Charting the Path: Navigating Embryonic Development to Potentially Safeguard against Congenital Heart Defects.

Congenital heart diseases (CHDs) are structural or functional defects present at birth due to improper heart development. Current therapeutic approaches to treating severe CHDs are primarily palliative surgical interventions during the peri- or prenatal stages, when the heart has fully developed from faulty embryogenesis. However, earlier interventions during embryonic development have the potential for better outcomes, as demonstrated by fetal cardiac interventions performed in utero, which have shown improved neonatal and prenatal survival rates, as well as reduced lifelong morbidity. Extensive research on heart development has identified key steps, cellular players, and the intricate network of signaling pathways and transcription factors governing cardiogenesis. Additionally, some reports have indicated that certain adverse genetic and environmental conditions leading to heart malformations and embryonic death may be amendable through the activation of alternative mechanisms. This review first highlights key molecular and cellular processes involved in heart development. Subsequently, it explores the potential for future therapeutic strategies, targeting early embryonic stages, to prevent CHDs, through the delivery of biomolecules or exosomes to compensate for faulty cardiogenic mechanisms. Implementing such non-surgical interventions during early gestation may offer a prophylactic approach toward reducing the occurrence and severity of CHDs.

Human Stem Cells for Cardiac Disease Modeling and Preclinical and Clinical Applications-Are We on the Road to Success?

Cardiovascular diseases (CVDs) are pointed out by the World Health Organization (WHO) as the leading cause of death, contributing to a significant and growing global health and economic burden. Despite advancements in clinical approaches, there is a critical need for innovative cardiovascular treatments to improve patient outcomes. Therapies based on adult stem cells (ASCs) and embryonic stem cells (ESCs) have emerged as promising strategies to regenerate damaged cardiac tissue and restore cardiac function. Moreover, the generation of human induced pluripotent stem cells (iPSCs) from somatic cells has opened new avenues for disease modeling, drug discovery, and regenerative medicine applications, with fewer ethical concerns than those associated with ESCs. Herein, we provide a state-of-the-art review on the application of human pluripotent stem cells in CVD research and clinics. We describe the types and sources of stem cells that have been tested in preclinical and clinical trials for the treatment of CVDs as well as the applications of pluripotent stem-cell-derived in vitro systems to mimic disease phenotypes. How human stem-cell-based in vitro systems can overcome the limitations of current toxicological studies is also discussed. Finally, the current state of clinical trials involving stem-cell-based approaches to treat CVDs are presented, and the strengths and weaknesses are critically discussed to assess whether researchers and clinicians are getting closer to success.

Necro-inflammatory activity grading in chronic viral hepatitis with three-dimensional multifrequency MR elastography.

The purpose of this study was to assess the diagnostic value of multifrequency MR elastography for grading necro-inflammation in the liver. Fifty participants with chronic hepatitis B or C were recruited for this institutional review board-approved study. Their liver was examined with multifrequency MR elastography. The storage, shear and loss moduli, and the damping ratio were measured at 56 Hz. The multifrequency wave dispersion coefficient of the shear modulus was calculated. The measurements were compared to reference markers of necro-inflammation and fibrosis with Spearman correlations and multiple regression analysis. Diagnostic accuracy was assessed. At multiple regression analysis, necro-inflammation was the only determinant of the multifrequency dispersion coefficient, whereas fibrosis was the only determinant of the storage, loss and shear moduli. The multifrequency dispersion coefficient had the largest AUC for necro-inflammatory activity A ≥ 2 [0.84 (0.71-0.93) vs. storage modulus AUC: 0.65 (0.50-0.79), p = 0.03], whereas the storage modulus had the largest AUC for fibrosis F ≥ 2 [AUC (95% confidence intervals) 0.91 (0.79-0.98)] and cirrhosis F4 [0.97 (0.88-1.00)]. The measurement of the multifrequency dispersion coefficient at three-dimensional MR elastography has the potential to grade liver necro-inflammation in patients with chronic vial hepatitis.

Molecular Magnetic Resonance Imaging of Fibrin Deposition in the Liver as an Indicator of Tissue Injury and Inflammation.

