Effect of spironolactone on hyperthyroxine-induced atrial fibrillation and atrial remodeling in rabbits

AIM: To detect the effect of spironolactone on hyperthyroxine-induced atrial remodeling. METHODS: New Zealand rabbits were divided into control group (C), hyperthyroxine group (H) and spironolactone group (S). Thyroxin was given to the rabbits in group H and group S by intraperitoneal injection for 4 weeks, and then spironolactone was given in group S by gavage for 2 weeks. Atrial fibrillation (AF) was induced by "burst" stimulation after administration. The inducing rate of AF and atrial effective refractory period (AERP) were tested by intra-cardiac electrophysiologic instrument. The expression of AF-related Ca²⁺ channel (Cav1.2), K⁺ channels (Kv1.5 and Kv4.3) and connexins (Cx40 and Cx43) at mRNA and protein levels was detected by real-time PCR, immunohistochemistry and Western blot. RESULTS: Spironolactone reduced the inducing rate of AF. No significant difference of AERP between group H and group S was observed (CONCLUSION: Spironolactone attenuates the hyperthyroxine-induced atrial remodeling in rabbits, and reduces the susceptibility of the myocardium to AF.     

Expression of MPO,MMP-2 and MMP-9 in atrial myocardium of rabbit atrial fibrillation model

ATM: To investigate the expression of myeloperoxidase (MPO), matrix metalloproteinase (MMP)-2 and MMP-9 in the atrial myocardium, and their potential effects on atrial structural remodeling in a rabbit atrial fibrillation (AF) model. METHODS: The sternotomy was performed and the pacing electrode was fixed to the left atria of 20 New Zealand white rabbits. The animals were randomly divided into 2 groups:rapid atrial pacing (RAP) group and sham group. The rabbits in RAP group were subjected to RAP for 3 weeks. The structure and function of the atria and ventricle were analyzed by echocardiography. Atrial burst stimulation was performed to test AF inducibility. The atrial fibrosis was evaluated by Masson trichrome-staining. The mRNA and protein levels of MPO, MMP-2 and MMP-9 were detected by RT-qPCR and Western blot. RESULTS: After 3 weeks of RAP, obvious left atrial enlargement and dysfunction were observed, but almost no change of left ventricular diameter and function was found in RAP group compared with sham group. AF inducibility, atrial interstitial fibrosis and the mRNA and protein levels of MPO, MMP-2 and MMP-9 were all significantly increased in RAP group compared with sham group. CONCLUSION: Obvious atrial structural remodeling is found in the rabbit AF model induced by sustained RAP, and the up-regulation of MPO, MMP-2 and MMP-9 may be the potential molecular mechanism of atrial structural remodeling.     

Effects of spironolactone on atrial structural remodeling in rabbit model of chronic atrial fibrillation

AIM: To evaluate the effects and potential mechanism of spironolactone (SP) on atrial structural remodeling in rabbit model of chronic atrial fibrillation (AF). METHODS: The sternotomy was performed and the pacing electrodes were fixed to the left atria of New Zealand white rabbits. The animals were randomly divided into 3 groups. The rabbits were subjected to rapid atrial pacing (RAP) for 3 weeks in RAP group (intragastric administration with placebo) and RAP+SP group (intragastric administration with spironolactone at 20 mg·kg^-1·d^-1), respectively. The rabbits in sham group did not receive RAP and drugs. Before and after RAP, the structure and function of the atria were evaluated and AF inducibility was tested. After RAP, the atrial fibrosis was evaluated, and the expression levels of collagen I, collagen Ⅲ, matrix metalloproteinase (MMP)-2 and MMP-9 were determined. RESULTS: After 3 weeks of RAP, compared with sham group, obvious left atrial enlargement and dysfunction were observed in RAP group and RAP+SP group, but those had no significant differences in these 2 groups. Sustained AF was induced in 7, 5, and 0 rabbits in RAP group, RAP+SP group, and sham group, respectively. Compared with sham group, atrial interstitial fibrosis and the protein expression levels of collagen Ⅰ, collagen Ⅲ, MMP-2 and MMP-9 were all significantly increased in RAP group and RAP+SP group(P<0.05). Compared with RAP group, the the above indexes were all decreased in RAP+SP group(P<0.05). CONCLUSION: Spironolactone suppresses the atrial interstitial fibrosis and collagen expression, thus preventing atrial structural remodeling in rabbit model of chronic AF. The effect of spironolactone on reducing atrial MMP-2 and MMP-9 levels may be the potential mechanism.     

