title: Increased sarcolipin expression and adrenergic drive in humans with preserved left ventricular ejection fraction and chronic isolated mitral regurgitation.
abstract: BACKGROUND
  There is currently no therapy proven to attenuate left ventricular (LV) dilatation and dysfunction in volume overload induced by isolated mitral regurgitation (MR). To better understand molecular signatures underlying isolated MR, we performed LV gene expression analyses and overlaid regulated genes into ingenuity pathway analysis in patients with isolated MR.
  
  
  RESULTS
  Gene arrays from LV tissue of 35 patients, taken at the time of surgical repair for isolated MR, were compared with 13 normal controls. Cine-MRI was performed in 31 patients before surgery to measure LV function and volume from serial short-axis summation. LV end-diastolic volume was 2-fold (P=0.005) higher in MR patients than in normal controls, and LV ejection fraction was 64±7% (50%-79%) in MR patients. Ingenuity pathway analysis identified significant activation of pathways involved in β-adrenergic, cAMP, and G-protein-coupled signaling, whereas there was downregulation of pathways associated with complement activation and acute phase response. SERCA2a and phospholamban protein were unchanged in MR versus control left ventricles. However, mRNA and protein levels of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) regulatory protein sarcolipin, which is predominantly expressed in normal atria, were increased 12- and 6-fold, respectively. Immunofluorescence analysis confirmed the absence of sarcolipin in normal left ventricles and its marked upregulation in MR left ventricles.
  
  
  CONCLUSIONS
  These results demonstrate alterations in multiple pathways associated with β-adrenergic signaling and sarcolipin in the left ventricles of patients with isolated MR and LV ejection fraction>50%, suggesting a beneficial role for β-adrenergic blockade in isolated MR.
authors.affiliation: Birmingham Veteran Affairs Medical Center.
authors.forename: Junying
authors.initials: J
authors.lastname: Zheng
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Yancey
authors.forename: Mustafa I
authors.initials: MI
authors.lastname: Ahmed
authors.forename: Chih-Chang
authors.initials: CC
authors.lastname: Wei
authors.forename: Pamela C
authors.initials: PC
authors.lastname: Powell
authors.forename: Mayilvahanan
authors.initials: M
authors.lastname: Shanmugam
authors.forename: Himanshu
authors.initials: H
authors.lastname: Gupta
authors.forename: Steven G
authors.initials: SG
authors.lastname: Lloyd
authors.forename: David C
authors.initials: DC
authors.lastname: McGiffin
authors.forename: Chun G
authors.initials: CG
authors.lastname: Schiros
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Denney
authors.forename: Gopal J
authors.initials: GJ
authors.lastname: Babu
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'Italia
mesh_terms: D018663:Adrenergic Agents / Q000378:metabolism*; D000328:Adult; D000368:Aged; D001706:Biopsy; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008944:Mitral Valve Insufficiency / Q000378:metabolism* / Q000503:physiopathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D011510:Proteolipids / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013318:Stroke Volume / Q000502:physiology*; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D018663:Adrenergic Agents; D009124:Muscle Proteins; D011510:Proteolipids; C077258:sarcolipin
keywords: heart ventricles; mitral valve insufficiency