肺静脉隔离对迷走神经功能及心房颤动易感性的影响

目的研究肺静脉隔离(PVI)对犬的心房迷走神经功能及心房颤动(简称房颤)易感性的影响。方法9条成年杂种犬,全麻下行颈交感-迷走神经干剥离术。静脉应用美托洛尔阻断交感神经活性。分别于肺静脉消融前后在基础状态及迷走神经刺激时测量窦性周长(SCL)、右心耳(RAA)、左心耳(LAA)、冠状静脉窦近端(CSp)和冠状静脉窦远端(CSd)的不应期(ERP)及心房易感窗口(VW)。结果①PVI前迷走神经刺激能明显降低SCL(P<0.001),PVI后迷走神经刺激对SCL影响较小(P>0.05)。②PVI前,迷走神经刺激能明显缩短心房各部位ERP(P均<0.05)。PVI后,迷走神经刺激对心房ERP的影响较小(P均>0.05)。③PVI前后基础状态下测得的VW无变化。PVI后迷走神经介导的房颤诱发率明显下降(P均<0.05)。结论PVI能导致迷走神经介导的窦房结抑制、心房不应期缩短能力及房颤易感窗口增加能力明显下降。     

Modulation of vagal activity to atria electrical remodeling resulted from rapid atrial pacing

Background Atrial electrical remodeling(AER) plays an important role in the pathogenesis and maintenance of atrial fibrillation.However,little is known about modulation of vagal activity to AER.This study aimed to investigate the relationship between vagal moduation and AER.Methods Twenty four adult mongrel dogs under general anesthesia were randomized into 3 groups.Sympathetic activity was blocked by administration of metoprolol in 3 groups.The changes in vagal modulation to atria after AER were observed in 10 dogs without vagal interruption in group A.The effects ofvagal intervention on AER were investigated in 8 dogs with administration of atropine in group B.The impact of aggressively vagal activity on AER was studied in 6 dogs with bilateral cervical vag sympathetic trunks stimulation during AER in group C.Bilateral cervical vagosympathetic trunks were decentralized. Multipolar catheters were placed into high right atria (RA),coronary sinus (CS) and right ventricle (RV).AER was induced by 600 bpm pacing through RA catheter for 30 minutes.Atrial effective refractory period (ERP) and vulnerability window (VW) of atrial fibrillation were measured with and without vagal stimulation before and after AER.Results In group A,ERP decreased significantly at baseline and during vagal stimulation after AER compared with that before AER (all P<0.05).In group B,ERP remained unchanged at baseline and vagal stimulation after AER compared with that before AER (all P>0.05).In group C,ERP shortened significantly at baseline and vagal stimulation after AER compared with that before AER (all P<0.05).ERP shortening after AER in Groups A and C increased significantly than that in group B (all P<0.05).Atrial fibrillation could not be induced at baseline (VW close to 0) before and after AER in three groups.VW became widen significantly during vagal stimulation after AER compared with that before AER in Groups A and C (all P<0.05),while VW remained unchanged in group B (VW close to 0).Conclusions Short-term AER result     

房室结慢径区域消融对迷走神经功能及心房颤动易感性的影响

目的心房颤动（房颤）与房室结折返性心动过速有着某种程度的关联性,慢径区域消融可能影响了心房自主神经功能而导致窦性心动过速。但慢径区消融对心房自主神经功能的具体影响目前尚不清楚。本文旨在探讨慢径区消融对心房迷走神经调节功能及房颤易感性的影响。方法11条成年杂种犬,全身麻醉下行颈交感一迷走神经干剥离术。经右颈内静脉穿刺放置冠状静脉窦导管,经左股静脉穿刺放置右心室导管及右心房标测电极导管（Halo导管）,经右股静脉穿刺放置消融导管和希氏束导管。静脉应用美托洛尔阻断交感神经活性。测量慢径区域消融前后基础状态及迷走神经刺激下的窦性周长（SCL）及高位右心房（HRA）、低位右心房（IRA）、冠状静脉窦近端（CSp）和冠状静脉窦远端（CSd）的有效不应期（ERP）及心房易感窗口（VW）。结果（1）SCL的变化：消融前后迷走神经刺激导致的SCL缩短值无明显改变[（107±19）次／min对（108±8）次／min,P〉0．05],提示慢径区域消融没有明显改变迷走神经对窦房结的调节作用。（2）ERP的变化：消融前后迷走神经刺激导致的ERP缩短值在HRA分别为[（69±37）ms对（55±34）ms,P〉0．05],CSd分别为[（55±30）ms对（42±32）ms,P=0．08],IRA分别为[（66±24）ms对（19±21）ms,P〈0．001],CSp分别为[（46±24）ms对（7±18）ms,P〈0．001]。提示慢径区域消融对HRA及窦房结区域的迷走神经调节功能无明显影响,对CSd区域的迷走神经调节功能有一定的影响,而导致了IRA及CSp区域去迷走神经效应。（3）心房VW的变化：消融前后基础状态下各个部位刺激均较难诱发房颤（VW接近0）。消融后,HRA迷走神经刺激诱发房颤的能力较消融前没有明显变化[（63±31）ms对（63±25）ms,P〉0．05],CSd的VW有一定程度的降低[（35±37）ms对（57±28）ms,P     

