Extracorporeal shock wave treatment attenuated left ventricular dysfunction and remodeling in mini-pig with cardiorenal syndrome

Jiunn-Jye Sheu; Hani E E Ali; Ben-Chung Cheng; Hsin-Ju Chiang; Pei-Hsun Sung; Kuan-Hung Chen; Chih-Chao Yang; Yen-Ta Chen; John Y Chiang; Pao-Yuan Lin; Sarah Chua; Han-Tan Chai; Sheng-Ying Chung; Cheuk-Kwan Sun; Hon-Kan Yip

doi:10.18632/oncotarget.18287

Extracorporeal shock wave treatment attenuated left ventricular dysfunction and remodeling in mini-pig with cardiorenal syndrome

Oncotarget. 2017 May 30;8(33):54747-54763. doi: 10.18632/oncotarget.18287. eCollection 2017 Aug 15.

Authors

Jiunn-Jye Sheu¹, Hani E E Ali¹, Ben-Chung Cheng², Hsin-Ju Chiang³, Pei-Hsun Sung⁴, Kuan-Hung Chen⁵, Chih-Chao Yang², Yen-Ta Chen⁶, John Y Chiang⁷, Pao-Yuan Lin⁸, Sarah Chua⁴, Han-Tan Chai⁴, Sheng-Ying Chung⁴, Cheuk-Kwan Sun⁹, Hon-Kan Yip^{4

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Affiliations

¹ Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
² Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
³ Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁴ Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁵ Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁶ Division of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁷ Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan.
⁸ Department of Plastic and Reconstructive Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁹ Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan.
¹⁰ Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
¹¹ Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
¹² Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
¹³ Department of Nursing, Asia University, Taichung, Taiwan.

Abstract

This study tested the hypothesis that extracorporeal shock wave (ECSW) treatment can improve ischemia-induced left ventricular (LV) dysfunction in mini-pig with co-existing chronic kidney disease (CKD). LV ischemia in mini-pigs was induced by applying an ameroid constrictor over mid-left anterior descending artery (LAD), while model of CKD was established by right nephrectomy with partial ligation of left renal arterioles 2 weeks before LAD constriction. Thirty mini-pigs were randomly divided into group 1 (sham-control), group 2 (LV-ischemia), group 3 (LV-ischemia + CKD), Group 4 [LV-ischemia + ECSW (applied 1200 shots at 0.1 mJ/m²/equally to 4-ischemic regions by day-90 after LAD constriction], and group 5 (LV-ischemia-CKD + ECSW). By day-180 after CKD induction, echocardiography showed that LV ejection fraction (LVEF) was highest in group 1, lowest in group 3, significantly lower in group 2 than that in groups 4 and 5, and significantly lower in group 5 than that in group 4, whereas LV-end systolic and diastolic dimensions displayed an opposite pattern (all p<0.001). Protein expressions of oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptotic (cleaved-caspase-3/cleaved-PARP/mitochondrial-Bax), fibrotic (TGF-β/Smad3), pressure/volume-overload (BNP/β-MHC), endothelial (CD31/vWF) and mitochondrial-integrity (PGC-1/mitochondrial-cytochrome-C) biomarkers exhibited a pattern identical to that of LVEF, whereas angiogenesis factors (VEGF/CXCR4/SDF-1α) showed significant progressive increase among all groups (all p<0.0001). Microscopic findings of CD31+cells/vWF+cells/small-vessel density/sarcomere-length showed an identical pattern, whereas collagen-deposition area/fibrotic area/apoptotic nuclei expressed an opposite pattern compared to that of LVEF among all groups (all p<0.0001). In conclusion, CKD aggravated ischemia-induced LV dysfunction and remodeling and molecular-cellular perturbations that were reversed by ECSW treatment.

Keywords: LV remodeling; angiogenesis; cardiorenal syndrome; extracorporeal shock wave; myocardial ischemia.