Myocardial Extracellular Volume Fraction and Change in Hematocrit Level: MR Evaluation by Using T1 Mapping in an Experimental Model of Anemia.

Purpose To evaluate the effect of changes in hematocrit level on myocardial extracellular volume (ECV) fraction, as quantified with cardiac magnetic resonance (MR) imaging in an animal model. Materials and Methods Thirteen adult male Sprague-Dawley rats underwent cardiac MR imaging before and after induction of anemia. MR imaging procedures, including unenhanced and contrast material-enhanced T1 mapping, were performed by using a saturation recovery Look-Locker sequence with a 9.4-T unit. An optimized T1 mapping sequence was established in the phantom study. Systolic function of the left ventricle (LV) was calculated from the cine images. Native and postcontrast T1 values of the LV myocardium at the midcavity level and LV blood pool, partition coefficients, and ECV were calculated. Histopathologic examination of the heart was performed after sacrifice. Intergroup comparison of variables was performed with the paired t test. Results The postanemia models exhibited lower hematocrit levels, postcontrast T1 values of the LV pool, and partition coefficients (mean, 45.7% ± 5.2 [standard deviation]; 563.8 msec ± 155.7; and 29.2 ± 3.5, respectively) than did the preanemia models (mean, 59.0% ± 4.1; 690.2 msec ± 109.7; and 38.2 ± 4.4, respectively) (P < .05 for all comparisons). There were no differences between the pre- and postanemia groups in terms of LV ejection fraction (mean, 72.7% ± 2.1 vs 73.2% ± 4.7; P = .78) and ECV (mean, 15.5% ± 2.0 vs 16.0% ± 1.9; P = .24). Conclusion Myocardial ECV measured with contrast-enhanced T1 mapping cardiac MR imaging did not significantly change despite changes in hematocrit level in anemic rat models. Extrapolation of this finding from animal models to human subjects suggests that ECV measured with MR imaging could be a robust parameter in anemic patients.

Functional Profiling of CFTR-Directed Therapeutics Using Pediatric Patient-Derived Nasal Epithelial Cell Models.

Functional profiling of CFTR-directed therapeutics offers the potential to provide significant benefits to young people with cystic fibrosis (CF). However, the development of 2D airway epithelial cell models for individual response tests in CF children remains a central task. The objective of this study was to determine the utility of EpiXTM technology for expansion of nasal epithelial cells for use in electrophysiological CFTR function measurements. An initial harvest of as few as 20,000 cells was sufficient to expand up to 50 million cells that were used to generate air-liquid interface (ALI) cultures for ion transport studies with the Ussing assay. CFTR function was assessed by measuring responses to forskolin and the CFTR potentiator VX-770 (ivacaftor) in ALI cultures generated from passage 3 and 4 cells. Short-circuit current (Isc) measurements of blocked CFTR currents (ΔICFTRinh) discriminated CFTR function between healthy control (wild type, WT) and patients with intermediate (F508del/R117H-7T: 56% WT) and severe (F508del/F508del: 12% WT) CF disease. For the mixed genotypes, CFTR activity for F508del/c.850dupA was 12% WT, R334W/406-1G>A was 24% WT, and CFTRdele2,3(21 kb)/CFTRdele2,3(21 kb) was 9% WT. The CFTR correctors VX-809 (lumacaftor) and VX-661 (tezacaftor) significantly increased CFTR currents for F508del/R117H to 73 and 67% WT, respectively. Cultures with the large deletion mutation CFTRdele2,3(21 kb) unexpectedly responded to VX-661 treatment (20% WT). Amiloride-sensitive sodium currents were robust and ranged between 20-80 µA/cm2 depending on the subject. In addition to characterizing the electrophysiological profile of mutant CFTR activity in cultures for five genotypes, our study exemplifies the promising paradigm of bed-to-bench side cooperation and personalized medicine.

Early Detection and Serial Monitoring of Anthracycline-Induced Cardiotoxicity Using T1-mapping Cardiac Magnetic Resonance Imaging: An Animal Study.

A reliable, non-invasive diagnostic method is needed for early detection and serial monitoring of cardiotoxicity, a well-known side effect of chemotherapy. This study aimed to assess the feasibility of T1-mapping cardiac magnetic resonance imaging (CMR) for evaluating subclinical myocardial changes in a doxorubicin-induced cardiotoxicity rabbit model. Adult male New Zealand White rabbits were injected twice-weekly with doxorubicin and subjected to CMR on a clinical 3T MR system before and every 2-4 weeks post-drug administration. Native T1 and extracellular volume (ECV) values were measured at six mid-left ventricle (LV) and specific LV lesions. Histological assessments evaluated myocardial injury and fibrosis. Three pre-model and 11 post-model animals were included. Myocardial injury was observed from 3 weeks. Mean LV myocardium ECV values increased significantly from week 3 before LV ejection fraction decreases (week 6), and ECVs of the RV upper/lower insertion sites and papillary muscle exceeded those of the LV. The mean native T1 value in the mid-LV increased significantly increased from week 6, and LV myocardium ECV correlated strongly with the degree of fibrosis (r = 0.979, p < 0.001). Myocardial T1 mapping, particularly ECV values, reliably and non-invasively detected early cardiotoxicity, allowing serial monitoring of chemotherapy-induced cardiotoxicity.