Electrophysiological characters in a noble model of atrial fibrillation induced by left atrium pacing after right atrial infarction

AIM: To explore a noble chronic atrial fibrillation model induced by left atrium pacing after right atrial infarction and to investigate the atrial electrophysiological characters of the model. METHODS: 24 rabbits were randomly divided into 3 groups: control group (C group, n=8), pacing group (P group, n=8), artial infarction+pacing group (I group, n=8). C group: a pacing pole was fixed under adventitia of the left atrium without pacing; P group: a pacing pole was fixed under adventitia of the left atrium with 1 000 beats/min of pacing; I group: the animals were placed under 1 000 beats/min of left atrial pacing after ligating the atrial branch of right coronary artery. The technique of programmed stimulating was used to measure electrophysiological indexes of atrial in the groups. RESULTS: (1) After 3 weeks pacing AF was induced with a higher rates, and reached to 100% in I group. (2) At driving cycle length of 200 ms, ERPA was (115.0±7.6) ms in C group, (81.3±12.5) ms in P group and (87.5±12.8) ms in I group, which were statistically shorter in the later two groups compared to control group (both P<0.01). (3) I group and P group showed a significantly poor performance of frequency adaptability compared to control group after 3 week stimulation (P<0.01, P<0.05, respectively). (4) 3 weeks after pacing, the interval of P-wave in I group was significantly prolonged compared to P group and C group (P<0.05, P<0.01, respectively). (5) ERPA was obviously shortened and RRPA was prolonged significantly in I group compared to control group (P<0.01, respectively). Inter-atrial conduction defect (IACD) was significantly prolonged in I group compared to C group and P group after 1 h to 3 week stimulation (P<0.01, respectively). CONCLUSION: Compared to the traditional AF model induced by pacing only, a noble model of left atrium pacing after right atrial infarction has a higher AF incidence. The apparent electrophysiological changes of the AF model include: shortening of ERPA, the frequency inadaptability, extension of P-wave interval and prolonged RRPA as well as IACD.     

Effect of high-rate left atrial pacing on atrial remodeling and functions of sinoatrial node and atrioventricular node in dogs

AIM: To determine whether sinoatrial node (SAN) and atrioventricular node (AVN) undergo functional remodeling during atrial fibrillation (AF). METHODS: The Beagle dogs were randomized into pacing group (n=9) and control group (n=6). In open-chest dogs, the electrode catheters were sutured at left atria for pacing and data recording. SAN and AVN conductive properties were studied. The dogs in pacing group underwent 4 weeks of high-rate left atrial pacing (400 min-1). The dogs in control group were not subject to pacing. RESULTS: The animal model of chronic AF was successfully established by pacing the left atrium at 400 min-1 in the dogs. Two of those animals were recorded with spontaneous AF at the end of 2 weeks, and the induction rate of AF reached 100% following 4 weeks of pacing. The incidences of paroxysmal AF and permanent AF were significantly increased by pacing compared to control group. After 4 weeks of pacing, atrial effective refractory periods (AERP) at various at pacing cycle lengths (PCL; 250 ms, 300 ms and 350 ms) were all statistically shorter than those in control group. Compared with control group, a longer AVN Wenckebach point ［(294.44±26.06)min-1 vs (328.33±24.01)min-1,P<0.05］ and longer atrioventricular node effective refractory period (AVERP) (P<0.01) in pacing group were observed. The sinus node recovery time (SNRT) and corrected SNRT both showed significant increases. No significant change of P-wave and PA interval between the two groups was found. The left atrial dimensions (anteroposterior, superoinferior and left-right diameters) and the right atrial superoinferior diameter were measured to be significantly increased after 2 weeks of pacing. CONCLUSION: The animal model of left atrium pacing can induce AF occurrence with a higher incidence. The characteristic electrophysiological indexes about atria, AVN and SAN were observed during AF in the canine model, indicating that electrical and structural remodeling accompanies with AVN and SAN remodeling during AF.     

