Prolonged Relaxation Time Research Articles

Multivalent Design of Low-Entropy-Penalty Ion–Dipole Interactions for Dynamic Yet Thermostable Supramolecular Networks

Dynamic supramolecular networks are constantly accompanied by thermal instability. The fundamental reason is most reversible noncovalent bonds quickly decay at elevated temperatures and dissociate below 100 °C. Here, in this paper, we realize a reversible ion-dipole interaction with high-temperature stability exceeding 150 °C. The resultant supramolecular network can simultaneously possess mechanical strength of 1.32 MPa (14.8 times that of pristine material), dynamic self-healing capability, and a stable working temperature of up to 200 °C. From the prolonged characteristic relaxation time of 600 s even at 100 °C, our material represents one of the most thermally stable dynamic supramolecular polymers. These remarkable performances are achieved by using a new multivalent yet low-entropy-penalty molecular design. In this way, the noncovalent bond can reach a high enthalpy while minimizing the entropy-dominated thermal dissociations.

Quantitative evaluation of the lumbar ligamentum flavum using MRI T2-mapping: Efficacy of its clinical application in patients with lumbar spinal stenosis

ObejectiveTo perform a magnetic resonance imaging T2-mapping of the ligamentum flavum in healthy individuals and patients with lumbar spinal stenosis scheduled for surgery and compare the T2 relaxation times. Subjects and MethodsThe T2 relaxation time of the ligamentum flavum was compared among 3 groups, healthy young individuals (H group (age< 50)), healthy middle-aged and older individuals (H group (age≥50)), and patients with lumbar spinal stenosis (L group). Additionally, the thickness of the ligament was measured in the axial image plane, and the occupied area ratio of each fiber was measured by staining the surgically obtained ligament, and each was correlated with the T2 relaxation time. We also evaluated the adhesion of the ligamentum flavum with the dura mater during the surgery. ResultsThe T2 relaxation times were significantly prolonged in H group (age ≥50) and L group (P < 0.001) compared to H group (age<50). The relationship between collagen fiber and T2 relaxation times was significantly positive (r = 0.720, P < 0.001). Moreover, the relaxation times were significantly prolonged in those with adhesion of the ligamentum flavum with the dura mater (P < 0.05). The cut-off for the relaxation time was 50 ms (sensitivity: 62.50%, false positive rate: 10.8%). ConclusionHealthy middle-aged and older individuals and patients with lumbar spinal stenosis and adhesion of the ligamentum flavum with the dura mater have prolonged T2 relaxation times. Hence, the adhesion between the ligamentum flavum and dura mater should be considered in cases with a relaxation time ≥50 ms.

Abstract 15247: A Novel Patient-Derived Stem Cell Model of Restrictive Cardiomyopathy Exhibits Impaired Cardiomyocyte Relaxation Secondary to Increased Myocardial Calcium Sensitivity

Introduction: Restrictive Cardiomyopathy (RCM) is a rare disease characterized by profound, isolated defects in myocardial relaxation, normal or near-normal myocardial wall thickness, and preserved contractile function. Outcomes for patients with RCM are poor, with increased morbidity and mortality compared to other forms of cardiomyopathy. In some patients, RCM can be caused by genetic mutations, notably in genes encoding for components of the sarcomere. While many mutations have been described in RCM patients, the molecular and cellular mechanisms leading from these mutations to the patient’s physiological phenotype are poorly described. Hypothesis: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) derived from RCM patients will recapitulate the myocardial relaxation defects seen in RCM and provide a novel in vitro model for investigating the molecular mechanisms underpinning this disease. Methods: Induced pluripotent stem cells (iPSCs) were derived from a pediatric patient with RCM caused by a TNNT2 R94C mutation. CRISPR was used to correct the mutation, and cellular mechanics and calcium handling properties were compared to the patient line using a novel high-throughput traction-force imaging platform. Transcriptional profiles were compared using RNA-seq. Results: RCM cells carrying the TNNT2 R94C mutation show increased calcium sensitivity leading to increased resting tension at baseline, as well as prolonged calcium kinetics leading to prolonged relaxation times. Gene expression profiling reveals changes in expression of ECM genes, which may further contribute to the impaired myocardial relaxation seen in RCM. Conclusions: Patient-derived hiPSC-CMs from an RCM patient recapitulate the relaxation defects seen in RCM and highlight the central role of increased calcium sensitivity in impaired myocardial relaxation.

