-Original-

Effect of Gonadectomy and Angiotensin II Receptor Blockade in a Mouse Model of Isoproterenol-induced Cardiac Diastolic Dysfunction

Kuniya Asai¹, Koji Murai², Akihiro Shirakabe¹, Masataka Kamiya², Satsuki Noma², Naoki Sato², Kyoichi Mizuno³ and Wataru Shimizu²

¹Intensive Care Unit, Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan
²Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan
³Mitsukoshi Health and Welfare Foundation, Tokyo, Japan

Background: Although heart failure (HF) with preserved ejection fraction (HFpEF) is more common in postmenopausal women than in men, the effect of sex hormones on cardiac diastolic function remains unclear. We examined the effect of gonadectomy with or without the angiotensin receptor blocker olmesartan (Olm) in an isoproterenol (ISO)-induced mouse model of left ventricular hypertrophy (LVH) and cardiac diastolic dysfunction.
Methods: ISO or ISO with Olm were administered for 28 days in sham-operated male and female, castrated (CAS), and ovariectomized (OVX) mice. LV ejection fraction (EF) and E/A ratio were analyzed by echocardiography, and the LV and lung weight corrected by tibial length were used as indices of LVH and lung congestion, respectively.
Results: On echocardiography, systolic function did not differ between the four groups. LV/tibial length (TL) and Lung/TL significantly increased in all groups. The LV/TL ratio was lower in castrated-ISO vs. Male-Sham-ISO but did not differ between Female-Sham-ISO and OVX-ISO. However, the Lung/TL ratio of OVX-ISO was greater than that of Female-Sham-ISO. Olm prevented LV hypertrophy in all groups. The decrease in E/A and increase in lung weight were improved by Olm in Male-Sham and OVX-ISO but not in the other groups.
Conclusion: These sex differences suggest that sex hormones play a pivotal role in modulating cardiac hypertrophy and diastolic dysfunction induced by chronic β-adrenoceptor stimulation, and thus affect the therapeutic potential of angiotensin receptor blockade.

J Nippon Med Sch 2021; 88: 113-120

Keywords
left ventricular hypertrophy, heart failure, postmenopause, angiotensin receptors, gonadal steroid hormones

Correspondence to
Kuniya Asai, MD, PhD, Intensive Care Unit, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamagari, Inzai, Chiba 270-1694, Japan
kasai@nms.ac.jp

Received, February 17, 2020
Accepted, April 20, 2020