structured-exercise-regimen-pulmonary-hypertension-right-ventricular

Structured Exercise Regimen in Pulmonary Hypertension-Right Ventricular Failure in an Ovine Model

Right heart failure (RHF) is a significant cause of morbidity and mortality from pulmonary hypertension (PH). To better understand the pathophysiology and ...

Vanderbilt University

Right ventricular failure (RVF) is a major cause of mortality in pulmonary hypertension (PH). Mechanical circulatory support holds promise for patients with medically refractory PH, but there are no clinical devices for long-term right ventricular (RV) support. Investigations into optimal device parameters and circuit configurations for PH-induced RVF (PH-RVF) are needed.

Large animal preclinical investigation into the optimal extracorporeal life support configuration for pulmonary hypertension and right ventricular failure.

Improved approaches to expanding the pool of donor lungs suitable for transplantation are critically needed for the growing population with end-stage lung disease. Cross-circulation (XC) of whole blood between swine and explanted human lungs has previously been reported to enable the extracorporeal recovery of donor lungs that declined for transplantation due to acute, reversible injuries. However, immunologic interactions of this xenogeneic platform have not been characterized, thus limiting potential translational applications. Using flow cytometry and immunohistochemistry, we demonstrate that porcine immune cell and immunoglobulin infiltration occurs in this xenogeneic XC system, in the context of calcineurin-based immunosuppression and complement depletion. Despite this, xenogeneic XC supported the viability, tissue integrity, and physiologic improvement of human donor lungs over 24 hours of xeno-support. These findings provide targets for future immunomodulatory strategies to minimize immunologic interactions on this organ support biotechnology.

Immune characterization of a xenogeneic human lung cross-circulation support system.

Right heart failure is the major cause of death in pulmonary hypertension. Lung transplantation is the only long-term treatment option for patients who fail medical therapy. Due to the scarcity of donor lungs, there is a critical need to develop durable mechanical support for the failing right heart. A major design goal for durable support is to reduce the size and complexity of devices to facilitate ambulation. Toward this end, we sought to deploy wearable mechanical support technology in a sheep disease model of chronic right heart failure.

Ambulatory 7-day mechanical circulatory support in sheep model of pulmonary hypertension and right heart failure.

Static cold storage with ice has been the mainstay of cardiac donor preservation. Early preclinical data suggest that allograft preservation at 10 °C may be beneficial. We tested this hypothesis by using a static 10 °C storage device to preserve and transport cardiac allografts.

Out of the ice age: Preservation of cardiac allografts with a reusable 10 °C cooler.

Donation after circulatory death (DCD) livers face increased risks of critical complications when preserved with static cold storage (SCS). Although machine perfusion (MP) may mitigate these risks, its cost and logistical complexity limit widespread application. We developed the Dynamic Organ Storage System (DOSS), which delivers oxygenated perfusate at 10°C with minimal electrical power requirement and allows real-time effluent sampling in a portable cooler. In a porcine DCD model, livers were preserved using DOSS or SCS for 10 hours and evaluated with 4 hours of normothermic MP, with n = 5 per group. After 4 hours of normothermic MP, the DOSS group demonstrated significantly lower perfusate lactate (p = 0.023), increased perfusate fibrinogen (p = 0.005), higher oxygen consumption (p = 0.018), greater bile production (p = 0.013), higher bile bicarbonate levels (p = 0.035) and bile/perfusate sodium ratio (p = 0.002), and lower hepatic arterial resistance after phenylephrine administration (p = 0.018). Histological analysis showed lower apoptotic markers in DOSS-preserved livers, with fewer cleaved caspase-3 (p = 0.039) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL; p = 0.009) positive cells. These findings suggest that DOSS can enhance DCD allograft function during transport, offering potential clinical benefits and contributing to the expansion of the donor pool.

Novel Dynamic Organ Storage System Enhances Liver Graft Function in a Porcine Donation After Circulatory Death Model.

Optimized static cold storage has the potential to improve preservation of organs most vulnerable to ischemia reperfusion injury. Data from lung transplantation suggest that storage at 10°C improves mitochondrial preservation and subsequent allograft function compared to conventional storage on ice. Using a porcine model of donation after circulatory death (DCD), we compared static storage of livers at 10°C to ice. Livers (N=5 per group) underwent ten hours of storage followed by four hours of normothermic machine perfusion (NMP) for real-time allograft assessment. Allografts were compared using established NMP viability criteria, tissue immunostaining, and tissue metabolomics. 10°C stored livers demonstrated lower portal venous vascular resistance and greater hepatic artery vasoresponsiveness. Lactate clearance during NMP was similar between groups. 10°C stored livers showed favorable biochemical parameters of biliary viability, including greater bile volume, pH, and bicarbonate. Metabolomics analysis revealed increased aerobic respiration, improved electron transport chain function, and less DNA damage after reperfusion of livers stored at 10°C. Static storage of DCD livers with extended cold ischemic time at 10°C demonstrates superior allograft function with evidence of improved biliary viability and mitochondrial function compared to ice. These data suggest that storage at 10°C should be considered for translation to clinical practice.

10°C static storage of porcine donation after circulatory death livers improves biliary viability and mitigates ischemia reperfusion injury.

Access to life-saving lung transplantation remains limited by a shortage of donor organs. We have previously described rehabilitation of discarded human donor lungs to a quality suitable for transplantation using cross-circulation of whole blood between xeno-support swine and human lungs. However, the immunologic implications of transplanting rehabilitated lungs remain unknown.

Lung rehabilitation using xenogeneic cross-circulation does not lead to hyperacute rejection in a human lung transplantation model.

Comparison of Cellular and Acellular Perfusate in the Dynamic Organ Storage System Using a Porcine Donation After Circulatory Death Model.

Chronic obstructive pulmonary disease (COPD) is the most prevalent chronic end stage lung disease. There are few long-term treatment options for end stage COPD due to donor lung scarcity. Durable artificial lung therapies may provide alternatives for long-term respiratory support. Veno-venous extracorporeal membrane oxygenation can provide physiologic support, but current cannulation configurations are suboptimal for durable support.

Article	Year
Large animal preclinical investigation into the optimal extracorporeal life support configuration for pulmonary hypertension and right ventricular failure. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation\| PubMed ID: 36435685	2023
Immune characterization of a xenogeneic human lung cross-circulation support system. Science advances\| PubMed ID: 37000867	2023
Ambulatory 7-day mechanical circulatory support in sheep model of pulmonary hypertension and right heart failure. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation\| PubMed ID: 37907183	2024
Out of the ice age: Preservation of cardiac allografts with a reusable 10 °C cooler. JTCVS open\| PubMed ID: 39534335	2024
Novel Dynamic Organ Storage System Enhances Liver Graft Function in a Porcine Donation After Circulatory Death Model. ASAIO journal (American Society for Artificial Internal Organs : 1992)\| PubMed ID: 39693205	2024
10°C static storage of porcine donation after circulatory death livers improves biliary viability and mitigates ischemia reperfusion injury. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons\| PubMed ID: 40120647	2025
Lung rehabilitation using xenogeneic cross-circulation does not lead to hyperacute rejection in a human lung transplantation model. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation\| PubMed ID: 40120998	2025
Comparison of Cellular and Acellular Perfusate in the Dynamic Organ Storage System Using a Porcine Donation After Circulatory Death Model. ASAIO journal (American Society for Artificial Internal Organs : 1992)\| PubMed ID: 40853322	2026
Determining an optimal central cannulation strategy for ambulatory veno-venous extracorporeal life support. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation\| PubMed ID: 41949527	2026

Elizabeth Simonds

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