内源性心脏自主神经调控在心房颤动中的研究
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摘要
目的：
1探讨外源性心脏自主神经低强度刺激(LL-VNS)对心房颤动及内源性心脏自主神经活性的影响
2探讨经静脉途径外源性心脏自主神经低强度刺激(LL-SVCS)对心房颤动及内源性心脏自主神经活性的影响
3探讨携带神经毒素的磁性纳米颗粒(MNPs)对心房颤动及内源性心脏自主神经活性的影响。
方法：
体重在20-30kg的成年犬,戊巴比妥钠(50mg/kg)麻醉,在通风的房间通过呼吸机给予正压通气。在犬下方放置控制电热垫,从而通过传感器将犬的中心体温维持在36.5±0.5℃。股动脉和股静脉分别插管用于电极置入(主动脉根部做希氏束记录)、血压记录、药物和盐水。持续监测ECG和血压。
1、观察外源性心脏自主神经低强度刺激(LL-VNS)对心房颤动及其内源性心脏自主神经活性的影响。以90%或50%阂值(TH)进行双侧迷走神经刺激,(阈值定义：引起窦律或者房室传导减慢的最低电压值)。在心房、心耳及所有肿静脉上缝合多电极导管。在右前GP (ARGP)和左上GP(SLGP)同时行电刺激以模拟ICANS的高活性状态。分别于基线状态和ARGP+SLGP刺激时测量伴或不伴LL-VNS时各位点的有效不应期(ERP)和心房颤动(AF)的易损窗(WOV)。在ARGP和SLGP记录神经元电活动。
2、观察经静脉途径外源性心脏自主神经低强度刺激(LL-SVCS)对心房颤动及其内源性心脏自主神经活性的影响。将多管电极导管固定于犬的心房、所有的肺静脉和右侧的星状神经节上(RSG)。再将一环形的导管置于上腔静脉,20Hz高频刺激(HFS)其毗邻的迷走神经。将微电极插入前右侧神经节丛(ARGP)记录神经活动。在基线水平,程序性的刺激得到有效不应期(ERP)和心房颤动(AF)的易损窗(WOV)在接下来的3个小时,快速心房起搏(RAP)诱发AF。在窦性心律下,每隔一小时测量相同的参数。在第4-6小时的RAP期间,以50%的阈值强度在上腔静脉处低强度刺激迷走神经(LL-SVC)。另六只犬,2小时LL-SVCS后比较在RSG和ARGP的电压(Voltage)/窦性心律(SR)反应曲线。
3、观察携带神经毒素的磁性纳米颗粒对心房颤动及其内源性心脏自主神经活性的影响。MNPs由Fe3O4(核心),温度敏感型多聚水凝胶(壳)以及神经毒介质(NIPA-M)组成。23只犬,经右侧开胸暴露ARGP和右下GP (IRGP)。用高频刺激(HFS,20Hz,0.1ms) ARGP, IRGP引起窦性心律(SR)和心室率(VR)减慢分别作为检测ARGP和IRGP生理功能的指标。其中6只犬,将附有0.4mgNIPA-M的MNPs注射到ARGP.另4只犬,将一个柱状的磁石(2600G)放在心外膜的IRGP上。再将附有0.8mgNIPA-M的MNPs注入给IRGP供血的冠状动脉左侧回旋支上在体内当温度≥37℃时,水凝胶壳收缩,释放出NIPA-M。
结果：
1同时高频电刺激ARGP和SLGP刺激引起ERP缩短,ERP离散度增加以及WOV增加,且以上指标均被LL-VNS(低于阈值10%或50%的电压)抑制。假LL-VNS组没有引起上述改变。LL-VNS通过抑制ICANS发挥效应：(1)LL-VNS抑制了ARGP刺激对窦律的影响；(2)ARGP和SLGP神经电活动的频率及幅度均被LL-VNS显著抑制；(3)从肺静脉-心房连接处到心耳的ERP和WOV空间梯度被LL-VNS消除。
2第1-3个小时进行RAP后,相对基线水平,ERP逐渐缩短,而WOV和神经活动逐渐延长(P<0.05)。第4-6小时进行LL-SVCS后,ERP、WOV和神经活动回到基线水平(与第3小时末比较P<0.05)。(2)对RSG和ARGP处刺激分别增加或减慢SR的能力可以被LL-SVCS消弱。
3 MNPs注射入ARGP后抑制了HFS诱发的窦性心律减慢的反应(基线水平40±8%；2小时21±9%；P=0.006)。ARGP处HFS诱发AF的最低电压从5.9±0.8V(基线水平)增加到10.2±0.9V(2小时；P=0.009)。冠状动脉注入MNPs抑制了IRGP而没有抑制ARGP的功能(心室率减慢：在基线水平57±8%,在2小时20±8%；P=0.002；窦性心律减慢：基线水平31±7%,2小时33±8%；P=0.604)。普鲁士蓝染色显示MNP聚集物仅出现在IRGP,而在ARGP没有出现。
结论：
1 LL-VNS通过抑制ICANS内主要GP的神经活性抑制房颤的发生
2 LL-SVCS可以显著抑制AF的可诱导性,逆转RAP中的心房电重构及ICANS重构,减弱交感神经和副交感神经对SR的影响效果。
3注入附有NIPA-M的MNPs可以通过体外磁力定向于IRGP并释放NIPA-M来降低GP活性。这种新的靶向药物系统可用于靶向的经血管途径自主神经去支配。
Objectives:
1 To investigate the the effect of LL-VNS on ICANS activity and the atrial fibrillation
2 To investigate the effect of LL-SVCS on the ICANS activity and atrial fibrillation.
3 To investigate the effects of MNPs on ICANS activity and atrial fibrillation.