Novel electrophysiologic parameter of dispersion of atrial repolarization: comparison of different atrial pacing methods

INTRODUCTION: Heterogeneity of ventricular repolarization plays a major role in reentrant tachyarrhythmias in cardiac tissue. However, the role of atrial repolarization added activation time (AT) to refractoriness in atrial vulnerability has not been investigated in detail. METHODS AND RESULTS: The study population consisted of 34 patients: 18 with atrial fibrillation (AF) and 16 without AF (control group). The effective refractory periods (ERPs) in the right atrial appendage, low lateral right atrium, high right septum, and distal coronary sinus, and ATs from P wave onset to each electrogram during sinus rhythm and right atrial appendage, low lateral right atrial, high right septal, distal coronary sinus, and biatrial pacing were measured. Atrial recovery time, defined as the sum of AT and ERP, and its dispersions during sinus rhythm, right atrial appendage, low lateral right atrial, high right septal, distal coronary sinus, and biatrial pacing were calculated. Both ERP dispersion and atrial recovery time dispersion during sinus rhythm were significantly greater in the AF group than in the control group. Atrial recovery time dispersion during distal coronary sinus, high right septal, or biatrial pacing was significantly smaller than that during right atrial appendage or low lateral right atrial pacing in each group. In particular, atrial recovery time dispersion during distal coronary sinus pacing was the smallest of the five pacing methods in the AF group. P wave duration during biatrial or high right septal pacing was significantly shorter than during right atrial appendage, low lateral right atrial, or distal coronary sinus pacing in each group. CONCLUSION: Atrial recovery time dispersion is suitable as an electrophysiologic parameter of atrial vulnerability. Distal coronary sinus pacing may prevent AF by increasing homogeneity of atrial repolarization, whereas biatrial and high right septal pacing contribute not only homogeneity of atrial repolarization but also improvement of atrial depolarization.     

快速右心房起搏对实验犬心房胶原纤维分布的影响

目的 实验探讨切除上腔静脉中部和主动脉根部脂肪垫(简称脂肪垫)对快速右心房(RA)起搏实验犬的心房胶原容积分数(CVF)的空间分布变化意义.方法 24只成年健康杂种犬雌雄不限,随机分为切除脂肪垫组、保留脂肪垫组和假手术组,每组8只.RA心外膜起搏6周,按左心房(LA)、RA、左心耳(LAA)、右心耳(RAA)、房间隔(AS)5个部位取材,Masson染色测算CVF,荧光定量聚合酶链反应技术检测缝隙连接蛋白(Cx)40和Cx43mRNA表达.结果 (1)假手术组和切除脂肪垫组CVF在部位分布上差异无统计学意义;保留脂肪垫组胶原增生明显,见于LAA和AS,P＜0.01.(2)假手术组Cx40mRNA含量分布在LA、RA、RAA、AS间差异无统计学意义;Cx40mRNA表达在切除脂肪垫组与保留脂肪垫组以LA、LAA增多且组间差异有统计学意义(P＜0.01).(3)假手术组Cx43mRNA含量优势表达于RA、RAA,P＜0.01;而在切除脂肪垫组LA、RA、RAA、AS其含量增多,在保留脂肪垫组的相应部位,其含量减少,P＜0.01.结论 快速RA起搏所致心房间质纤维增生具有空间各异向性,去迷走神经能抑制此效应.迷走神经效应影响起搏后Cx40mRNA与Cx43mRNA在心房与心耳间含量的表达.     

