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Temporary Suppression of Cardiac Ganglionated Plexi Leads to Long ‐ Term Suppression of Atrial Fibrillation: Evidence of Early Autonomic Intervention to Break the Vicious Cycle of “ AF Begets AF ”

View Article: PubMed Central - PubMed

ABSTRACT

Background: Botulinum toxin (BTX), temporarily suppressing cholinergic transmission (<3 weeks), has been reported to suppress atrial fibrillation (AF) for ≥1 year. We aimed to investigate the mechanism underlying long‐term suppression of AF caused by injecting BTX into major atrial ganglionated plexi (GPs).

Methods and results: Bilateral thoracotomies in anesthetized dogs allowed programmed stimulation at 4 pulmonary veins, biatrial appendages, and the superior vena cava to determine the effective refractory period (ERP) in the first operation. Group 1 (n=10) received BTX injection into all GPs; group 2 (n=7) received no injection. Groups 1 and 2 received rapid atrial pacing (800 bpm) 6 days a week. Group 3 (n=7) did not undergo thoracotomy or rapid atrial pacing to serve as controls for histological studies. A second operation and the same measurements were made 3 months later. During the first operation in group 1, ERPs of 4 pulmonary veins, but not biatrial appendages or superior vena cava, increased immediately after BTX injection. AF burdens increased significantly from the fifth week after the first operation in group 2 but not in group 1. In the second operation, ERPs remained unchanged compared with ERPs before BTX injection in group 1, whereas ERPs shortened significantly at all sites except the superior vena cava in group 2. There was no difference of autonomic nerve density between group 1 and group 3. The GP choline acetyltransferase (+) and atrial tyrosine hydroxylase (+) nerve densities were higher in group 2 than in group 1 and group 3.

Conclusions: Temporary suppression of major atrial GPs by BTX prevents autonomic remodeling and provides long‐term suppression of AF, indicating the critical role of GPs in AF progression.

No MeSH data available.


Atrial effective refractory period (ERP) of biatrial regions in the first and second operations. A and B, ERPs in group 1 and group 2 with 2X pacing threshold (TH). C and D, ERPs in group 1 and group 2 with 10X TH. After botulinum toxin (BTX) injection into 4 ganglionated plexi (GP), ERPs significantly prolonged in the right superior pulmonary vein (RSPV), right inferior pulmonary vein (RIPV), left superior pulmonary vein (LSPV), and left inferior pulmonary vein (LIPV) but remained comparable in right atrial appendage (RAA), left atrial appendage (LAA), and superior vena cava (SVC) in the first operation compared with those before BTX injection in group 1. In the second operation, ERPs returned to baseline levels at all sites in group 1, but ERPs shortened at RSPV, RIPV, RAA, LSPV, LIPV, and LAA but not SVC compared with those in the first operation in group 2. *P<0.05.
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jah31615-fig-0001: Atrial effective refractory period (ERP) of biatrial regions in the first and second operations. A and B, ERPs in group 1 and group 2 with 2X pacing threshold (TH). C and D, ERPs in group 1 and group 2 with 10X TH. After botulinum toxin (BTX) injection into 4 ganglionated plexi (GP), ERPs significantly prolonged in the right superior pulmonary vein (RSPV), right inferior pulmonary vein (RIPV), left superior pulmonary vein (LSPV), and left inferior pulmonary vein (LIPV) but remained comparable in right atrial appendage (RAA), left atrial appendage (LAA), and superior vena cava (SVC) in the first operation compared with those before BTX injection in group 1. In the second operation, ERPs returned to baseline levels at all sites in group 1, but ERPs shortened at RSPV, RIPV, RAA, LSPV, LIPV, and LAA but not SVC compared with those in the first operation in group 2. *P<0.05.

Mentions: Table 1 shows the pacing threshold before and after BTX injections in group 1. The pacing thresholds were similar at each location before and after BTX injections. In the first operation, the ERPs were checked at both 2× and 10× pacing threshold at the RSPV, RIPV, RA appendage, LSPV, LIPV, LA appendage, and SVC sites in groups 1 and 2. The baseline sinus rhythm cycle length and PR interval were similar for the 2 groups (see Table 2). Before BTX injection, the ERPs were similar for groups 1 and 2 at all sites (both 2× and 10×, Figure 1). The sinus rhythm cycle length and PR interval in group 1 were prolonged after BTX in the first procedure (Table 2). The ERPs lengthened significantly (both 2× and 10×) at RSPV (2×: 140±7 versus 148±8 ms, P<0.05; 10×: 97±6 versus 104±6 ms, P<0.05), RIPV (2×: 130±10 versus 145±9 ms, P<0.05; 10×: 85±10 versus 98±8 ms, P<0.05), LSPV (2×: 127±5 versus 133±6 ms, P<0.05, 10×: 106±6 versus 111±7 ms, P<0.05), and LIPV (2×: 131±7 versus 138±8 ms, P<005; 10×: 104±6 versus 112±7 ms, P<0.05) after BTX, compared with those before BTX in group 1 dogs. The ERPs of biatrial appendages (RAA 2×: 143±7 versus 139±8 ms, P=NS; 10×: 93±9 versus 95±7 ms, P=NS, LAA 2×: 118±7 versus 117±5 ms, P=NS; 10×: 108±7 versus 106±5 ms, P=NS) and SVC (2×: 143±7 versus 139±6 ms, P=NS; 10×: 116±5 versus 113±4, P=NS) remained unchanged after BTX compared with that without BTX in group 1 (Figure 1A).