Smoothelin-like 1 knockout mice display sex-dependent alterations in blood flow and cardiac function.

Smoothelin-like 1 (SMTNL1) modulates the contractile performance of smooth muscle and thus has a key role in vascular homeostasis. Elevated vascular tone, recognized as a contributor to the development of progressive cardiac dysfunction, was previously found with SMTNL1 deletion. In this study, we assessed cardiac morphology and function of male and female, wild-type (Smtnl1+/+) and global SMTNL1 knockout (Smtnl1-/-) mice at 10 weeks of age. Gross dissection revealed distinct cardiac morphology only in males; Smtnl1-/- hearts were significantly smaller than Smtnl1+/+, but the left ventricle (LV) proportion of heart mass was greater. Male Smtnl1-/- mice also displayed increased ejection fraction and fractional shortening, as well as elevated aortic and pulmonary flow velocities. The impact of cardiac stress with pressure overload by transverse aortic constriction (TAC) was examined in male mice. With TAC banding, systolic function was preserved, but the LV filling pressure was selectively elevated due to relaxation impairment. Smtnl1-/- mice displayed higher early/passive filling velocity of LV/early mitral annulus velocity ratio (E/E' ratio) and myocardial performance index along with a prolonged isovolumetric relaxation time. Taken together, the findings support a novel, sex-dimorphic role for SMTNL1 in modulating cardiac structure and function of mice.

Cardiac adverse reactions of COVID-19 vaccination: cardiac MRI findings.

The rapid development of COVID-19 vaccines in the wake of the COVID-19 pandemic has led to an equally expediently deployed vaccination campaign with more than 12billion vaccinations administered worldwide. Reports of vaccine-associated adverse reactions (VAARs) have ranged from headaches and pain at the injection site to potentially life-threatening events such as cerebral venous sinus thrombosis. The heart has also not been spared of VAARs, as vaccine-associated myocardial infarction and more commonly, albeit still rare, myocarditis and perimyocarditis have been reported in predominantly young male recipients. Cardiac magnetic resonance imaging findings of vaccine-associated myocarditis such as prolonged T1 and T2 relaxation times, increased T2 signal intensity ratio, and subepicardial late gadolinium enhancement have been demonstrated to be similar to those in virus-induced myocarditis, enabling the use of the modified 2018 Lake Louise Criteria for diagnostic purposes to confirm vaccination-associated myocardial inflammation. Other reported cardiac findings such as cardiomyopathies and arrhythmias were confined to case reports. The incidence of myocardial infarction was not noted to be higher than in the overall population. The overall preliminary prognosis of vaccine- associated myocarditis seems to be good as suggested by initial reports, but long-term follow-up is needed to sufficiently assess possible sequelae and consequences.

Engineered skeletal muscle recapitulates human muscle development, regeneration and dystrophy.

Human pluripotent stem cell-derived muscle models show great potential for translational research. Here, we describe developmentally inspired methods for the derivation of skeletal muscle cells and their utility in skeletal muscle tissue engineering with the aim to model skeletal muscle regeneration and dystrophy in vitro. Key steps include the directed differentiation of human pluripotent stem cells to embryonic muscle progenitors followed by primary and secondary foetal myogenesis into three-dimensional muscle. To simulate Duchenne muscular dystrophy (DMD), a patient-specific induced pluripotent stem cell line was compared to a CRISPR/Cas9-edited isogenic control line. The established skeletal muscle differentiation protocol robustly and faithfully recapitulates critical steps of embryonic myogenesis in two-dimensional and three-dimensional cultures, resulting in functional human skeletal muscle organoids (SMOs) and engineered skeletal muscles (ESMs) with a regeneration-competent satellite-like cell pool. Tissue-engineered muscle exhibits organotypic maturation and function (up to 5.7±0.5mN tetanic twitch tension at 100Hz in ESM). Contractile performance could be further enhanced by timed thyroid hormone treatment, increasing the speed of contraction (time to peak contraction) as well as relaxation (time to 50% relaxation) of single twitches from 107±2 to 75±4ms (P<0.05) and from 146±6 to 100±6ms (P<0.05), respectively. Satellite-like cells could be documented as largely quiescent PAX7+ cells (75±6% Ki67- ) located adjacent to muscle fibres confined under a laminin-containing basal membrane. Activation of the engineered satellite-like cell niche was documented in a cardiotoxin injury model with marked recovery of contractility to 57±8% of the pre-injury force 21days post-injury (P<0.05 compared to Day 2 post-injury), which was completely blocked by preceding irradiation. Absence of dystrophin in DMD ESM caused a marked reduction of contractile force (-35±7%, P<0.05) and impaired expression of fast myosin isoforms resulting in prolonged contraction (175±14ms, P<0.05 vs. gene-edited control) and relaxation (238±22ms, P<0.05 vs. gene-edited control) times. Restoration of dystrophin levels by gene editing rescued the DMD phenotype in ESM. We introduce human muscle models with canonical properties of bona fide skeletal muscle in vivo to study muscle development, maturation, disease and repair.