Methods:
1 Wire electrodes inserted into both vagosympathetic trunks allowed LL-VNS at 10% or 50% below the voltage required to slow the sinus rate or atrioventricular conduction. Multielectrodecatheters were attached to atria, atrial appendages and all pulmonary veinsElectrical stimulation at theanterior right and superior left ganglionated plexi (ARGP, SLGP) was used to simulate a hyperactive state ofthe ICANS. Effective refractory period (ERP) and window of vulnerability (WOV) for AF were determined at baseline and during ARGP+SLGP stimulation in the presence or absence of LL-VNS. Neural activity was recorded from the ARGP or SLGP.
2 In 29 anesthetized dogs, we attached multi-electrode catheters on atria, all pulmonary veins and right stellate ganglion (RSG). A basket catheter was expanded in the superior vena cava (SVC) for high frequency stimulation (HFS,20 Hz) of the adjacent vagal preganglionics. Microelectrodes inserted into the anterior right ganglionated plexi (ARGP) recorded neural activity. At baseline, programmed stimulation determined the effective refractory period (ERP) and window of vulnerability (WOV), a measure of AF inducibility. For the next 3 hours, AF was induced by rapid atrial pacing (RAP), and the same parameters were measured hourly, during sinus rhythm. During hours 4-6 of RAP, we delivered low-level vagal stimulation at the SVC (LL-SVCS),50% below that which induced slowing of the sinus rate (SR). In six other dogs, the voltage/SR response curve during RSG and ARGP stimulation was compared after 2-hour LL-SVCS.
3 Superparamagnetic nanoparticles (MNPs) made of Fe3O4 (core), thermor-esponsive polymeric hydrogel (shell), and neurotoxic agent (N-isopropylacry-lamide monomer [NIPA-M]) were synthesized. In 23 dogs, a right thoracotomy exposed the anterior right GP (ARGP) and inferior right GP (IRGP). The sinus rate and ventricular rate slowing responses to high-frequency stimulation (20 Hz,0.1 ms) were used as the surrogate for the ARGP and IRGP functions, respectively. In 6 dogs, MNPs carrying 0.4 mg NIPA-M were injected into the ARGP. In 4 other dogs, a cylindrical magnet (2600 G) was placed epicardially on the IRGP. MNPs carrying 0.8 mg NIPA-M were then infused into the circumflex artery supplying the IRGP. The hydrogel shell reliably contracted in vitro at temperatures 37℃, releasing NIPA-M.