Effects of cardiac contractility modulation on ventricular electrical remodeling in rabbits with chronic heart failure

AIM: To investigate the effects of cardiac contractility modulation (CCM) on ventricular electrical remodeling in a rabbit model of chronic heart failure. METHODS: The rabbits were divided into sham group, heart failure(HF) group and HF+ CCM group. The rabbit model of chronic heart failure was established by ligating the ascending aortic root. Then electrical stimulations during the absolute refractory period were delivered lasting 6 h everyday for 4 weeks in rabbits of HF+ CCM group. The QTc and ventricular effective refrective period (VERP) were recorded. The protein and mRNA levels of Kv1.4, Kv4.3 and connexin 43 (Cx43) were determined by Western blot and RT-qPCR. RESULTS: Compared with sham group, QTc were significantly prolonged in HF rabbits at week 12 (P<0.05). CCM therapy shortened QTc of rabbits with heart failure at week 16 (P<0.05). Compared with sham group, VERP significantly increased in HF group and HF+ CCM group, while CCM therapy shortened VERP of rabbits with heart failure at week 16 (P<0.05). Compared with sham group, the mRNA and protein levels of Kv1.4, Kv4.3 and Cx43 were decreased in HF group and HF+ CCM group (P<0.05). However, CCM therapy restored the mRNA and protein levels of Kv1.4, Kv4.3 and Cx43 of rabbits with heart failure (P<0.05). CONCLUSION: CCM suppresses ventricular electrical remodeling in heart failure and the underlying mechanism may be associated with increasing Kv1.4, Kv4.3 and Cx43 expression.     

Resveratrol reduces electrical remodeling in atrial fibrillation by down-regulating microRNA-21 in neonatal rat atrial myocytes

AIM: To detect the effects of resveratrol (RSV) on the expression of microRNA-21 (miR-21) in primarily cultured neonatal rat atrial myocytes with electric remodeling induced by rapid electrical stimulation (RES). Furthermore, to find out the possible mechanism of miR-21 regulating electrical remodeling. METHODS: The neonatal rat atrial myocytes were isolated by double-enzyme (trypsin and collagenase I) digestion and differential adhesion method. The atrial fibrillation (AF) model was induced by RES. Atrial myocytes were randomly divided into 4 groups:control group, RSV group, RES group, and RSV+RES group. To further detect whether RSV regulated electric remodeling by miR-21, except the 4 groups, we add miR-21 over-expression group and miR-21 inhibitor group:RES+negative control (NC) group, RES+miR-21 mimics group, RES+miR-21 mimics+RSV group, RES+miR-21 inhibitor group, and RES+miR-21 inhibitor+RSV group. The optimal concentration and pretreatment time of resveratrol were determined by CCK-8 assay. The expression of miR-21 and the mRNA expression of L-type calcium channels CACNA1C and CACNB2 in atrial myocytes were detected by qPCR. The protein expression of L-type calcium channels Cav1.2 and Cavβ₂ in the atrial myocytes was analyzed by Western blot. RESULTS: The expression of miR-21 in RES group was significantly increased compared with control group, while preconditioning with RSV decreased the expression of miR-21. Compared with RES+miR-21 mimics group, the expression of miR-21 in RES+miR-21 mimics+RSV group was significantly decreased. Meanwhile, the mRNA expression of CACNA1C and CACNB2, and the protein levels of Cav1.2 and Cavβ₂ were increased (P<0.05). Compared with RES group, the expression of miR-21 in RES+miR-21 inhibitor group and RES+miR-21 inhibitor+RSV group was decreased, while the mRNA expression of CACNA1C and CACNB2, and the protein levels of Cav1.2 and Cavβ₂ were increased. However, no difference of the expression of miR-21, the mRNA expression of CACNA1C and CACNB2, and the protein levels of Cav1.2 and Cavβ₂ among RSV+RES, RES+miR-21 inhibitor and RES+miR-21 inhibitor+RSV groups was observed (P<0.05).CONCLUSION: In AF model induced by RES, RSV may reduce electric remodeling by inhibiting the expression of miR-21 and regulating the downstream target genes.     

