R97 at "Handlebar" Binding Mode in Active Pocket Plays an Important Role in Fe(II)/α-Ketoglutaric Acid-Dependent Dioxygenase cis-P3H-Mediated Selective Synthesis of (2S,3R)-3-Hydroxypipecolic Acid.

Pipecolic acid (Pip) and its derivative hydroxypipecolic acids, such as (2S,3R)-3-hydroxypipecolic acid (cis-3-L-HyPip), are components of many natural and synthetic bioactive molecules. Fe(II)/α-ketoglutaric acid (Fe(II)/2-OG)-dependent dioxygenases can catalyze the hydroxylation of pipecolic acid. However, the available enzymes with desired activity and selectivity are limited. Herein, we compare the possible candidates in the Fe(II)/2-OG-dependent dioxygenase family, and cis-P3H is selected for potentially catalyzing selective hydroxylation of L-Pip. cis-P3H was further engineered to increase its catalytic efficiency toward L-Pip. By analyzing the structural confirmation and residue composition in substrate-binding pocket, a "handlebar" mode of molecular interactions is proposed. Using molecular docking, virtual mutation analysis, and dynamic simulations, R97, E112, L57, and G282 were identified as the key residues for subsequent site-directed saturation mutagenesis of cis-P3H. Consequently, the variant R97M showed an increased catalytic efficiency toward L-Pip. In this study, the kcat/Km value of the positive mutant R97M was about 1.83-fold that of the wild type. The mutation R97M would break the salt bridge between R97 and L-Pip and weaken the positive-positive interaction between R97 and R95. Therefore, the force on the amino and carboxyl groups of L-Pip was lightly balanced, allowing the molecule to be stabilized in the active pocket. These results provide a potential way of improving cis-P3H catalytic activity through rational protein engineering.

The Role of α7nAChR-Mediated Cholinergic Anti-Inflammatory Pathway in Vagal Nerve Regulated Atrial Fibrillation.

The aim was to investigate the role of the α7nAChR-mediated cholinergic anti-inflammatory pathway in vagal nerve regulated atrial fibrillation (AF).18 beagles (standard dogs for testing) were used in this study, and the effective refractory period (ERP) of atrium and pulmonary veins and AF inducibility were measured hourly during rapid atrial pacing at 800 beats/minute for 6 hours in all beagles. After cessation of 3 hours of RAP, the low-level vagal nerve stimulation (LL-VNS) group (n = 6) was given LL-VNS and injection of salinne (0.5 mL/GP) into four GPs, the methyllycaconitine (MLA, the antagonist of α7nAChR) group (n = 6) was given LL-VNS and injection of MLA into four GPs, and the Control group (n = 6) was given saline into four GPs and the right cervical vagal nerve was exposed without stimulation. Then, the levels of the tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), acetylcholine (ACh), STAT3, and NF-κB proteins were measured. During the first 3 hours of RAP, the ERPs gradually decreased while the dispersion of ERPs (dERPs) and AF inducibility gradually increased in all three groups. During the last 3 hours of 6 hours' RAP in this study, the ERPs in the LL-VNS group were higher, while the dERPs and AF inducibility were significantly lower when compared with the Control and MLA groups at the same time points. The levels of ACh in the serum and atrium in the LL-VNS and MLA groups were higher than in the Control group, and the levels of TNF-α and IL-6 were higher in the Control and MLA groups than in the LL-VNS group. The concentrations of STAT3 in RA and LA tissues were higher in the LL-VNS group while those of NF-κB were lower.In conclusion, the cholinergic anti-inflammatory pathway mediated by α7nACh plays an important role in low-level vagal nerve-regulated AF.

Median nerve stimulation prevents atrial electrical remodelling and inflammation in a canine model with rapid atrial pacing.