Results:
1 ARGP+SLGP stimulation induced shortening of ERP, increase of ERP dispersion and increase of AF inducibility (WOV), all of which were suppressed by LL-VNS (10% or 50% below threshold) at all tested sites. Sham LL-VNS failed to induce these changes. The effects of LL-VNS were mediated by inhibition of the 1CANS, as evidenced by (1) LL-VNS suppression of the ability of the ARGP stimulation to slow the sinus rate, (2) the frequency and amplitude of the neural activity recorded from the ARGP or SLGP was markedly suppressed by LL-VNS, and (3) the spatial gradient of the ERP and WOV from the PV-atrial junction toward the atrial appendage was eliminated by LL-VNS.
2 During hours 1-3 of RAP, there was a progressive decrease in the ERP, increase in WOV and increase in neural activity vs. baseline (all p<0.05). With LL-SVCS during hours 4-6, ERP, WOV and neural activity returned towards baseline levels (all p<0.05, compared to the 3rd hour values). (2) The ability of RSG and ARGP stimulation to increase and decrease SR. respectively, was blunted by LL-SVCS.
3 MNPs injected into the ARGP suppressed high-frequency stimulation-induced sinus rate slowing response (40±8% at baseline; 21±9% at 2 hours; P<0.006). The lowest voltage of ARGP high-frequency stimulation inducing atrial fibrillation was increased from 5.9±0.8 V (baseline) to 10.2±0.9 V (2 hours; P<0.009). Intracoronary infusion of MNPs suppressed the IRGP but not ARGP function (ventricular rate slowing:57±8% at baseline,20±8% at 2 hours; P<0.002; sinus rate slowing:31±7% at baseline,33±8% at 2 hours; P<0.604). Prussian Blue staining revealed MNP aggregates only in the IRGP, not the ARGP.
Conclusions:
1 LL-VNS suppressed AF inducibility by inhibiting the neural activity of major GP within the ICANS.
2 LL-SVCS can significantly suppress AF inducibility and mitigate sympathetic and parasympathetic effects on SR. This transvenous approach suggests a feasible clinical method for treating AF or inappropriate sinus tachycardia.
3 Intravascularly administered MNPs carrying NIPA-M can be magnetically targeted to the IRGP and reduce GP activity presumably by the subsequent release of NIPA-M and/or microvascular embolization. This novel targeted drug delivery system can be used intravascularly for targeted autonomic denervation.
1探讨外源性心脏自主神经低强度刺激(LL-VNS)对心房颤动及内源性心脏自主神经活性的影响
2探讨经静脉途径外源性心脏自主神经低强度刺激(LL-SVCS)对心房颤动及内源性心脏自主神经活性的影响
3探讨携带神经毒素的磁性纳米颗粒(MNPs)对心房颤动及内源性心脏自主神经活性的影响。
方法：
体重在20-30kg的成年犬,戊巴比妥钠(50mg/kg)麻醉,在通风的房间通过呼吸机给予正压通气。在犬下方放置控制电热垫,从而通过传感器将犬的中心体温维持在36.5±0.5℃。股动脉和股静脉分别插管用于电极置入(主动脉根部做希氏束记录)、血压记录、药物和盐水。持续监测ECG和血压。
