Biventricular Noncompaction Cardiomyopathy in a Patient Presenting With a New Cerebrovascular Event.

Noncompaction (NC) cardiomyopathy (NCCM) is a rare, genetically heterogeneous cardiomyopathy (CM) caused by failure to compact the intertrabecular recesses of the myocardium. This condition usually affects the apical segment of the left ventricle, yet there are noted basal segment, biventricular, and right ventricular predominant cases. NCCM is largely diagnosed in the pediatric population; however, there is increasing recognition in older patients with heart failure and stroke and patients with arrhythmias. Treatment focuses on symptomatic management of heart failure, anticoagulation, and implantable cardiac defibrillators.

Novel NMP split liver model recapitulates human IRI and demonstrates ferroptosis modulators as a new therapeutic strategy.

BACKGROUND: Almost 9%of deceased donor livers are discarded as marginal donor livers (MDL) due to concern of severe ischemia reperfusion injury (IRI). Emerging data supports ferroptosis (iron regulated hepatocellular death) as an IRI driver, however lack of robust preclinical model limits therapeutic testing. In this manuscript we describe the development of a novel rigorous internal control system utilizing normothermic perfusion of split livers to test ferroptosis regulators modulating IRI. METHODS: Upon institutional approval, split human MDLs were placed on our normothermic perfusion machine, Perfusion Regulated Organ Therapeutics with Enhanced Controlled Testing (PROTECT), pumping arterial and portal blood. Experiment 1 compared right (UR) and left (UL) lobes to validate PROTECT. Experiment 2 assessed ferroptosis regulator Deferoxamine in Deferoxamine Agent Treated (DMAT) vs. No Agent Internal Control (NAIC) lobes. Liver serology, histology, and ferroptosis genes were assessed. RESULTS: Successful MDL perfusion validated PROTECT with no ALT or AST difference between UR and UL (∆ALT UR: 235, ∆ALT UL: 212; ∆AST UR: 576, ∆AST UL: 389). Liver injury markers increased in NAIC vs. DMAT (∆ALT NAIC: 586, ∆ALT DMAT: -405; ∆AST NAIC: 617, ∆AST DMAT: -380). UR and UL had similar expression of ferroptosis regulators RPL8,HO-1 and HIFα. Significantly decreased intrahepatic iron (p = .038), HO-1 and HIFα in DMAT (HO-1 NAIC: 6.93, HO-1 DMAT: 2.74; HIFαNAIC: 8.67, HIFαDMAT: 2.60)and no hepatocellular necrosis or immunohistochemical staining (Ki67/Cytokeratin-7) differences were noted. CONCLUSION: PROTECT demonstrates the therapeutic utility of a novel normothermic perfusion split liver system for drug discovery and rapid translatability of therapeutics, driving a paradigm change in organ recovery and transplant medicine. Our study using human livers, provides preliminary proof of concept for the novel role of ferroptosis regulators in driving IRI.

Development and validation of an ambulatory piglet model for short bowel syndrome with ileo-colonic anastomosis.

IMPACT STATEMENT: Short bowel syndrome is associated with significant comorbidities and mortality. This study is important as unlike current systems, it provides a validated piglet model which mirrors anatomical, histological, and serological characteristics observed in human SBS. This model can be used to advance knowledge into mechanistic pathways and therapeutic modalities to improve outcomes for SBS patients. This study is novel in that in addition to significant reduction in the remnant bowel and noted liver disease, we also developed a method to emulate ileocecal valve resection and described gut adaptive responses which has important clinical implications in humans.

Mechanisms of Parenteral Nutrition-Associated Liver and Gut Injury.