Aims: Studies have shown that stellate ganglion nerve activity has association with atrial electrical remodelling and atrial fibrillation (AF) inducibility, while median nerve stimulation (MNS) decreases cardiac sympathetic drive. In this study, we tested the hypothesis that MNS suppresses atrial electrical remodelling and AF vulnerability. Methods and results: The atrial effective refractory period (AERP) and AF inducibility at baseline and after 3 h of rapid atrial pacing were determined in dogs undergoing MNS (n = 7), MNS+ application of methyllycaconitine (n = 7) or sham procedure (n = 6). Then, the levels of tumour necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and acetylcholine (Ach) in the plasma and atrial tissues were measured. The control dogs (n = 4) were assigned to measure atrial inflammation cytokines. Short-term rapid atrial pacing induced shortening of the AERP, an increase in AERP dispersion, and an increase AF vulnerability in the sham dogs, which were all suppressed by MNS. Levels of TNF-a and IL-6 were higher, and Ach levels were lower in the left and the right atrium in the sham dogs than in the MNS dogs. Methyllycaconitine blunted the effects of MNS on the AERP, AERP dispersion, the AF vulnerability, and TNF-a and IL-6 levels in the atrium, but had no impact on the levels of Ach. Conclusions: The effects of MNS on atrial electrical remodelling and AF inducibility might be associated with the cholinergic anti-inflammatory pathway.

Effects of extrinsic cardiac nerve stimulation on atrial fibrillation inducibility: The regulatory role of the spinal cord.

OBJECTIVE: To investigate the effect of the mutual regulation of the extrinsic cardiac nerves on atrial electrophysiology and atrial fibrillation (AF) vulnerability. METHODS AND RESULTS: Fourteen dogs were randomly divided into two groups: spinal cord stimulation (SCS) group (n = 7) and spinal cord block (SCB) group (n = 7). SCS was performed with 90% of the threshold voltage stimulating the T1 -T2 spinal level, while SCB was performed by injecting 2% lidocaine into the epidural space at the T2-3 level. The effective refractory period (ERP), ERP dispersion, and AF inducibility were measured during atrial pacing combined with different extrinsic cardiac nerve stimulation. ERPs were decreased in the atrium and pulmonary veins and ERP dispersion was increased from baseline during left cervical vagus nerve stimulation (VNS) or left stellate ganglion stimulation (SGS) in the two groups. When combined with SCS, VNS resulted in diminished ERPs at all recording sites, longer ERP dispersion and more episodes of AF than were observed during VNS, whereas ERPs were greater and correspondingly fewer episodes of AF occurred during SCS combined with SGS than SGS. In the SCB group, ERPs were shortened, ERP dispersion was lengthened, and episodes of AF were increased during SGS after SCB. SCS enhanced the activity of the left vagus nerve but attenuated the left stellate ganglion and superior left ganglionated plexus. CONCLUSION: SCS modulates extrinsic and intrinsic cardiac nerve activity among the vagus nerve, stellate ganglion, and ganglionated plexus. SCS facilitates the effect of VNS and attenuates the effect of SGS on atrial electrophysiology.

Effect of renal sympathetic denervation on the progression of paroxysmal atrial fibrillation in canines with long-term intermittent atrial pacing.

AIMS: The aim of the present study was to explore the effect of renal sympathetic denervation (RSD) on the progression of paroxysmal atrial fibrillation (AF) in canines with long-term intermittent atrial pacing. METHODS AND RESULTS: Nineteen beagles were randomly divided into sham-operated group (six dogs), control group (six dogs), and RSD group (seven dogs). Sham-operated group were implanted with pacemakers without pacing; control group were implanted with pacemakers with long-term intermittent atrial pacing; and RSD group underwent catheter-based RSD bilaterally and were simultaneously implanted with pacemakers. Atrial pacing was maintained for 8 h a day and a total of 12 weeks in the control group and RSD group. Echocardiography showed that the left atrial structure and function were significantly improved in the RSD group compared with the control group (P < 0.05). Compared with the control group, the RSD group had fewer incidences of AF and a shorter duration of AF (P < 0.05) after long-term intermittent atrial pacing. In addition to increased atrial effective refractory period (AERP) and AF cycle length, AERP dispersion and P-wave duration and dispersion were significantly decreased in the RSD group compared with the control group (P < 0.05). Atrial morphological evaluation suggested that fibrosis and ultrastructural changes induced by long-term intermittent atrial pacing were markedly suppressed in the RSD dogs compared with controls (P < 0.05). Immunohistochemistry results showed that connexin 43 distribution in RSD mid-myocardial was significantly fewer heterogeneous than that in control mid-myocardial (P < 0.05). CONCLUSION: Renal denervation inhibits the progression of paroxysmal AF, which might be related to the suppression of atrial electrophysiology and structural heterogeneity.

