title: Mitochondrial apoptotic pathway activation in the atria of heart failure patients due to mitral and tricuspid regurgitation.
abstract: Apoptosis occurs in atrial cardiomyocytes in mitral and tricuspid valve disease. The purpose of this study was to examine the respective roles of the mitochondrial and tumor necrosis factor-α receptor associated death domain (TRADD)-mediated death receptor pathways for apoptosis in the atrial cardiomyocytes of heart failure patients due to severe mitral and moderate-to-severe tricuspid regurgitation. This study comprised eighteen patients (7 patients with persistent atrial fibrillation and 11 in sinus rhythm). Atrial appendage tissues were obtained during surgery. Three purchased normal human left atrial tissues served as normal controls. Moderately-to-severely myolytic cardiomyocytes comprised 59.7±22.1% of the cardiomyocytes in the right atria and 52.4±12.9% of the cardiomyocytes in the left atria of mitral and tricuspid regurgitation patients with atrial fibrillation group and comprised 58.4±24.8% of the cardiomyocytes in the right atria of mitral and tricuspid regurgitation patients with sinus rhythm. In contrast, no myolysis was observed in the normal human adult left atrial tissue samples. Immunohistochemical analysis showed expression of cleaved caspase-9, an effector of the mitochondrial pathways, in the majority of right atrial cardiomyocytes (87.3±10.0%) of mitral and tricuspid regurgitation patients with sinus rhythm, and right atrial cardiomyocytes (90.6±31.4%) and left atrial cardiomyocytes (70.7±22.0%) of mitral and tricuspid regurgitation patients with atrial fibrillation. In contrast, only 5.7% of cardiomyocytes of the normal left atrial tissues showed strongly positive expression of cleaved caspase-9. Of note, none of the atrial cardiomyocytes in right atrial tissue in sinus rhythm and in the fibrillating right and left atria of mitral and tricuspid regurgitation patients, and in the normal human adult left atrial tissue samples showed cleaved caspase-8 expression, which is a downstream effector of TRADD of the death receptor pathway. Immunoblotting of atrial extracts showed that there was enhanced expression of cytosolic cytochrome c, an effector of the mitochondrial pathways, but no expression of membrane TRADD and cytosolic caspase-8 in the right atrial tissue of mitral and tricuspid regurgitation patients with sinus rhythm, and right atrial and left atrial tissues of mitral and tricuspid regurgitation patients with atrial fibrillation. Taken together, this study showed that mitochondrial pathway for apoptosis was activated in the right atria in sinus rhythm and in the left and right atria in atrial fibrillation of heart failure patients due to mitral and tricuspid regurgitation, and this mitochondrial pathway activation may contribute to atrial contractile dysfunction and enlargement in this clinical setting.
authors.affiliation: Division of Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan.
authors.forename: Jen-Ping
authors.initials: JP
authors.lastname: Chang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan. Electronic address: chenmien@ms76.hinet.net.
authors.forename: Mien-Cheng
authors.initials: MC
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan.
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Liu
authors.affiliation: Division of Cardiology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Yao-Kuang
authors.initials: YK
authors.lastname: Huang
authors.affiliation: Division of Cardiology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Kuo-Li
authors.initials: KL
authors.lastname: Pan
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan.
authors.forename: Wan-Chun
authors.initials: WC
authors.lastname: Ho
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan.
authors.forename: Chih-Yuan
authors.initials: CY
authors.lastname: Fang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan.
authors.forename: Chien-Jen
authors.initials: CJ
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan.
authors.forename: Huang-Chung
authors.initials: HC
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D001281:Atrial Fibrillation / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006325:Heart Atria / Q000473:pathology*; D006333:Heart Failure / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D008944:Mitral Valve Insufficiency / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D053199:TNF Receptor-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism; D014262:Tricuspid Valve Insufficiency / Q000503:physiopathology*
chemical_list: D053199:TNF Receptor-Associated Death Domain Protein; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9
keywords: Apoptosis; Atrium; Mitral insufficiency; Myocytes; Tricuspid insufficiency