Parenteral nutrition (PN) has revolutionized the care of patients with intestinal failure by providing nutrition intravenously. Worldwide, PN remains a standard tool of nutrition delivery in neonatal, pediatric, and adult patients. Though the benefits are evident, patients receiving PN can suffer serious cholestasis due to lack of enteral feeding and sometimes have fatal complications from liver injury and gut atrophy, including PN-associated liver disease or intestinal failure-associated liver disease. Recent studies into gut-systemic cross talk via the bile acid-regulated farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) axis, gut microbial control of the TGR5-glucagon-like peptide (GLP) axis, sepsis, and role of prematurity of hepatobiliary receptors are greatly broadening our understanding of PN-associated injury. It has also been shown that the composition of ω-6/ω-3 polyunsaturated fatty acids given parenterally as lipid emulsions can variably drive damage to hepatocytes and cell integrity. This manuscript reviews the mechanisms for the multifactorial pathogenesis of liver disease and gut injury with PN and discusses novel ameliorative strategies.

Mechanisms and predictors of recurrent tachycardia after catheter ablation for d-transposition of the great arteries after the Mustard or Senning operation.

BACKGROUND: The Senning and Mustard operations for dextro-transposition of the great arteries are associated with an increased risk for supraventricular tachycardia. Catheter ablation has been shown to be acutely successful for achieving rhythm control in this population, but the mechanisms of recurrence are ill-defined. OBJECTIVE: We hypothesized that the type and degree of recurrence would vary by the surgical technique used. METHODS: All consecutive catheter ablation procedures for dextro-transposition of the great arteries after the Mustard or Senning operation between 2004 and 2016 at a single center were reviewed. Tachycardia mechanisms were determined by complete 3-dimensional mapping in addition to a standard electrophysiological technique for all cases. RESULTS: Twenty-eight patients underwent 38 procedures during the study period. The most common mechanism at the index procedure was intra-atrial reentrant tachycardia using the cavotricuspid isthmus. Over a median follow-up period of 1.6 years, 9 patients experienced recurrent tachycardia (32%), all of whom underwent repeat catheter ablation. Tachycardia recurrence was more common after the Senning vs the Mustard operation (6 of 10 [60%] vs 3 of 18 [17%]; P = .034). In addition, substrates for recurrence were different from those encountered at the index procedure in 10 of 13 tachycardias (77%), with the single most common location being the posterior anastomosis after the Senning operation. Complete control was ultimately achieved in 27 patients (96%) when considering all procedures. CONCLUSION: Recurrent tachycardia after catheter ablation appears to be more common after the Senning operation and to involve substrates unique to this repair. The posterior anastomosis is commonly implicated and should not be overlooked.

Speeding up PET/MR for cancer staging of children and young adults.

OBJECTIVE: Combining 18F-FDG PET with whole-body MR for paediatric cancer staging is practically feasible if imaging protocols can be streamlined. We compared 18F-FDG PET/STIR with accelerated 18F-FDG PET/FSPGR for whole-body tumour imaging in children and young adults. METHODS: Thirty-three children and young adults (17.5 ± 5.5 years, range 10-30) with malignant lymphoma or sarcoma underwent a 18F-FDG PET staging examination, followed by ferumoxytol-enhanced STIR and FSPGR whole-body MR. 18F-FDG PET scans were fused with MR data and the number and location of tumours on each integrated examination were determined. Histopathology and follow-up imaging served as standard of reference. The agreement of each MR sequence with the reference and whole-body imaging times were compared using Cohen's kappa coefficient and Student's t-test, respectively. RESULTS: Comparing 18F-FDG PET/FSPGR to 18F-FDG PET/STIR, sensitivities were 99.3 % for both, specificities were statistically equivalent, 99.8 versus 99.9 %, and the agreement with the reference based on Cohen's kappa coefficient was also statistically equivalent, 0.989 versus 0.992. However, the total scan-time for accelerated FSPGR of 19.8 ± 5.3 minutes was significantly shorter compared to 29.0 ± 7.6 minutes for STIR (p = 0.001). CONCLUSION: F-FDG PET/FSPGR demonstrated equivalent sensitivities and specificities for cancer staging compared to 18F-FDG PET/STIR, but could be acquired with shorter acquisition time. KEY POINTS: • Breath-hold FSPGR sequences shorten the data acquisition time for whole-body MR and PET/MR. • Ferumoxytol provides long-lasting vascular contrast for whole-body MR and PET/MR. • 18 F-FDG PET/FSPGR data provided equal sensitivity and specificity for cancer staging compared to 18 F-FDG PET/STIR.