The Continuing Story of ²⁰¹Tl Reverse Redistribution: Reverse Redistribution Is Still Alive, but Is the Myocardium Still Viable?

Recent Revascularized Myocardial Infarction with Patent Coronary Artery

In this particular situation, RR is frequently observed soon after thrombolysis or direct percutaneous transluminal balloon angioplasty (3–6) and has been reported with either ²⁰¹Tl- or ^99mTc-labeled compounds (7,8). RR is common (approximately 80% of TIMI-3 patients (9)), marked, and related to vessel patency and restoration of adequate reperfusion. Some jeopardized myocardial cells in the reperfused area appear to be capable of a transient tracer uptake but not over several hours. Different hypotheses may be raised to explain this transient tracer uptake: metabolic stunning, impairment of membrane permeability to ions, postischemic alteration of water repartition within extracellular and intracellular compartments (3,10–13). Whatever the cellular mechanism is, the defect displayed on early images is smaller than the one seen on late images and is closely related to the restoration of the microvascular perfusion. Because these jeopardized cells will probably ultimately recover as adequate microvascular perfusion is restored, early images are associated with functional recovery. RR indicates indirectly that these myocytes are not injured definitively by the ischemic process (14,15). Conversely, when initial and late defects are similar and severe, the necrotic process is probably complete and the absence of myocardial viability may be dreaded. The size of this severe fixed defect is then a reliable indicator of the definitive infarct size and is related to left ventricular (LV) remodeling, as evidenced by the increase of the end-diastolic volume 4 wk after the acute phase (16). However, the major point is not that RR occurs and indicates indirectly myocardial viability but that early images reflect precisely myocardial salvage. In practice, if the prediction of myocardial viability and functional recovery is required after successful coronary reperfusion of recent myocardial infarction (MI), the extent of the defect and the tracer uptake must be quantified on early (stress or rest) images after injection and not on redistribution images.

Patients Referred for Positive Diagnosis of CAD or Patients With Known CAD But Without Previous MI

In this setting, the mechanism of RR is controversial. Poststress RR may indicate myocardial ischemia in patients with severe and extensive multivessel disease. After a stress test, widespread and severe myocardial ischemia may be induced, globally lowering myocardial tracer uptake. Therefore, normal or slightly abnormal myocardial slices may be observed. During the rest period, after resolution of the ischemic phase, some myocardial segments may exhibit a different tracer washout and/or a different tracer uptake. Therefore, rest images may evidence a more heterogeneous repartition of the tracer than stress images. The redistribution defect may then delineate the most metabolically stunned (and ischemic) myocardial area. In fact, this simple scheme could be wrong and the mechanisms involved in the genesis of RR could be much more complex. First, coronary stenoses have variable impact on myocardial perfusion, and the area supplied by the tightest coronary artery stenosis is not necessarily the most ischemic area. Second, the duration and the intensity of myocardial stunning are also variable, and repeated bouts of myocardial ischemia may induce myocardial preconditioning, decreasing the impact of this phenomenon. Third, after a stress test, hyperemia interferes with the interpretation of the RR pattern. In normally perfused segments, hyperemia increases ²⁰¹Tl washout and these segments may show later a relative decreased uptake (17). Conversely, in ischemic segments, hyperemia may increase ²⁰¹Tl supply and ²⁰¹Tl uptake, if the cells are not metabolically stunned. Therefore, hyperemia may have opposite effects on ²⁰¹Tl uptake, according to the cell condition. However, patients with severe CAD who present with RR frequently have markedly positive electrocardiograms and signs of ischemic LV dysfunction on stress images, such as transient LV dilation and marked visualization of lung uptake (18). When considering these signs as a whole, in patients with a high prevalence of CAD, the diagnosis of myocardial ischemia should be raised independently of the presence or the absence of RR. RR is then only suggestive of multivessel disease, and the opportunity of coronary artery angiography must be strongly discussed.

In the other patients, with a low prevalence of CAD and without indirect signs of ischemic LV dysfunction, the reality of RR is much more questionable. The best way to manage these patients is to avoid meeting this hypothetic or unusual phenomenon by releasing patients with a negative contributive stress test, and no SPECT abnormalities, without performing any redistribution images! In these patients, we know that the negative predictive value of CAD is high, and the rate of coronary events is low (19).

