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Ventricular arrhythmias (VAs) are the leading cause of sudden cardiac death in patients with myocardial infarction (MI). We sought to compare effects of renal denervation (RDN) and metoprolol on VAs after MI. Fifty-four male Sprague-Dawley rats underwent ligation of left anterior descending coronary artery to induce MI, while 6 rats served as Control. Metoprolol was given 20 mg/kg/day for 5 weeks after MI surgery. RDN/Sham-RDN procedure was performed at 1 week after MI. At 5 weeks after MI, electrical programmed stimulation (EPS) was performed in all groups for evaluation of VAs. After EPS, heart and kidneys were harvested. Compared with MI group, RDN and metoprolol significantly decreased the incidence of VAs, and RDN is superior to metoprolol. Compared with metoprolol group, Masson staining showed that RDN significantly reduced the myocardial fibrosis. Both RDN and metoprolol decreased the protein expression of connexin43 (Cx43) compared with MI group, while only RDN lighted this decrease remarkably. Immunohistochemical staining of Tyrosine hydroxylase (TH) and growth associated protein 43 (GAP43) revealed that RDN and metoprolol had similar effect on reducing densities of sympathetic nerve in infarction border zone. According to this study, RDN is more effective in reducing VAs than metoprolol in ischemic cardiomyopathy model.

Background/aims: To investigate the impact of renal denervation (RDN) on myocardial fibrosis and ventricular arrhythmias (VAs) in rats with ischemic cardiomyopathy., Methods: An ischemic cardiomyopathy model was reproduced with myocardial infarction (MI) in adult Sprague-Dawley male rats. The RDN/Sham-RDN procedure was performed at 2 weeks after MI. Sham-MI and sham-RDN rats served as the control group. At 4 weeks after RDN, programmed electrical stimulation (PES) was used to induce VAs, including ventricular tachycardia and ventricular fibrillation, in all 3 groups (MI+RDN, MI, and control groups). At the end of PES, heart and kidney samples were harvested. Immunofluorescence labeling was used to investigate the distribution of connexin 43 (Cx43) in the infarcted border zone. Masson's trichrome stain was adopted to determine the degree of cardiac fibrosis. Western blotting was performed to identify the expression of transforming growth factor beta 1 (TGF-β1), α-smooth muscle actin (α-SMA), and Cx43. An enzyme-linked immunosorbent assay (ELISA) was used to detect the serum levels of B-type natriuretic peptide (BNP) and the amino-terminal pro-peptides of type I and III collagen (PINP and PIIINP, respectively) and the expression level of renal norepinephrine., Results: Compared with the MI group, RDN significantly decreased the inducibility of VAs (MI+RDN 3/8 rats vs. MI 8/9 rats, P < 0.05; control 1/8 rats) with PES, reduced myocardial fibrosis estimated by collagen volume fraction (MI+RDN 31.10 ± 3.97% vs. MI 54.80 ± 16.39%, P < 0.001; control 4.41 ± 0.92% ), suppressed TGF-β1 (P < 0.01) and α-SMA (P < 0.001) levels, and attenuated both PINP (MI+RDN 41.44 ± 10.10 ng/mL vs. MI 95.49 ± 24.83 ng/mL, P < 0.001; control 11.90 ± 4.96 ng/mL) and PIIINP (MI+RDN 82.12 ± 30.79 ng/mL vs. MI 124.60 ± 26.64 ng/mL, P < 0.05; control 64.69 ± 23.84 ng/mL) levels. Moreover, RDN reversed the abnormal myocardial distribution of Cx43 and its reduction by MI damage (P < 0.01)., Conclusions: RDN reduced myocardial fibrosis and suppressed VAs in a rat model of ischemic cardiomyopathy., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Pulmonary artery hypertension (PAH) is a rapidly progressive disorder, which leads to right heart failure and even death. Overactivity of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system accounts for the development and progression of PAH. The role of renal denervation (RDN) in different periods of PAH has not been fully elucidated. A single intraperitoneal injection of monocrotaline (MCT, 60 mg/kg) was used to induce pulmonary remodeling in male Sprague Dawley rats (n = 40). After 24-hour of MCT administration, a subset of rats underwent RDN (RDN24h, n = 10); after 2-week of MCT injection, another ten rats received RDN treatment (RDN2w, n = 10) and the left 20 rats were divided to MCT group with sham RDN operation (MCT, n = 20). Eight rats in Control group received intraperitoneal injection of normal saline (60 mg/kg) once and sham RDN surgery. After 35 days, tissue and blood samples were collected. Histological analysis demonstrated that the collagen volume fraction of right ventricle, lung tissue and pulmonary vessel reduced significantly in RDN24h group but not in the RDN2w group, compared with MCT group. Moreover, the earlier RDN treatment significantly decreased SNS activity and blunted RAAS activation. Importantly, RDN treatment significantly improved the survival rate. In summary, earlier RDN treatment could attenuate cardio-pulmonary fibrosis and therefore might be a promising approach to prevent the development of PAH.

