Exosomes isolated from human cardiosphere-derived cells attenuate pressure overload-induced right ventricular dysfunction.

OBJECTIVES: Cardiosphere-derived cell (CDC) transplantation has been shown to attenuate right ventricular (RV) dysfunction in patients with hypoplastic left heart syndrome. However, live cell transplantation requires complex handling protocols that may limit its use. Exosomes are protein and nucleic acid-containing nanovesicles secreted by many cell types, including stem cells, which have been shown to exert a cardioprotective effect comparable with whole cells following myocardial injury. We therefore sought to evaluate 3 human CDC-derived exosome preparations in a juvenile porcine model of acute pressure-induced RV dysfunction. METHODS: Twenty immunocompetent juvenile Yorkshire pigs (7-10 kg) underwent pulmonary arterial banding followed by intramyocardial test agent administration: control (n = 6), XO-1 (n = 4), XO-2 (n = 5), and XO-3 (n = 5). Animals were monitored for 28 days postoperatively with periodic phlebotomy and echocardiography, followed by extensive postmortem gross and histopathologic analysis. RESULTS: All animals survived the banding operation. One died suddenly on postoperative day 1; another was excluded due to nonstandard response to banding. Of the remaining animals, there were no clinical concerns. RV fractional area change was improved in the XO-1 and XO-2 groups relative to controls at postoperative day 28. On histologic analysis, exosome-treated groups exhibited decreased cardiomyocyte hypertrophy with respect to controls. CONCLUSIONS: Human CDC-derived exosome administration was associated with significant preservation of RV systolic function in the setting of acute pressure overload. Such acellular preparations may prove superior to whole cells and may represent a novel therapeutic approach to clinical myocardial injury.

Strategic application of modular risk components to safely increase lung transplantation volume.

OBJECTIVES: Considerable growth of individual lung transplant programs remains challenging. We hypothesized that the systematic implementation of modular risk components to a lung transplantation program would allow for expeditious growth without increasing mortality. METHODS: All consecutive patients placed on the lung transplantation waitlist were reviewed. Patients were stratified by an 18-month period surrounding the systematic implementation of the modular risk components Era 1 (1/2014-6/2015) and Era 2 (7/2015-12/2016). Modular risk components were separately evaluated for donors, recipients, and perioperative features. RESULTS: One hundred and thirty-two waitlist patients (Era 1: 48 and Era 2: 84) and 100 transplants (Era 1: 32 and Era 2: 68) were identified. There was a trend toward decreased waitlist mortality (P = .07). In Era 2, the use of ex vivo lung perfusion (P = .05) and donor-recipient over-sizing (P = .005) significantly increased. Moreover, transplantation with a lung allocation score greater than 70 (P = .05), extracorporeal support (P = .06), and desensitization (P = .008) were more common. Transplant rate significantly improved from Era 1 to Era 2 (325 vs 535 transplants per 100 patient years, P = .02). While primary graft dysfunction (PGD) grade 3 at 72 hours (P = .05) was significantly higher in Era 2, 1-year freedom from rejection was similar (86% vs 90%, P = .69) and survival (81% vs 95%, P = .02) was significantly greater in Era 2. CONCLUSIONS: The systematic implementation of a modular risk components to a lung transplantation program can result in a significant increase in center volume. However, measures to mitigate an expected increase in the incidence of PGD must be undertaken to maintain excellent short and midterm outcomes.

Stem Cell Therapy for Hypoplastic Left Heart Syndrome: Mechanism, Clinical Application, and Future Directions.

