[Transplantation of pedicled autologous sinoatrial node tissue for treatment of complete atrioventricular block in dogs].

OBJECTIVE: To observe the changes of surface ECG and cell couplings between sinoatrial node cells and myocardial cells following transplantion of pedicled autologous sinoatrial node tissue graft into the right ventricle of a canine model of complete atrioventricular block. METHODS: Ten healthy dogs were randomized into transplantation group and control group. Pedicled autologous sinoatrial node tissue grafts were transplanted into the right ventricle in the transplantation group, while the sinoatrial nodes were only excised in the control group after placement of temporary myocardial pacing wires. The changes of surface ECG were observed at 1, 2, 3 and 4 weeks postoperatively. At 4 weeks, complete atrioventricular block was induced in the dogs by radiofrequency ablation of the His bundle. The heart rate of the dogs in both groups were recorded after the injection of isoproternol (ISO) from the femoral vein, and the transplanted tissue graft was observed under optical and transmission electron microscopes. RESULTS: No significant changes occurred in the surface ECG. All the dogs showed ECG waveforms specific of complete heart block after the ablation, and the ventricular heart rates were similar between the two groups (P>0.05). The ventricular heart rate did not undergo obvious changes after ISO injection (P>0.05). The transplanted pedicled autologous sinoatrial node survived in the dogs and the sinoatrial node cells established desmosome junctions with the myocardial cells, but the number of junctions was not sufficient to support heart pacing. CONCLUSION: Desmosome junction can occur between ventricular myocardial cells and sinoatrial node cells at the edge of transplanted pedicled autologous sinoatrial node tissue.

Implantation of sinoatrial node cells into canine right ventricle: biological pacing appears limited by the substrate.

Biological pacing has been proposed as a physiologic counterpart to electronic pacing, and the sinoatrial node (SAN) is the general standard for biological pacemakers. We tested the expression of SAN pacemaker cell activity when implanted autologously in the right ventricle (RV). We induced complete heart block and implanted electronic pacemakers in the RV of adult mongrel dogs. Autologous SAN cells isolated enzymatically were studied by patch clamp to confirm SAN identity. SAN cells (400,000) were injected into the RV subepicardial free wall and dogs were monitored for 2 weeks. Pacemaker function was assessed by overdrive pacing and IV epinephrine challenge. SAN cells expressed a time-dependent inward current (I(f)) activating on hyperpolarization: density = 4.3 ± 0.6 pA/pF at -105 mV. Four of the six dogs demonstrated >50% of beats originating from the implant site at 24 h. Biological pacemaker rates on days 7-14 = 45-55 bpm and post-overdrive escape times = 1.5-2.5 s. Brisk catecholamine responsiveness occurred. Dogs implanted with autologous SAN cells manifest biological pacing properties dissimilar from those of the anatomic SAN. This highlights the importance of cell and substrate interaction in generating biological pacemaker function.

[Experimental study on xenogenic sino-atrial nodal tissue transplanted into left ventricular wall].