房室结慢径消融对心房电生理性质的影响

目的 慢径消融降低了心房颤动(房颤)的易感性,但具体机制不明.本文旨在探讨消融后心房电生理性质的改变及其具体机制.方法 32例房室结折返性心动过速患者,测量射频消融前后窦性心率及高位右心房、低位右心房、冠状静脉窦近端和远端各部位的有效不应期和易感窗口,以及房室结快径前传不应期的变化.结果 (1)慢径消融前后下列部位的有效不应期的变化分别为:冠状静脉窦近端(21 8.1±21.8)ms,(235.3±23.6)ms,P＜0.0001;冠状静脉窦远端(230.9±21.0)ms,(244.7±25.1)ms,P＜0.01;低位右心房(198.8±26.7)ms,(219.7±28.7)ms,P＜0.005;高位右心房(214.4±35.1)ms,(213.4±37.3)ms,P=0.6.(2)在消融术后,房颤的诱发比例下降,冠状静脉窦近端的易感窗口显著降低(P=0.03),冠状静脉窦远端和低位右心房的易感窗口有所降低,高位右心房的易感窗口不变,但差异无统计学意义.(3)消融后窦性心率有一定程度的上升(72.1±5.6)次/min对(74±6.8)次/min,但差异无统计学意义(P=0.17).(4)慢径消融使快径前传不应期缩短,消融前后分别为(391±55)ms,(369±78)ms,P＜0.01.结论 慢径消融使心房多部位的电生理性质发生了改变,导致冠状静脉窦近端和远端,以及低位右心房的有效不应期延长,房颤诱发几率降低.该现象的原因可能与消融造成的迷走神经功能改变有关.     

不同部位起搏对阵发性心房颤动患者心房激动时间的影响

目的　比较右心耳 (RAA)、冠状窦远端 (DCS)、右心房双部位 (右心耳加冠状窦口 ,DSA)和双房 (右心耳加冠状窦远端 ,Bi A)起搏对阵发性心房颤动 (PAf)患者心房激动时间的影响。方法 2 2例接受心脏电生理评价试验的PAf患者在窦性心律下行心房不同部位起搏 ,同步记录 12导心电图 ,测量最大 P波时限。结果　与窦性 P波时限相比 ,RAA起搏明显延长 P波时限 (P<0 .0 1) ,DCS、DSA及 Bi A起搏则明显缩短 P波时限 (P<0 .0 1,P<0 .0 1,P<0 .0 1)。结论　 DCS、DSA及 Bi A起搏明显缩短心房激动时间 ,减少心房电活动的离散度 ,有利于 PAf的防治。     

Daily oral verapamil before but not after rapid atrial excitation prevents electrical remodeling

BACKGROUND: Intravenous verapamil has been reported to prevent electrical remodeling induced by rapid atrial excitation of several minutes to several hours. However, the clinical efficacy of verapamil when taken orally and daily remains controversial. PURPOSE: We attempted to demonstrate our hypothesis that if verapamil prevents calcium (Ca) overload, its efficacy would be greater when taken before, rather than after, the onset of rapid atrial excitation. METHODS: In 24 dogs, pacing and recording electrodes were sutured onto the right atrium. After a 5-day recovery period, rapid atrial pacing at 400 ppm was started, followed 2 days later by oral verapamil (8 mg/kg per day) in eight dogs (After group; A). In another eight dogs, oral verapamil administration was begun 1 week before the initiation of rapid pacing (Before group; B). In the remaining eight dogs, only rapid atrial pacing was started, without oral verapamil (Control group; C). We measured the effective refractory period (ERP) and conduction velocity (CV), and calculated wavelength (WL) at cycle lengths 200 and 300 ms on the day before (P0), and after 2 (P2), 7 (P7), 14(P14) days of rapid pacing. RESULTS: In response to rapid atrial pacing, ERP, CV, WL decreased and progressively and comparably in A and C (P<0.05 vs. P0). In contrast, in B, these parameters did not change significantly and remained greater than those in A and C (P<0.05). Moreover, the adaptation of ERP to rate was preserved only in B. The duration of atrial fibrillation (AF) was shorter in B than in A and C (P<0.05). The inducibility of AF tended to be lower, and the fibrillation cycle length was longer in B than in A and C. CONCLUSIONS: Oral verapamil started before but not after rapid atrial excitation prevents electrical remodeling. Verapamil may exert beneficial effects when it is taken during sinus rhythm, but not after more than 2 days of atrial tachyarrhythmia.     

