Korean Circ J.  2016 May;46(3):335-342. 10.4070/kcj.2016.46.3.335.

Effects of Angiotensin-II Receptor Blocker on Inhibition of Thrombogenicity in a Canine Atrial Fibrillation Model

• Choi JI
• Jung JS
• Kim MK
• Sim J
• Kim JS
• Lim HE
• Park SW
• Kim YH

• KMID: 2344446
• DOI: http://doi.org/10.4070/kcj.2016.46.3.335

Abstract

BACKGROUND AND OBJECTIVES
Angiotensin-II receptor blockers (ARBs) are known to reduce the development of atrial fibrillation (AF) through reverse-remodeling. However, the effect of ARBs on thrombogenicity in AF remains unknown.
MATERIALS AND METHODS
Twelve dogs were assigned to control (n=4), ARB (candesartan cilexitil 10 mg/kg/day p.o., 12 weeks; n=4), or sham (n=4) groups. Sustained AF was induced by rapid atrial pacing. Both arterial and venous serum levels of tissue inhibitor of matrix metalloproteinase-1, von Willebrand factor, P-selectin, and vascular cell adhesion molecule-1 (VCAM-1) were measured at baseline and during AF (0, 4, and 12 weeks) with enzyme-linked immunosorbent assay. Biopsies from both atria including the appendages were performed to semi-quantitatively assess endocardial and myocardial fibrosis after 12 weeks.
RESULTS
The serum levels of bio-markers were not significantly different at baseline or during AF between the control and the candesartan groups. The levels were not significantly different over time, but there was a trend toward a decrease in arterial VCAM-1 from 4 to 12 weeks in the candesartan group compared to the control group. The grades of endocardial fibrosis after 12 weeks but not those of myocardial fibrosis were slightly reduced in the candesartan group compared to the control group.
CONCLUSION
This study did not show that the ARB candesartan significantly reverses thrombogenicity or fibrosis during AF. Future studies using a larger number of subjects are warranted to determine the therapeutic effect of renin-angiotensin-aldosterone system blockade on prothrombogenic processes in AF.

Keyword

Atrial fibrillation; Angiotensin II; Fibrosis; Biological markers; Thromboembolism

MeSH Terms

Angiotensin II
Animals
Atrial Fibrillation*
Biomarkers
Biopsy
Dogs
Enzyme-Linked Immunosorbent Assay
Fibrosis
Matrix Metalloproteinase 1
P-Selectin
Renin-Angiotensin System
Thromboembolism
Vascular Cell Adhesion Molecule-1
von Willebrand Factor
Angiotensin II
Biomarkers
Matrix Metalloproteinase 1
P-Selectin
Vascular Cell Adhesion Molecule-1
von Willebrand Factor

Figure

• 

  Fig. 1 The procedure under thoracostomy and electrograms during device interrogation. (A) Implantation of pacemaker with a generator and a lead for rapid atrial pacing. (B) Sinus rhythm before pacing. (C) Rapid pacing in the right atrial appendage. (D) Atrial fibrillation was identified after four weeks of pacing. RAA: right atrial appendage.

• 

  Fig. 2 Study design. AF: atrial fibrillation, ECG: electrocardiogram.

• 

  Fig. 3 Serum levels of the biomarkers at 0, 4, and 12 weeks following AF onset in the control group and the candesartan group (A to D). AF: atrial fibrillation, TIMP-1: tissue inhibitor of matrix metalloproteinase-1.

• 

  Fig. 4 Representative figures of atrial fibrosis in endocardium and myocardium. Subendocardial fibrosis was evaluated with Masson-Trichrome (MT) stain, in which bright blue-colored collagen bundles were easily identified. (A) Endocardial fibrosis in sham group. Subendocardial collagen deposition was marked in the control group (B) and mild in the candesartan group (C). Myocardial fibrosis was also evaluated on MT stain. (D) Myocardiual fibrosis in sham group. Intermyositic collagen deposition was slightly increased in the control (E) and candesartan groups (F). However, there was no statistically significant difference. Original magnification×200.

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