Whole-body galactose oxidation as a robust functional assay to assess the efficacy of gene-based therapies in a mouse model of Galactosemia.

Despite the implementation of lifesaving newborn screening programs and a galactose-restricted diet, many patients with classic galactosemia develop long-term debilitating neurological deficits and primary ovarian insufficiency. Previously, we showed that the administration of human GALT mRNA predominantly expressed in the GalT gene-trapped mouse liver augmented the expression of hepatic GALT activity, which decreased not only galactose-1 phosphate (gal-1P) in the liver but also peripheral tissues. Since each peripheral tissue requires distinct methods to examine the biomarker and/or GALT effect, this highlights the necessity for alternative strategies to evaluate the overall impact of therapies. In this study, we established that whole-body galactose oxidation (WBGO) as a robust, noninvasive, and specific method to assess the in vivo pharmacokinetic and pharmacodynamic parameters of two experimental gene-based therapies that aimed to restore GALT activity in a mouse model of galactosemia. Although our results illustrated the long-lasting efficacy of AAVrh10-mediated GALT gene transfer, we found that GALT mRNA therapy that targets the liver predominantly is sufficient to sustain WBGO. The latter could have important implications in the design of novel targeted therapy to ensure optimal efficacy and safety.

Improvements in Extracorporeal Membrane Oxygenation for Primary Graft Failure After Heart Transplant.

BACKGROUND: Severe primary graft failure is a life-threatening complication of heart transplantation that may require venoarterial extracorporeal membrane oxygenation (VA-ECMO) support. Surgical practices and management strategies regarding VA-ECMO vary between and within centers. METHODS: We performed a single-center retrospective cohort study on adult patients who received VA-ECMO for primary graft failure between 2013 and 2020. Clinical data were obtained from chart review and national databases. Patients were stratified by transplantation before or after 2017, when our center adopted additional objective criteria for VA-ECMO, adopted partial-flow support, and changed from central cannulation to chimney graft arterial cannulation of brachiocephalic, axillary, or aorta. The primary outcome was survival to device weaning. Secondary outcomes were survival to discharge, survival to 1 year, complications on support, and time to sedation weaning and extubation. RESULTS: From 276 heart transplant recipients, 39 severe primary graft failure patients requiring VA-ECMO were identified. Incidence of graft failure was 13% (n = 18 of 135) pre-2017 and 15% (n = 21 of 141) post-2017. Survival at all time points improved significantly after 2017, with greatest difference in survival to device weaning (61% pre-2017 vs 100% post-2017). After controlling for other factors in multivariable Cox regression modeling, transplantation after 2017 was a predictor of reduced mortality (hazard ratio, 0.209; 95% CI, 0.06-0.71; P = .01). Significant differences were not observed in other secondary outcomes of recovery. CONCLUSIONS: The new VA-ECMO strategy displayed reasonable survival and a remarkable improvement from the prior system.

Increased severe primary graft dysfunction in left ventricular assist device patients following united network for organ sharing allocation changes.

INTRODUCTION: In 2018, the United Network for Organ Sharing (UNOS) implemented a new heart allocation system which prioritized patients on temporary support devices and left-ventricular assist device (LVAD) patients with complications. These changes have the potential to impact outcomes for patients bridged to transplant with an LVAD. METHODS: We performed a retrospective study of 168 adult heart transplant recipients at our center between 2016 and 2020 evaluating post-transplant outcomes before and after UNOS allocation changes. Donor and recipient data were retrieved from chart review and national databases. The primary outcome of this study was severe primary graft dysfunction (PGD) with secondary outcomes of 30-day readmission, 30-day mortality, and 1-year mortality. RESULTS: Incidence of severe PGD was similar in the overall cohort before and after the changes (10% vs. 15%, respectively, p = .3) and increased in the LVAD-bridged cohort (12% vs. 40%, respectively, p < .01). Secondary outcomes of readmission and survival were similar between all groups. Blood transfusion was predictive of severe PGD in multivariable modeling (OR 1.3 [1.11-1.59], p < .01).

Worsening Renal Function in Cardiac Mechanical Support.

