a-large-animal-model-for-acute-kidney-injury-temporary-bilateral

A Large Animal Model for Acute Kidney Injury by Temporary Bilateral Renal Artery Occlusion

Acute kidney injury (AKI) is associated with higher risk for morbidity and mortality post-operatively. Ischemia-reperfusion injury (IRI) is the most ...

Harvard Medical School

Mitochondrial dysfunction is the determinant insult of ischemia-reperfusion injury. Autologous mitochondrial transplantation involves supplying one's healthy mitochondria to the ischemic region harboring damaged mitochondria. The authors used in vivo swine to show that mitochondrial transplantation in the heart by intracoronary delivery is safe, with specific distribution to the heart, and results in significant increase in coronary blood flow, which requires intact mitochondrial viability, adenosine triphosphate production, and, in part, the activation of vascular K channels. Intracoronary mitochondrial delivery after temporary regional ischemia significantly improved myocardial function, perfusion, and infarct size. The authors concluded that intracoronary delivery of mitochondria is safe and efficacious therapy for myocardial ischemia-reperfusion injury.

A Novel Biological Strategy for Myocardial Protection by Intracoronary Delivery of Mitochondria: Safety and Efficacy.

Congenital heart valve disease has life-threatening consequences that warrant early valve replacement; however, the development of a growth-accommodating prosthetic valve has remained elusive. Thousands of children continue to face multiple high-risk open-heart operations to replace valves that they have outgrown. Here, we demonstrate a biomimetic prosthetic valve that is geometrically adaptable to accommodate somatic growth and structural asymmetries within the heart. Inspired by the human venous valve, whose geometry is optimized to preserve functionality across a wide range of constantly varying volume loads and diameters, our balloon-expandable synthetic bileaflet valve analog exhibits similar adaptability to dimensional and shape changes. Benchtop and acute in vivo experiments validated design functionality, and in vivo survival studies in growing sheep demonstrated that mechanical valve expansion accommodated growth. As illustrated in this work, dynamic size adaptability with preservation of unidirectional flow in prosthetic valves thus offers a paradigm shift in the treatment of heart valve disease.

A geometrically adaptable heart valve replacement.

Left ventricular failure is strongly associated with secondary mitral valve regurgitation. Implantable soft robotic devices are an emerging technology that enables augmentation of a native function of a target tissue. We demonstrate the ability of a novel soft robotic ventricular assist device to dynamically augment left ventricular contraction, provide native pulsatile flow, simultaneously reshape the mitral valve apparatus, and eliminate the associated regurgitation in an Short-term large animal model of acute left ventricular systolic dysfunction.

Dynamic Augmentation of Left Ventricle and Mitral Valve Function With an Implantable Soft Robotic Device.

Acute kidney injury is a common clinical disorder and one of the major causes of morbidity and mortality in the postoperative period. In this study, the safety and efficacy of autologous mitochondrial transplantation by intra-arterial injection for renal protection in a swine model of bilateral renal ischemia-reperfusion injury were investigated. Female Yorkshire pigs underwent percutaneous bilateral temporary occlusion of the renal arteries with balloon catheters. Following 60 min of ischemia, the balloon catheters were deflated and animals received either autologous mitochondria suspended in vehicle or vehicle alone, delivered as a single bolus to the renal arteries. The injected mitochondria were rapidly taken up by the kidney and were distributed throughout the tubular epithelium of the cortex and medulla. There were no safety-related issues detected with mitochondrial transplantation. Following 24 h of reperfusion, estimated glomerular filtration rate and urine output were significantly increased while serum creatinine and blood urea nitrogen were significantly decreased in swine that received mitochondria compared with those that received vehicle. Gross anatomy, histopathological analysis, acute tubular necrosis scoring, and transmission electron microscopy showed that the renal cortex of the vehicle-treated group had extensive coagulative necrosis of primarily proximal tubules, while the mitochondrial transplanted kidney showed only patchy mild acute tubular injury. Renal cortex IL-6 expression was significantly increased in vehicle-treated kidneys compared with the kidneys that received mitochondrial transplantation. These results demonstrate that mitochondrial transplantation by intra-arterial injection provides renal protection from ischemia-reperfusion injury, significantly enhancing renal function and reducing renal damage.

Mitochondrial transplantation by intra-arterial injection for acute kidney injury.

Donation after circulatory death (DCD) offers an additional source of cardiac allografts, potentially allowing expansion of the donor pool, but is limited owing to the effects of ischemia. In this study, we investigated the efficacy of mitochondrial transplantation to enhance myocardial function of DCD hearts.

Mitochondrial transplantation for myocardial protection in ex-situ‒perfused hearts donated after circulatory death.

Right ventricular hypertrophy and failure are major causes of cardiac morbidity and mortality. A key event in the progression to right ventricular hypertrophy and failure is cardiomyocyte apoptosis due to mitochondrial dysfunction. We sought to determine whether localized intramyocardial injection of autologous mitochondria from healthy muscle treats heart failure.

Article	Year
A Novel Biological Strategy for Myocardial Protection by Intracoronary Delivery of Mitochondria: Safety and Efficacy. JACC. Basic to translational science\| PubMed ID: 31909298	2019
A geometrically adaptable heart valve replacement. Science translational medicine\| PubMed ID: 32075944	2020
Dynamic Augmentation of Left Ventricle and Mitral Valve Function With an Implantable Soft Robotic Device. JACC. Basic to translational science\| PubMed ID: 32215347	2020
Mitochondrial transplantation by intra-arterial injection for acute kidney injury. American journal of physiology. Renal physiology\| PubMed ID: 32686525	2020
Mitochondrial transplantation for myocardial protection in ex-situ‒perfused hearts donated after circulatory death. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation\| PubMed ID: 32703639	2020
Autogenous mitochondria transplantation for treatment of right heart failure. The Journal of thoracic and cardiovascular surgery\| PubMed ID: 32919774	2020

Mossab Y. Saeed

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