Nanoscale Synergetic Effects on Ag-TiO2 Hybrid Substrate for Photoinduced Enhanced Raman Spectroscopy (PIERS) with Ultra-Sensitivity and Reusability.

Here, a 4N-in-1 hybrid substrate concept (nanocolumnar structures, nanocrack network, nanoscale mixed oxide phases, and nanometallic structures) for ultra-sensitive and reliable photo-induced-enhanced Raman spectroscopy (PIERS), is proposed. The use of the 4N-in-1 hybrid substrate leads to an ≈50-fold enhancement over the normal surface-enhanced Raman spectroscopy, which is recorded as the highest PIERS enhancement to date. In addition to an improved Raman signal, the 4N-in-1 hybrid substrate provides a high detection sensitivity which may be attributed to the activation possibility at extremely low UV irradiation dosage and prolonged relaxation time (long measurement time). Moreover, the 4N-in-1 hybrid substrate exhibits a superior photocatalytic degradation performance of analytes, allowing its reuse at least 18 times without any loss of PIERS activity. The use of the 4N-in-1 concept can be adapted to biomedicine, forensic, and security fields easily.

The Variation in the Diastolic Period with Interventricular Septal Displacement and Its Relation to the Right Ventricular Function in Pulmonary Hypertension: A Preliminary Cardiac Magnetic Resonance Study.

Background: Pulmonary hypertension (PH) is known to alter the biventricular shape and temporal phases of the cardiac cycle. The presence of interventricular septal (IVS) displacement has been associated with the severity of PH. There has been limited cardiac magnetic resonance (CMR) data regarding the temporal parameters of the cardiac cycle in PH. This study aimed to quantify the temporal changes in the cardiac cycle derived from CMR in PH patients with and without IVS displacement and sought to understand the mechanism of cardiac dysfunction in the cardiac cycle. Methods: Patients with PH who had CMR and right heart catheterization (RHC) examinations were included retrospectively. Patients were divided into an IVS non-displacement (IVSND) group and an IVS displacement (IVSD) group according to IVS morphology, as observed on short-axis cine CMR images. Additionally, age-matched healthy volunteers were included as the health control (HC). Temporal parameters, IVS displacement, ventricular volume and functional parameters were obtained by CMR, and pulmonary hemodynamics were obtained by RHC. The risk stratification of the PH patients was also graded according to the guidelines. Results: A total of 70 subjects were included, consisting of 33 IVSD patients, 15 IVSND patients, and 22 HC patients. In the IVSND group, only the right ventricle ejection fraction (RVEF) was decreased in the ventricular function, and no temporal change in the cardiac cycle was found. A prolonged isovolumetric relaxation time (IRT) and shortened filling time (FT) in both ventricles, along with biventricular dysfunction, were detected in the IVSD group (p < 0.001). The IRT of the right ventricle (IRTRV) and FT of the right ventricle (FTRV) in the PH patients were associated with pulmonary vascular resistance, right cardiac index, and IVS curvature, and the IRTRV was also associated with the RVEF in a multivariate regression analysis. A total of 90% of the PH patients in the IVSD group were stratified into intermediate- and high-risk categories, and they showed a prolonged IRTRV and a shortened FTRV. The IRTRV was also the predictor of the major cardiovascular events. Conclusions: The temporal changes in the cardiac cycle were related to IVS displacement and mainly impacted the diastolic period of the two ventricles in the PH patients. The IRT and FT changes may provide useful pathophysiological information on the progression of PH.