Enalapril preserves sinus node function in a canine atrial fibrillation model induced by rapid atrial pacing

METHODS AND RESULTS: Seventeen beagles were pretreated with either placebo (group I, n = 9) or enalapril 1 mg/kg/day (group II, n = 8) and paced at 500/min from the right atrial appendage for 4 weeks. Every week, corrected sinus node recovery time (CSNRT) and sinus cycle length (SCL) were measured. Quantitative analysis of interstitial fibrosis (IF) and adipose tissue (AT) in the SN was performed with Masson's trichrome stain, and apoptosis of the sinus nodal cells were detected with terminal deoxynucleotidyl transferase nick end-labeling. In group I, rapid atrial pacing prolonged both CSNRT and SCL. After 4 weeks of pacing, CSNRT and SCL were significantly shorter in group II (CSNRT, 410 +/- 37 msec; SCL, 426 +/- 34 msec) than in group I (CSNRT, 717 +/- 52 msec, P < 0.005; SCL, 568 +/- 73 msec, P < 0.05). Both IF and AT of the SN were greater in group I (IF, 9.7 +/- 1.9%; AT, 32.6 +/- 5.9%) than in seven sham dogs (IF, 2.4 +/- 0.9%, P < 0.05; AT, 4.0 +/- 1.7%, P < 0.05) and in group II dogs (IF, 4.0 +/- 2.0%, P < 0.05; AT, 4.0 +/- 1.7%, P < 0.05). End-labeling assay was positive in three of nine dogs in group I, but negative in group II and sham dogs. CONCLUSIONS: Rapid atrial pacing impaired SN function through IF and AT of the SN. Enalapril prevented these pacing-induced degenerative changes and improved SN function.     

左房快速起搏对肺静脉口及心房肌电重构的影响

目的探讨左房快速起搏对肺静脉口、左右心耳电重构的影响。方法运用快速起搏左心耳的方法建立心房颤动(AF)模型,在起搏前及起搏后的第1,3,5,7d对左、右心耳;左上、左下肺静脉口;右上、右下肺静脉口的有效不应期(ERP)、ERP频率适应性、ERP离散度及心房间的传导时间进行测定。采用S1S2程序刺激,基础起搏周长(PCL)分别为400,300,200ms,S2为200ms,以5ms的步长递减。程序刺激结合Burst刺激对上述心房部位进行AF的诱发,记录AF的发生率。在第8天关闭起搏器,采用上述相同方法对起搏停止后即刻;2,4,6,24h的上述各部位的ERP进行测定。结果起搏1d后各个基础起搏周长下各部位的ERP明显缩短,ERP频率适应性降低,ERP离散度增大(P<0.05),而心房间传导时间无明显变化(P>0.05);起搏终止后各部位的ERP逐渐延长,但起搏终止后6hERP与快速起搏前相比仍有明显缩短(P<0.05);24h后ERP基本恢复到起搏前水平,两者相比无明显差异(p>0.05);随着起搏时间的延长各部位AF的诱发率逐渐增高(P<0.05)。结论快速心房起搏不仅引起心房肌电重构,亦引起肺静脉电重构。     

Vagal stimulation prior to atrial rapid pacing protects the atrium from electrical remodeling in anesthetized dogs.

