Introduction

Debates are often used to highlight attributes and limitations of various diagnostic modalities in medicine. With this format, however, debaters may gravitate toward an extreme and unbalanced position, away from scientific facts and clinical realities. I accepted the invitation to debate the pro-MRI position on the assessment of myocardial viability with the intent to present a balanced point-of-view, especially that my own research has been focused on the use of PET for evaluating myocardial viability.

Rational management of patients with coronary artery disease (CAD) and poor left ventricular (LV) function relies on proper identification of the subgroup at high risk and those who have the highest potential of benefiting from a particular type of treatment. Before the advent of imaging techniques to determine myocardial viability, many patients with CAD and low ejection fractions (EFs) were relegated to medical therapy. It is now well recognized that patients with CAD and LV dysfunction have a high but variable mortality rate while receiving medical therapy. Many of these patients who have intractable heart failure are considered candidates for cardiac transplantation. Despite favorable survival after cardiac transplantation, this procedure cannot be performed in many heart failure patients who are potentially eligible because of the shortage of donor hearts, limited number of qualified transplant centers, and the expense of the procedure. In many patients with heart failure, LV dysfunction is reversible after myocardial revascularization.

The potential for recovery of LV dysfunction after myocardial revascularization represents a practical clinical definition for myocardial viability. Two myocardial viability patterns have emerged as the most common conditions associated with chronic dysfunctional myocardium with the potential for recovery of dysfunction after revascularization: hibernating myocardium and repetitively stunned myocardium. The classic definition of hibernation postulated that myocardial function is reduced to match chronic and severe reduction of resting myocardial blood flow.1 More recent evidence that resting perfusion is not always significantly reduced in areas of hibernating myocardium,2 lead to the stipulation that repetitive stunning caused by repeated ischemic episodes may result in chronic LV dysfunction.2

MRI vs. PET: Technical Aspects

Technical aspects of MRI and PET are summarized and compared in Table 1. MRI is not associated with radiation exposure to the patient. Its inherent resolution is 1-2 mm in the imaging plane with slice thickness of about 4 mm. Contrast-enhanced MR imaging protocol consists of a bolus, intravenous injection of 0.1 to 0.2 mmol · kg−1 of Gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), and imaging in approximately 20 min, using inversion-recovery-prepared T-1 weighted gradient echo pulse sequences. Image acquisition may be very fast, using a single or repeated breath-hold. At the time of delayed imaging, Gd-DTPA is accumulated and retained in the infarcted tissue, but washes out of the normal myocardium, resulting in delayed enhancement of the acutely infarcted myocardium or chronic scar tissue.3-11 Due to its high resolution, MRI allows visualization of small subendocardial myocardial infarctions that may be missed by SPECT. In a study of 91 patients with suspected or known coronary artery disease,12 MRI identified 100 of the 109 segments (92%) with subendocardial infarction (<50% transmural extent of the left-ventricular wall), whereas SPECT identified only 31 (28%). On a per patient basis, six (13%) individuals with subendocardial infarcts visible by MRI had no evidence of infarction by SPECT. Although MRI and PET have not been systematically compared for detection of subendocardial myocardial infarction, it is reasonable to assume that MRI is superior to PET in this regard. Nevertheless, as patients with no evidence of infarction by nuclear imaging methods have excellent prognosis, the clinical significance of small subendocardial infarctions that are detected by MRI and missed by PET is unclear.

Table 1 Comparison of technical aspects of MRI and PET for assessment of myocardial viability
Full size table

Concern for contrast-induced nephropathy existed with gadolinium-contrast as its hyperosmolarity and renal excretion via glomerular filtration were similar to iodinated radiocontrast.13 Although early studies in low risk patients suggested a benign renal profile, recent studies raise the possibility of nephrotoxicity. In addition, reports of a previously rare condition entitled nephrogenic systemic fibrosis (NSF) have recently emerged in patients with advanced kidney disease and have been linked to exposure to gadolinium-contrast.12 Nephrogenic systemic fibrosis is a debilitating disorder in which progressive and severe fibrosis of the skin and other systemic organs that leads to significant disability and is associated with increased mortality. Initially reported most commonly in end stage renal disease (ESRD) patients receiving dialysis, it is also described in patients with severe acute kidney injury (AKI) and advanced chronic kidney disease (stages 4 and 5) not requiring dialysis. In addition to underlying kidney disease, the risk of developing NSF is increased with larger doses of gadolinium (or multiple exposures), exposure to specific gadolinium chelates (non-ionic, linear), underlying pro-inflammatory states (in particular vascular endothelial dysfunction), and perhaps some currently unrecognized cofactors. Avoidance of gadolinium exposure appears to be the best approach for patients who maintain risk factors.

