Bunch T Jared, Mahapatra Srijoy, Bruce G Keith, Johnson Susan B, Miller Dylan V, Horne Benjamin D, Wang Xiao-Li, Lee Hon-Chi, Caplice Noel M, Packer Douglas L
Division of Cardiovascular Disease, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55902, USA.
Circulation. 2006 May 30;113(21):2485-94. doi: 10.1161/CIRCULATIONAHA.105.570796. Epub 2006 May 22.
Atrioventricular (AV) nodal ablation for management of atrial fibrillation (AF) is irreversible and requires permanent pacemaker implantation. We hypothesized that as an alternative, implantation of autologous fibroblasts in the perinodal region would focally modify AV nodal conduction and that this modulation would be enhanced by pretreatment with transforming growth factor-beta1 (TGF-beta1), a stimulant of fibroblasts.
Skin biopsies were taken from 12 mongrel dogs, and derived fibroblasts were dissociated and grown in culture for 2 weeks. Multiple injections (0.25 mL) were made through an 8F NOGA catheter along the fast/slow AV nodal pathways as guided by an electroanatomic mapping system. Seven dogs received fibroblasts alone (1x10(6) cells/mL), 7 dogs received TGF-beta1 (5 microg), 4 dogs received fibroblasts and TGF-beta1 (1x10(6) cells/mL+5 microg), and 4 dogs received saline only. AV node function was assessed at baseline and after 4 weeks. Saline (80 mL) with assigned therapy (0.25 mL per injection) was injected into the peri-AV nodal region in each dog. At baseline, the AH interval (66+/-3 ms) and the average RR interval (331+/-17 ms) in pacing-induced AF were similar in each cohort. The increase in AH interval in normal sinus rhythm was longer after fibroblast (23+/-4 versus 5+/-5 ms; P=0.05) and fibroblast plus TGF-beta1 (50+/-5 versus 5+/-5 ms; P<0.001) injections than with saline alone, with similar findings during high right atrium and distal coronary sinus pacing. The AH interval was not significantly increased after TGF-beta1 injections. The AH interval was significantly longer after fibroblast plus TGF-beta1 injections than with either therapy (TGF-beta1 or fibroblasts) alone. The RR interval during AF was increased in dogs that received fibroblasts alone (110+/-36 versus -41+/-34 ms) and to a greater extent with the addition of TGF-beta1 (294+/-108 versus -41+/-34 ms). No AV block was seen in any cohort at 4 weeks. Labeled fibroblasts that expressed vimentin were identified in all dogs that received cell injections at 4 weeks.
AV nodal modification can be achieved with injected fibroblasts without the creation of AV block. The effect on AV node conduction is substantially enhanced by pretreatment of fibroblasts with TGF-beta1. These data have therapeutic potential for the management of rapid ventricular rate during AF without pacemaker implantation.
用于治疗心房颤动（AF）的房室（AV）结消融是不可逆的，且需要植入永久性起搏器。我们推测，作为一种替代方法，在结周区域植入自体成纤维细胞可局部改变房室结传导，并且这种调节作用会因用成纤维细胞刺激剂转化生长因子-β1（TGF-β1）进行预处理而增强。
从12只杂种犬身上获取皮肤活检组织，分离出成纤维细胞并在培养中生长2周。在电解剖标测系统的引导下，通过一根8F NOGA导管沿着快慢房室结路径进行多次注射（0.25 mL）。7只犬单独接受成纤维细胞（1×10⁶个细胞/mL），7只犬接受TGF-β1（5微克），4只犬接受成纤维细胞和TGF-β1（1×10⁶个细胞/mL + 5微克），4只犬仅接受生理盐水。在基线和4周后评估房室结功能。将含有指定治疗药物（每次注射0.25 mL）的生理盐水（80 mL）注入每只犬的房室结周围区域。在基线时，各队列中起搏诱发房颤时的AH间期（66±3毫秒）和平均RR间期（331±17毫秒）相似。在正常窦性心律下，注射成纤维细胞（23±4对5±5毫秒；P = 0.05）和成纤维细胞加TGF-β1（50±5对5±5毫秒；P < 0.001）后AH间期的增加比仅注射生理盐水时长，在高位右心房和远端冠状窦起搏时也有类似发现。注射TGF-β1后AH间期没有显著增加。注射成纤维细胞加TGF-β1后AH间期比单独使用任何一种治疗方法（TGF-β1或成纤维细胞）都显著更长。单独接受成纤维细胞的犬在房颤时的RR间期增加（110±36对 -41±34毫秒），添加TGF-β1后增加幅度更大（294±108对 -41±34毫秒）。4周时任何队列中均未观察到房室传导阻滞。在4周时接受细胞注射的所有犬中均鉴定出表达波形蛋白的标记成纤维细胞。
注射成纤维细胞可实现房室结的改变而不产生房室传导阻滞。用TGF-β1对成纤维细胞进行预处理可显著增强对房室结传导的影响。这些数据对于在不植入起搏器的情况下治疗房颤时的快速心室率具有治疗潜力。