[Renal sympathetic denervation suppresses ventricular substrate remodeling in a canine high-rate pacing model].

OBJECTIVE: To explore the role of renal sympathetic denervation (RSD) on ventricular substrate remodeling in dogs with pacing-induced heart failure (HF). METHODS: A total of 19 dogs were randomized into 3 groups of sham-operated control (n = 7), right ventricular pacing induction of HF (n = 6) and RSD (n = 6). After 8-week pacing induction of HF. Hemodynamic variables were monitored at baseline and after HF. Masson's trichrome staining, enzyme-linked immunosorbent assay (ELISA) and Western blot were used to measure ventricular interstitial fibrosis, brain natriuretic peptide (BNP), angiotensin II (Ang II), aldosterone and transforming growth factor-beta (TGF-ß). RESULTS: All dogs in HF and HF+RSD groups showed increased left and right ventricular diastolic dimensions [left ventricle: (27.0 ± 2.4) vs (37.0 ± 2.8) mm, P < 0.01 and (30.0 ± 2.5) vs (36.0 ± 2.8) mm, P < 0.05; right ventricle: (11.0 ± 1.5) vs (14.0 ± 1.7) mm, P = 0.03 and (12.0 ± 1.1) vs (14.0 ± 1.2) mm, P < 0.05]. Compared with HF + RSD dogs, HF dogs had higher left ventricular end-diastolic pressure (LVEDP) [(25.0 ± 3.7) vs (3.3 ± 1.6) mmHg, P < 0.01] and more fibrous tissue (left ventricle:24.1% ± 4.8% vs 8.5% ± 1.9%, P < 0.01; right ventricle:17.2% ± 5.2% vs 11.8% ± 3.9%, P < 0.01). The levels of BNP, Ang II, aldosterone and TGF-ß in ventricular tissue increased in HF dogs compared to sham-operated and HF+RSD dogs. CONCLUSION: RSD could suppress ventricular substrate remodeling induced by long-term rapid ventricular pacing.

[Beneficial effects of renal denervation on pulmonary vascular remodeling in experimental pulmonary artery hypertension].

OBJECTIVE: To explore the effects of renal sympathetic denervation (RSD) on pulmonary vascular remodeling in a model of pulmonary arterial hypertension (PAH). METHODS: According to the random number table, 24 beagles were randomized into control, PAH and PAH+RSD groups (n=8 each). The levels of neurohormone, echocardiogram and dynamics parameters were measured. Then 0.1 ml/kg dimethylformamide (control group) or 2 mg/kg dehydromonocrotaline (PAH and PAH+RSD groups) were injected. The PAH+RSD group underwent RSD after injection. At week 8 post-injection, the neurohormone levels, echocardiogram, dynamics parameters and pulmonary tissue morphology were observed. RESULTS: The values of right ventricular systolic pressure (RVSP) and pulmonary arterial systolic pressure (PASP) in PAH and PAH+RSD groups were both significantly higher than those in control group ((42.8±8.7), (30.8±6.8) vs (23.2±5.7) mmHg (1 mmHg=0.133 kPa) and (45.1±11.2), (32.6±7.9) vs (24.7±7.1) mmHg). Meanwhile, the values of RVSP and PASP in PAH group were higher than those in PAH+RSD group (all P<0.01). The levels of serum angiotensin II (Ang II) and endothelin-1 significantly increased after 8 weeks in PAH dogs ((228±41) vs (113±34) pg/ml and (135±15) vs (77±7) pg/ml, all P<0.01). And Ang II and endothelin-1 were higher in lung tissues of PAH group ((65±10) and (96±10) pg/ml) than in those of control group ((38±7) and (54±6) pg/ml) and PAH+RSD group ((46±8) and (67±9) pg/ml) (all P<0.01). Pulmonary tissues had marked collagen hyperplasia and lamellar corpuscles of type 2 alveolar cells were damaged more severely in PAH dogs than in PAH+RSD dogs. CONCLUSIONS: RSD suppresses pulmonary vascular remodeling and decreases pulmonary arterial pressure in experimental PAH. And the effect of RSD on PAH may contribute to decreased neurohormone levels.