Background: Renal denervation (RDN), a novel therapy for resistant hypertension, has been shown to have an effect on cardiac remodeling in several small studies. We aimed to pool currently available data to assess the effects of RDN on left ventricular hypertrophy (LVH) and left atrial (LA) enlargement., Methods and Results: Two investigators independently searched PubMed, EMBASE and Cochrane Library Central Register of Controlled Trials database for studies reporting change in left ventricular mass index (LVMI) or LA size before and after RDN. Twelve publications met our pre-defined inclusion criteria. Echocardiographic data showed that RDN markedly reduced both LVMI [weighted mean difference (WMD) = -15.77 g/m(2); 95 % confidence interval (CI) -22.51 to -9.02 g/m(2)] and LA diameter [WMD = -2.48 mm; 95 % CI -4.12 to -0.83 mm] after 6 months. Data from cardiac magnetic resonance also showed a significant reduction in LVMI [WMD = -5.43 g/m(2), 95 % CI -10.01 to -0.35 g/m(2)) at 6 months. Changes in LVH and LA size at 12 months were more pronounced than those at 6 months. Meta-regression analysis failed to demonstrate a significant relationship between RDN-induced LVMI reduction and BP lowering at 6 months., Conclusions: RDN led to significant regressions of both LVH and LA enlargement at 6 months, which were sustained at least up to 12 months.

To investigate the effects of renal denervation (RDN) on comprehensive cardiac and renal fibrosis in cardiomyopathy. Five weeks after successful transverse aortic constriction (TAC)-induced cardiomyopathy model building, Sprague-Dawley rats were randomly assigned to three groups: (1) RDN, (2) sham, and (3) losartan. Sham TAC rats served as control group. Compared with control, TAC groups showed a significant decrease in left ventricle ejection fraction and increase in ventricular septum thickness and left atrium diameter on echocardiography after 5 weeks. At 10 weeks post-TAC, venous blood samples were collected for fibrosis biochemical assay. Heart and kidney samples were also harvested for fibrosis pathophysiological detection. Cardiac and renal fibrosis quantity results showed that, compared with sham group, collagen volume fraction was significantly decreased in RDN group more than in losartan group. Biochemical parameters such as tumor necrosis factor α, aldosterone, and B-type natriuretic peptide levels as well as biomarkers for fibrosis such as procollagen type I N-terminal propeptide and procollagen type III N-terminal propeptide concentrations were significantly decreased in RDN group in comparison with sham. In addition, compared with sham group, left ventricle tissue protein expression of transforming growth factor-β1 and angiotensin II type I receptor was downregulated, and angiotensin-converting enzyme 2 was upregulated in RDN but not in losartan group. RDN significantly attenuates cardiac and renal fibrosis in cardiomyopathy. Differing from losartan, which only has angiotensin II type I receptor inhibition effects, RDN comprehensively suppresses cardiac and renal fibrogenesis through multiple pathways., (Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Background/aims: To investigate the effects of renal denervation (RDN) on multi-organ fibrosis and vascular remodeling in cardiomyopathy., Methods: Thirty-six male Sprague-Dawley rats underwent transverse aortic constriction (TAC). Five weeks later, 28 surviving TAC rats were randomly assigned to three groups: (1) RDN, (2) Sham, (3) Carvedilol. Six male Sham TAC rats served as the Control. Ten weeks after TAC, samples were collected., Results: TAC rats showed an increased diastolic interventricular septal thickness at week 5. At 10 weeks, Masson staining showed that left ventricular and renal glomerular fibrosis were significantly reduced in RDN compared with Sham group. In comparison to Sham group, hepatic perivascular fibrosis was attenuated in both RDN and Carvedilol group, so were the media thickness and the media/lumen of aorta. The plasma levels of B-type natriuretic peptide (BNP), Cystatin C (Cys-C), Alanine Transaminase, angiotensin II (Ang II), transforming growth factor beta 1 (TGF-β1), and malondialdehyde increased, and total superoxide dismutase (T-SOD) decreased in Sham but not in RDN group, compared with Control group. Both RDN and Carvedilol reduced the Cys-C and TGF-β1 levels, and restored T-SOD concentration, compared with Sham group. While only RDN lowered the plasma