Therapeutic Effect of Fimasartan in a Rat Model of Myocardial Infarction Evaluated by Cardiac Positron Emission Tomography with [18F]FPTP.

Original Article www.cmj.ac.kr Therapeutic Effect of Fimasartan in a Rat Model of Myocardial Infarction Evaluated by Cardiac Positron Emission Tomography with [18F]FPTP Hyukjin Park1,† , Hyeon Sik Kim2,† , Young Joon Hong1,*, Jung-Joon Min3,*, Han Byul Kim1, 1 1 1 3 4 1 Min Chul Kim , Doo Sun Sim , Ju Han Kim , Dong-Yeon Kim , Jae Sung Lee , Youngkeun Ahn , and Myung Ho Jeong1 1 Division of Cardiology, Chonnam National University Hospital, Gwangju, 2Institute for Biomedical Science, Chonnam National University 3 4 Hwasun Hospital, Department of Nuclear Medicine, Chonnam National University Hwasun Hospital, Hwasun, Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Korea We evaluated the efficacy of fimasartan on perfusion defects and infarction size in an animal model of myocardial infarction (MI), with echocardiography and positron emis18 18 sion tomography (PET) using a F-labeled phosphonium cation (5-[ F]-fluoropentyl18 triphenylphosphonium salt, [ F]FPTP) as a mitochondrial voltage sensor for myocardial imaging. We induced MI in 33 rats by ligation of the left coronary artery, and 18 checked their cardiac PET image using [ F]FPTP for evaluation of myocardial perfusion. Rats were grouped into 3 groups according to their administered drugs: no drug (n=11), fimasartan 3 mg/kg (n=10), and fimasartan 10 mg/kg (n=12). Each designated drug was administered for 4 weeks, and follow-up PET and histologic examinations were done. In the PET analysis, a perfusion defect size was markedly improved in fimasartan 10 mg/kg group (35.9±7.0% to 28.4±6.9%, p<0.001), whereas treatment with fimasartan 3 mg/kg induced only an insignificant reduction of perfusion defect size (35.9±7.9% to 33.9±7.3%, p=0.095). Using 2, 3, 5-triphenyltetrazolium chloride staining, infarction size was the largest in the control group (36.5±8.3%), and was insignificantly lower in the fimasartan 3 mg/kg group (31.5±6.5%, p for the difference between the control group=0.146) and was significantly lower in the fimasartan 10 mg/kg group (26.3±7.6%, p for the difference between the control group=0.011). PET imaging using 18 18 a F-labeled mitochondrial voltage sensor, [ F]FPTP, is useful in evaluation and monitoring of myocardial perfusion states, and treatment with fimasartan decreases the infarction size in animal MI model. Key Words: Myocardial Infarction; Positron Emission Tomography; Angiotensin Receptor Antagonists This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Corresponding Author: Young Joon Hong Division of Cardiology, Cardiovascular Convergence Research Center Nominated by Korea Ministry of Health and Welfare, Chonnam National University Hospital, 42 Jaebong-ro, Dong-gu, Gwangju 61469, Korea Tel: +82-62-220-6978 Fax: +82-62-223-3105 E-mail: Jung-Joon Min Department of Nuclear Medicine, Chonnam National University Hwasun Hospital, 322 Seoyang-ro, Hwasun-eup, Hwasun 58128, Korea Tel: +82-61-379-2876 E-mail: † These authors contributed equally to this work. fect cannot be easily restored and therefore, is not always indicated for revascularization. Therefore, the extent of viable myocardium is important for recovery of cardiac function and prognosis. To detect myocardial activity and evaluate the viability of myocardium, various imaging modalities, such as echocardiography, cardiac magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET) have been used, INTRODUCTION Not all affected myocardial tissue is irreversibly damaged during acute myocardial infarction (MI). Dysfunctional myocardial tissue occurring during acute MI consists of necrotic, hibernating, or stunned myocardial cells, and the viable (hibernating or stunned) tissue can be salvaged by revascularization.1 On the other hand, totally infarcted myocardial tissue, with prolonged and fixed perfusion de- https://doi.org/10.4068/cmj.2019.55.2.109 Ⓒ Chonnam Medical Journal, 2019 Article History: Received January 23, 2019 Revised March 13, 2019 Accepted April 2, 2019 109 Chonnam Med J 2019;55:109-115 Fimasartan in Myocardial Infarction Model but each modality has its limitations: echocardiography is highly dependent on the echocardiographic windows and cutting plane, MRI cannot easily distinguish between epicardial fat layers and the myocardium and have limitations in evaluating myocardial perfusion, SPECT has low spatial resolution, and an unintended spread of the SPECT tracers to adjacent organs may compromise accurate diagnosis.2 PET is known to provide more accurate and highly qualified images due to its higher spatial resolution, and may enable quantitative measurements of myocardial tracer uptake.3 In particular, our group previously proposed the value of 18F-labeled phosphonium cations as myocardial imaging agents that accumulate in cardiomyocytes as a result of the higher mitochondrial membrane potential (MMP), and our group reported that [18F]FPTP provided excellent image quality when compared with [13N]NH3 in normal and MI rats.2,4,5 18F-labeled phosphonium cations accurately evaluated the size of MI early after tracer injection, and yielded excellent image quality in a rat model of coronary occlusion.5 As the renin-angiotensin-aldosterone system (RAAS) plays an important role in tissue fibrosis, cardiac remodeling, fluid and sodium accumulation, and inflammation, the blockade of RAAS has been a standard therapy in both heart failure and MI.6 Fimasartan, a selective type 1 angiotensin II (AT1) receptor blocker, has shown good tolerability and blood pressure-lowering effect for hypertension7,8 and has shown efficacy in rat doxorubicin-induced cardiotoxicity models.9 However, to date, its efficacy in MI has not been well demonstrated, only conflicting results exist,10,11 and no study has examined its efficacy in cardiac PET using 18F-labeled phosphonium cations yet. We aimed both to verify anti-adverse remodeling effect of fimasartan, and also to evaluate the efficacy of cardiac PET using a 18F-labeled phosphonium cation, (5-[18F]fluoropentyl)triphenylphosphonium salt ([18F]FPTP), in measuring area of perfusion defect in rat MI model after the MI event and after medical treatment. MATERIALS AND METHODS 1. MI induction and imaging studies All procedures were performed in accordance with 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Induction of MI and breeding were conducted at the animal laboratory of Chonnam National University Hospital, Gwangju, South Korea. The study protocol was approved by the Institutional Review Board at Chonnam National University Hospital. The study protocol is illustrated in Fig. 1. Eight-week old male Sprague-Dawley rat (...truncated)