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

SIMPLE SUMMARY: High blood pressure (arterial hypertension) is a major public health problem as far as it has a high prevalence in the adult population and it entails significant cardiovascular and cerebrovascular risks. New ways of treating hypertension include catheter-based renal denervation, i.e., modulation of the autonomic nervous system that has a crucial role in the regulation of blood pressure. We have designed a hypertensive animal model to test the efficacy and safety of this kind of treatment. After the induction of mineralocorticoid mediated hypertension in minipigs, we have analyzed the durability of hypertensive state, the response to drugs and the effects of renal denervation obtained with a radiofrequency catheter (Symplicity(®), Medtronic, Santa Rosa, CA, USA). The attrition rate was high, mainly caused by infections in this instrumentalized animal model. The effect of renal denervation was confirmed by pathology (nerve damage), biochemical parameters and blood pressure measurements. The conclusion is that this model could be used in the assessment of different therapies aimed to modulate the influence of the autonomic nervous system on hypertension if the high mortality rate is reduced with a less invasive monitorization system. 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.