Effects of renal sympathetic denervation on the atrial electrophysiology in dogs with pacing-induced heart failure.

BACKGROUND: Heart failure (HF) and atrial fibrillation (AF) are associated with sympathetic activation. Renal sympathetic denervation (RSD) can suppress AF vulnerability. The impact of RSD on atrial electrophysiology in experimental HF is unclear. METHODS: Twenty-two beagles were randomized into control, HF, and HF + RSD groups. Control dogs were implanted cardiac pacemakers without pacing. Dogs in the HF group underwent right ventricular pacing for 3 weeks at 240 beats/min to induce HF. The dogs in the HF + RSD group received RSD and underwent the same HF-inducing procedure. RESULTS: The P-wave dispersion was higher in HF dogs than in the control and HF + RSD dogs (19 ± 3.1 ms vs 13 ± 2.3 ms, 15 ± 2.9 ms, P = 0.04). Conduction time within the interatrium was significantly longer in the HF dogs than that in the control and HF + RSD dogs (39 ± 4 ms vs 31 ± 3 ms, 33 ± 4 ms; P = 0.03). Window of vulnerability (WOV) of AF was widened in the HF dogs than in the HF + RSD dogs (37 ± 5 ms vs 14 ± 3 ms; P < 0.01), while AF could not be induced (WOV = 0) in the control dogs during S1 S2 stimulation. The voltage in the threshold for AF inducibility was lower during ganglionated plexi stimulation in the HF dogs than in the control and HF + RSD dogs (1.8 ± 0.6 V vs 2.5 ± 0.6 V, 2.4 ± 0.4 V; P = 0.04). CONCLUSIONS: RSD could reverse the atrial electrical remodeling and decrease AF inducibility in dogs with pacing-induced HF.

Wenxin Keli suppresses atrial substrate remodelling after epicardial ganglionic plexi ablation.

BACKGROUND: The chronic effects of ganglionic plexi (GP) ablation on atrial fibrillation (AF) inducibility have not been elucidated. OBJECTIVE: To investigate the effect of Wenxin Keli (WK) on the inducibility of AF and atrial substrate remodelling after epicardial GP ablation. METHODS: Twenty dogs were randomly divided into a sham-operated group, a GP ablation group and a WK-treated group. All animals underwent a left thoracotomy at the fourth intercostal space. AF inducibility was assessed by burst rapid pacing at the right atrium. Both the GP ablation group and the WK-treated group received four major GP ablations. In the WK-treated group, dogs were treated with oral WK once per day, and all animals were allowed to recover for eight weeks, after which AF inducibility and AF duration were measured again. RESULTS: After eight weeks of WK treatment, AF inducibility was lower than in the GP ablation group, and was similar to that of the sham-operated group. Compared with the sham-operated group, the levels of atrial natriuretic peptide (ANP), tumour necrosis factor-alpha (TNF-α) and interleukin (IL)-6 in right atrial tissues were increased in GP ablation group (143.6±33.7 pg/mg versus 206.2±41.4 pg/mg, P=0.02; 75.3±12.1 pg/mg versus 141.3±64 pg/mg, P=0.03; and 175.1±42.5 pg/mg versus 351.7±101 pg/mg, P<0.01, respectively). There were no significant differences in levels of ANP, TNF-α and IL-6 in atrial tissues between the sham-operated group and WK treated group. Expression of connexin 43 in atrial tissues was increased after eight weeks of GP ablation, while WK administration inhibited connexin 43 remodelling. CONCLUSIONS: Epicardial GP ablation can induce atrial substrate remodelling, including Cx43 upregulation and increased levels of ANP, TNF-α and IL-6. These changes may be suppressed by long-term oral WK administration.

