Comparison of thallium deposition with segmental perfusion in pigs with chronic hibernating myocardium

Viable, chronically dysfunctional myocardium with reduced resting flow (or hibernating myocardium) is an important prognostic factor in ischemic heart disease. Although thallium-201 imaging is frequently used to assess myocardial viability in patients with ischemic cardiomyopathy, there are limited data regarding its deposition in hibernating myocardium, and this data suggest that thallium retention may be supernormal compared with control myocardium. Accordingly, pigs ( n = 7) were chronically instrumented with a 1.5 mm Delrin stenosis on the proximal left anterior descending coronary artery (LAD) to produce hibernating myocardium. Four months later, severe anteroapical hypokinesis was documented with contrast ventriculography (wall motion score, 0.7 ± 0.8; normal = 3), and microsphere measurements confirmed reduced resting flow (LAD subendocardium, 0.78 ± 0.34 vs. 0.96 ± 0.24 ml·min−1·g−1 in remote; P < 0.001). Absolute deposition of thallium-201 and insulin-stimulated [18F]-2 fluoro-2-deoxyglucose (FDG) were assessed over 1 h and compared with resting flow ( n = 704 samples). Thallium-201 deposition was only weakly correlated with perfusion ( r2 = 0.20; P < 0.001) and was more homogeneously distributed (relative dispersion, 0.12 ± 0.03 vs. 0.29 ± 0.10 for microsphere flow; P < 0.01). Thus after 1 h relative thallium-201 (subendocardium LAD/remote, 0.96 ± 0.16) overestimated relative perfusion (0.78 ± 0.32; P < 0.0001) and underestimated the relative reduction in flow. Viability was confirmed by both histology and preserved FDG uptake. We conclude that under resting conditions, thallium-201 redistribution in hibernating myocardium is nearly complete within 1 h, with similar deposition to remote myocardium despite regional differences in flow. These data suggest that in this time frame thallium-201 deposition may not discriminate hibernating myocardium from dysfunction myocardium with normal resting flow. Since hibernating myocardium has been associated with a worse prognosis, this limitation could have significant clinical implications.

Activation of p38 MAPK and increased glucose transport in chronic hibernating swine myocardium

In preconditioned myocardium, activation of the mitogen-activated protein kinase (MAPK) p38 leads to increased glucose uptake via enhanced GLUT-4 translocation. Glucose uptake is also increased in chronic hibernating myocardium, but the role of p38 MAPK and GLUT-4 translocation has not been studied. Nine swine underwent instrumentation of the proximal left anterior descending coronary artery (LAD) with a small, external constrictor. At 3 mo after instrumentation, myocardial glucose uptake by PET imaging was higher in the LAD than in the remote region under basal, fasted conditions (0.08 ± 0.02 vs. 0.04 ± 0.01 μmol·min−1·g−1, P < 0.05). Compared with the remote region, the LAD region demonstrated increased membrane-bound GLUT-4 relative to total content (61 ± 04 vs. 45 ± 06%, P < 0.05), higher glycogen (28.37 ± 4.41 vs. 19.26 ± 1.87 mg/g wet wt, P < 0.05), and increased inducible nitric oxide synthase (NOS) activity (1.43 ± 0.34 vs. 0.51 ± 0.21 activity/mg protein, P < 0.05). p38 MAPK was 47 ± 14% higher in the LAD than in the remote region ( P < 0.05) and correlated well with the absolute degree of GLUT-4 membrane-bound translocation ( r = 0.81, P < 0.01), relative increase in glycogen ( r = 0.70, P < 0.05), and total NOS activity ( r = 0.68, P < 0.05). In chronic hibernating myocardial tissue, p38 MAPK activation is increased under basal fasted conditions and correlates well with the increased degree of GLUT-4 translocation, glycogen accumulation, and NOS activity. As in preconditioned myocardium, activation of p38 MAPK may play an important role in the metabolic adaptations that characterize chronic hibernating myocardium.