OBJECTIVE: To observe the change of sino-atrial nodal tissue structure and ectopic pacing function after xenogenic sino-atrial nodal tissue transplanted into left ventricular wall, so as to provide new ideas for the treatment of sick sinus syndrome and severe atrioventricular block. METHODS: Seventy healthy rabbits were selected, male or female, and weighing 1.5-2.0 kg. Of them, 42 were used as recipient animals and randomly divided into sham operation group, warm ischemia transplantation group, and cold ischemia transplantation group (n = 14), the other 28 were used as donors of warm ischemia and cold ischemia transplantation groups, which were sibling of the recipients. In recipients, a 6-mm-long and about 2-mm-deep incision was made in the vascular sparse area of left ventricular free wall near the apex. In sham operation group, the incision was sutured directly by 7-0 Prolene suture; in cold ischemia transplantation group, after the aortic roots cross-clamping, 4 degrees C cold crystalloid perfusion fluid infusion to cardiac arrest, then sinoatrial node were cut 5 mm x 3 mm for transplantation; in warm ischemia transplantation group, the same size of the sinus node tissue was captured for transplantation. After 1, 2, 3, and 4 weeks, 3 rabbits of each group were harvested to make bradycardia by stimulating bilateral vagus nerve and the cardiac electrical activity was observed; the transplanted sinus node histology and ultrastructural changes were observed. RESULTS: Thirty-six recipient rabbits survived (12 rabbits each group). At 1, 2, 3, and 4 weeks after bilateral vagus nerve stimulation, the cardiac electrical activity in each group was significantly slower, and showed sinus bradycardia. Four weeks after operation the heart rates of sham operation group, warm ischemia, and cold ischemia transplantation group were (81.17 +/- 5.67), (82.42 +/- 7.97), and (80.83 +/- 6.95) beats/minute, respectively; showing no significant difference among groups (P > 0.05). And no ectopic rhythm of ventricular pacing occurred. Sino-atrial nodal tissue survived in 6 of warm ischemic transplantation group and in 8 of cold ischemia transplantation group; showing no significant difference between two groups (P > 0.05). Two adjacent sinoatrial node cells, vacuole-like structure in the cytoplasm, a few scattered muscle microfilaments, and gap junctions between adjacent cells were found in transplanted sinus node. CONCLUSION: The allograft sinus node can survive, but can not play a role in ectopic pacing.

Electrical connection of native and transplanted sinus nodes via atrial to atrial pacing improves exercise performance after cardiac transplantation.

Chronotropic incompetence limits exercise performance in cardiac transplant patients. Electrical linkage of the innervated native sinus node and the denervated donor atrium or direct donor atrium pacing improves exercise performance in patients early after transplant.

Development of cardiac beat rate in early chick embryos is regulated by regional cues.

The mesoderm of each of the paired lateral heart-forming regions (HFRs) in the stage 5-7 chick embryo includes prospective conus (pre-C), ventricle (pre-V), and sinoatrial (pre-SA) cells, arranged in a rostrocaudal sequence (C-V-SA). With microsurgery we divided each HFR into three rostrocaudally arranged segments. After 24 hr of further incubation, each segment differentiated into a spontaneously beating vesicle of heart tissue to form a multiheart embryo. The cardiac vesicles in these embryos expressed left-right and rostrocaudal beat rate gradients: the left caudal pre-SA mesoderm produced tissue with the fastest beat rate of the six while the rostral vesicle formed from right pre-C was the slowest. In another operation, we prevented the HFRs from fusing in the midline by cutting through the anterior intestinal portal at stage 8, to produce cardia bifida (CB) embryos with an independently beating half-heart on each side. In these cases, the left half-heart of 87.2% of CB embryos beat faster than the right, confirming the left-right difference in intrinsic beat rate. To assess whether the future beat rate of each region is already determined in the st 5-7 HFR, we exchanged rectangular fragments of left pre-SA mesoderm and attached endoderm with right pre-C fragments to yield a left HFR with the sequence C-V-C and a right HFR with the sequence SA-V-SA. A CB operation was subsequently performed on these exchange embryos to prevent fusion of the lateral HFRs. Preconus mesoderm, transplanted to the pre-SA region, differentiated into tissue with a rapid beat rate, while pre-SA mesoderm relocated to the preconus region formed heart tissue with a slow spontaneous rate typical of the conus. In 73% of the exchange CB embryos, the left half-heart beat faster than the right, despite the origins of its mesoderm. The exchanged mesoderm developed a rate that was appropriate for its new location rather than the site of origin of the mesodermal fragment. In a third set of operations, we implanted a fragment of st 15 differentiated conus tissue into a site lateral to the left caudal HFR in st 5, 6, and 7 embryos, and subsequently performed CB operations on them. The implant caused the adjacent half-heart to develop with a slower beat rate than in unoperated or sham-operated controls.(ABSTRACT TRUNCATED AT 400 WORDS)

Myocyte transplantation for treatment of complete heart block.

We hypothesize that it may be possible to treat complete heart block by transplanting right atrial myocytes directly into the ventricular wall where they may set the rate of ventricular contraction at their own intrinsic rate. The biologic background for this conjecture has already been determined to a large extent. However, a few critical unanswered biologic questions must be addressed before the development of this suggested new therapy becomes a mere technologic exercise.