[Effects of renal sympathetic denervation on inducibility of atrial fibrillation during rapid atrial pacing].

OBJECTIVE: To explore the effects of renal sympathetic denervation on inducibility of atrial fibrillation (AF) during rapid atrial pacing. METHODS: Thirteen dogs were selected and divided into control group (n=7) and renal artery ablation group (RAA) (n=6). In the control group, the animals were subjected to atrial pacing at 800 beats/min for 7 hours. And atrial effective refractory period (AERP) and induced AF were measured hourly during non-pacing. In the RAA group, after each renal artery ablation, the procedures of pacing and electrophysiological measurement were nearly the same as those in the control group. Blood was collected before and after pacing to measure the levels of rennin, angiotensin AngII (AngII) and aldosterone. RESULTS: There was a persistent decrease in AERP in both groups. However, after a 7-hour pacing, induced number of times and duration of AF were higher in the control group than those in the RAA group. The plasma concentrations of rennin and aldosterone increased significantly after 7-hour rapid pacing in the control group (rennin: (120±31) to (185±104) pg/ml, P<0.01, aldosterone: (288±43) to (370±110) pg/ml, P=0.01). No significant difference existed in the levels of AngII at pre- and post-pacing in the control group ((160±48) to (189±164) pg/ml, P=0.23). The levels of rennin and aldosterone showed a decreasing trend in the RAA group. But there was no statistical significance. CONCLUSIONS: Episodes of AF during short-time rapid atrial pacing may be decreased by renal sympathetic denervation. This effect is probably related with the decreased activity of RAAS.

Effect of Shensong Yangxin on the Progression of Paroxysmal Atrial Fibrillation is Correlated with Regulation of Autonomic Nerve Activity.

BACKGROUND: Shensong Yangxin (SSYX), a traditional Chinese herbal medicine, has long been used clinically to treat arrhythmias in China. However, the mechanism of SSYX on atrial fibrillation (AF) is unknown. In this study, we tested the hypothesis that the effect of SSYX on the progression of paroxysmal AF is correlated with the regulation of autonomic nerve activity. METHODS: Eighteen mongrel dogs were randomly divided into control group (n = 6), pacing group (n = 6), and pacing + SSYX group (n = 6). The control group was implanted with pacemakers without pacing; the pacing group was implanted with pacemakers with long-term intermittent atrial pacing; the pacing + SSYX group underwent long-term intermittent atrial pacing and SSYX oral administration. RESULTS: Compared to the pacing group, the parameters of heart rate variability were lower after 8 weeks in the pacing + SSYX group (low-frequency [LF] component: 20.85 ± 3.14 vs. 15.3 ± 1.89 ms 2 , P = 0.004; LF component/high-frequency component: 1.34 ± 0.33 vs. 0.77 ± 0.15, P < 0.001). The atrial effective refractory period (AERP) was shorter and the dispersion of the AERP was higher after 8 weeks in the pacing group, while the changes were suppressed by SSYX intake. The dogs in the pacing group had more episodes and longer durations of AF than that in the pacing + SSYX group. SSYX markedly inhibited the increase in sympathetic nerves and upregulation of tumor necrosis factor-alpha and interleukin-6 expression in the pacing + SSYX group. Furthermore, SSYX suppressed the decrease of acetylcholine and α7 nicotinic acetylcholine receptor protein induced by long-term intermittent atrial pacing. CONCLUSIONS: SSYX substantially prevents atrial electrical remodeling and the progression of AF. These effects of SSYX may have association with regulating the imbalance of autonomic nerve activity and the cholinergic anti-inflammatory pathway.

Effects of Intrinsic and Extrinsic Cardiac Nerves on Atrial Arrhythmia in Experimental Pulmonary Artery Hypertension.