Patients with Chronic CAD and Remote MI

The literature shows that RR occurs primarily with ²⁰¹Tl, in a stress-redistribution (1,20,21) or a rest-redistribution (22,23) sequence. Roelants et al. (1) focus on this clinical situation. Their study design compared ²⁰¹Tl uptake at stress, during redistribution, and after reinjection and prospectively evaluated the clinical impact of RR on the prediction of functional recovery 3–8 mo after revascularization. RR occurring in the infarcted area has been reported to be associated with preserved regional flow, patent infarct-related artery, or functional collateral supply (20–22,24). Although RR and myocardial viability are significantly associated, this link appears weaker than the one observed early after the onset of MI (1,23). Roelants et al. confirm that functional recovery (used as the gold standard for myocardial viability) is poorly related to the presence of RR in dysfunctional segments and that the clinical impact of RR is low when compared with the predictive value of the quantification of the tracer uptake in the infarcted area (23,25). Furthermore, RR happens much less frequently in chronic CAD than in the acute phase of MI (3.3% of the total number of segments and 8% of the dysfunctional segments), and the extent and the magnitude of RR are also reduced more than in acute MI. It is worth noting that ²⁰¹Tl reinjection drastically reduces the frequency of RR, as reported by Marin-Neto et al. (20). In the series of Roelants et al., the amplitude of RR is reduced by 50% after ²⁰¹Tl reinjection in either viable or nonviable segments.

Why Does Significance of RR in Chronic CAD and Remote MI Appear Less Obvious than in Other Situations and Particularly in Acute MI?

In this setting, the interpretation of RR is difficult because all of the different mechanisms described above are often involved. In the study of Roelants et al. (1), indirect arguments may be raised to incriminate, at least partially, myocardial ischemia as a confounding factor to explain RR. Eighty percent of patients had 2- or 3-vessel disease, and RR occurred primarily in segments with normal contractility (which, therefore, are not involved by MI). Marin-Neto et al. (20) reported that 85% of the segments with RR had normal or mildly abnormal contractile function and were, for most of them, supplied by critically stenosed arteries. Although dysfunctional segments without RR tended to enhance ²⁰¹Tl uptake after redistribution and reinjection (suggesting myocardial ischemia), no data on the coronary supply of nondysfunctional segments with RR were available in the study of Roelants et al. A larger series will be required to address this point.

In dysfunctional segments with RR, the only clinically relevant question is to assess the presence of residual myocardial viability. Although the same mechanisms as those existing in the acute phase may be evoked, the prediction of myocardial viability is probably impaired by the presence of large myocardial fibrosis (which does not exist yet in the acute phase of MI). Practically, for cardiologists, the gold standard for myocardial viability remains functional recovery after coronary revascularization. However, functional recovery of asynergic segments is dependent not only on the amount of viable myocytes but also on the spatial organization of the myocytes in the myocardium. If the architecture of the muscular fibers is disrupted by myocardial fibrosis, it is likely that functional recovery will not occur after coronary revascularization, even if residual myocardial viability was detected previously. In the chronic phase of MI, hibernating myocardium and myocardial fibrosis are therefore responsible for persistent LV dysfunction and deleterious remodeling. Furthermore, rest ²⁰¹Tl uptake is closely and inversely related to the degree of myocardial fibrosis (26). If we hypothesize that the infarct area represents a mixture of normal cells, jeopardized but viable myocytes, and myocardial fibrosis, the latter is responsible for the nonreversible part of the defect into this patchy myocardium. This fixed defect reduces the changes between stress and redistribution images. Consequently, myocardial fibrosis decreases the magnitude of ²⁰¹Tl (conventional or reverse) redistribution, and the correlation between the presence of RR and late functional recovery is impaired. Therefore, an indirect evaluation of the amount of viable myocytes (or the amount of myocardial fibrosis) is more informative for this purpose than the observation of RR itself. Although the quantification of ²⁰¹Tl uptake within the defect area is probably methodologically perfectible, this index remains powerful and Roelants et al. (1) report an accuracy of 77% for predicting functional recovery. However, we must be aware that the absence of functional recovery after coronary revascularization does not strictly exclude the presence of viable myocytes and that coronary revascularization may have benefits other than improvement of regional contractility, such as preventing LV remodeling and severe arrhythmias. The study of Roelants et al. brings another significant contribution to the reconsideration of the clinical impact of RR. Despite often appearing spectacular and somewhat mysterious, RR in chronic CAD and remote MI is simply a warning to remind us that myocardial viability should be assessed with more reliable tools.