| Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and a major cause of morbidity and mortality. The prevalence of AF increases with age, from0.1%in people aged less than55years to8%in people over80years. Although the multi-factor mechanism underlying the genesis of AF has been the focus of many studies, it only remains partially understood. So far, no ideal therapy can be applied to all patients with AF. Available antiarrhythmic drugs for preventing AF recurrence is far from ideal because of limited efficacy and potential side effects, particularly proarrhythmia. Catheter ablation of AF is now a realistic therapeutic option in a broad spectrum of patients, but they are at risks for major complications including potential recurrence, systemic thromboembolism, pericardial effusion, cardiac tamponade, and so on. These limitations stimulate research toward the development of effective but less aggressive procedures for the treatment and prevention of AF.Studies have indicated that the renin-angiotensin-aldosterone system (RAAS) has been shown to an important hormonal system in the initiation and pathogenesis of AF. Inhibitors of the RAAS, such as angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are now emerged as novel drugs for the prevention and treatment of AF. Although these drugs may not possess direct anti-arrhythmic properties, a large number of research on AF have shown that RAAS blockade has beneficial effects on cardiac remodeling, which is specially related to RAAS inhibition. Catheter-based renal artery ablation selectively reduces both renal sympathetic efferent and afferent nerve activity and causes renal sympathetic denervation (RSD), which is indicated by a reduction in renal noradrenaline spillover measurements and plasma renin activity. The aim of the study was to investigate the effect of RSD on the inducibility of AF, atrial substrate, remodeling and electrophysiology in the rapid atrial-paced canine model, in order to provide a new technology for the treatment and prevention of AF. This study included four parts.Part I Effect of renal sympathetic denervation on inducibility of atrial fibrillation during rapid atrial pacingObjective:To explore the effects of RSD on inducibility of AF during rapid atrial pacing. Methods:Thirteen mongrel dogs were randomly divided into control group (n=7) and renal sympathetic denervation group (RSD, n=6). In the control group, the animals were subjected to rapid atrial pacing (RAP) at800beats per minute for7hours. And induced AF and atrial effective refractory period (AERP) were measured hourly during non-pacing. In the RSD group, the procedures of pacing and electrophysiological measurement were nearly the same as those in the control group after renal artery bilaterally ablation. The plasma levels of rennin, angiotensin II (Ang Ⅱ) and aldosterone were measured before and after pacing.Results:There was a persistent decrease in AERP in both groups (P<0.05), but the differences between the two groups were no statistical significance (P>0.05). Induced duration and number of times of AF were higher in the control group than those in the RSD group after a7h rapid pacing (P<0.05). After7h rapid pacing, the plasma levels of rennin and aldosterone increased significantly in the control group (rennin,120±31pg/ml vs185±104pg/ml, P<O.01; aldosterone,288±43pg/ml vs370±110pg/ml, P<O.05). There was no significant difference existed in the levels of Ang Ⅱ between before and after pacing in the control group (160±48pg/ml vs189±64pg/ml, P>0.05). Although the plasma levels of rennin, Ang Ⅱ and aldosterone showed a decreasing trend in the RSD group, there was no statistical significance (rennin,136±46pg/ml vs132±38pg/ml, P>0.05; AngⅡ,164±36pg/ml vs157±59pg/ml, P>0.05; aldosterone,335±121pg/ml vs327±60pg/ml, P>0.05).Conclusions:Catheter-based RSD could decrease the episodes of AF during short-time rapid atrial pacing. The inhibition of renin-angiotensin-aldosterone systematic activity may be a mechanism underlying these results.Part II Effect of renal sympathetic denervation on the inducibility of atrial fibrillation and atrial substrate after prolonged atrial pacingObjective:To investigate the effect of RSD on the inducibility