Atrial arrhythmia, which includes atrial fibrillation (AF) and atrial flutter (AFL), is common in patients with pulmonary arterial hypertension (PAH), who often have increased sympathetic nerve activity. Here, we tested the hypothesis that autonomic nerves play important roles in vulnerability to AF/AFL in PAH. The atrial effective refractory period and AF/AFL inducibility at baseline and after anterior right ganglionated plexi ablation were determined during left stellate ganglion stimulation or left renal sympathetic nerve stimulation in beagle dogs with or without PAH. Then, sympathetic nerve, ß-adrenergic receptor densities and connexin 43 expression in atrial tissues were assessed. The sum of the window of vulnerability to AF/AFL was increased in the right atrium compared with the left atrium at baseline in the PAH dogs but not in the controls. The atrial effective refractory period dispersion was increased in the control dogs, but not in the PAH dogs, during left stellate ganglion stimulation. The voltage thresholds for inducing AF/AFL during anterior right ganglionated plexi stimulation were lower in the PAH dogs than in the controls. The AF/AFL inducibility was suppressed after ablation of the anterior right ganglionated plexi in the PAH dogs. The PAH dogs had higher sympathetic nerve and ß1-adrenergic receptor densities, increased levels of nonphosphorylated connexin 43, and heterogeneous connexin 43 expression in the right atrium when compared with the control dogs. The anterior right ganglionated plexi play important roles in the induction of AF/AFL. AF/AFL induction was associated with right atrium substrate remodeling in dogs with PAH.

Renal sympathetic denervation suppresses ventricular substrate remodelling in a canine high-rate pacing model.

AIMS: This study sought to assess whether renal sympathetic denervation (RSD) could suppress ventricular substrate remodelling and attenuate heart failure (HF) progression. METHODS AND RESULTS: Nineteen dogs were randomised into three groups - seven sham-operated controls, six with right ventricular pacing to induce HF, and six with RSD followed eight weeks later by pacing induction of HF. Haemodynamic variables were monitored at baseline and after HF. Levels of ventricular interstitial fibrosis, BNP, Ang II, aldosterone and TGF-ß were measured. All the dogs in the HF and HFï¹¢RSD groups showed increased left and right ventricular diastolic dimensions, but the dogs in the HFï¹¢RSD group had a higher left ventricular ejection fraction (LVEF) than the HF dogs (0.42±0.05 vs. 0.35±0.04, p<0.01). Compared with the dogs with HF alone, the HF+RSD dogs had lower left ventricular end-diastolic pressure (LVEDP) (3.3±1.6 vs. 25±3.7 mmHg, p<0.01) and less fibrous tissue. The levels of BNP, Ang II, aldosterone and TGF-ß expression in ventricular tissue were higher in the HF dogs than in the sham-operated and HFï¹¢RSD dogs. CONCLUSIONS: RSD suppressed ventricular substrate remodelling induced by long-term rapid ventricular pacing.

Changes of serum neurohormone after renal sympathetic denervation in dogs with pacing-induced heart failure.

BACKGROUND: Neurohormonal activation is a commonly cited array of phenomena in the body's physiologic response to heart failure (HF). The aim of the present study was to determine the change law of serum neurohormones after renal sympathetic denervation (RSD) in dogs with pacing-induced HF. METHODS: Twenty-eight beagles were randomly divided into control group, RSD group, HF group and HF + RSD group. The control group was implanted pacemakers without pacing; the RSD group underwent renal artery ablation without pacing; the HF group was implanted pacemakers with ventricular pacing at 240 bpm for 3 weeks; and HF + RSD group underwent renal artery ablation and with ventricular pacing at 240 bpm for 3 weeks. Blood samples were taken at baseline, and 3, 6, 9, 12, 15, 18, 21 days in all the dogs for neurohormones measurement. RESULTS: After 3 weeks, the systolic femoral artery pressures in the HF and HF + RSD groups were reduced after pacing 3 weeks. There was an increase significantly in BNP, angiotensin II, aldosterone, endothelin-1 and decrease in renalase after 3 weeks when compared with baseline in HF group. RSD significantly suppressed the changes of plasma neurohormones concentration in experimental HF, but RSD had not obviously impact on the levels of plasma neurohormones during 3 weeks in RSD group. CONCLUSIONS: RSD attenuates the changes of levels of plasma neurohormones in the activated renin-angiotensin-aldosterone system (RAAS) but had not obviously effect in the normal physiology of RAAS.