Hypoplastic left heart syndrome is a type of congenital heart disease characterized by underdevelopment of the left ventricle, outflow tract, and aorta. The condition is fatal if aggressive palliative operations are not undertaken, but even after the complete 3-staged surgical palliation, there is significant morbidity because of progressive and ultimately intractable right ventricular failure. For this reason, there is interest in developing novel therapies for the management of right ventricular dysfunction in patients with hypoplastic left heart syndrome. Stem cell therapy may represent one such innovative approach. The field has identified numerous stem cell populations from different tissues (cardiac or bone marrow or umbilical cord blood), different age groups (adult versus neonate-derived), and different donors (autologous versus allogeneic), with preclinical and clinical experience demonstrating the potential utility of each cell type. Preclinical trials in small and large animal models have elucidated several mechanisms by which stem cells affect the injured myocardium. Our current understanding of stem cell activity is undergoing a shift from a paradigm based on cellular engraftment and differentiation to one recognizing a primarily paracrine effect. Recent studies have comprehensively evaluated the individual components of the stem cells' secretomes, shedding new light on the intracellular and extracellular pathways at the center of their therapeutic effects. This research has laid the groundwork for clinical application, and there are now several trials of stem cell therapies in pediatric populations that will provide important insights into the value of this therapeutic strategy in the management of hypoplastic left heart syndrome and other forms of congenital heart disease. This article reviews the many stem cell types applied to congenital heart disease, their preclinical investigation and the mechanisms by which they might affect right ventricular dysfunction in patients with hypoplastic left heart syndrome, and finally, the completed and ongoing clinical trials of stem cell therapy in patients with congenital heart disease.

Regenerative medicine therapy for single ventricle congenital heart disease.

One of the most complex forms of congenital heart disease (CHD) involving single ventricle physiology is hypoplastic left heart syndrome (HLHS), characterized by underdevelopment of the left ventricle (LV), mitral and aortic valves, and narrowing of the ascending aorta. The underdeveloped LV is incapable of providing long-term systemic flow, and if left untreated, the condition is fatal. Current treatment for this condition consists of three consecutive staged palliative operations: the first is conducted within the first few weeks of birth, the second between 4 to 6 months, and the third and final surgery within the first 4 years. At the conclusion of the third surgery, systemic perfusion is provided by the right ventricle (RV), and deoxygenated blood flows passively to the pulmonary vasculature. Despite these palliative interventions, the RV, which is ill suited to provide long-term systemic perfusion, is prone to eventual failure. In the absence of satisfying curative treatments, stem cell therapy may represent one innovative approach to the management of RV dysfunction in HLHS patients. Several stem cell populations from different tissues (cardiac and non-cardiac), different age groups (adult- vs. neonate-derived), and different donors (autologous vs. allogeneic), are under active investigation. Preclinical trials in small and large animal models have elucidated several mechanisms by which these stem cells affect the injured myocardium, and are driving the shift from a paradigm based upon cellular engraftment and differentiation to one based primarily on paracrine effects. Recent studies have comprehensively evaluated the individual components of the stem cells' secretomes, shedding new light on the intracellular and extracellular pathways at the center of their therapeutic effects. This research has laid the groundwork for clinical application, and there are now several trials of stem cell therapies in pediatric populations that will provide important insights into the value of this therapeutic strategy in the management of HLHS and other forms of CHD. This article reviews the many stem cell types applied to CHD, their preclinical investigation and the mechanisms by which they might affect RV dysfunction in HLHS patients, and finally, the completed and ongoing clinical trials of stem cell therapy in patients with CHD.

A novel crosslinking method for improved tear resistance and biocompatibility of tissue based biomaterials.

Over 300,000 heart valve replacements are performed annually to replace stenotic and regurgitant heart valves. Bioprosthetic heart valves (BHVs), derived from glutaraldehyde crosslinked (GLUT) porcine aortic valve leaflets or bovine pericardium are often used. However, valve failure can occur within 12-15 years due to calcification and/or progressive degeneration. In this study, we have developed a novel fabrication method that utilizes carbodiimide, neomycin trisulfate, and pentagalloyl glucose crosslinking chemistry (TRI) to better stabilize the extracellular matrix of porcine aortic valve leaflets. We demonstrate that TRI treated leaflets show similar biomechanics to GLUT crosslinked leaflets. TRI treated leaflets had better resistance to enzymatic degradation in vitro and demonstrated better tearing toughness after challenged with enzymatic degradation. When implanted subcutaneously in rats for up to 90 days, GLUT control leaflets calcified heavily while TRI treated leaflets resisted calcification, retained more ECM components, and showed better biocompatibility.