Abstract
Heart failure (HF) has been proposed as a potential indication of renal denervation (RDN). However, the mechanisms enabling RDN to attenuate HF are not well understood, especially the central effects of RDN. The aim of this study was to decipher the mode of operation of RDN in the treatment of HF using a canine model of right ventricular rapid pacing-induced HF. Accordingly, 24 Chinese Kunming dogs were randomly grouped to receive sham procedure (sham-operated group), bilateral RDN (RDN group), rapid pacing to induce HF (HF-control group), and bilateral RDN plus rapid pacing (RDN + HF group). Echocardiography, plasma brain natriuretic peptide (BNP), and norepinephrine (NE) concentrations of randomized dogs were measured at baseline and 4 weeks after interventions, followed by histological and molecular analyses. Twenty dogs completed the research successfully and were enrolled for data analyses. Results showed that the average optical density of renal efferent and afferent nerves were significantly lower in the RDN and RDN + HF groups than in the sham-operated group, with a significant reduction of renal NE concentration. Rapid pacing in the RDN + HF and HF-control groups, compared with the sham-operated group, induced a significant increase in left ventricular end-diastolic volume and decrease in left ventricular ejection fraction and correspondingly resulted in cardiac fibrosis and dysfunction. Cardiac fibrosis evaluated by Masson’s trichrome staining and the expression of transforming growth factor-β1 (TGF-β1) were significantly higher in the HF-control group than in the sham-operated group, which were remarkably attenuated by the application of the RDN technique in the RDN + HF group. In terms of central renin–angiotensin system (RAS), the expression of angiotensin II (AngII)/angiotensin-converting enzyme (ACE)/AngII type 1 receptor (AT1R) in the hypothalamus of dogs in the HF-control group, compared with the sham-operated group, was upregulated and that of the angiotensin-(1-7) [Ang-(1-7)]/ACE2 was downregulated. Furthermore, both of them were significantly attenuated by the RDN therapy in the RDN + HF group. In conclusion, the RDN technique could damage renal nerves and suppress the cardiac remodeling procedure in canine with HF while concomitantly attenuating the overactivity of central RAS in the hypothalamus.
Highlights
Renal denervation (RDN) has been proposed to treat resistant hypertension by damaging the afferent sensory and efferent sympathetic renal nerves (Schlaich et al, 2012; Mahfoud et al, 2013)
These alterations in the renal efferent sympathetic nerve lead to a significant increase in cardiac preload and activation of renin–angiotensin system (RAS), which results in a continuous progression of cardiac remodeling and exacerbated Heart failure (HF) (Booth et al, 2015; Schiller et al, 2015)
There were no significant differences in various parameters at baseline among the different groups, viz., left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), brain natriuretic peptide (BNP), systolic blood pressure (SBP), and diastolic blood pressure (DBP)
Summary
Renal denervation (RDN) has been proposed to treat resistant hypertension by damaging the afferent sensory and efferent sympathetic renal nerves (Schlaich et al, 2012; Mahfoud et al, 2013). It has been demonstrated that the increased renal efferent sympathetic nerve activity induces renal vasoconstriction, decreases renal blood flow with a reduction in glomerular filtration rate, and increases sodium and water reabsorption and renal fibrosis (Booth et al, 2015; Schiller et al, 2015). By damaging the renal efferent sympathetic nerves, it has been proved in animal experiments that the RDN technique improves renal blood flow and renal vascular resistance (Clayton et al, 2011; Schiller et al, 2015), suppresses the over-activation of RAS (Clayton et al, 2011), inhibits renal neprilysin activity (Polhemus et al, 2017), and increases sodium and water excretion (DiBona and Sawin, 1991; Villarreal et al, 1994; Booth et al, 2015)
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