Atrial electrical remodeling is thought to be the cause of the maintenance of atrial fibrillation (AF). Although the initiation and maintenance of AF is partially associated with autonomic nervous tone, vagally mediated AF does not tend to become permanent. Therefore, the effects of preceding vagal stimulation (VS) on the atrial effective refractory period (ERP) under electrical remodeling conditions were investigated in anesthetized dogs. Atrial ERPs were measured at 5 sites before and after a 7-h period of atrial rapid pacing in the control group. In the VS group, the vagus nerve was stimulated for 20 min before a period of atrial rapid pacing. Atrial rapid pacing shortened the ERP at each site in the control group (electrical remodeling). On the other hand, atrial rapid pacing after VS did not shorten the ERP at any site in the VS group. Tetrodotoxin, which was administered into the fatty tissue overlying the right atrial side of the right pulmonary vein junctions, blocked the protective effect of VS against the shortening of the ERP induced by atrial rapid pacing. In contrast, atropine did not interfere with such protective effects. These results suggest that VS prior to atrial rapid pacing protects the atrium from atrial electrical remodeling.     

去自主神经条件下迷走神经刺激对肺静脉不同部位有效不应期的影响

目的探讨去自主神经条件下迷走神经刺激对肺静脉不同部位有效不应期(ERP)的影响。方法10只成年健康杂种犬,常规戊巴比妥钠麻醉,气管插管,接呼吸机,暴露并切断双侧颈迷走神经干,破坏颈交感神经节。双侧开胸,刺激电极分别与左、右心耳、左房及四支肺静脉缝合,行程序刺激,观察在基础状态、双侧强迷走刺激及阿托品作用时肺静脉不同部位ERP的变化。结果迷走神经刺激明显缩短肺静脉不同部位的ERP,而阿托品则可拮抗这种缩短。结论迷走神经刺激缩短肺静脉的ERP并参与房颤的发生。     

消融犬右肺静脉脂肪垫对心房及右上肺静脉电生理特性及房颤诱发的影响

目的探讨消融右肺静脉脂肪垫对心房及右上肺静脉电生理特性及房颤诱发的影响。方法犬18只分别在颈部迷走神经未刺激和刺激的情况下,观察射频消融肺静脉脂肪垫前后心房不同部位及右上肺静脉有效不应期、房颤诱发率及房颤诱发窗口的变化。结果在刺激迷走神经的情况下,与消融前相比,消融后高位右心房有效不应期延长（P<0.05）,其余部位有效不应期无显著差异,消融后高位右心房房颤诱发率降低（P<0.01）,房颤诱发窗口变窄（P<0.05）,左心房（P<0.01）及右上肺静脉（P<0.01）房颤诱发率升高,诱发窗口增宽。同时,心房有效不应期离散度增加（P<0.01）。结论消融右肺静脉脂肪垫使高位右心房房颤诱发率降低及房颤诱发窗口变窄,却使左房、右上肺静脉房颤诱发率升高及房颤诱发窗口增宽。     

Effect of gender on atrial electrophysiologic changes induced by rapid atrial pacing and elevation of atrial pressure

INTRODUCTION: The incidence of atrial fibrillation is greater in men than in women, but the reasons for this gender difference are unclear. The purpose of this study was to evaluate the effects of gender on the atrial electrophysiologic effects of rapid atrial pacing and an increase in atrial pressure. METHODS AND RESULTS: Right atrial pressure and effective refractory period (ERP) were measured during sinus rhythm and during atrial and simultaneous AV pacing at a cycle length of 300 msec in 10 premenopausal women, 11 postmenopausal women, and 24 men. The postmenopausal women were significantly older than the premenopausal women (61 +/- 8 years vs 34 +/- 10 years; P < 0.01). During sinus rhythm, mean atrial ERP in premenopausal women was shorter (211 +/- 19 msec) than in postmenopausal women and age-matched men (242 +/- 18 msec and 246 +/- 34 msec, respectively; P < 0.05). Atrial ERPs in all patients shortened significantly during atrial and simultaneous AV pacing. However, the degree of shortening during atrial pacing (43 +/- 8 msec vs 70 +/- 20 msec and 74 +/- 21 msec; P < 0.05) and during simultaneous AV pacing (48 +/- 16 msec vs 91 +/- 27 msec and 84 +/- 26 msec; P < 0.05) was significantly less in premenopausal women than in postmenopausal women or age-matched men. CONCLUSION: The results of this study demonstrate a significant gender difference in atrial electrophysiologic changes in response to rapid atrial pacing and an increase in atrial pressure. The effect of menopause on the observed changes suggests that the gender differences may be mediated by the effects of estrogen on atrial electrophysiologic properties.     