Non-contact mapping and frequency analysis of vagal-mediated atrial fibrillation

AIM: To explore the mechanism of the initiation and maintenance of vagal-mediated atrial fibrillation (AF) by non-contact mapping and frequency analysis of vagal-mediated atrial fibrillation in canine.METHODS: Atrial effective refractory period (AERP) and dispersion of AERP were measured in 8 canine during baseline and bilateral cervical vagal nerve stimulation (CVNS). Left atrium (LA) and right atrium (RA) electrical activity of AF was assessed by non-contact mapping and frequency analysis.RESULTS: Compared with baseline, CVNS attenuated left and right AERP, but only increased the dispersion of left AERP. During CVNS, AF was easily induced and maintained, repetitive organized activations rotated around a preferential route were only found in the LA, and dominant frequencies (DFs) from LA were higher than those of the RA ［(12.5±1.5)Hz vs (9.3±1.2)Hz, P<0.01］. After the cessation of CVNS, DFs of AF decreased in the LA and RA ［(9.2±0.5)Hz vs (8.5±0.6)Hz, P>0.05］, and AF was spontaneously terminated.CONCLUSION: The change of electrophysiological character, difference of activation pattern, and frequency gradient between the LA and RA suggest that the initiation and maintenance of vagal-mediated AF dependent on the LA.     

Establishment of a rabbit chronic atrial fibrillation model with long-term rapid atrial stimulation

AIM: The aim of this study was to investigate the possibility of establishing a chronic atrial fibrillation model with long-term rapid atrial stimulation (1 000 bpm), which was performed in rabbits in vivo. METHODS: 20 rabbits were randomly divided into 2 groups: 1) control group (n=10): pacemaker was implanted but no pacing; 2) experimental group (n=10): a left intercostal thoracotomy was performed and the pericardium was opened to expose the heart and a steel-wire pacing electrode was fixed on the epicardium of the left atria in 10 rabbits. Then the rapid pulse generator was implanted subcutaneously in the left abdominal region and rapid atrial pacing (1 000 beats/min) was initiated and continued for 30 days. Electrocardiogram (ECG) was monitored and recorded on day 1, 3, 5, 7, 14, 21 and 30. The atrial effective refractory period (AERP) was measured before pacing and at the time of fibrillation. RESULTS: On day 14, atrial fibrillation was developed in 8 rabbits (80%) and sustained at least till to day 30 (P＜0.01). There was no atrial fibrillation occurred in control group. The ventricular rate of atrial fibrillation was fast initially (P＜0.05) and decreased gradually later (P＜0.05). The AERP was shortened and the rate adaptation of AERP was lost when atrial fibrillation occurred. CONCLUSION: Long-term rapid left atria stimulating is an effective method in the establishment of a chronic atrial fibrillation model in rabbits.     

Effects of cardiac remodeling on atrial arrhythmogenesis in aged rabbit left atrium

AIM: To investigate the effects of myocardial remodeling of aged left atrium (LA) on atrial arrhythmogenesis in rabbits.METHODS: The male New Zealand rabbits were divided into young LA and aged LA groups. By observing the changes of monophasic action potential (MAP) and burst-pacing in LA of the rabbits in vivo, the main cardioelectrophysiological parameters such as resting membrane potential (RMP), action potential amplitude (APA), ma-ximum rise veloctiy of action potential (dv/dt_max), plateau potential and action potential duration at 30%, 50% and 90% (APD₃₀, APD₅₀ and APD₉₀), as well as the inducibility and duration of atrial arrhythmias were recorded. L-type calcium current (I_Ca,L) was analyzed via whole-cell patch-clamp technique in enzymatically dissociated single rabbit LA myocytes. The myocardial collagen content was quantified after Masson staining, and the ultrastructure of the LA cells was observed under scanning electron microscope. The expression of Cav1.2 in LA tissue of the 2 groups was detected by Western blot.RESULTS: Compared with young LA group, dv/dt_max and plateau potential were significantly decreased, APD₃₀ and APD₅₀ were shortened, and APD₉₀ was notably prolongated in aged LA group (P<0.01). The inducibility or duration of atrial arrhythmias was severely increased or prolongated in aged LA group (P<0.01). With voltage clamp model, the density of I_Ca,L in aged LA group was significantly decreased, and current-voltage curve was notably moved upward compared with young LA group. When the clamp potential was +20 mV, the density of I_Ca,L was notably modified from (11.72±1.39) pA/pF in young LA group to (6.08±0.98) pA/pF in aged LA group (P<0.01). Compared with young LA group, the protein level of collagen was significantly increased (P<0.01), and the arrange of atrial myocytes was irregular in LA of rabbits in aged LA group. The atrial myocytes of the LA wall in aged LA group exhibited abnormal ultrastructural alterations, such as karyopyknosis, irregular and swelling mitochondria with the presence of vacuoles, and mild and severe sarcomere degeneration. Compared with those in LA tissues of young rabbits, the expression levels of Cav1.2 in the LA tissues of aged rabbits were severely reduced (P<0.01), and had a significant positive correlation with the reduction of I_Ca,L (r=0.83, P<0.01).CONCLUSION: The pathophysiological characteristics of aged LA are significantly altered, and might contribute to vulnerability and susceptibility of occurrence of atrial fibillation in aged rabbits. The mechanisms might completely attribute to the notable reduction of I_Ca,L, abnormal alterations of ultrastructures and obvious decrease in the expression of Cav1.2 in the aged LA of aged rabbits.     