Abstract P2113: A Novel Patient-derived Stem Cell Model Of Restrictive Cardiomyopathy Exhibits Impaired Cardiomyocyte Relaxation Secondary To Increased Myocardial Calcium Sensitivity

Introduction: Restrictive Cardiomyopathy (RCM) is a rare disease characterized by profound, isolated defects in myocardial relaxation, normal or near-normal myocardial wall thickness, and preserved contractile function. Outcomes for patients with RCM are poor, with increased morbidity and mortality compared to other forms of cardiomyopathy. In some patients, RCM can be caused by genetic mutations, notably in genes encoding for components of the sarcomere. While many mutations have been described in RCM patients, the molecular and cellular mechanisms leading from these mutations to the patient’s physiological phenotype are poorly described. Hypothesis: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) derived from RCM patients will recapitulate the myocardial relaxation defects seen in RCM and provide a novel in vitro model for investigating the molecular mechanisms underpinning this disease. Methods: Induced pluripotent stem cells (iPSCs) were derived from a pediatric patient with RCM caused by a TNNT2 R94C mutation. CRISPR was used to correct the mutation, and cellular mechanics and calcium handling properties were compared to the patient line using a novel high-throughput traction-force imaging platform. Transcriptional profiles were compared using RNA-seq. Results: RCM cells carrying the TNNT2 R94C mutation show increased calcium sensitivity leading to increased resting tension at baseline, as well as prolonged calcium kinetics leading to prolonged relaxation times. Gene expression profiling reveals changes in expression of ECM genes, which may further contribute to the impaired myocardial relaxation seen in RCM. Conclusions: Patient-derived hiPSC-CMs from an RCM patient recapitulate the relaxation defects seen in RCM and highlight the central role of increased calcium sensitivity in impaired myocardial relaxation.

Suppression of zero-field quantum tunneling of magnetization by a fluorido bridge for a "very hard" 3d-4f single-molecule magnet

<h2>Summary</h2> Single-molecule magnets (SMMs) have been proposed for ultra-high-density information storage due to prolonged relaxation times below blocking temperature (<i>T</i>_B). However, many SMMs suffer from fast magnetization loss at zero-field regime due to the quantum tunneling of magnetization (QTM) effect. Here we show the creation of large ground magnetic momentum is crucial to suppress zero-field QTM for SMMs. The recipe is to use bridging fluoride, which creates ferromagnetic couplings among the lanthanide ions in the complex [Dy₃Cr₃(<i>μ</i>₃-F) (<i>μ</i>₃-OH)₃(mdea)₃(piv)₈DMF]·H₂O·CH₃CN. As such, the molecule owns a large ground magnetic moment of <mml:math><mml:mrow><mml:mn>10.7</mml:mn><mml:mi>μ</mml:mi><mml:mi>B</mml:mi></mml:mrow></mml:math> and is confirmed to be an SMM with <i>T</i>_B of 5 K. More importantly, a "very hard" magnetic hysteresis loop with a coercive field of 1.3 T and more than 97% remanence is observed up to 0.7 K. <i>Ab initio</i> calculations fully support such observations, rendering the importance of fluorido bridge to suppress zero-field QTM for lanthanide-based SMMs.

Unique Random-Block Polymer Architecture for Site-Specific Mitochondrial Sequestration-Aided Effective Chemotherapeutic Delivery and Enhanced Fluorocarbon Segmental Mobility-Facilitated 19F Magnetic Resonance Imaging.

The elevation of the chemotherapeutic efficacy and attenuation of its side effects on healthy cells and tissues become one of the prime targets for the treatment of cancer. Toward this direction, a sequential receptor and mitochondria dual-targeting strategy was implemented in the DX TP PG BN 19F theranostic polymer that was anchored with the chemotherapeutic agent doxorubicin, receptor-targeting biotin, and mitochondria-targeting triphenylphosphonium cations. The polymer was flourished with a unique 19F magnetic resonance imaging (MRI) tracer that exhibited high segmental mobility and eventually led to prolonged T2 relaxation time. Furthermore, for the sake of amphiphilicity, the DX TP PG BN 19F polymer spontaneously aggregated into nano-sphere with positive zeta potential, where the MRI tracer and biotin embedded at the exterior and displayed site-specific targeting and remarkable 19F MRI capability simultaneously. The mitochondria-targeting competency of the DX TP PG BN 19F theranostic polymer was investigated by comparing the non-mitochondrial-targeting DX PG BN 19F polymer using fluorescence microscopic cell imaging in human cervical, HeLa, and breast MCF-7 carcinoma cell lines. Moreover, cytotoxicity experiments of the aforementioned theranostic polymers clarified the enhancement of the chemotherapeutic efficacy of DX TP PG BN 19F theranostic polymers through effective and precise mitochondrial doxorubicin delivery that forced to follow the apoptotic path.

