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

Decompensated right ventricular failure (RVF) in pulmonary hypertension (PH) is fatal, with limited medical treatment options. Developing and testing novel therapeutics for PH requires a clinically relevant large animal model of increased pulmonary vascular resistance and RVF. This manuscript describes the method to induce an ovine PH-RVF model that utilizes left pulmonary artery (LPA) ligation, progressive main pulmonary artery (MPA) banding, and insertion of an RV pressure line for monitoring. The PA cuff and RV pressure tubing are connected to subcutaneous access ports. This model of PH-RVF is a versatile platform to control not only the disease severity, but also the RV's phenotypic response. Subjects undergo progressive PA band adjustments twice per week for approximately 9 weeks with sequential measures of RV pressure, PA cuff pressures, and mixed venous blood gas (SvO). Subjects can further be exercised on a livestock treadmill while hemodynamic parameters are captured. At the initiation and endpoint of this model, ventricular function and dimensions are assessed using echocardiography. In this model, RV mean and systolic pressure increased to 28 ± 5 and 57 ± 7 mmHg at week 1, and further to 44 ± 7 and 93 ± 18 mmHg by week 9, respectively. Echocardiography demonstrates characteristic findings of PH-RVF, notably RV dilation, increased wall thickness, and septal bowing. The rate of PA banding has a significant impact on SvO and thus the model can be titrated to elicit varying RV phenotypes. When the PA cuff is tightened rapidly, it can lead to a precipitous decline in SvO, leading to RV decompensation, whereas a slower, more paced strategy leads to an adaptive RV stress-load response that maintains physiologic SvO. A faster rate of PA banding will also lead to more severe liver fibrosis. The addition of controlled exercise provides a useful platform for assessing the effects of physical exertion in a PH-RVF model. This chronic PH-RVF model provides a valuable tool for studying molecular mechanisms, developing diagnostic biomarkers, and evaluating mechanical circulatory support systems.

A Dynamic Sheep Model to Induce Pulmonary Hypertension and Right Ventricular Failure.

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.

Clinical blood pump consoles for extracorporeal membrane oxygenation (ECMO) are poorly accessible to researchers due to their high cost. Furthermore, clinical machines are built and designed at a high level of information security, which limits their integration with third-party machines and software. These barriers hinder researchers from customizing blood pump consoles for their investigational needs, limiting innovations and advancements in the areas of blood pump automation and pulsation. To address these needs, we present on a programmable Smart Blood Pump console. This console can be assembled for under $200 and uses open-source tools including Arduino. Using this console, centrifugal blood pump heads can be operated at clinically relevant levels of flow and pressure needed in extracorporeal life support applications (>250 mmHg pressure head, >4 L/min of blood flow). Additionally, the programmable nature allows for utility beyond the standard indications of clinical extracorporeal blood pumps, including pulsatility and servo control. For future directions, this console will be further developed to accommodate a wider range of clinical pump heads. We envision that this will be an affordable, open-access platform to suit the varying needs of engineers and researchers for fostering innovations in ECMO technology.

Article	Year
A Dynamic Sheep Model to Induce Pulmonary Hypertension and Right Ventricular Failure. Methods in molecular biology (Clifton, N.J.)\| PubMed ID: 38676898	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
Open-access smart blood pump platform for controlling extracorporeal membrane oxygenation. HardwareX\| PubMed ID: 40230885	2025

Gabriella Glomp

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