Microstructural and Microvascular Phenotype of Sarcomere Mutation Carriers and Overt Hypertrophic Cardiomyopathy.

BACKGROUND: In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups-overt, either genotype-positive (G+LVH+) or genotype-negative (G-LVH+), and subclinical (G+LVH-) HCM-exploring relationships with electrical changes and genetic substrate. METHODS: This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G-LVH+), 77 patients with G+LVH-, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation). RESULTS: Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all P<0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both P<0.001). Patients with G-LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle (P<0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G- patients (100% [51/51] versus 82% [41/50]; P=0.001). Patients with G+LVH- compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; P<0.001), and MVD (reduced stress myocardial blood flow [P=0.015] with perfusion defects in 28% versus 0 healthy volunteers [P=0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, P=0.01; stress myocardial blood flow: odds ratio, 2.8, P=0.015; subclinical: fractional anisotropy odds ratio, 4.0, P=0.001; myocardial perfusion reserve odds ratio, 2.2, P=0.049). CONCLUSIONS: Microstructural alteration and MVD occur in overt HCM and are different in G+ and G- patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy.

Developing a medical device-grade T2 phantom optimized for myocardial T2 mapping by cardiovascular magnetic resonance.

INTRODUCTION: A long T2 relaxation time can reflect oedema, and myocardial inflammation when combined with increased plasma troponin levels. Cardiovascular magnetic resonance (CMR) T2 mapping therefore has potential to provide a key diagnostic and prognostic biomarkers. However, T2 varies by scanner, software, and sequence, highlighting the need for standardization and for a quality assurance system for T2 mapping in CMR. AIM: To fabricate and assess a phantom dedicated to the quality assurance of T2 mapping in CMR. METHOD: A T2 mapping phantom was manufactured to contain 9 T1 and T2 (T1|T2) tubes to mimic clinically relevant native and post-contrast T2 in myocardium across the health to inflammation spectrum (i.e., 43-74 ms) and across both field strengths (1.5 and 3 T). We evaluated the phantom's structural integrity, B0 and B1 uniformity using field maps, and temperature dependence. Baseline reference T1|T2 were measured using inversion recovery gradient echo and single-echo spin echo (SE) sequences respectively, both with long repetition times (10 s). Long-term reproducibility of T1|T2 was determined by repeated T1|T2 mapping of the phantom at baseline and at 12 months. RESULTS: The phantom embodies 9 internal agarose-containing T1|T2 tubes doped with nickel di-chloride (NiCl2) as the paramagnetic relaxation modifier to cover the clinically relevant spectrum of myocardial T2. The tubes are surrounded by an agarose-gel matrix which is doped with NiCl2 and packed with high-density polyethylene (HDPE) beads. All tubes at both field strengths, showed measurement errors up to ≤ 7.2 ms [< 14.7%] for estimated T2 by balanced steady-state free precession T2 mapping compared to reference SE T2 with the exception of the post-contrast tube of ultra-low T1 where the deviance was up to 16 ms [40.0%]. At 12 months, the phantom remained free of air bubbles, susceptibility, and off-resonance artifacts. The inclusion of HDPE beads effectively flattened the B0 and B1 magnetic fields in the imaged slice. Independent temperature dependency experiments over the 13-38 °C range confirmed the greater stability of shorter vs longer T1|T2 tubes. Excellent long-term (12-month) reproducibility of measured T1|T2 was demonstrated across both field strengths (all coefficients of variation < 1.38%). CONCLUSION: The T2 mapping phantom demonstrates excellent structural integrity, B0 and B1 uniformity, and reproducibility of its internal tube T1|T2 out to 1 year. This device may now be mass-produced to support the quality assurance of T2 mapping in CMR.

Pyrrolidinium Containing Ionic Liquid Electrolytes for Li-Based Batteries.

Ionic liquids are potential alternative electrolytes to the more conventional solid-state options under investigation for future energy storage solutions. This review addresses the utilization of IL electrolytes in energy storage devices, particularly pyrrolidinium-based ILs. These ILs offer favorable properties, such as high ionic conductivity and the potential for high power drain, low volatility and wide electrochemical stability windows (ESW). The cation/anion combination utilized significantly influences their physical and electrochemical properties, therefore a thorough discussion of different combinations is outlined. Compatibility with a wide array of cathode and anode materials such as LFP, V2O5, Ge and Sn is exhibited, whereby thin-films and nanostructured materials are investigated for micro energy applications. Polymer gel electrolytes suitable for layer-by-layer fabrication are discussed for the various pyrrolidinium cations, and their compatibility with electrode materials assessed. Recent advancements regarding the modification of typical cations such a 1-butyl-1-methylpyrrolidinium, to produce ether-functionalized or symmetrical cations is discussed.

