Impact of transforming growth factor-beta1 on atrioventricular node conduction modification by injected autologous fibroblasts in the canine heart.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Bunch
T Jared
TJ
Division of Cardiovascular Disease, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55902, USA.
Mahapatra
Srijoy
S
Bruce
G Keith
GK
Johnson
Susan B
SB
Miller
Dylan V
DV
Horne
Benjamin D
BD
Wang
Xiao-Li
XL
Lee
Hon-Chi
HC
Caplice
Noel M
NM
Packer
Douglas L
DL
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000628:therapy*; D001283:Atrioventricular Node; D018780:Body Surface Potential Mapping; D002304:Cardiac Pacing, Artificial; D017690:Cell Transplantation / Q000379:methods*; D004285:Dogs; D005347:Fibroblasts / Q000637:transplantation*; D006329:Heart Conduction System / Q000166:cytology / Q000187:drug effects; D008297:Male; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1; D014182:Transplantation, Autologous
D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1