title: Increased myocardial gene expression of tumor necrosis factor-alpha and nitric oxide synthase-2: a potential mechanism for depressed myocardial function in hibernating myocardium in humans.
abstract: BACKGROUND
  Whether cardioinhibitory cytokines are elevated in regions of hibernating myocardium and account in part for the depression in resting function is currently not known. Methods and Results- Thirteen patients with stable ischemic ventricular dysfunction scheduled for bypass surgery underwent preoperative dobutamine echocardiography (DE) and intraoperative myocardial biopsies. The numbers of copies of mRNA for the negatively inotropic cytokines tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (NOS2) were quantified by reverse transcription-polymerase chain reaction. In normal segments, myocardial TNF-alpha was barely detectable (1.2+/-0.4 copies per 10(6) copies of beta-actin). A 13.7-fold increase in myocardial TNF-alpha was observed in dysfunctional segments with a biphasic response to DE (contractile reserve and ischemia) and was highest (45.5-fold) in segments with ischemia and without contractile reserve (P<0.001). A similar graded increase was seen for NOS2. Cytokine results were also similar if analysis was performed using recovery of function at 3 months as the index of viability. The change in serum TNF-alpha and nitrite levels from baseline to 3 months after surgery correlated inversely with both the change in ejection fraction and the number of DE viable segments (r=-0.92 to -0.93; P<0.001).
  
  
  CONCLUSIONS
  TNF-alpha and NOS2 gene expression is regionally upregulated in hibernating myocardium to a level intermediate between that of normal regions and ischemic regions without contractile reserve. This, along with a decline in serum cytokine levels after revascularization proportional to the extent of myocardial viability, suggests a contributing role for cardioinhibitory cytokines in the observed depression of function seen in hibernating myocardium.
authors.affiliation: Section of Cardiology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Dinesh K
authors.initials: DK
authors.lastname: Kalra
authors.forename: Xi
authors.initials: X
authors.lastname: Zhu
authors.forename: Mahesh K
authors.initials: MK
authors.lastname: Ramchandani
authors.forename: Gerald
authors.initials: G
authors.lastname: Lawrie
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reardon
authors.forename: Dorellyn
authors.initials: D
authors.lastname: Lee-Jackson
authors.forename: William L
authors.initials: WL
authors.lastname: Winters
authors.forename: Natarajan
authors.initials: N
authors.lastname: Sivasubramanian
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
authors.forename: William A
authors.initials: WA
authors.lastname: Zoghbi
mesh_terms: D005260:Female; D006321:Heart / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D017682:Myocardial Stunning / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D012333:RNA, Messenger / Q000096:biosynthesis; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000503:physiopathology
chemical_list: D009573:Nitrites; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D014409:Tumor Necrosis Factor-alpha; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II