Metabolites Alterations and Liver Injury in Hepatic Encephalopathy Models Evaluated by Use of 7T-MRI.

This study is to observe a thioacetamide (TAA) administered Hepatic encephalopathy (HE) model rats at three and ten days after TAA administration using liver MRI and brain MR Spectroscopy (MRS) by use of 7T-MRI. Forty-two Wistar rats (control group, n = 14) were intraperitoneally administered at 300 mg/kg (low-dose group, n = 14) or 400 mg/kg (high-dose group, n = 14) doses of TAA for induced of HE. At three days after TAA administration, glutamine (Gln) measured by MRS in high-dose and low-dose TAA groups showed significant increases in comparison to those of the control group (p < 0.05). Other metabolites measured by MRS showed no significant changes. Liver T1ρ and T2 relaxation times significantly increased three days after TAA injection compared to pre-injection. There was a correlation between Gln levels in the brain and the relaxation time of the liver. Furthermore, Gln levels and relaxation time changed depending on the TAA dose. The Gln concentration in the brain increased with the deterioration of liver function, as inferred from the prolonged relaxation time of the liver. The prolonged relaxation time of the liver corresponded with the level of Gln in the brain. Gln concentration for the alterations of brain metabolites and T1ρ relaxation time for the assessment of liver damage are useful markers for inter-organ association analysis in the HE model.

History-Dependent Stress Relaxation of Liquids under High-Confinement: A Molecular Dynamics Study

When liquids are confined into a nanometer-scale slit, the induced layering-like film structure allows the liquid to sustain non-isotropic stresses and thus be load-bearing. Such anisotropic characteristics of liquid under confinement arise naturally from the liquids’ wavenumber dependent compressibility, which does not need solidification to take place as a prerequisite. In other words, liquids under confinement can still retain fluidity with molecules being (sub-)diffusive. However, the extensively prolonged structural relaxation times can cause hysteresis of stress relaxation of confined molecules in response to the motions of confining walls and thereby rendering the quasi-static stress tensors history-dependent. In this work, by means of molecular dynamics, stress tensors of a highly confined key base-oil component, i.e., 1-decene trimer, are calculated after its relaxation from being compressed and decompressed. A maximum of 77.1 MPa normal stress discrepancy has been detected within a triple-layer boundary film. Analyses with respect to molecular morphology indicate that among the effects (e.g., confinement, molecular structure, and film density) that can potentially affect confined stresses, the ordering status of the confined molecules plays a predominant role.

Abstract 14365: Interrogating Diastolic Dysfunction Using a Novel Stem Cell Model of Restrictive Cardiomyopathy

Introduction: Diastolic dysfunction is an important cause of morbidity and mortality in both children and adults. Unfortunately, investigation of new therapies is limited by a lack of in vitro models of diastolic dysfunction. Idiopathic Restrictive Cardiomyopathy (RCM) is a serious genetic condition in which children have an isolated defect in myocardial relaxation. Though some of the genetic lesions have been identified, there is still an incomplete understanding of the mechanisms that lead to diastolic dysfunction in this condition. Hypothesis: Cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) derived from patients with RCM will provide an in vitro model of diastolic dysfunction and will allow elucidation of cellular and molecular pathways involved in myocardial relaxation. Methods: Patients with RCM and a known pathogenic sarcomeric mutation were identified through speaking with providers in our heart failure and cardiac transplant program. hiPSCs were derived from patient blood samples and differentiated into cardiomyocytes. Isogenic controls were generated using CRISPR-mediated homologous directed repair. Calcium handling, contraction kinetics, and resting tension of RCM hiPSC-CMs were compared to control hiPSC-CMs on substrates with defined stiffness using high-throughput quantitative imaging techniques. Results: hiPSC-CMs derived from a patient with a pathogenic mutation in troponin T (TNNT2) display prolonged calcium kinetics and relaxation times compared to controls, as well as increased resting tension. Conclusions: RCM hiPSC-CMs represent a novel model of diastolic dysfunction that can be interrogated on a high-throughput platform. We plan to use these cells to perform proteome-scale functional screens, providing a novel opportunity to discover previously unknown contributors to diastolic dysfunction.

