stained slice; and B3, triphenyltetrazolium chloride and thioflavine S staining of the same slice confirming the size and location of the microvascular obstruction.

(From Lardo AC, Cordeiro MA, Silva C, et al. Contrast-enhanced multidetector computed tomography viability imaging after myocardial infarction: characterization of myocyte death, microvascular obstruction, and chronic scar. Circulation 2006; 113:394-404.)