Correlation between atrial ZnT-1 expression and atrial fibrillation in humans: a pilot study

Background : Until recently, the membrane protein ZnT-1 was studied mainly in the context of zinc homeostasis. However, new findings indicate that it acts as an inhibitor of L-type calcium channels. We recently found that acute rapid pacing of the rat atria in vivo augments the expression of ZnT-1, while knockdown of ZnT-1 in culture can oppose the inhibition of L-type calcium channels following rapid pacing. This pilot study, the first to assess cardiac ZnT-1 in humans, was designed to look for possible correlation between the atrial expression of ZnT-1 and atrial fibrillation.
Methods: Right atrial appendage tissue was collected from 39 patients (27 with sinus rhythm and 12 with atrial fibrillation; 6-permanent, 6- paroxysmal or persistent) undergoing open-heart surgery. The expression of ZnT-1 was analyzed by Western blot utilizing β-actin as an internal loading control and a standard rat heart sample (STD) for inter-blot comparison.
Results: Overall atrial fibrillation patients (n = 12) had median ZnT-1/β-actin of 1.80 STD (inter-quartile range 1.26 to 2.85) versus 0.73 STD (0.24 to 1.64) in the sinus rhythm group (P = 0.002). No association was found between ZnT-1 level and most other clinical parameters tested. Multivariate analysis determined that atrial fibrillation and increased body mass index were the only independent variables clearly associated with higher ZnT-1 levels (Standardized coefficients Beta = 0.62, 0.31; P = 0.002, P = 0.04, respectively).
Conclusions: This pilot study provides evidence for increased ZnT-1 expression in the atria of patients with atrial fibrillation.     

Effects of pulmonary vein ablation on regional atrial vagal innervation and vulnerability to atrial fibrillation in dogs

INTRODUCTION: Pulmonary vein (PV) isolation has proven to be an effective therapy for atrial fibrillation (AF). However, clinical evidence suggests that suppression of AF after PV isolation could not be fully attributed to the interruption of electrical conduction in and out of the PVs. Furthermore, little is known regarding the effects of ablation around the PVs on the atrial electrophysiological properties. We aimed to study the changes in atrial response to vagal stimulation (VS) after PV ablation (PVA). METHODS: We studied 11 adult mongrel dogs under general anesthesia. Bilateral cervical sympathovagal trunks were decentralized. Propranolol was given to block sympathetic effects. Multipolar catheters were placed into right atrial appendage (RAA), distal and proximal coronary sinus (CSD, CSP), and left atrial free wall (LAFW). PVA was performed via trans-septal approach. Atrial effective refractory period (AERP) and vulnerability window (VW) of AF were measured with and without VS before and after ablation to isolate the PVs. RESULTS: After ablation, AERP shortening in response to VS significantly decreased in the left atrium (43.64 +/- 21.57 vs 11.82 +/- 9.82 msec, P < 0.001 at LAFW; 50.91 +/- 26.25 vs 11.82 +/- 14.01 msec, P < 0.001 at CSP; 50 +/- 31.94 vs 17.27 +/- 20.54 msec, P < 0.005 at CSD), while the response to VS did not change significantly at RAA (58.18 +/- 28.22 vs 50.91 +/- 22.12 msec, P = 0.245). After ablation, atrial fibrillation VW during VS narrowed (20.63 +/- 11.48 vs 5.63 +/- 8.63 msec, P < 0.03 at LAFW; 26.25 +/- 12.46 vs 5.00 +/- 9.64 msec, P = 0.001 at CSP; 28.75 +/- 18.47 vs 6.88 +/- 7.53 msec, P < 0.02 at CSD, and 33.75 +/- 24.5 vs 16.25 +/- 9.91 msec, P = 0.03 at RAA). CONCLUSIONS: Ablation around the PV ostia diminishes left atrial response to VS and decreases the atrial VW. The attenuated vagal response after ablation may contribute to the suppression of AF.     