Effects of the calpain system expression on atrial structural remodeling in canine with atrial fibrillation

AIM: To evaluate the influence of the calpain system mRNA and protein expression on the progress of atrial structural remodeling in fibrillating canine.METHODS: 17 dogs were randomly divided into 2 groups: normal control group (SR,n=6) and atrial fibrillation (AF,n=11) group.AF was induced by rapid pacing for 8 weeks and all dogs underwent transthoratic echocardiography before and after rapid pacing.The mRNA and protein expression of calpainⅠ,calpainⅡand calpastatin were assessed by real-time quantitative PCR and Western blotting,respectively.RESULTS: Compared with SR group,the left atrial diameters and the content of calcium in atrial myocardium increased significantly in AF group (P<0.05).There was no significant difference in mRNA expression of calpainⅠand calpainⅡ (P>0.05) between two groups.The expression of calpastatin mRNA was upregulated significantly in AF group (P<0.05).The levels of calpainⅠand calpainⅡprotein were significantly increased in AF group compared with SR group (P<0.05).The expression of calpastatin protein was significantly decreased in AF group (P<0.05).The calpainⅠand calpainⅡprotein levels were positively correlated with the left atrial diameter.The calpastatin protein level was negatively correlated with the left atrial diameter (P<0.05).CONCLUSION: The changes of the calpain system protein expression in AF result in the disturbance of calpain/calpastatin system and degradation of many proteins,which may play an important role in mechanism of atrial remodeling.     

Protein kinase A regulates small-conductance calcium-activated potassium type 2 channel in chronic atrial fibrillation patients

AIM：To investigate the alteration of small-conductance calcium-activated potassium type 2 (SK2) channel currents in atrial myocytes from atrial fibrillation (AF) patients, and the relationship between protein kinase A (PKA) and SK2 channel. METHODS：Right auricular tissues were obtained from the patients undergoing open-heart surgery with extracorporeal circulation. Single atrial myocytes were isolated by modified enzymatic dissociation method. The SK2 channel currents in the isolated human atrial myocytes were recorded using whole-cell patch-clamp technique. The alteration of SK2 channel currents and the regulation of SK2 channel by PKA were compared between sinus rhythm (SR) group and AF group. The total protein and PKA levels in human atrial tissues were detected by BCA assay and ELISA, respectively. RESULTS：The SK2 channel current densities and the proportion of SK2 channel currents in the integrated inward currents were significantly increased in AF group (all P<0.05 vs SR group). PKA-selective inhibitor H-89 reduced SK2 channel current densities and the proportion of SK2 channel currents in the integrated inward currents in both SR and AF groups, with larger reduction in AF group (all P<0.05 vs SR group). The PKA level was significantly decreased in AF atrial tissues (P<0.05 vs SR group). CONCLUSION: The increase in SK2 channel currents underlies the occurrence and maintenance of AF. PKA-dependent regulation may be involved in the remodeling of SK2 channel in both SR and AF human atrial myocytes, with a more powerful effect in AF.     

