Abstract Rationale Inhaled hyperpolarized 129Xe exhibits a unique frequency shift in pulmonary capillary red blood cells (RBCs), which increases with blood oxygenation and, therefore, decreases with reduced capillary blood volume. In pre-capillary pulmonary hypertension (PH) patients, this shift can be paradoxically elevated downstream of arteriolar occlusions that slow capillary flow and lengthen transit times. In the rest of the lung, preserved cardiac output necessitates increased flow and shorter transit times, thus reducing oxygenation and RBC shift. This heterogeneity can be mapped using 129Xe chemical shift imaging (CSI), providing direct sensitivity to PH pathology. However, interpreting these maps requires robust healthy reference values to classify abnormal voxels. To date, these have exclusively been reported for whole-lung spectroscopy, reflecting only inter-subject mean variability. Here, we establish a dedicated RBC CSI healthy reference distribution with thresholds to quantify frequency-shift heterogeneity in PH. Methods Healthy 18-30-year-old volunteers (N = 11) and PH patients (N = 6) underwent hyperpolarized 129Xe CSI, acquiring spatially resolved spectra. RBC shift maps were derived as the voxel-wise difference between the RBC and gas peak center frequencies. Maps from healthy volunteers were compiled into a reference distribution. Thresholds at the mean±1 and ±2 standard deviations (SDs) were used to calculate the percentage of defect, low, and high shift voxels in all patients. Corresponding maps of voxel-wise RBC to membrane peak area ratio (RBC:M) were used to visualize regional gas-exchange efficiency. Results The healthy reference RBC shift distribution yielded a mean of 217.9ppm, with thresholds of -0.7/+0.8ppm (1 SD) and -1.4/+1.5ppm (2 SD) (Figure 1A). With these thresholds, healthy volunteers exhibited small percentages of extreme values (Figure 1B). In contrast, PH patients exhibited significant percentages of defect/low-shift voxels and moderately elevated percentages of high shift, with uniformly reduced RBC:M (Figure 1C). On average, healthy volunteers exhibited 3.2% defect, 15.9% low, and 4.6% high shift, compared to 41.9% defect, 63.9% low, and 6.0% high in PH patients (Figure 1D). Conclusion The mean CSI-derived healthy reference RBC shift agrees with the published whole-lung value of 218.2±0.5ppm. The slightly larger CSI SD captures intra-subject variability. PH patients exhibited enhanced heterogeneity, with elevated percentages of both low and high shift, driven by redistribution of blood flow in the presence of arteriolar occlusions, despite relatively uniform RBC:M maps. Particularly pronounced defect/low shift may reflect vascular remodeling like systemic-to-pulmonary artery collaterals. Thus, the robust healthy reference distribution and functional thresholds enable rigorous quantification of RBC shift heterogeneity associated with PH pathology. This abstract is funded by: NIH/NHLBI R01HL105643, R01HL126771, R01HL153872
Costelle et al. (Fri,) studied this question.