Taui, A high-resolution metabolic imaging biomarker for myocardium
Journal of Cardiovascular Magnetic Resonance volume 16, Article number: O111 (2014)
Contrast-enhanced 1H2O T1-weighted cardiovascular MRI is usually interpreted using tracer paradigms; e.g., the extra-/intravascular contrast agent (CA) partition coefficient. However, the signal molecule is water, not CA. Consequently, the myocardial extracellular volume fraction (ECV) is underestimated in proportion to its magnitude. Even more importantly, intercompartmental water exchange kinetics are inaccessible. The mean intracellular water molecule lifetime [taui] is assumed effectively 0; though it is a fraction of a second. For cylindrical myocytes with mean cytolemmal water permeability coefficient PW and diameter d: taui-1= 4(PW/d). taui-1 is linearly related to PW and to d-1. However, PW dominates and is itself dominated by active trans-membrane water cycling. Thus, taui-1 is proportional to the driving cytolemmal ATPase ion pump activity.
We acquired serial 1.5T T1-weighted 1H2O data from 6 normal human subjects before and after a single bolus 0.15 mmol/kg CA IV injection. The tissue and blood ROIs comprised ~300 LV wall and ~25 LV voxels [(2 × 2 × 8) mm3]. Hematocrit values allowed R1p estimation.
Figure 1 plots ROI 1H2O LV wall tissue (R1t) vs. corresponding LV plasma (R1p) values during the bolus passage [R1 ≡ T1-1]: 3 post-CA points and 1 pre-CA, for one subject. These are fitted with a shutter-speed (SS) two-site-exchange [2SX] expression approximating CA extravasation steady-state, [CAo] = [CAp] (o, interstitial); the solid curve [only ve and taui varied]. The extracellular volume fraction ve(SS) [≡ ECV(SS)] is 0.38. The tracer paradigm (TP) predicts a straight line for the R1t R1p-dependence, with slope ve: the dashed asymptote. In order to fit the non-linear data, the TP straight line must be pivoted down about the origin: this yields ECV(TP) = 0.25, a 34% reduction. SS success is not a fitting goodness issue: the TP line through the data incurs residuals scarcely larger than for the 2SX curve. Crucial is the systematic TP ECV depression, which increases in pathology. Even more important is the SS access to taui - because of the active trans membrane water cycling link to metabolic activity. We obtain taui = 0.34 s for this subject, the first reported for human myocardium [means in Table 1]. (Since [CAo] > [CAp], ve and taui are over- and underestimated.) Pixel by-pixel ve and taui values allow parametric mapping.
The first taui metabolic sensitivity hint came in a 2006 perfused ex vivo rat heart study (with other collaborators) finding that (no flow) ischemia increased taui by 56% - from 0.18 to 0.28 s. For control mice taui = 0.19 s, and for a hypertensive mouse model taui = 0.44 s, values have been reported. The very large (132%) taui increase is accompanied by an only 30% d increase; from 20 to 26 μm. These results demonstrate PW dominance of taui, and sensitivity to metabolic activity slowing caused by both ischemia and chronic hypertension.
NIH [RO1 NS40801].
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Springer, C.S., Broberg, C.S. & Rooney, W.D. Taui, A high-resolution metabolic imaging biomarker for myocardium. J Cardiovasc Magn Reson 16 (Suppl 1), O111 (2014). https://doi.org/10.1186/1532-429X-16-S1-O111