Korean Circ J.  2013 Oct;43(10):686-693. 10.4070/kcj.2013.43.10.686.

Preventive Effects of the Angiotensin-II Receptor Blocker on Atrial Remodeling in an Ischemic Heart Failure Model of Rats

• Yoon N
• Kim KH
• Park KH
• Sim DS
• Youn HJ
• Hong YJ
• Park HW
• Kim JH
• Ahn Y
• Jeong MH
• Cho JG
• Park JC

• KMID: 1826560
• DOI: http://doi.org/10.4070/kcj.2013.43.10.686

Abstract

BACKGROUND AND OBJECTIVES
It is widely known that angiotensin-II receptor blockers (ARBs) have reverse remodeling effects in atrium. Although atrial fibrillation is frequent in ischemic heart failure clinically, experiments to demonstrate ARB's effects on atrial remodeling in a heart failure model are rare.
MATERIALS AND METHODS
A heart failure model and a sham-operated group were formed in 25 Sprague-Dawley male rats of roughly 260 g in weight. Ischemic heart failure models were obtained via ligation of the left anterior descending coronary artery. In the ARB group, 30 mg/kg of losartan was administrated over a day for 4 weeks. Echocardiography was performed to measure left ventricle ejection fraction and left atrial diameter (LAD) at the baseline and 4 weeks after the operation. 4 weeks later, histologic and immunohistochemical evaluation were performed.
RESULTS
Groups were divided into the sham group, heart failure group, and heart failure-ARB group. We maintained 5 rats in each group for 4 weeks after operation. The decrease of left ventricular ejection fraction in the heart failure-ARB group was less than that in the heart failure group (p=0.023). The increase of LAD in the heart failure-ARB group was less than that in the heart failure group (p=0.025). Masson's trichrome stain revealed less fibrosis in the heart failure-ARB group. Immunohistochemical stain and western blot for connexin 43 showed less expression in the heart failure-ARB group.
CONCLUSION
In the ischemic heart failure model of rats, structurally and histologically, the ARB, losartan, has atrial reverse-remodeling effects. However, electrically, its role as an electrical stabilizer should be studied further.

Keyword

Angiotensin-II receptor blocker; Atrial remodeling; Atrial fibrillation

MeSH Terms

Animals
Angiotensin Receptor Antagonists*
Atrial Fibrillation
Azo Compounds
Blotting, Western
Connexin 43
Coronary Vessels
Echocardiography
Eosine Yellowish-(YS)
Fibrosis
Heart Failure*
Heart Ventricles
Heart
Ligation
Losartan
Male
Methyl Green
Rats*
Rats, Sprague-Dawley
Stroke Volume
Azo Compounds
Connexin 43
Eosine Yellowish-(YS)
Losartan
Methyl Green

Figure

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  Fig. 1 Echocardiography in parasternal short axis view (A) and parasternal long axis view (B).

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  Fig. 2 To induce atrial fibrillation, the burst stimulation at a frequency of 25 millisecond intervals was performed during 35 seconds each in the rats.

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  Fig. 3 Serial change of body weight (A), left ventricular ejection fraction (B), left atrial diameter (C). ARB: angiotensin-II receptor blocker, LVEF: left ventricular ejection fraction, LAD: left atrial diameter, ICM: ischemic cardiomyopathy, Wt: weight.

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  Fig. 4 Photography after formalin fixation, gross view of hematoxylin eosin stain, gross view of Masson's trichrome stain, and Masson's trichrome stain of left atrial appendage (×20) (from top to bottom, A: heart failure-ARB, B: heart failure, C: Sham). Gross size of the heart failure model was larger than that of the sham model. The whitish areas in the left ventricle are found in infarcted areas (A and B). Ventricular enlargement and wall thinning in infarcted areas were found in the gross findings of H&E stain (A and B). Fibrosis was found in the gross finding of Masson's trichrome stain (A and B). ARB: angiotensin-II receptor blocker, H&E: hematoxylin and eosin.

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  Fig. 5 Representative Masson's trichrome stain sections of the left atrium from the heart failure group (A and C) and the heart failure-ARB group (B and D). In the heart failure group, atrial myocytes showed a loss of some contractile materials and abnormal sarcomeres. In addition, extensive interstitial fibrosis, evidenced by Masson's trichrome stain, was observed. Thick blue colored fibrosis is seen in the heart failure group (A and C). Thick layers of fibrous tissue were observed in the endocardium and epicardium (C). Furthermore, the amount of connective tissue was increased, and this extended around the parenchymal cells. In the heart failure-ARB group, interstitial fibrosis was attenuated. Magnification: ×400 (A and B), ×200 (C and D). The bar graph shows that fibrosis in the heart failure-ARB group was less than that in the heart failure group (E). ARB: angiotensin-II receptor blocker.

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  Fig. 6 Even distribution of connexin 43 protein on the intercalated disc was observed in the sham group (A: magnification: ×400). Connexin 43 protein stain was not observed on the intercalated disc in the heart failure group (B: magnification: ×400). A slight connexin 43 protein stain was observed on the intercalated disc in the heart failure-ARB group (C: magnification: ×400). Western blot of connexin 43 protein showed a lower expression in the heart failure-ARB group (D). ARB: angiotensin-II receptor blocker.

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