title: Effects of left ventricular volume overload on mitochondrial and death-receptor-mediated apoptotic pathways in the transition to heart failure.
abstract: Cardiomyocyte apoptosis has been implicated in the pathogenesis of heart failure (HF). This study was performed in patients with left ventricular (LV) volume overload at different stages in the development of HF to correlate apoptotic gene expression with LV echocardiographic phenotype. LV biopsies were procured from 24 cardiac surgical patients selected from 4 distinct clinical groups (n = 6) in the progression from preserved LV function to HF. Group I consisted of control patients with normal LV function (e.g., with atrial myxoma), group II had aortic regurgitation with LV hypertrophy and preserved systolic function (ejection fraction >50%), group III had aortic regurgitation with LV dysfunction (ejection fraction 30% to 40%), and group IV had end-stage HF (ejection fraction <20%). Biopsies were used to measure mRNA expression of the genetic regulators of mitochondrial (Bad, Bax, Bcl-2, Bcl-xL, and p53) and death-receptor- (Fas and tumor necrosis factor receptor 1 [TNFR1]) mediated apoptotic pathways by reverse transcription-polymerase chain reaction. Caspase activity was determined using specific fluorogenic peptide substrates and immunohistochemistry. Evidence for apoptosis was obtained using terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling and in situ oligo ligation assays. Expression of proapoptotic factors (Bax, p53, TNFR1), antiapoptotic mitochondrial factor (Bcl-xL), and caspases 3, 8, and 9 increased progressively during the transition from preserved LV function to HF (p <0.05, analysis of variance). No significant difference was found for Bad, Bcl-2, or Fas. No evidence of DNA fragmentation was identified. In conclusion, activation of the cardiomyocyte apoptotic cascade occurs during the development of volume overload-induced HF. Mitochondrial (Bax, p53, caspase 9) and death-receptor mediated (TNFR1, caspase 8) pathways are upregulated but without completion of DNA fragmentation.
authors.affiliation: Department of Cardiothoracic Surgery, Oxford Heart Centre, John Radcliffe Hospital, Oxford, United Kingdom. narain.moorjani@doctors.org.uk
authors.forename: Narain
authors.initials: N
authors.lastname: Moorjani
authors.forename: Stephen
authors.initials: S
authors.lastname: Westaby
authors.forename: Jagat
authors.initials: J
authors.lastname: Narula
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Catarino
authors.forename: Robin
authors.initials: R
authors.lastname: Brittin
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Kemp
authors.forename: Navneet
authors.initials: N
authors.lastname: Narula
authors.forename: Peter H
authors.initials: PH
authors.lastname: Sugden
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015415:Biomarkers / Q000032:analysis; D001707:Biopsy, Needle; D002303:Cardiac Output, Low / Q000503:physiopathology*; D053938:DNA Fragmentation; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D011336:Probability; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D053218:Receptors, Death Domain / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D053218:Receptors, Death Domain; D051028:bcl-2-Associated X Protein