BACKGROUND: Venous congestion in heart failure (HF) may lead to worsening renal failure (WRF). We hypothesised that WRF in patients hospitalised for left ventricular assist device (LVAD) implantation is associated with increased 1-year mortality. There is limited data regarding WRF in HF patients with mechanical support. The objective of this paper is to determine whether WRF in HF patients hospitalised for LVAD implantation is associated with increased 1-year mortality and to identify risk factors for WRF. METHODS: We performed a single centre retrospective chart analysis of 162 patients who received an LVAD between August 2006 and December 2014 with pre-LVAD right heart catheterisation data. We stratified patients to those who demonstrated WRF and the use of haemodialysis (HD) or ultrafiltration (UF). RESULTS: Patients with a higher central venous pressure (CVP) >16 mmHg (17-24 mmHg range) developed WRF (29.7% vs. 14.1%, p=0.019). A CVP ≥16 and glomerular filtration rate (GFR) <30 ml/min/1.74m2 increased the odds of WRF. Worsening renal failure and HD/UF use were associated with increased 1-year mortality. Furthermore GFR <30, atherosclerosis, and right ventricular failure were independent predictors for increased 1-year mortality. A GFR <30 increased the odds of developing WRF five-fold (OR 4.14, CI [1.95-8.78], p<0.0001), and GFR <30 and central venous pressure (CVP) >16 increased the odds of requiring HD/UF. CONCLUSIONS: Worsening renal failure is associated with a higher CVP at the time of LVAD implantation and increases the risk of 1-year mortality and the odds of requiring HD/UF. Careful evaluation of renal function and comorbid conditions during LVAD implantation is critical to reduce mortality and for risk stratification.

The Impact of Pazopanib on the Cardiovascular System.

Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult. This approach will be vital in keeping patients on these life-saving therapies and may be applicable to other tyrosine kinase inhibitors as well. In this review, we provide a comprehensive overview of the preclinical and clinical side effects of pazopanib with a focus on the mechanisms responsible for its toxicity to the cardiovascular system.

Pazopanib for renal cell carcinoma leads to elevated mean arterial pressures in a murine model.

BACKGROUND: In the setting of metastatic RCC (mRCC), pazopanib is approved as first line therapy. Unfortunately treatment may lead to cardiotoxicity such as hypertension, heart failure, and myocardial ischemia. OBJECTIVE: Define the in vivo role of pazopanib in the development of cardiotoxicity. METHODS: Wild type mice were dosed for 42 days via oral gavage, and separated into control and treatment (pazopanib) groups. Baseline ECG's, echocardiograms, and blood pressures were recorded. At the conclusion of the study functional parameters were again recorded, and animals were used for pathological, histological, and protein analysis. RESULTS: After 2 weeks of dosing with pazopanib, the treatment group exhibited a statistically significant increase in mean arterial pressure compared to control mice (119 ± 11.7 mmHg versus 108 ± 8.2 mmHg, p = 0.049). Treatment with pazopanib led to a significant reduction in the cardiac output of mice. CONCLUSION: Our findings in mice clearly demonstrate that treatment with pazopanib leads to a significant elevation in blood pressure after 2 weeks of dosing and this persists for the duration of dosing. The continued development of the cardio-oncology field will be paramount in providing optimal oncologic care while simultaneously improving cardiac outcomes through further investigation into the mechanisms of CV toxicity.

The role of ßII spectrin in cardiac health and disease.

Spectrins are large, flexible proteins comprised of α-ß dimers that are connected head-to-head to form the canonical heterotetrameric spectrin structure. Spectrins were initially believed to be exclusively found in human erythrocytic membrane and are highly conserved among different species. ßII spectrin, the most common isoform of non-erythrocytic spectrin, is found in all nucleated cells and forms larger macromolecular complexes with ankyrins and actins. Not only is ßII spectrin a central cytoskeletal scaffolding protein involved in preserving cell structure but it has also emerged as a critical protein required for distinct physiologic functions such as posttranslational localization of crucial membrane proteins and signal transduction. In the heart, ßII spectrin plays a vital role in maintaining normal cardiac membrane excitability and proper cardiac development during embryogenesis. Mutations in ßII spectrin genes have been strongly linked with the development of serious cardiac disorders such as congenital arrhythmias, heart failure, and possibly sudden cardiac death. This review focuses on our current knowledge of the role ßII spectrin plays in the cardiovascular system in health and disease and the potential future clinical implications.