Ectopic right atrial rhythms: experimental and clinical data

In 18 out of 25 canine hearts studied with bipolar plunge electrodes, ectopic right atrial (RA) beats were observed occurring (1) spontaneously, (2) during vagal stimulation, (3) after destruction of the sinus node, and (4) during ventricular pacing. In these beats the RA appendage was activated first, followed by Bachmann's bundle, sinus node, left atrial appendage, posterior left atrium, and proximal coronary sinus. This sequence was consistently reproduced by pacing through the RA appendage recording electrode.     

Effects of simultaneous atrioventricular pacing on atrial refractoriness and atrial fibrillation inducibility: role of atrial mechanoelectrical feedback

INTRODUCTION: The purpose of this study was to evaluate the effects of an acute increase in atrial pressure on refractoriness (mechanoelectrical feedback) and the vulnerability to atrial fibrillation (AF) and to investigate the effects of autonomic blockade and verapamil on mechanoelectrical feedback in humans. METHODS AND RESULTS: Right atrial pressure and effective refractory period (ERP) at the right atrial appendage (RAA) and high right atrial septum were measured during sinus rhythm, and during atrial and simultaneous AV pacing at a cycle length of 300 msec, either in the absence (n = 25) or presence (n = 22) of pharmacologic autonomic blockade. In another 15 patients, the protocol was performed before and after infusion of verapamil 0.15 mg/kg. In the absence of autonomic blockade, AV pacing resulted in a higher mean right atrial pressure (11.7 +/- 3.3 vs 4.3 +/- 3.0 mmHg, P < 0.001) and a shorter atrial RAA ERP (144 +/- 23 msec vs 161 +/- 21 msec; P < 0.001) compared with atrial pacing; AF was induced more often during AV pacing (87%) than during atrial pacing (20%) and was related directly to the right atrial pressure (r = 0.39, P = 0.004) and indirectly to the RAA ERP (r = -0.42, P < 0.001). The susceptibility to sustained AF was greatly enhanced by autonomic blockade. Verapamil markedly attenuated the shortening of ERP and the propensity for AF that occurred during simultaneous AV pacing. CONCLUSION: An acute increase in atrial pressure during tachycardia is associated with shortening of atrial refractoriness and a propensity for AF, i.e., atrial mechanoelectrical feedback, which may be enhanced by autonomic blockade and attenuated by calcium channel blockade.     

犬心房颤动模型缝隙连接蛋白40、45与心肌纤维化的相关性

目的 心房颤动(房颤)的发生及维持机制与心房结构重构和电重构有关.缝隙连接蛋白(connexin,Cx)是心肌闰盘的重要组成结构.一旦Cx出现重构,可影响心肌细胞电传导的极性,出现传导阻滞或折返,引发心律失常.实验通过快速心房起搏建立房颤模型,观察其对心房Cx40和Cx45及心房心肌纤维化的影响,并对两者相关性进行研究.方法 16只健康杂种犬随机分为模型组和对照组,2组犬均在X线下置入心房"J"型电极于右心耳,模型组予以400次/min快速起搏,而对照组维持窦性心律.连续起搏10周,分别在2、4、6、8周检测肢导联心电图.对于10周后未出现房颤的犬予以房颤诱发.实验结束后,取左心房组织制备心肌组织切片.Masson染色观察心房心肌胶原改变,电镜观察心房心肌超微结构及闰盘改变,放射免疫法测定血清中Ⅲ型前胶原氨基端肽和Ⅳ型胶原,免疫组化法检测Cx40及Cx45的表达.结果 模型组在快速起搏10周后均未出现自发性房颤,但其中有2只犬分别出现心房扑动和房性早搏,模型组和对照组予以Burst刺激后,模型组房颤诱发率可达66.7%,而对照组均正常.与对照组相比,模型组心房心肌胶原容积分数(collagen volume fraction,CVF)增加(P＜0.05),尤以心内膜和心房肌细胞间质纤维化明显.电镜下,模型组心房肌细胞超微结构可见肌纤维紊乱、断裂,胶原纤维增生,闰盘结构扭曲、扩张,部分闰盘缝隙消失.模型组血清中Ⅲ型前胶原氨基端肽和Ⅳ型胶原水平较对照组显著增高(P＜0.05);模型组心房心肌Cx40表达较对照组增加(P＜0.05),而Cx45蛋白改变二组差异无统计学意义(P＞0.05).将心房心肌组织CVF与Cx40行相关性分析,结果显示CVF与Cx40呈正相关(r=0.671).结论 犬心房快速起搏能诱导左心房组织心肌纤维化和Cx40表达增加,但对Cx45无影响,同时发现Cx40的改变程度受心房心肌纤维化程度的影响.