Effect of atorvastatin on myocardial fibrosis induced by aldosterone

AIM: To investigate the effects and mechanisms of atorvastatin on myocardial fibrosis induced by aldosterone in SD rats. METHODS: Forty male uninephrectomized SD rats were limited to drink 1% NaCl water for 4 weeks and assigned to the follow groups: vehicle control rats (CON group); aldosterone treated rats (ALD group); spironolactone + aldosterone treated rats (SPI+ALD group); atorvastatin + aldosterone treated rats (ATO+ALD group). Blood pressure was measured by catheterization. Expression of platelet-derived growth factor (PDGF-A, PDGF-B), platelet-derived growth factor receptor (PDGFR-α, PDGFR-β) and ectodermal dysplasia-1 (ED-1) were analyzed by immunohistochemistry. Collagen volume fraction (CVF) and perivascular collagen area (PVCA) were analyzed by Sirius-Red staining. Myocardium osteopontin protein was detected by Western blotting analysis. RESULTS: Mean arterial blood pressure in ALD group, SPI+ALD group and ATO+ALD group was elevated, and significant difference was observed between the three groups and vehicle control group (P<0.01 or P<0.05). Myocardial fibrosis was observed in ALD group. Compared to other three groups, the index of CVF and PVCA was increased significantly (P<0.01 or P<0.05). No significant difference of the index of CVF and PVCA between ATO+ALD group and SPI+ALD group was observed (P>0.05). Compared to other groups, the levels of PDGF-A, PDGF-B, PDGFR-α, ED-1 and OPN in ALD group were significantly increased (P<0.01 or P<0.05). The levels of PDGF-A, PDGF-B, PDGFR-α and OPN were no significant difference between ATO+ALD group and SPI+ALD group (P<0.01 or P<0.05). However, the level of ED-1 in ATO+ALD group was significantly decreased compared to SPI+ALD group (P<0.05). No significant difference of PDGFR-β level among four groups was found (P>0.05). CONCLUSION: These results suggest that atorvastatin may attenuate myocardial fibrosis induced by aldosterone. The mechanisms concern with reduction of macrophage infiltration, expression of inflammatory cytokines OPN, partially inhibition of platelet-derived growth factor and its receptor expression.     

Effect of chronic atrial fibrillation on Ca2+/calmodulin dependent protein kinase Ⅱ expression in human atrial myocytes

AIM: To investigate the effect of chronic atrial fibrillation (AF) on free calcium concentration and expression of Ca2+/calmodulin dependent protein kinase Ⅱ (CaMKⅡ) in human atrial myocytes. METHODS: The intracellular free calcium concentration in acute isolated atrial myocytes and the expression of CaMKⅡ in atrial tissue of rheumatic heart disease patients with atrial fibrillation (AF) and with normal sinus rhythm were measured by laser scanning cofocal microscopy technique and Western blotting, respectively. RESULTS: The intracellular Ca2+ concentration in patients with atrial fibrillation was significantly higher than that in patients with normal sinus rhythm ［(276.38±38.12） nmol/L vs （122.28±45.63) nmol/L, P<0.05］. Western blotting analysis of atrial samples showed that CaMKⅡ expression was enhanced during chronic atrial fibrillation (10.14±0.31 vs 6.86±0.89，P<0.05). CONCLUSION: Chronic AF leads to intracellular calcium overload in human atrial myocytes. Ca2+/calmodulin dependent protein kinase signaling cascades may play an important role in maintenance of chronic AF.     

Relationship between fibrosis and remodeling of gap junction in atrium of patients with atrial fibrillation