Effect of renal sympathetic denervation on atrial substrate remodeling in ambulatory canines with prolonged atrial pacing.

We have previously demonstrated that catheter-based renal sympathetic denervation (RSD) could suppress atrial fibrillation (AF) in canines with short-time rapid right atrial pacing (RAP). However, the role of renal denervation on atrial remodeling is unclear. The aim of the present study was to explore the long-term effect of RSD on the atrial remodeling during prolonged RAP. Twenty mongrel dogs were implanted with a high-frequency cardiac pacemaker with a transvenous lead inserted into the right atrial appendage. The dogs were divided into three groups: a sham-operated group (n = 6), the chronic RAP (CRAP) group (n = 7), and the CRAP+RSD group (n = 7). In the CRAP+RSD group, a pacemaker was implanted 6 weeks after RSD was performed bilaterally for recovery. RAP was maintained for 5 weeks in CRAP group and CRAP+RSD group. The plasma levels of Angiotensin II and aldosterone were significantly increased in CRAP group compared with sham-operated group, but the increasing trend was inhibited in CRAP+RSD group compared with CRAP group (P<0.05). Similarly, RSD suppressed the increasing trend that prolonged RAP produced in the left atrial levels of ANP, TNF-α and IL-6. Compared with the sham-operated group, the CRAP group had significantly increased levels of caspase-3, bax and Cx40 whereas the level of Bcl-2 decreased (P<0.05). RSD markedly reduced the upregulation of caspase-3, bax and Cx40 and the downregulation of Bcl-2 expression compared with the CRAP group (P<0.05). Picric acid-sirius red staining study suggested that RSD could markedly alleviate the lesion degree of cardic fibrosis induced by CRAP (P<0.05). Immunohistochemistry results showed that the densities of TH- and GAP43- positive nerves were significantly elevated in the CRAP group compared with the sham-operated group, while RSD operation signicantly inhibited the these changes produced by CRAP. These findings suggest that renal denervation could suppress the atrial remodeling after prolonged RAP in ambulatory canines.

Effect of renal sympathetic denervation on the inducibility of atrial fibrillation during rapid atrial pacing.

BACKGROUND: Atrial fibrillation (AF) is associated with activity of renin-angiotensin-aldosterone system (RAAS). Reduction in renal noradrenaline spillover could be achieved after renal sympathetic denervation (RSD). The relationship between RSD and AF is unknown. OBJECTIVE: The objective of the study was to investigate the inducibility of AF during atrial rapid pacing after RSD. METHODS: Thirteen dogs were used for the study as follows: control group (seven dogs) and RSD group (six dogs). In the control group, dogs were subjected to atrial pacing at 800 beats/min for 7 h, and atrial effective refractory period (AERP) was measured every hour in the status of non-pacing. Subsequently, pacing was stopped and the burst pacing (500 bpm) was repeated to induce AF three times. In the RSD group, after each renal artery ablation, the procedure of pacing and electrophysiological measurement was exactly same as in the control group. Blood was collected before and after pacing to measure the levels of renin, angiotensin II and aldosterone. RESULTS: There was a persistent decrease in AERP in both groups. However, 7 h after cessation of pacing, the induced number of times and duration of AF were higher in the control group than that in the RSD group (1.0 ± 1.26 vs 3.14 ± 2.54, P = 0.03; 16.5 ± 25.1 vs 86.6 ± 116.4, P = 0.02). The plasma aldosterone concentration increased significantly 7 h after rapid pacing in control group (renin, 119.8 ± 31.1 vs 185.3 ± 103.5 pg/ml, P < 0.01; aldosterone, 288.2 ± 43.1 vs 369.6 ± 109.8 pg/ml, P = 0.01). The levels of renin and aldosterone showed a decreasing trend in RSD group, but this did not attain statistical significance. CONCLUSIONS: Episodes of AF could be decreased by renal sympathetic denervation during short-time rapid atrial pacing. This effect might have relationship with decreased activity of RAAS.