PET imaging of myocardial viability is based on imaging both myocardial perfusion and FDG uptake using two separate tracer injections and imaging. Myocardial perfusion may be imaged at rest or both at rest and during pharmacologic stress, using a PET perfusion tracer such as N-13 ammonia, Rubidium-82, or O-15 water. Alternatively, myocardial perfusion may be imaged using a Tc-99m labeled perfusion tracer (such as Tc-99m sestamibi or Tc-99m tetrofosmin) and SPECT imaging. Depending on the tracer that is used, the perfusion imaging protocol may be as short as 10 minutes (for resting Rb-82 imaging) or as long as about one hour (for rest-stress N-13 ammonia imaging). The protocol for FDG imaging is not always straightforward, especially in patients with diabetes mellitus (DM) because of poor uptake of FDG.14-16 Generally, three different protocols have been used: (1) the standard protocol, consisting of oral glucose loading or a supplemental insulin bolus based on fasting glucose; (2) the niacin protocol, consisting of pretreatment with niacin to lower free fatty acids; and (3) the insulin clamp protocol, consisting of hyperinsulinemic euglycemic clamp. In a study by Vitale et al,16 these three protocols were compared in 10 patients with non-insulin dependent DM, CAD, and severe LV dysfunction. The results demonstrated that the hyperinsulinemic euglycemic clamp yielded the highest FDG PET image quality, however, larger clinical trials are needed to assess whether accuracy is greater with this approach.

MRI and PET Patterns of Myocardial Viability

Table 2 outlines the underlying etiologies for myocardial contractile dysfunction and criteria that are used by PET17-19 and contrast enhancement (CE) MRI20-24 for assessing these conditions. In transmural or near transmural myocardial infarction, matched reduction (>50% normal) of perfusion and FDG uptake are noted. Similarly, with MRI contrast enhancement of >50% of myocardial wall thickness is present. In non-transmural myocardial infarction, matched reduction of ≤50% is noted on the perfusion and FDG images and MRI contrast enhancement involves ≤50% of myocardial wall thickness. In hibernating myocardium, PET shows the distinct pattern of mismatch (reduced perfusion and normal or near normal FDG uptake) and with MRI there is no contrast enhancement. In repetitively stunned myocardium, myocardial perfusion is normal or near normal and FDG uptake is normal. There is no MR contrast enhancement in this condition. In nonischemic myopathy, PET and MR show either a normal pattern or patchy pattern of perfusion-FDG and contrast enhancement. Of these conditions, only hibernating and repetitively stunned myocardium are associated with improvement of contractile dysfunction following revascularization.

Table 2 Different patterns of myocardial viability by MRI CE and PET
Full size table

MRI vs. PET: Clinical Efficacy

Prediction of Recovery of Function After Revascularization

Several studies have evaluated the positive and negative predictive values (PPV and NPV) of transmural extent of MRI delayed enhancement for prediction of recovery of function after revascularization 20-24. In the initial study of Kim et al,20 the likelihood of improvement in regional contractility after revascularization decreased progressively as the transmural extent of hyperenhancement (TEH) before revascularization increased. Re-analysis of their data shows that after revascularization, contractility did not improve (NPV) in 92% (168/182) of dysfunctional segments with >50% TEH, while it improved (PPV) in 66% (410/622) of dysfunctional segments with ≤50% TEH. Similarly, in the study of Selvanayagam et al,21 NPV and PPV for MRI-delayed enhancement were 81% (71/88 segments) and 62% (326/524 segments). Van Hoe et al,22 using 75% criterion for transmural extent of delayed enhancement, reported that NPV of MRI was 92% (22/24) and PPV was 75% (70/93). These studies20-22 have consistently shown that the PPV of delayed enhancement is lower than its NPV (Figure 1). Importantly, PPV is even lower when segments with no enhancement are excluded from analysis. Using this analysis, PPV were, respectively, 53% (155/293), 51% (170/334), and 44% (14/32) in the studies of Kim et al,20 Selvanayagam et al,21 and Van Hoe et al.22

