Novel therapies for improvement of left ventricular function following hypertension

Abstract

Hypertension (HT) is considered to be one of the largest risk factors of cardiovascular disease. Heart failure with preserved ejection fraction (HFpEF) usually occurs in patients with uncontrolled essential HT, manifested as normal left ventricular (LV) systolic function and impaired diastolic function. In spite of the availability of multiple effective pharmacological therapeutics, a number of patients fail to achieve adequate blood pressure (BP) control to meet guideline targets. Hence, the exploration of novel approaches for the management of high BP, especially for refractory HT, is of profound importance. Renal systemic spillover as a treatment target in HT has been applied in clinical practice. However, a portion of hypertensive patients do not respond effectively to this method. Evidence was found that splanchnic sympathetic activity might play a role in HT. Spinal cord stimulation (SCS) has demonstrated significant effects on ischemic heart failure and recently showed influence on BP reduction in myocardial infarction (MI) model. However, there are limited studies showed the availability of this novel surgical method in the treatment of HFpEF. Therefore, the goal of our current study was to (1) establish a large animal hypertensive model; (2) reveal the potential mechanism of the development of HFpEF in the hypertensive model; and (3) evaluate the efficacy of splanchnic denervation and SCS in this animal model. In our study, using the combination of Angiotensin (Ang II) and Desoxycorticosterone acetate (DOCA), a large animal hypertensive model was created and detailed hemodynamic and echocardiographic assessment was made. After HT was established, we observed a sustained elevation in BP, systemic norepinephrine (NE), and the renal and splanchnic NE venoarterial gradient in the HT group. Catheter-based renal denervation (RD) and splanchnic denervation (SD), and SCS at the T13-T15 spinal cord region were performed for the hypertensive model. Significant BP reduction and LV diastolic function improvement were observed in the SD group, but not in the RD and SCS groups. The mechanism was further explored. Regional NE assessment revealed that SD showed a significant effect on preventing the progressively increased NE in myocardium and decreased the NE level in the splanchnic venoarterial gradient. Tissue ELISA further proved SD markedly lowered NE distribution in the spleen compared with the HT group without any treatment. Immunohistochemical staining directly showed reduced sympathetic innervation in splanchnic organs. Although RD and SCS failed to demonstrate a significant effect in HT treatment, these methods showed a tendency in LV function improvement in the hypertensive models. These findings collectively indicated that enhanced splanchnic sympathetic nerve activity (SNA), rather than renal SNA, was the prominent mechanism in our established HFpEF model. Catheter-based SD could be an alternative treatment approach in patients with resistant HT. Further experiments to confirm the efficiency of RD and SCS in our hypertensive model are needed.