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Impact of Renal Denervation on Atrial Arrhythmogenic Substrate in Ischemic Model of Heart Failure.

ABSTRACT: BACKGROUND:Myocardial infarction increases the risk of heart failure (HF) and atrial fibrillation. Renal denervation (RDN) might suppress the development of atrial remodeling. This study aimed to elucidate the molecular mechanism of RDN in the suppression of atrial fibrillation in a HF model after myocardial infarction. METHODS AND RESULTS:HF rabbits were created 4 weeks after coronary ligation. Rabbits were classified into 3 groups: normal control (n=10), HF (n=10), and HF-RDN (n=6). Surgical and chemical RDN were approached through midabdominal incisions in HF-RDN. Left anterior descending coronary artery in HF and HF-RDN was ligated to create myocardial infarction. After electrophysiological study, the rabbits were euthanized and the left atrial appendage was harvested for real-time polymerase chain reaction analysis and Trichrome stain. Left atrial dimension and left ventricular mass were smaller in HF-RDN by echocardiography compared with HF. Attenuated atrial fibrosis and tyrosine hydroxylase levels were observed in HF-RDN compared with HF. The mRNA expressions of Cav1.2, Nav1.5, Kir2.1, KvLQT1, phosphoinositide 3-kinase, AKT, and endothelial nitric oxide synthase in HF-RDN were significantly higher compared with HF. The effective refractory period and action potential duration of HF-RDN were significantly shorter compared with HF. Decreased atrial fibrillation inducibility was noted in HF-RDN compared with HF (50% versus 100%, P<0.05). CONCLUSIONS:RDN reversed atrial electrical and structural remodeling, and suppressed the atrial fibrillation inducibility in an ischemic HF model. The beneficial effect of RDN may be related to prevention of the downregulation of the phosphoinositide 3-kinase/AKT/endothelial nitric oxide synthase signaling pathway.

SUBMITTER: Yamada S

PROVIDER: S-EPMC5850156 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Impact of Renal Denervation on Atrial Arrhythmogenic Substrate in Ischemic Model of Heart Failure.

Yamada Shinya S Fong Man-Cai MC Hsiao Ya-Wen YW Chang Shih-Lin SL Tsai Yung-Nan YN Lo Li-Wei LW Chao Tze-Fan TF Lin Yenn-Jiang YJ Hu Yu-Feng YF Chung Fa-Po FP Liao Jo-Nan JN Chang Yao-Ting YT Li Hsing-Yuan HY Higa Satoshi S Chen Shih-Ann SA

Journal of the American Heart Association 20180122 2

<h4>Background</h4>Myocardial infarction increases the risk of heart failure (HF) and atrial fibrillation. Renal denervation (RDN) might suppress the development of atrial remodeling. This study aimed to elucidate the molecular mechanism of RDN in the suppression of atrial fibrillation in a HF model after myocardial infarction.<h4>Methods and results</h4>HF rabbits were created 4 weeks after coronary ligation. Rabbits were classified into 3 groups: normal control (n=10), HF (n=10), and HF-RDN (n ...[more]

PMID: 29358197

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Project description: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.

Project description:The aim of the present study was to determine if renal sympathetic denervation (RSD) may alleviate isoproterenol-induced left ventricle remodeling, and to identify the underlying mechanism. A total of 70 rats were randomly divided into control (n=15), sham operation (n=15), heart failure (HF) with sham operation (HF + sham; n=20) and HF with treatment (HF + RSD; n=20) groups. The HF model was established by subcutaneous injection of isoproterenol; six weeks later, 1eft ventricular internal diameter at end?systole (LVIDs), left ventricular systolic posterior wall thickness (LVPWs), 1eft ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were measured. Plasma norepinephrine (NE), angiotensin II (Ang II) and aldosterone (ALD) levels were measured by ELISA. Myocardial collagen volume fraction (CVF) was determined by Masson's staining. Reverse transcription?quantitative polymerase chain reaction was used to determine the mRNA expression levels of ventricular transforming growth factor?? (TGF??), connective tissue growth factor (CTGF) and microRNAs (miRs), including miR?29b, miR?30c and miR?133a. The results demonstrated that LVIDs and LVPWs in the HF + RSD group were significantly decreased compared with the HF + sham group. By contrast, LVFS and LVEF in the HF + RSD group were significantly increased compared with the HF + sham group. RSD significantly reduced the levels of plasma NE, Ang II and ALD. CVF in the HF + RSD group was reduced by 38.1% compared with the HF + sham group. Expression levels of TGF?? and CTGF were decreased, whereas those of miR?29b, miR?30c and miR?133a were increased, in the HF + RSD group compared with the HF + sham group. These results indicated that RSD alleviates isoproterenol?induced left ventricle remodeling potentially via downregulation of TGF??/CTGF and upregulation of miR?29b, miR?30c and miR?133a. RSD may therefore be an effective non?drug therapy for the treatment of heart failure.

Project description:Renal denervation (RD) was reported to reduce the susceptibility of atrial fibrillation (AF), but the underlying mechanism has not been well understood. This study was performed to investigate the effect of RD on the inducibility of AF in a rabbit model for atrial fibrosis and to explore the potential mechanisms. Thirty-five rabbits were randomly assigned into sham-operated group (n = 12), abdominal aortic constriction (AAC) group (n = 12) and AAC with RD (AAC-RD) group (n = 11). The incidence of AF induced by burst pacing in atriums was determined. Blood was collected to measure the levels of rennin, angiotensin II and aldosterone. Atrial samples were preserved to evaluate protein and gene expression of collagen, connective tissue growth factor (CTGF) and transforming growth factor-β1 (TGF-β1). Our data suggested cardiac structure remodeling and atrial fibrosis were successfully induced by AAC. Compared with the AAC group, the AAC-RD rabbits had smaller ascending aortic diameter and left ventricular end-systolic diameter. For burst pacing at the left atrium (LA), AF was induced in two of the 12 rabbits in the sham-operated group, 10 of the 12 rabbits in the AAC group, and 2 of the 11 rabbits in the AAC-RD group, with great difference among the three groups (P = 0.001). The percentage of LA burst stimulations with induced AF achieved 47.2% in the AAC group, which was higher than those in both the AAC-RD (12.1%) and the Sham-operated (5.6%) groups. Significantly increasing intercellular space in the AAC group (P<0.001) compared with the sham-operated rabbits. RD clearly decreased the volume fraction of collagen in LA and right atrium compared with that of the AAC group (P< 0.01). AAC-induced elevation of collagen I, CTGF and TGF-β1 was suppressed by RD. In conclusion, RD suppressed the inducibility of AF in a rabbit model for pressure associated atrial fibrosis, potentially by modulating renin-angiotensin-aldosterone system and decreasing pro-fibrotic factors.

Dataset Information

Impact of Renal Denervation on Atrial Arrhythmogenic Substrate in Ischemic Model of Heart Failure.

Publications

Impact of Renal Denervation on Atrial Arrhythmogenic Substrate in Ischemic Model of Heart Failure.

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