Abstract 9852: Targeting Mek/Erk Signaling in the Treatment of Mitral Valve Prolapse

Introduction: Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease, affecting 1 in 40 humans and ~70% of small breed dogs. There are no effective nonsurgical treatments for MVP and therapeutic efforts have been hindered due to an incomplete understanding of its fundamental causes. Recent studies by our group have described the genetic basis for non-syndromic MVP and have provided new insights into molecular processes that underlie the disease. We have used this genetic information to identify druggable targets that can provide a non-surgical option for humans. In particular, we have identified the MEK/ERK pathway as the major disease initiating pathway and prolonged hyperactivation of MEK/ERK drives disease progression and severity. Hypothesis: Pharmacological blockade of MEK/ERK activities will sufficiently arrest the disease pathway and maintain the valves in a sub-clinical condition. Methods and Results: The FDA-approved MEK1 inhibitor Trametinib was administered to Dzip1 S24R/+ mice; a disease model that phenocopies human MVP. Preliminary results suggest safety concerns in mice associated with chronic administration of Trametinib (1 mg/kg/day). Animals demonstrated signs of cardiotoxicity on echocardiography, including left atrial enlargement; a reduction in E/A wave intensity; left ventricular wall movement abnormalities; prolonged isovolumetric relaxation time, and a reduced ejection fraction. As such, our lab has focused our efforts on identifying novel MEK1 inhibitors with a favorable safety profile. Utilizing a machine learning based workflow, we have identified highly selective MEK1 inhibitors with retained activity (&lt;100nM IC50 values); high gastrointestinal absorption (&gt;85%); favorable predicted LD50 values (&gt;1,000 mg/kg), and devoid of major cytochrome interactions. Conclusions: MEK1 may serve as a druggable target in the treatment of mitral valve prolapse; however, currently available MEK inhibitors demonstrate limiting toxicities. Future studies will involve in vivo administration of our novel compounds to Dzip1 S24R/+ mice. We envision results from this study will help guide the development of systemic or targeted therapies for the use in human patients with mitral valve prolapse.

Longer sustained Fontan circulation is associated with prolonged hepatic T1 relaxation time on T1 mapping

Abstract Funding Acknowledgements Type of funding sources: None. Background Patients with single ventricle defects may develop Fontan-associated liver disease. T1 mapping has been successfully used for evaluating chronic liver disease in adults. Liver T1 mapping has been also studied in the pediatric patients with single ventricles, and these patients show higher T1 relaxation times compared to the healthy controls. Purpose Our objective was to study the relationship between the cardiac MRI (CMR) T1 mapping relaxation time of the liver and 1) CMR derived hemodynamic parameters, 2) peripheral venous pressure (PVP) measured from a cubital cannula 3) systemic ventricle morphology [LV vs. RV], 4) the age of patient, and 5) alanine transaminase (P-ALAT) levels. Methods This retrospective study included 46 patients with functional single ventricle, which underwent routine CMR at our hospital. Table 1 shows demographic and clinical data of the study population. Statistical analysis were performed with IBM SPSS Statistics v.25 software using independent samples t test, Mann-Whitney U-test or Pearson correlation as appropriate. A p-value less than 0.05 was considered significant. Results The average T1 relaxation time of the liver was longer in patients with RV morphology (p = 0.004). There was a significant moderate positive correlation between the age of the patients and hepatic T1 relaxation time (r = 0.45, p = 0.002), and between hepatic T1 relaxation time and P-ALAT levels (r = 0.5, p = 0.016) (Fig.1). No significant correlations were detected between the T1 times of the liver and hemodynamic parameters of the heart (all tested parameters are listed in the Table1). Ejection fraction and PVP showed a non-significant weak correlation with a hepatic T1 relaxation times (r=-0.3, p = 0,056 and r = 0.3, p = 0,070, respectively). Conclusions T1 mapping times of the liver may reflect Fontan-associated liver disease. We observed connections between the hepatic T1 relaxation times and 1) patients age, 2) systemic ventricle morphology and 3) P-ALAT levels.

