Emerging preclinical data suggest that splanchnic sympathetic nerve activation may play an important role in the pathophysiology of hypertension. We sought to determine the potential therapeutic application of catheter-based splanchnic denervation in a clinically relevant large animal model of hypertensive cardiomyopathy (hCMP). Sustained elevated blood pressure was induced in adult pigs using a combination of intravenous infusion of Ang II (angiotensin II) and subcutaneous implantation of deoxycorticosterone acetate pellets to establish a large animal model of hCMP. Serial changes in cardiac echocardiographic and invasive hemodynamic parameters and neurohumoral biomarkers were investigated in animals with hypertension alone (n=9) and hypertension with catheter-based splanchnic denervation (n=6). Another 6 pigs without hypertension induction served as controls. At 10 weeks, hypertensive animals developed sustained elevated blood pressure and phenotype of hCMP with significant systolic and diastolic dysfunction, and left ventricular remodeling and hypertrophy as determined by invasive hemodynamic and echocardiogram assessments, respectively, and increased venoarterial norepinephrine gradient over the myocardium, kidneys, and splanchnic organs compared with baseline. Catheter-based splanchnic denervation decreased the venoarterial norepinephrine gradient over the splanchnic organs associated with the reduced splenic sympathetic nerve innervation; attenuated the elevated blood pressure, left ventricular remodeling, and hypertrophy; and preserved left ventricular systolic and diastolic function at 20 weeks in pigs with hCMP. Our results provide novel mechanistic insight into the role of splenic sympathetic nerve innervation in hypertension and important proof-of-principle data for the therapeutic application of catheter-based splanchnic denervation in a large animal model of hCMP.
Keywords: biomarkers; cardiomyopathies; denervation; hypertension; models, animal.