AIM: To examine fibrosis and remodeling of gap junction in atrial myocardium of patients with or without atrial fibrillation and to investigate the relationship between them. METHODS: Right atrial appendage (RAA) samples were collected from 44 patients with rheumatic heart disease during heart operation, 28 of which were clinically diagnosed as atrial fibrillation (AF), the left remained sinus rhythm (SR). Fibrosis and remodeling of connexin 43 were examined by polarization microscope and microscopy respectively, and analyzed with an image analyzer. Meanwhile, intercalated disc was counted under transmission electron microscope. The collagen volume fraction of type I (CVF-I) and the volume fraction of Cx43 (Cx43VF) were studied between groups of atrial fibrillation and sinus rhythm. The relationship between CVF-I and fraction of remodeled intercalated disc was studied as well. RESULTS: (1) Polarization microscope demonstrated that CVF-I collagen increased (P<0.01) in atrial fibrillation group. (2) The ratio of remodeled of intercalated disc in patients with AF was higher (P<0.01) than that in SR group whereas the number of intercalated disc was not different (P>0.05) between the two groups. (3) Cx43VF decreased (P<0.01) in the AF patients compared to those with SR. (4) A positive correlation between fibrosis and the remodeling of intercalated disc (r=0.96, P<0.01) was observed. The CVF-I was negatively correlated with the Cx43VF (r=-0.98, P<0.01). CONCLUSION: These results suggest that both fibrosis of atrial muscle and remodeling of intercalated disc are involved in the pathogenesis of human atrial fibrillation. Fibrosis of atrial muscle may play an important role in the process of atrial fibrillation by interfering with remodeling of intercalated disc and thereby involves in the remodeling of connexins.     

Downregulated transient outward potassium channel protein Kv4.2 and Kv4.3 expression in PVN contributes to sympathoexcitation in rats with chronic heart failure

AIM: To investigate the transient outward potassium channel protein expression in paraventricular nucleus(PVN) and its contribution to renal sympathetic nerve activity(RSNA) in rats with chronic heart failure(CHF).METHODS: A rat model of CHF was prepared by acute myocardial infarction that was induced by ligation of the left anterior descending coronary artery. Four weeks after heart failure, echocardiogram was applied to identify the CHF model and plasma norepinephrine(NE), serum NH₂-terminal pro-brain natriuretic peptide(NT-proBNP) were detected by ELISA. The expression of ransient outward potassium channel proteins Kv4.2 and Kv4.3 at mRNA and protein levels was determined by real-time PCR and Western blot. The mean arterial pressure(MAP), heart rate(HR) and RSNA were measured in anesthetized rats with PVN microinjection of potassium channel blockers 4-AP. RESULTS: In CHF group, the rat cardiac function and Kv4.2 and Kv4.3 expression in PVN were obviously lower while plasma NE and serum NT-proBNP were obviously higher than those in sham group. Microinjection of 4-AP into PVN induced an increase in MAP, HR and RSNA in both sham and CHF rats, while the CHF rats exhibited smaller responses to 4-AP than sham-operated rats.CONCLUSION: Downregulation of Kv4.2 and Kv4.3 expression in the PVN may be a potential mechanism for sympathoexciation in the rats with chronic heart failure.     

Effects of renal denervation on inflammatory factors in a rabbit model of early atherosclerosis

AIM: To evaluate the effects of renal denervation (RDN) on the expression of tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α) and interleukin-6 (IL-6) in a rabbit model of early atherosclerosis. METHODS: New Zealand male rabbits were divided into control group, RDN+ high-fat diet (HFD) group (RDN group), sham+HFD group (sham group) and HFD group. The rabbits in later 3 groups were fed with 2% cholesterol for 8 weeks to establish an early atherosclerosis model. The blood samples were collected to test the levels of lipids, norepinephrine (NE), TNF-α, IL-1α and IL-6. The protein expression of angiotensin Ⅱ (Ang Ⅱ) was detected by the method of immunohistochemistry. The levels of nuclear factor-κB (NF-κB) and Ang II 1 type receptor (AT1R) were evaluated by Western blot. The mRNA expression of TNF-α, IL-1α and IL-6 was determined by real-time PCR. RESULTS: After 1 d of RDN procedure, the NE level was lower in RDN group than that in sham group (P<0.01). After 8 weeks, the NE level was lower in RDN group than that in sham group and HFD group (P<0.05), and triglyceride (TG) was lower in RDN group than that in HFD group (P<0.05). The protein expression of Ang II was decreased in RDN group compared with sham group and HFD group (P<0.01). The protein expression of NF-κB was lower in RDN group than that in sham group (P<0.05). The plasma levels of TNF-α and IL-1α were reduced in RDN group compared with sham group and HFD group (P<0.05). The mRNA expression of TNF-α, IL-1α and IL-6 was reduced in RDN group compared with sham group (P<0.05). CONCLUSION: RDN inhibits sympathetic activity, decreases the plasma level of TG, and alleviates inflammatory reactions in the rabbits with atherosclerosis.