of AF and atrial substrate in ambulatory canines with prolonged atrial pacing.Methods:Twenty mongrel dogs were implanted with a high-frequency cardiac pacemaker with a transvenous lead inserted into the right atrial appendage. The dogs were randomly divided into three groups:a sham-operated group (n=6), the chronic RAP (CRAP) group (n=7) and the RSD+CRAP group (n=7). Sham-operated group dogs were only implanted with pacemakers without pacing. In the RSD+CRAP group, a pacemaker was implanted6weeks after RSD was performed bilaterally for recovery. RAP was maintained for5weeks in both CRAP group and RSD+CRAP group. The inducibility of AF, blood pressure and the plasma levels of Ang II and aldosterone were measured in all the animals at the baseline and endpoint of the protocol. Then the heart was quickly excised and tissue specimens were obtained from the left atria. The tissue levels of ANP, TNF-a and IL-6was examined by ELISA, and the expression levels of Caspase-3, Bax, Bcl-2, TIMP-1, MMP-9, TGF-βl and Smad2were examined by western blotting.Results: Systolic blood pressure was significantly decreased after RSD for6weeks in CRAP+RSD group (P<0.01). Similarly, systolic blood pressure was decreased after RAP for a mean of5weeks in both CRAP group (P<O.01) and RSD+CRAP group (P<0.05). However, compared with the CRAP group dogs, the RSD+CRAP group dogs had a lower systolic blood pressure (P<O.01) at the endpoint of the study. AF was induced easily in the CRAP group than in the sham-operated group and RSD+CRAP group after5week atrial pacing (P<O.05). The plasma level of Ang II was significantly increased in both CRAP group and RSD+CRAP group compared with sham-operated group after5week atrial pacing, but the increasing trend was inhibited in RSD+CRAP group compared with CRAP group (P<O.05). Similarly, RSD suppressed the increasing trend that prolonged RAP produced in the left atrial levels of ANP, TNF-a and IL-6. Compared with the sham-operated group, the CRAP group had significantly increased levels of caspase-3, bax, MMP-9, TGF-β1and Smad2whereas the level of Bcl-2and TIMP-1decreased (P<O.05). RSD markedly reduced the upregulation of caspase-3, bax, MMP-9, TGF-βl and Smad2and the downregulation of Bcl-2and TIMP-1expression compared with the CRAP group (P<O.05). Masson’s trichrome staining of atrial myocardium suggested that extensive fibrosis was especially visible in CRAP group, but attenuated in RSD+CRAP group. Tunel staining studies further showed that RSD treatment markedly reduced cardiocyte apoptosis produced by chronic RAP.Conclusions: Catheter-based renal denervation can attenuate AF vulnerability produced by prolonged atrial pacing and alter the atrial substrate including the significantly increased atrial fibrosis, inflammation and apoptosis by inhibiting the activity of RAAS. Part Ⅲ Effect of renal sympathetic denervation on atrial remodeling after prolonged atrial pacingObjective:To assess the effect of RSD on atrial remodeling in ambulatory canines with prolonged atrial pacing.Methods:Twenty mongrel dogs were implanted with a high-frequency cardiac pacemaker with a transvenous lead inserted into the right atrial appendage. The dogs were randomly divided into three groups:a sham-operated group (n=6), the chronic RAP (CRAP) group (n=7) and the RSD+CRAP group (n=7). Sham-operated group dogs were only implanted with pacemakers without pacing. In the RSD+CRAP group, a pacemaker was implanted6weeks after RSD was performed bilaterally for recovery. RAP was maintained for5weeks in both CRAP group and RSD+CRAP group. Echocardiography and electrophysio logical test were measured in all the animals at the baseline and endpoint of the protocol. The heart was quickly excised at the endpoint of the protocol and tissue specimens were obtained from the left atria for test.Results:AERP was significantly shortened from142±8ms to115±9ms in CRAP group after prolonged atrial pacing (P<O.01). Although the AERP of RSD+CRAP group decreased from140+±10to127±11ms after prolonged RAP, the probability value was not significantly different (P>0.05). Echocardiography showed left atrial volume (LAVmax and LAVmin) was significantly reduced in RSD+CRAP group than that in CRAP group (P<0.05) after prolonged rapid pacing, although left atrial diameter (LAD), left ventricle end-diastolic dimension (LVEDD), LAVmax and LAVmin were significantly increased after atrial pacing for5weeks compared with values observed before atrial pacing both in CRAP group and RSD+CRAP group. Ultrastructural changes that mitochondrial swelling with a decrease in the density, severe disintegration of myofilaments, and loss of banding pattern and integrity of contractile elements observed after5week atrial pacing were markedly attenuated by RSD. And RSD inhibited the increasing trend that chronic rapid pacing produced in the left atrial levels of Ang Ⅱ and aldosterone. Compared with the sham-operated group, the CRAP group and RSD+CRAP group had significantly increased levels of Cx40(P<O.05), whereas RSD operation markedly reduced the upregulation of Cx40expression compared with the CRAP group (P<O.05). However, the expression levels of Cx43were not significantly different among the three groups (P>0.05). Immunohistochemistry results suggested that the densities of TH-and GAP43-positive nerves were significantly elevated in the CRAP group compared with the sham-operated group, while RSD signicantly suppressed these changes produced by prolonged RAP.Conclusions: Renal denervation could suppress the renin-angiotensin-aldosterone systematic hyperactivity and atrial remodeling, including the significantly increased AERP, structural and ultrastructural changes, together with atrial gap junctional remodeling and neural remodeling that are produced by long-term RAP.Part IV Effect of renal sympathetic denervation on the progression of paroxysmal atrial fibrillationObjective: To explore the effect of RSD on the progression of paroxysmal AF and atrial electrophysiology in canines with long-term intermittent atrial pacing.Methods: Nineteen beagles were randomly divided into sham-operated group (6dogs), control group (6dogs), and RSD+RAP group (7dogs). Sham-operated group were implanted with pacemakers without pacing; control group were implanted with pacemakers with long-term intermittent atrial pacing; and RSD+RAP group underwent catheter-based RSD bilaterally and were simultaneously implanted with pacemakers. RAP was maintained for8hours a day and a total of12weeks in control group and RSD+RAP group. Echocardiography, electrophysio logical test and hemodynamic parameters were measured in all the animals at the baseline and endpoint of the protocol. The plasma levels of Ang II and aldosterone were examined by ELISA. The heart was quickly excised and tissue specimens were obtained from the atria for test.Results: Echocardiography showed that the left atrial structure and function were significantly improved in RSD+RAP group compared with control group (P<0.05). Compared with the control group, RSD prevented the increase of right atrial pressure, mean pulmonary artery pressure and pulmonary capillary wedge pressure induced by long-term intermittent atrial pacing (P<O.05). Similarly, RSD decreased systolic and diastolic blood pressure after long-term intermittent atrial pacing (P<0.05). Compared with control group, RSD+RAP group had fewer incidences of AF and a shorter duration of AF (P<O.05) after long-term intermittent atrial pacing. In addition to increased AERP and AF cycle length, AERP dispersion and P-wave duration and dispersion were significantly decreased in the RSD+RAP group compared with the control group (P<O.05). The plasma levels of Ang II and aldosterone increased significantly in control group, but the increasing trend was inhibited by RSD (P<O.05). Atrial morphological evaluation suggested that myolysis, fibrosis, and ultrastructural changes induced by long-term intermittent atrial pacing were markedly suppressed in the RSD+RAP dogs compared with the controls (P<0.05). Immunohistochemistry results showed that Cx43distribution in RSD+RAP subepicardium and midmyocardial was significantly fewer heterogeneous than that in control group (P<0.05).Conclusions: Renal denervation could inhibit the progression of paroxysmal AF and suppress the atrial electrophysiology and structural heterogeneity after long-term intermittent RAP. |
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