Development and Evaluation of a Disease Large Animal Model for Preclinical Assessment of Renal Denervation Therapies

用于肾脏去神经支配疗法临床前评估的疾病大型动物模型的开发和评估

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作者:Armando Pérez de Prado, Claudia Pérez-Martínez, Marta Regueiro-Purriños, Carlos Cuellas-Ramón, María López-Benito, José Manuel Gonzalo-Orden, Rodrigo Estévez-Loureiro, Ana Isabel Cortina-Rivero, David Viñuela-Baragaño, José R Altonaga, Armando Tellez, Felipe Fernández-Vázquez

Abstract

New-generation catheters-based renal denervation (RDN) is under investigation for the treatment of uncontrolled hypertension (HTN). We assessed the feasibility of a large animal model of HTN to accommodate the human RDN devices. Ten minipigs were instrumented to measure blood pressure (BP) in an awake-state. HTN was induced with subcutaneous 11-deoxycorticosterone (DOCA, 100 mg/kg) implants. Five months after, the surviving animals underwent RDN with the Symplicity® system. Norepinephrine (NE) renal gradients were determined before and 1 month after RDN. Renal arteries were processed for histological (hematoxylin-eosin, Movat pentachrome) and immunohistochemical (S100, tyrosine-hydroxylase) analyses. BP significantly rose after DOCA implants. Six animals died prematurely, mainly from infectious causes. The surviving animals showed stable BP levels after 5 months. One month after RDN, nerve damage was showed in three animals, with impedance drop >10%, NE gradient drop and reduction in BP. The fourth animal showed no nerve damage, impedance drop <10%, NE gradient increase and no change in BP. In conclusion, the minipig model of DOCA-induced HTN is feasible, showing durable effects. High mortality should be addressed in next iterations of this model. RDN may partially offset the DOCA-induced HTN. Impedance drop and NE renal gradient could be markers of RDN success.

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