Ventricular Function and Pulmonary Artery Pressure in Children with Mild and Moderate Bronchial Asthma

Background: Bronchial asthma is a chronic airway disease. Cardiac affection in children with bronchial asthma was reported mainly in cases with severe asthma and during acute exacerbations. Aim of the Work: To study cardiac affection in children with mild and moderate bronchial asthma using conventional and tissue Doppler imaging [TDI] echocardiography. Patients and Methods: This was a prospective case control study. Study involved 160 children aged 6-14 years old who were following in outpatient pediatric clinic, Al-Hussein hospital, Al-Azhar University, Cairo, Egypt, during the period from January 4, 2016, till February 15, 2017. All children underwent peak expiratory flow rate [PEFR] assessment. Echocardiography was done for all to assess systolic and diastolic functions of right ventricle [RV] and left ventricle [LV] using conventional and tissue Doppler imaging [TDI] echocardiography. Results: TDI parameters showed evidence of RV diastolic dysfunction in patients with moderate asthma in the form of significantly lower tricuspid valve [TV] e’ [12.1 ± 2.7 cm/s], lower TV e’/a’ ratio [1.28 ± 0.18], prolonged RV isovolumetric relaxation time [IVRT] [71.8 ± 2.4 ms], and higher RV myocardial performance index [0.49 ± 0.04] compared to control group. Also, patients with mild asthma had impaired RV diastolic function in the form of significantly lower TV e’/a’ [1.51 ± 0.13] and longer RV IVRT [65 ± 2.9 ms] compared to control group. Pulmonary artery pressure was significantly elevated in moderate asthma group [18.4 ± 9.2 mmHg]. RV IVRT was the only parameter showing a significant negative correlation to PEFR Conclusion: Pediatric patients with mild and moderate bronchial asthma may have RV diastolic dysfunction. TDI is a good screening tool to detect early changes in cardiac function in such patients. RV IVRT measured by TDI is a sensitive tool to detect early diastolic impairment.

Cardiotoxicity assessment using 3D vascularized cardiac tissue consisting of human iPSC-derived cardiomyocytes and fibroblasts

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for cardiac safety assessment but have limitations for the evaluation of drug-induced contractility. Three-dimensional (3D) cardiac tissues are similar to native tissue and valuable for the assessment of contractility. However, a longer time and specialized equipment are required to generate 3D tissues. We previously developed a simple method to generate 3D tissue in a short period by coating the cell surfaces with extracellular matrix proteins. We hypothesized that this 3D cardiac tissue could be used for simultaneous evaluation of drug-induced repolarization and contractility. In the present work, we examined the effects of several compounds with different mechanisms of action by cell motion imaging. Consequently, human ether-a-go-go-related gene (HERG) channel blockers with high arrhythmogenic risk caused prolongation of contraction-relaxation duration and arrhythmia-like waveforms. Positive inotropic drugs, which increase intracellular Ca2+ levels or myocardial Ca2+ sensitivity, caused an increase in maximum contraction speed (MCS) or average deformation distance (ADD) (ouabain, 138% for MCS at 300 nM; pimobendane, 132% for ADD at 3 μM). For negative inotropic drugs, verapamil reduced both MCS and ADD (61% at 100 nM). Thus, this 3D cardiac tissue detected the expected effects of various cardiovascular drugs, suggesting its usefulness for cardiotoxicity evaluation.

Long-term evolution of multiple sclerosis iron rim lesions in 7 T MRI.