Temporary Suppression of Cardiac Ganglionated Plexi Leads to Long ‐ Term Suppression of Atrial Fibrillation: Evidence of Early Autonomic Intervention to Break the Vicious Cycle of “ AF Begets AF ”
Atrial effective refractory period (ERP) of biatrial regions in the first and second operations. A and B, ERPs in group 1 and group 2 with 2X pacing threshold (TH). C and D, ERPs in group 1 and group 2 with 10X TH. After botulinum toxin (BTX) injection into 4 ganglionated plexi (GP), ERPs significantly prolonged in the right superior pulmonary vein (RSPV), right inferior pulmonary vein (RIPV), left superior pulmonary vein (LSPV), and left inferior pulmonary vein (LIPV) but remained comparable in right atrial appendage (RAA), left atrial appendage (LAA), and superior vena cava (SVC) in the first operation compared with those before BTX injection in group 1. In the second operation, ERPs returned to baseline levels at all sites in group 1, but ERPs shortened at RSPV, RIPV, RAA, LSPV, LIPV, and LAA but not SVC compared with those in the first operation in group 2. *P<0.05.
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jah31615-fig-0001: Atrial effective refractory period (ERP) of biatrial regions in the first and second operations. A and B, ERPs in group 1 and group 2 with 2X pacing threshold (TH). C and D, ERPs in group 1 and group 2 with 10X TH. After botulinum toxin (BTX) injection into 4 ganglionated plexi (GP), ERPs significantly prolonged in the right superior pulmonary vein (RSPV), right inferior pulmonary vein (RIPV), left superior pulmonary vein (LSPV), and left inferior pulmonary vein (LIPV) but remained comparable in right atrial appendage (RAA), left atrial appendage (LAA), and superior vena cava (SVC) in the first operation compared with those before BTX injection in group 1. In the second operation, ERPs returned to baseline levels at all sites in group 1, but ERPs shortened at RSPV, RIPV, RAA, LSPV, LIPV, and LAA but not SVC compared with those in the first operation in group 2. *P<0.05.
Mentions: Table 1 shows the pacing threshold before and after BTX injections in group 1. The pacing thresholds were similar at each location before and after BTX injections. In the first operation, the ERPs were checked at both 2× and 10× pacing threshold at the RSPV, RIPV, RA appendage, LSPV, LIPV, LA appendage, and SVC sites in groups 1 and 2. The baseline sinus rhythm cycle length and PR interval were similar for the 2 groups (see Table 2). Before BTX injection, the ERPs were similar for groups 1 and 2 at all sites (both 2× and 10×, Figure 1). The sinus rhythm cycle length and PR interval in group 1 were prolonged after BTX in the first procedure (Table 2). The ERPs lengthened significantly (both 2× and 10×) at RSPV (2×: 140±7 versus 148±8 ms, P<0.05; 10×: 97±6 versus 104±6 ms, P<0.05), RIPV (2×: 130±10 versus 145±9 ms, P<0.05; 10×: 85±10 versus 98±8 ms, P<0.05), LSPV (2×: 127±5 versus 133±6 ms, P<0.05, 10×: 106±6 versus 111±7 ms, P<0.05), and LIPV (2×: 131±7 versus 138±8 ms, P<005; 10×: 104±6 versus 112±7 ms, P<0.05) after BTX, compared with those before BTX in group 1 dogs. The ERPs of biatrial appendages (RAA 2×: 143±7 versus 139±8 ms, P=NS; 10×: 93±9 versus 95±7 ms, P=NS, LAA 2×: 118±7 versus 117±5 ms, P=NS; 10×: 108±7 versus 106±5 ms, P=NS) and SVC (2×: 143±7 versus 139±6 ms, P=NS; 10×: 116±5 versus 113±4, P=NS) remained unchanged after BTX compared with that without BTX in group 1 (Figure 1A).

View Article: PubMed Central - PubMed

ABSTRACT

Background: Botulinum toxin (BTX), temporarily suppressing cholinergic transmission (&lt;3&nbsp;weeks), has been reported to suppress atrial fibrillation (AF) for &ge;1&nbsp;year. We aimed to investigate the mechanism underlying long&#8208;term suppression of AF caused by injecting BTX into major atrial ganglionated plexi (GPs).

Methods and results: Bilateral thoracotomies in anesthetized dogs allowed programmed stimulation at 4 pulmonary veins, biatrial appendages, and the superior vena cava to determine the effective refractory period (ERP) in the first operation. Group 1 (n=10) received BTX injection into all GPs; group 2 (n=7) received no injection. Groups 1 and 2 received rapid atrial pacing (800&nbsp;bpm) 6&nbsp;days a week. Group 3 (n=7) did not undergo thoracotomy or rapid atrial pacing to serve as controls for histological studies. A second operation and the same measurements were made 3&nbsp;months later. During the first operation in group 1, ERPs of 4 pulmonary veins, but not biatrial appendages or superior vena cava, increased immediately after BTX injection. AF burdens increased significantly from the fifth week after the first operation in group 2 but not in group 1. In the second operation, ERPs remained unchanged compared with ERPs before BTX injection in group 1, whereas ERPs shortened significantly at all sites except the superior vena cava in group 2. There was no difference of autonomic nerve density between group 1 and group 3. The GP choline acetyltransferase (+) and atrial tyrosine hydroxylase (+) nerve densities were higher in group 2 than in group 1 and group 3.

Conclusions: Temporary suppression of major atrial GPs by BTX prevents autonomic remodeling and provides long&#8208;term suppression of AF, indicating the critical role of GPs in AF progression.

No MeSH data available.