1、观察外源性心脏自主神经低强度刺激(LL-VNS)对心房颤动及其内源性心脏自主神经活性的影响。以90%或50%阂值(TH)进行双侧迷走神经刺激,(阈值定义：引起窦律或者房室传导减慢的最低电压值)。在心房、心耳及所有肿静脉上缝合多电极导管。在右前GP (ARGP)和左上GP(SLGP)同时行电刺激以模拟ICANS的高活性状态。分别于基线状态和ARGP+SLGP刺激时测量伴或不伴LL-VNS时各位点的有效不应期(ERP)和心房颤动(AF)的易损窗(WOV)。在ARGP和SLGP记录神经元电活动。
2、观察经静脉途径外源性心脏自主神经低强度刺激(LL-SVCS)对心房颤动及其内源性心脏自主神经活性的影响。将多管电极导管固定于犬的心房、所有的肺静脉和右侧的星状神经节上(RSG)。再将一环形的导管置于上腔静脉,20Hz高频刺激(HFS)其毗邻的迷走神经。将微电极插入前右侧神经节丛(ARGP)记录神经活动。在基线水平,程序性的刺激得到有效不应期(ERP)和心房颤动(AF)的易损窗(WOV)在接下来的3个小时,快速心房起搏(RAP)诱发AF。在窦性心律下,每隔一小时测量相同的参数。在第4-6小时的RAP期间,以50%的阈值强度在上腔静脉处低强度刺激迷走神经(LL-SVC)。另六只犬,2小时LL-SVCS后比较在RSG和ARGP的电压(Voltage)/窦性心律(SR)反应曲线。
3、观察携带神经毒素的磁性纳米颗粒对心房颤动及其内源性心脏自主神经活性的影响。MNPs由Fe3O4(核心),温度敏感型多聚水凝胶(壳)以及神经毒介质(NIPA-M)组成。23只犬,经右侧开胸暴露ARGP和右下GP (IRGP)。用高频刺激(HFS,20Hz,0.1ms) ARGP, IRGP引起窦性心律(SR)和心室率(VR)减慢分别作为检测ARGP和IRGP生理功能的指标。其中6只犬,将附有0.4mgNIPA-M的MNPs注射到ARGP.另4只犬,将一个柱状的磁石(2600G)放在心外膜的IRGP上。再将附有0.8mgNIPA-M的MNPs注入给IRGP供血的冠状动脉左侧回旋支上在体内当温度≥37℃时,水凝胶壳收缩,释放出NIPA-M。
结果：
1同时高频电刺激ARGP和SLGP刺激引起ERP缩短,ERP离散度增加以及WOV增加,且以上指标均被LL-VNS(低于阈值10%或50%的电压)抑制。假LL-VNS组没有引起上述改变。LL-VNS通过抑制ICANS发挥效应：(1)LL-VNS抑制了ARGP刺激对窦律的影响；(2)ARGP和SLGP神经电活动的频率及幅度均被LL-VNS显著抑制；(3)从肺静脉-心房连接处到心耳的ERP和WOV空间梯度被LL-VNS消除。
2第1-3个小时进行RAP后,相对基线水平,ERP逐渐缩短,而WOV和神经活动逐渐延长(P<0.05)。第4-6小时进行LL-SVCS后,ERP、WOV和神经活动回到基线水平(与第3小时末比较P<0.05)。(2)对RSG和ARGP处刺激分别增加或减慢SR的能力可以被LL-SVCS消弱。
3 MNPs注射入ARGP后抑制了HFS诱发的窦性心律减慢的反应(基线水平40±8%；2小时21±9%；P=0.006)。ARGP处HFS诱发AF的最低电压从5.9±0.8V(基线水平)增加到10.2±0.9V(2小时；P=0.009)。冠状动脉注入MNPs抑制了IRGP而没有抑制ARGP的功能(心室率减慢：在基线水平57±8%,在2小时20±8%；P=0.002；窦性心律减慢：基线水平31±7%,2小时33±8%；P=0.604)。普鲁士蓝染色显示MNP聚集物仅出现在IRGP,而在ARGP没有出现。
结论：
1 LL-VNS通过抑制ICANS内主要GP的神经活性抑制房颤的发生
2 LL-SVCS可以显著抑制AF的可诱导性,逆转RAP中的心房电重构及ICANS重构,减弱交感神经和副交感神经对SR的影响效果。
3注入附有NIPA-M的MNPs可以通过体外磁力定向于IRGP并释放NIPA-M来降低GP活性。这种新的靶向药物系统可用于靶向的经血管途径自主神经去支配。
Objectives:
1 To investigate the the effect of LL-VNS on ICANS activity and the atrial fibrillation
2 To investigate the effect of LL-SVCS on the ICANS activity and atrial fibrillation.
3 To investigate the effects of MNPs on ICANS activity and atrial fibrillation.
Methods:
1 Wire electrodes inserted into both vagosympathetic trunks allowed LL-VNS at 10% or 50% below the voltage required to slow the sinus rate or atrioventricular conduction. Multielectrodecatheters were attached to atria, atrial appendages and all pulmonary veinsElectrical stimulation at theanterior right and superior left ganglionated plexi (ARGP, SLGP) was used to simulate a hyperactive state ofthe ICANS. Effective refractory period (ERP) and window of vulnerability (WOV) for AF were determined at baseline and during ARGP+SLGP stimulation in the presence or absence of LL-VNS. Neural activity was recorded from the ARGP or SLGP.