Figure 1
figure 1

Average positive and negative predictive values of contrast-enhanced MRI for assessment of myocardial viability, derived from three studies.20-22 PPV, Positive predictive value; NPV, negative predictive value

Full size image

Kuhl et al23 compared MRI and PET/SPECT in 29 patients with ischemic cardiomyopathy. The PPV was identical for both techniques (73%). However, MRI achieved a higher NPV (93%) as compared to PET/SPECT (77%). Lauerma et al,24 comparing MRI and PET FDG, showed that sensitivity of MRI late enhancement was lower than FDG PET (62% vs. 81%), but specificities were comparable (84% vs. 86%). PPV and NPV, however, cannot be calculated from the presented data in this report, to allow comparison to the above-mentioned studies.

Possible explanation for relatively lower PPV of MRI for assessment of myocardial viability is shown in Figure 2. In dysfunctional myocardial segments with ≤50% transmural extent of MRI delayed enhancement, nontransmural myocardial infarction is present either alone or combined with hibernating myocardium. In the former condition, recovery of function following revascularization is not expected. Since MRI does not distinguish these two conditions from one another, its PPV is adversely affected. PET, however, does distinguish these two conditions from one another (resulting in improved PPV) by demonstrating the mismatch pattern in hibernating myocardium.

MRI is superior to PET in assessing myocardial viability in thinned out myocardial regions (Figure 3). Significant thinning of viable myocardium reduces the apparent regional FDG uptake due to partial volume effect, resulting in a false negative PET finding. The diagnostic accuracy of MRI, however, is preserved in thinned out myocardium, because the appearance of contrast enhancement is not adversely affected.

Figure 2
figure 2

Possible explanation for superiority of PET for assessment of myocardial viability in myocardial segments with ≤50% transmural extent of MRI-delayed enhancement. Please see text for details

Full size image
Figure 3
figure 3

Discrepancy between MRI and PET for assessment of thinned out, hibernating myocardium (Kuhl et al23). Contrast-enhanced cardiac MR (ce-CMR) image shows thinned out anterior and apical myocardial walls without contrast enhancement, indicating presence of viable, hibernating myocardium. This is confirmed by significant improvement in thickening and motion of the anterior wall and apex from pre- to post-revascularization. SPECT perfusion-PET FDG images, however, did not demonstrate evidence of viability due to matched, >50% reduction of perfusion and metabolism (FDG uptake). When the viable, but hibernating myocardium is thin, FDG uptake appears significantly reduced due to partial volume effect

Full size image

Additional Factors that Influence Heart Failure Response to Revascularization

It has been shown that in addition to myocardial viability, other factors may influence recovery of LV dysfunction after revascularization. These factors include LV size, LVEF, presence and extent of stress-induced ischemia (jeopardized myocardium), and presence of valvular regurgitation. MRI is uniquely suited for evaluation of concomitant valvular regurgitation, but the other factors may be assessed equally well by both modalities.

Prognostic Information

While the prognostic value of PET in predicting outcomes in patients with LV dysfunction is well documented in several studies,17-19,25-31 limited data are available for MRI in this regard. Wu et al32 showed that in patients with acute MI the extent of delayed enhancement was associated with an increased risk of adverse cardiovascular events during follow-up. In other studies, the extent of delayed enhancement predicted death better than LV size or ejection fraction33 or was associated with inducible ventricular tachycardia on electrophysiologic testing.34

Application in Special Populations

As summarized in Table 3, MRI method is not suitable for critically ill patients and those with a cardiac pacemaker. In addition, a certain percentage of patients may not tolerate the procedure due to claustrophobia. The PET technique, on the other hand, is suboptimal in patients with DM.

Table 3 Comparison of clinical efficacies of MRI and PET imaging for assessment of myocardial viability
Full size table

Summary

Proper selection of MRI vs. PET for assessment of myocardial viability in a given clinical scenario is significantly enhanced by full knowledge of advantages and limitations of these two modalities. Tables 4 and 5 summarize these features and are intended to provide a balanced point-of-view and help clinicians in selection of the right modality for the right patient.

Table 4 Advantages of MRI vs. PET for assessment of myocardial viability
Full size table
Table 5 Limitations of MRI vs. PET for assessment of myocardial viability
Full size table