Recent data suggest that multiple sclerosis white matter lesions surrounded by a rim of iron containing microglia, termed iron rim lesions, signify patients with more severe disease course and a propensity to develop progressive multiple sclerosis. So far, however, little is known regarding the dynamics of iron rim lesions over long-time follow-up. In a prospective longitudinal cohort study in 33 patients (17 females; 30 relapsing-remitting, three secondary progressive multiple sclerosis; median age 36.6 years (18.6-62.6), we characterized the evolution of iron rim lesions by MRI at 7 T with annual scanning. The longest follow-up was 7 years in a subgroup of eight patients. Median and mean observation period were 1 (0-7) and 2.9 (±2.6) years, respectively. Images were acquired using a fluid-attenuated inversion recovery sequence fused with iron-sensitive MRI phase data, termed FLAIR-SWI, as well as a magnetization prepared two rapid acquisition gradient echoes, termed MP2RAGE. Volumes and T1 relaxation times of lesions with and without iron rims were assessed by manual segmentation. The pathological substrates of periplaque signal changes outside the iron rims were corroborated by targeted histological analysis on 17 post-mortem cases (10 females; two relapsing-remitting, 13 secondary progressive and two primary progressive multiple sclerosis; median age 66 years (34-88), four of them with available post-mortem 7 T MRI data. We observed 16 nascent iron rim lesions, which mainly formed in relapsing-remitting multiple sclerosis. Iron rim lesion fraction was significantly higher in relapsing-remitting than progressive disease (17.8 versus 7.2%; P < 0.001). In secondary progressive multiple sclerosis only, iron rim lesions showed significantly different volume dynamics (P < 0.034) compared with non-rim lesions, which significantly shrank with time in both relapsing-remitting (P < 0.001) and secondary progressive multiple sclerosis (P < 0.004). The iron rims themselves gradually diminished with time (P < 0.008). Compared with relapsing-remitting multiple sclerosis, iron rim lesions in secondary progressive multiple sclerosis were significantly more destructive than non-iron rim lesions (P < 0.001), reflected by prolonged lesional T1 relaxation times and by progressively increasing changes ascribed to secondary axonal degeneration in the periplaque white matter. Our study for the first time shows that chronic active lesions in multiple sclerosis patients evolve over many years after their initial formation. The dynamics of iron rim lesions thus provide one explanation for progressive brain damage and disability accrual in patients. Their systematic recording might become useful as a tool for predicting disease progression and monitoring treatment in progressive multiple sclerosis.

Synthetic MRI demonstrates prolonged regional relaxation times in the brain of preterm born neonates with severe postnatal morbidity

BackgroundTo identify preterm infants at risk for neurodevelopment impairment that might benefit from early neurorehabilitation, early prognostic biomarkers of future outcomes are needed. ObjectiveTo determine whether synthetic MRI is sensitive to age-related changes in regional tissue relaxation times in the brain of preterm born neonates when scanned at term equivalent age (TEA, 37–42 weeks), and to investigate whether severe postnatal morbidity results in prolonged regional tissue relaxation times. Materials and methodsThis retrospective study included 70 very preterm born infants scanned with conventional and synthetic MRI between January 2017 and June 2019 at TEA. Infants with severe postnatal morbidity were allocated to a high-risk group (n = 22). All other neonates were allocated to a low-risk group (n = 48). Linear regression analysis was performed to determine the relationship between relaxation times and postmenstrual age (PMA) at scan. Analysis of covariance was used to evaluate the impact of severe postnatal morbidity in the high-risk group on T1 and T2 relaxation times. Receiver operating characteristic (ROC) curves were plotted and analysed with area under the ROC curve (AUC) to evaluate the accuracy of classifying high-risk patients based on regional relaxation times. ResultsA linear age-related decrease of T1 and T2 relaxation times correlating with PMA at scan (between 37 and 42 weeks) was found in the deep gray matter, the cerebellum, the cortex, and the posterior limb of the internal capsule (PLIC) (p < .005 each), but not in the global, frontal, parietal, or central white matter. Analysis of covariance for both risk groups, adjusted for PMA, revealed significantly prolonged regional tissue relaxation times in neonates with severe postnatal morbidity, which was best illustrated in the central white matter of the centrum semiovale (T1 Δ = 11.5%, T2 Δ = 13.4%, p < .001) and in the PLIC (T1 Δ = 9.2%, T2 Δ = 6.9%, p < .001). The relaxation times in the PLIC and the central white matter predicted high-risk status with excellent accuracy (AUC range 0.82–0.86). ConclusionSynthetic MRI-based relaxometry in the brain of preterm born neonates is sensitive to age-related maturational changes close to TEA. Severe postnatal morbidity correlated with a significant delay in tissue relaxation. Synthetic MRI may provide early prognostic biomarkers for neurodevelopment impairment.