2 In 29 anesthetized dogs, we attached multi-electrode catheters on atria, all pulmonary veins and right stellate ganglion (RSG). A basket catheter was expanded in the superior vena cava (SVC) for high frequency stimulation (HFS,20 Hz) of the adjacent vagal preganglionics. Microelectrodes inserted into the anterior right ganglionated plexi (ARGP) recorded neural activity. At baseline, programmed stimulation determined the effective refractory period (ERP) and window of vulnerability (WOV), a measure of AF inducibility. For the next 3 hours, AF was induced by rapid atrial pacing (RAP), and the same parameters were measured hourly, during sinus rhythm. During hours 4-6 of RAP, we delivered low-level vagal stimulation at the SVC (LL-SVCS),50% below that which induced slowing of the sinus rate (SR). In six other dogs, the voltage/SR response curve during RSG and ARGP stimulation was compared after 2-hour LL-SVCS.
3 Superparamagnetic nanoparticles (MNPs) made of Fe3O4 (core), thermor-esponsive polymeric hydrogel (shell), and neurotoxic agent (N-isopropylacry-lamide monomer [NIPA-M]) were synthesized. In 23 dogs, a right thoracotomy exposed the anterior right GP (ARGP) and inferior right GP (IRGP). The sinus rate and ventricular rate slowing responses to high-frequency stimulation (20 Hz,0.1 ms) were used as the surrogate for the ARGP and IRGP functions, respectively. In 6 dogs, MNPs carrying 0.4 mg NIPA-M were injected into the ARGP. In 4 other dogs, a cylindrical magnet (2600 G) was placed epicardially on the IRGP. MNPs carrying 0.8 mg NIPA-M were then infused into the circumflex artery supplying the IRGP. The hydrogel shell reliably contracted in vitro at temperatures 37℃, releasing NIPA-M.
Results:
1 ARGP+SLGP stimulation induced shortening of ERP, increase of ERP dispersion and increase of AF inducibility (WOV), all of which were suppressed by LL-VNS (10% or 50% below threshold) at all tested sites. Sham LL-VNS failed to induce these changes. The effects of LL-VNS were mediated by inhibition of the 1CANS, as evidenced by (1) LL-VNS suppression of the ability of the ARGP stimulation to slow the sinus rate, (2) the frequency and amplitude of the neural activity recorded from the ARGP or SLGP was markedly suppressed by LL-VNS, and (3) the spatial gradient of the ERP and WOV from the PV-atrial junction toward the atrial appendage was eliminated by LL-VNS.
2 During hours 1-3 of RAP, there was a progressive decrease in the ERP, increase in WOV and increase in neural activity vs. baseline (all p<0.05). With LL-SVCS during hours 4-6, ERP, WOV and neural activity returned towards baseline levels (all p<0.05, compared to the 3rd hour values). (2) The ability of RSG and ARGP stimulation to increase and decrease SR. respectively, was blunted by LL-SVCS.
3 MNPs injected into the ARGP suppressed high-frequency stimulation-induced sinus rate slowing response (40±8% at baseline; 21±9% at 2 hours; P<0.006). The lowest voltage of ARGP high-frequency stimulation inducing atrial fibrillation was increased from 5.9±0.8 V (baseline) to 10.2±0.9 V (2 hours; P<0.009). Intracoronary infusion of MNPs suppressed the IRGP but not ARGP function (ventricular rate slowing:57±8% at baseline,20±8% at 2 hours; P<0.002; sinus rate slowing:31±7% at baseline,33±8% at 2 hours; P<0.604). Prussian Blue staining revealed MNP aggregates only in the IRGP, not the ARGP.
Conclusions:
1 LL-VNS suppressed AF inducibility by inhibiting the neural activity of major GP within the ICANS.
2 LL-SVCS can significantly suppress AF inducibility and mitigate sympathetic and parasympathetic effects on SR. This transvenous approach suggests a feasible clinical method for treating AF or inappropriate sinus tachycardia.
3 Intravascularly administered MNPs carrying NIPA-M can be magnetically targeted to the IRGP and reduce GP activity presumably by the subsequent release of NIPA-M and/or microvascular embolization. This novel targeted drug delivery system can be used intravascularly for targeted autonomic denervation.
引文
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