levels of BNP and Ang II. No significant effects of RDN on blood pressure (BP) and heart rate (HR) were oberved., Conclusions: RDN can attenuate multi-organ fibrosis and improve vascular remodeling independent of BP and HR change in TAC-induced cardiomyopathy. These effects of RDN may be associated with the direct inhibition of renin-angiotensin-aldosterone system and oxidative stress., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Cardio-renal fibrosis plays key roles in heart failure and chronic kidney disease. We sought to determine the effects of renal denervation (RDN) on cardiac and renal fibrosis in rats with isoproterenol induced cardiomyopathy. Sixty male Sprague Dawley rats were randomly assigned to Control (n = 10) and isoproterenol (ISO)-induced cardiomyopathy group (n = 50). At week 5, 31 survival ISO-induced cardiomyopathy rats were randomized to RDN (n = 15) and Sham group (n = 16). Compared with Control group, ejection fraction was decreased, diastolic interventricular septal thickness and left atrial dimension were increased in ISO-induced cardiomyopathy group at 5 week. After 10 weeks, cardio-renal pathophysiologic results demonstrated that the collagen volume fraction of left atrio-ventricular and kidney tissues reduced significantly in RDN group compared with Sham group. Moreover the pro-fibrosis factors (TGF-β1, MMP2 and Collagen I), inflammatory cytokines (CRP and TNF-α), and collagen synthesis biomarkers (PICP, PINP and PIIINP) concentration significantly decreased in RDN group. Compared with Sham group, RDN group showed that release of noradrenaline and aldosterone were reduced, angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/angiotensin II type-1 receptor (AT1R) axis was downregulated. Meanwhile, angiotensin-converting enzyme 2 (ACE2)/angiotensin-1-7 (Ang-(1-7))/mas receptor (Mas-R) axis was upregulated. RDN inhibits cardio-renal fibrogenesis through multiple pathways, including reducing SNS over-activity, rebalancing RAAS axis.

Objective: To investigate the effects of renal denervation (RDN) on left atrial fibrosis in rats with chronic heart failure., Methods: Sixty healthy male Sprague Dawley rats were randomly assigned to control group (n=10, intraperitoneal injection with 5 mg/kg normal saline daily for 3 consecutive weeks), sham group (n=25) and RDN group (n=25). Rats in sham and RDN group were intraperitoneally injected with 5 mg/kg isoproterenol daily for 3 consecutive weeks. RDN and sham RDN procedure was implemented at week 5. The renal arteries and veins were not isolated and the nerves were left intact in sham group. The experiment ended at week 10. Cardiac function, diastolic interventricular septal thickness (IVSD) and left atrial dimension (LAD) were evaluated by echocardiography at baseline, week 5 and 10. The rats of all three groups were sacrificed at week 10 and the left atrial tissue was used for following analysis: fibrosis was detected by Masson staining, plasma BNP was measured by ELISA kit, the protein expression of AngII, TGF-β1, MMP2 and collagen I was determined by Western blot., Results: (1) Cardiac function: compared with control group, LVEF decreased (P<0.01), IVSD (P<0.01) and LAD (P<0.01) increased significantly in the sham and RDN group at week 5. Compared with sham group at week 10, LVEF and IVSD significantly improved (P<0.05) and LAD tended to be smaller (P>0.05) in RDN group. (2) The degree of left atrial tissue fibrosis: Masson staining (collagen volume fraction, CVF) showed significantly decreased fibrosis of left atrial tissue in RDN group compared with that in sham group (P<0.01). (3) Plasma BNP level: ELISA assay revealed that plasma BNP in sham group was significantly increased compared with that in control group (P<0.05) and was similar between RND group and control group at week 10. (4) Protein expression of AngII, TGF-β1, MMP2 and collagen I in rats left atrial: Western blot analysis demonstrated that the expression of AngII, TGF-β1, MMP2 and collagen I was significantly down-regulated in RDN group compared to sham group (all P<0.05) but still significantly higher than in control group (all P<0.05)., Conclusions: RDN can effectively attenuate the left atrial fibrosis in rats with isoproterenol induced chronic heart failure. The attenuation of left atrial fibrosis by RDN in these rats may be attributed to improved cardiac function and downregulated pro-fibrogenic factors (AngII, TGF-β1, MMP2 and collagen I).