Prognostic and Predictive Factors in Patients with Advanced HCC and Elevated Alpha-Fetoprotein Treated with Ramucirumab in Two Randomized Phase III Trials.

PURPOSE: Ramucirumab is an effective treatment for patients with advanced hepatocellular carcinoma (aHCC) and baseline alpha-fetoprotein (AFP) ≥400 ng/mL. We aimed to identify prognostic and predictive factors of response to ramucirumab in patients with aHCC with AFP ≥400 ng/mL from the phase III REACH and REACH-2 randomized trials. PATIENTS AND METHODS: Patients with aHCC, Child-Pugh class A with prior sorafenib treatment were randomized in REACH and REACH-2 (ramucirumab 8 mg/kg or placebo, biweekly). Meta-analysis of individual patient-level data (pooled population) from REACH (AFP ≥400 ng/mL) and REACH-2 was performed. A drug exposure analysis was conducted for those with evaluable pharmacokinetic data. To identify potential prognostic factors for overall survival (OS), multivariate analyses were performed using a Cox proportional hazards regression model. To define predictors of ramucirumab benefit, subgroup-by-treatment interaction terms were evaluated. RESULTS: Of 542 patients (316 ramucirumab, 226 placebo) analyzed, eight variables had independent prognostic value associated with poor outcome (geographical region, Eastern Cooperative Oncology Group performance score ≥1, AFP >1,000 ng/mL, Child-Pugh >A5, extrahepatic spread, high neutrophil-to-lymphocyte ratio, high alkaline phosphatase and aspartate aminotransferase). Ramucirumab survival benefit was present across all subgroups, including patients with very aggressive HCC [above median AFP; HR: 0.64; 95% confidence interval (CI): 0.49-0.84] and nonviral aHCC (HR: 0.56; 95% CI: 0.40-0.79). While no baseline factor was predictive of a differential OS benefit with ramucirumab, analyses demonstrated an association between high drug exposure, treatment-emergent hypertension (grade ≥3), and increased ramucirumab benefit. CONCLUSIONS: Ramucirumab provided a survival benefit irrespective of baseline prognostic covariates, and this benefit was greatest in patients with high ramucirumab drug exposure and/or those with treatment-related hypertension.

Use of rapid cardiac magnetic resonance imaging to guide chelation therapy in patients with transfusion-dependent thalassaemia in India: UMIMI study.

AIMS: To explore the impact of incorporating a faster cardiac magnetic resonance (CMR) imaging protocol in a low-middle-income country (LMIC) and using the result to guide chelation in transfusion-dependent patients. METHODS AND RESULTS: A prospective UK-India collaborative cohort study was conducted in two cities in India. Two visits 13 months apart included clinical assessment and chelation therapy recommendations based on rapid CMR results. Participants were recruited by the local patient advocate charity, who organized the patient medical camps. The average scanning time was 11.3 ± 2.5 min at the baseline and 9.8 ± 2.4 min (P < 0.001) at follow-up. The baseline visit was attended by 103 patients (mean age 25 years) and 83% attended the second assessment. At baseline, 29% had a cardiac T2* < 20 ms, which represents significant iron loading, and 12% had left ventricular ejection fraction <60%, the accepted lower limit in this population. Only 3% were free of liver iron (T2* ≥ 17 ms). At 13 months, more patients were taking intensified dual chelation therapy (43% vs. 55%, P = 0.002). In those with cardiac siderosis (baseline T2* < 20 ms), there was an improvement in T2*-10.9 ± 5.9 to 13.5 ± 8.7 ms, P = 0.005-and fewer were classified as having clinically important cardiac iron loading (T2* < 20 ms, 24% vs. 16%, P < 0.001). This is the first illustration in an LMIC that incorporating CMR results into patient management plans can improve cardiac iron loading. CONCLUSION: For thalassaemia patients in an LMIC, a simplified CMR protocol linked to therapeutic recommendation via the patient camp model led to enhanced chelation therapy and a reduction in cardiac iron in 1 year.

Ionic Liquid Based Polymer Gel Electrolytes for Use with Germanium Thin Film Anodes in Lithium Ion Batteries.

Thermally stable, flexible polymer gel electrolytes with high ionic conductivity are prepared by mixing the ionic liquid 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide (C4mpyrTFSI), LiTFSI and poly(vinylidene difluoride-co-hexafluoropropylene (PVDF-HFP). FT-IR and Raman spectroscopy show that an amorphous film is obtained for high (60 %) C4mpyrTFSI contents. Thermogravimetric analysis (TGA) confirms that the polymer gels are stable below ∼300 °C in both nitrogen and air environments. Ionic conductivity of 1.9×10-3 S cm-2 at room temperature is achieved for the 60 % ionic liquid loaded gel. Germanium (Ge) anodes maintain a coulombic efficiency above 95 % after 90 cycles in potential cycling tests with the 60 % C4mpyrTFSI polymer gel.