RATIONALE AND OBJECTIVES: Liver inflammation is associated with nonalcoholic steatohepatitis and other pathologies, but noninvasive methods to assess liver inflammation are limited. Inflammation causes endothelial disruption and leakage of plasma proteins into the interstitial space and can result in extravascular coagulation with fibrin deposition. Here we assess the feasibility of using the established fibrin-specific magnetic resonance probe EP-2104R for the noninvasive imaging of fibrin as a marker of liver inflammation. METHODS: Weekly 100 mg/kg diethylnitrosamine (DEN) dosing was used to generate liver fibrosis in male rats; control animals received vehicle. Magnetic resonance imaging at 1.5 T with EP-2104R, a matched non-fibrin-binding control linear peptide, or the collagen-specific probe EP-3533 was performed at 1 day or 7 days after the last DEN administration. Imaging data were compared with quantitative histological measures of fibrosis and inflammation. RESULTS: After 4 or 5 DEN administrations, the liver becomes moderately fibrotic, and fibrosis is the same if the animal is killed 1 day (Ishak score, 3.62 ± 0.31) or 7 days (Ishak score, 3.82 ± 0.25) after the last DEN dose, but inflammation is significantly higher at 1 day compared with 7 days after the last DEN dose (histological activity index from 0-4, 3.54 ± 0.14 vs 1.61 ± 0.16, respectively; P < 0.0001). Peak EP-2104R signal enhancement was significantly higher in animals imaged at 1 day post-DEN compared with 7 days post-DEN or control rats (29.0% ± 3.2% vs 22.4% ± 2.0% vs 17.0% ± 0.2%, respectively; P = 0.017). Signal enhancement with EP-2104R was significantly higher than control linear peptide at 1 day post-DEN but not at 7 days post-DEN indicating specific fibrin binding during the inflammatory phase. Collagen molecular magnetic resonance with EP-3533 showed equivalent T1 change when imaging rats 1 day or 7 days post-DEN, consistent with equivalent fibrosis. CONCLUSIONS: EP-2104R can specifically detect fibrin associated with inflammation in a rat model of liver inflammation and fibrosis.

Hepatic Fibrosis, Inflammation, and Steatosis: Influence on the MR Viscoelastic and Diffusion Parameters in Patients with Chronic Liver Disease.

Purpose To determine the relationship of liver fibrosis, inflammation, and steatosis with the magnetic resonance (MR) viscoelastic and diffusion parameters in patients with chronic liver disease and to compare the diagnostic accuracy of the imaging parameters in staging liver fibrosis. Materials and Methods Consecutive patients with chronic liver disease scheduled for liver biopsy were prospectively recruited from November 2010 to October 2012 for this institutional review board-approved study after they provided written informed consent. Sixty-eight patients underwent three-dimensional MR elastography and intravoxel incoherent motion diffusion-weighted MR imaging with a 1.5-T MR system. Fibrosis, inflammation, and steatosis were assessed with the METAVIR and steatosis, activity, and fibrosis (or SAF) scoring systems. Spearman correlation and multiple regression analyses were performed to determine the relationship between liver fibrosis, inflammation, steatosis, and alanine aminotransferase (ALT) levels and viscoelastic and diffusion parameters. The accuracy of three-dimensional MR elastography and diffusion-weighted MR imaging in the determination of fibrosis stage was assessed with Obuchowski measures. Results At multiple regression analysis, fibrosis was the only variable associated with viscoelastic parameters (ß = 0.6, P < .001, R2 = 0.33 for shear modulus; ß = 0.6, P < .001, R2 = 0.32 for elasticity). Fibrosis had a weaker independent association with the apparent diffusion coefficient (ß = -0.3, P = .02, R2 = 0.33) than did steatosis (ß = -0.5, P < .001, R2 = 0.33). Steatosis was the only factor independently associated with the pure diffusion coefficient (ß = -0.4, P = .002, R2 = 0.22). Inflammation and ALT level were not associated with the viscoelastic or diffusion parameters. The diagnostic accuracy of fibrosis staging was significantly higher when measuring the shear modulus rather than the apparent diffusion coefficient (Obuchowski measures, 0.82 ± 0.04 vs 0.30 ± 0.06; P < .001). Conclusion Fibrosis is independently associated with the MR viscoelastic parameters and is less associated with the diffusion parameters than is steatosis. These results and those of diagnostic accuracy suggest that MR elastography should be preferred over diffusion-weighted MR imaging in the staging of liver fibrosis. © RSNA, 2016.

MR fat fraction mapping: a simple biomarker for liver steatosis quantification in nonalcoholic fatty liver disease patients.