Abstract：

Objective Electrical and structural remodeling are of importance for the occurrence and maintenance of atrial fibrillation. We observed association between atrial connexin protein expression and fibrosis in a canine model of prolonged rapid atrial pacing. Methods "J"-type electrodes were placed in the right atrial appendage under the guidance of X-ray in 16 dogs, Animals in model group ( n = 8) received fast pacing (400 beats/min ) for 10 weeks while animals in control group (n =8) maintained at sinus rhythm.Limb-lead ECGs were recorded at 2,4,6,8 weeks respectively. Burst stimulation was applied to induce atrial fibrillation in all animals after 10 weeks, animals were sacrificed thereafter and the left atrial tissues were taken for myocardial collagen measurement ( Masson staining) and myocardial ultrastructure examination and detection of protein expression of connexin ( Cx ) 40 and 45 ( immune staining). Procollagen type Ⅲ N-terminal peptide and type Ⅳ collagen in serum were also detected by radioimmunoassay. Results Two dogs died in model group due to atrial rupture induced cardiac tamponade or lung emboli. Spontaneously atrial fibrillation was not observed in all animals, but two dogs developed atrial flutter and atrial premature beats. Atrial fibrillation was induced by burst stimulation in 4 out of 6 dogs in model group and in none of the dogs in control group. Atrial myocardial collagen volume fraction was significantly increased in model group compared with the control group (P ＜ 0. 05). Ultrastructure examination in atrial tissue evidenced disorder,fracture,collagen fiber proliferation, mitochondrial swelling, blurred cristae, and intercalated disc distortion,expansion, part of gap junction disappears in model group. The serum levels of procollagen type Ⅲ N-terminal peptide and type Ⅳ collagen in model group were significantly higher than in the control group ( P ＜ 0. 05 ). The protein expression of Cx40 in atrial myocardium in model group was significantly higher than in control group (P ＜ 0. 05 ), while Cx45 protein expression was similar between two groups (P ＞0. 05). The left atrial CVF was positively correlated with Cx40 ( r = 0. 671, P ＜ 0. 01 ). Conclusion Increased myocardial fibrosis is positively correlated with upregulation of myocardial Cx40 protein expression in left atrium in rapid atrial paced canine.     

Effect of pilsicainide on atrial electrophysiologic properties in the canine rapid atrial stimulation model.

The heterogeneous process of atrial electrical remodeling (AER) in the canine rapid atrial stimulation model has been previously reported although it has been reported that a sodium channel blocker might suppress the shortening of the atrial effective refractory period (AERP), its effect on long-term electrical remodeling is unknown. In the present study, the effect of pilsicainide on AER was evaluated. The right atrial appendage (RAA) was paced at 400 beats/min for 2 weeks. In the RAA, Bachmann's bundle (BB), the right atrium near the inferior vena cava (IVC) and in the left atrium (LA), AERP, AERP dispersion (AERPd) and the inducibility of atrial fibrillation (AF) were evaluated at several time points of the pacing phase and the recovery phase (1 week). The same protocol was performed during the administration of pilsicainide (4.5 mg/kg per day) and the parameters were compared with the controls. In the control dogs, the AERP was significantly shortened by rapid pacing at all atrial sites studied and the AERP shortening (DeltaAERP) was larger at the RAA and LA sites (p<0.03). However, pilsicainide decreased these DeltaAERPs at all 4 atrial sites. AERPd was increased during the pacing phase whereas it was decreased during the recovery phase in the control dogs. In contrast, this pacing-induced AERPd was attenuated by the administration of pilsicainide. The AF inducibility was highest at the LA site in both groups, and the inducibility was lower in the pilsicainide group than the control group at all atrial sites. During the rapid pacing phase, the ventricular heart rate was significantly lower in the pilsicainide group than the control because of intra-atrial conduction block. In a canine rapid right atrial stimulation model, pilsicainide suppressed the shortening of the AERP at all atrial sites, possibly through the improvement of the hemodynamics as well as the action of the Na - Ca exchanger.