RATIONALE AND OBJECTIVES: To assess the performance, postprocessing time, and intra- and interobserver agreement of a simple magnetic resonance-based mapping technique to quantify liver fat. MATERIALS AND METHODS: This prospective, single-center study included 26 patients who were overweight with type 2 diabetes and at risk for nonalcoholic fatty liver disease. Mapping of the liver was based on a triple echo gradient-echo sequence, and (1)H magnetic resonance spectroscopy was used as the reference standard. The nonparametric Spearman correlation coefficient and the Wilcoxon test were used for comparisons between mapping and spectroscopy. The mapping was assessed for its predictive performance using the area under the curve of a receiver operating characteristic curve. Intraclass correlation coefficients were used to calculate intra- and interobserver's agreement for mapping measurements. RESULTS: Patients had a mean fat percentage of 11.7% (range, 2-35.4%). A strong correlation was seen between mapping and spectroscopy (r = 0.89, P < .0001). A cutoff of 6.9% for fat fraction mapping was found to diagnose steatosis with 93% sensitivity and 100% specificity with an area under the curve of 0.99. Mapping of the liver had shorter acquisition and post-processing times than spectroscopy (5 min vs. 38 min; P < .0001). Mapping measurements had an intra- and interobserver agreement of 0.98 and 0.99, respectively. CONCLUSIONS: The magnetic resonance-based liver mapping can accurately quantify liver fat with a cutoff value of 6.9% and excellent intra- and interobserver agreement. This mapping technique, with its simple methodology and short postprocessing time, has the potential to be included in routine abdominal protocols.

Determination of malignancy and characterization of hepatic tumor type with diffusion-weighted magnetic resonance imaging: comparison of apparent diffusion coefficient and intravoxel incoherent motion-derived measurements.

OBJECTIVE: The objective of this study was to compare the value of the apparent diffusion coefficient (ADC) determined with 3 b values and the intravoxel incoherent motion (IVIM)-derived parameters in the determination of malignancy and characterization of hepatic tumor type. MATERIALS AND METHODS: Seventy-six patients with 86 solid hepatic lesions, including 8 hemangiomas, 20 lesions of focal nodular hyperplasia, 9 adenomas, 30 hepatocellular carcinomas, 13 metastases, and 6 cholangiocarcinomas, were assessed in this prospective study. Diffusion-weighted images were acquired with 11 b values to measure the ADCs (with b = 0, 150, and 500 s/mm) and the IVIM-derived parameters, namely, the pure diffusion coefficient and the perfusion-related diffusion fraction and coefficient. The diffusion parameters were compared between benign and malignant tumors and between tumor types, and their diagnostic value in identifying tumor malignancy was assessed. RESULTS: The apparent and pure diffusion coefficients were significantly higher in benign than in malignant tumors (benign: 2.32 [0.87] × 10 mm/s and 1.42 [0.37] × 10 mm/s vs malignant: 1.64 [0.51] × 10 mm/s and 1.14 [0.28] × 10 mm/s, respectively; P < 0.0001 and P = 0.0005), whereas the perfusion-related diffusion parameters did not differ significantly between the 2 groups. The apparent and pure diffusion coefficients provided similar accuracy in assessing tumor malignancy (areas under the receiver operating characteristic curve of 0.770 and 0.723, respectively). In the multigroup analysis, the ADC was found to be significantly higher in hemangiomas than in hepatocellular carcinomas, metastases, and cholangiocarcinomas. In the same manner, it was higher in lesions of focal nodular hyperplasia than in metastases and cholangiocarcinomas. However, the pure diffusion coefficient was significantly higher only in hemangiomas versus hepatocellular and cholangiocellular carcinomas. CONCLUSIONS: Compared with the ADC, the diffusion parameters derived from the IVIM model did not improve the determination of malignancy and characterization of hepatic tumor type.

Fat deposition decreases diffusion parameters at MRI: a study in phantoms and patients with liver steatosis.

PURPOSE: Assess the effect of fat deposition on the MRI diffusion coefficients in lipid emulsion-based phantoms and patients with proven isolated liver steatosis. MATERIALS AND METHODS: Diffusion-weighted MRI with 11 b values from 0-500 s/mm(2) was performed in phantoms (fat fractions 0-18 %) with and without fat suppression and in 19 patients with normal liver (n = 14) or isolated liver steatosis (n = 5) proven by histopathology. The apparent, pure and perfusion-related diffusion coefficients and the perfusion fraction were measured. Spearman correlation coefficient and Mann-Whitney U test were used for comparisons. RESULTS: A strong correlation between the apparent and pure diffusion coefficients and fat fractions was seen in phantoms. The pure diffusion coefficient decreased significantly in patients with liver steatosis (0.96 ± 0.16 × 10(-3) mm(2)/s versus 1.18 ± 0.09 × 10(-3) mm(2)/s in normal liver, P = 0.005), whereas the decrease in apparent diffusion coefficient did not reach statistical significance (1.26 ± 0.25 × 10(-3) mm(2)/s versus 1.41 ± 0.14 × 10(-3) mm(2)/s in normal liver, P = 0.298). CONCLUSIONS: Fat deposition decreases the apparent and pure diffusion coefficients in lipid emulsion-based phantoms and patients with isolated liver steatosis proven by histopathology.