title: Myocardial function with reduced expression of the sodium-calcium exchanger.
abstract: BACKGROUND
  The complete removal of the cardiac sodium-calcium exchanger (NCX1) is associated with embryonic lethality, whereas its overexpression is linked to heart failure. To determine whether or not a reduced expression of NCX1 is compatible with normal heart structure and function, we studied 2 knockout (KO) mouse models with reduced levels of NCX1: a heterozygous global KO (HG-KO) with a 50% level of NCX1 expression in all myocytes, and a ventricular-specific KO (V-KO) with NCX1 expression in only 10% to 20% of the myocytes.
  
  
  RESULTS
  Both groups of mice were evaluated at baseline, after transaortic constriction (TAC), and after acute or chronic beta-adrenergic stimulation. At baseline, the HG-KO mice had smaller hearts and the V-KO mice had larger hearts than their wild-type (WT) controls (P < .05). The HG-KO and their control WT mice had normal responses to TAC and beta-adrenergic stimulation. However, the V-KO group was intolerant to TAC and had a significantly (P < .05) blunted response to beta-adrenergic stimulation as compared with the HG-KO mice and WT controls. Unlike the HG-KO mice, the V-KO mice did not tolerate chronic isoproterenol infusion. Telemetric analysis of the electrocardiogram, body temperature, and activity revealed a normal diurnal rhythm in all groups of mice, but confirmed shorter QT intervals along with increased arrhythmias and reduced R wave to P wave amplitude ratios in the V-KO mice.
  
  
  CONCLUSIONS
  Though NCX1 can be reduced by half in all myocytes without significant functional alterations, it must be expressed in more than 20% of the myocytes to prevent severe remodeling and heart failure in mouse heart.
authors.affiliation: Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. mjordan@mednet.ucla.edu
authors.forename: Maria C
authors.initials: MC
authors.lastname: Jordan
authors.forename: Scott A
authors.initials: SA
authors.lastname: Henderson
authors.forename: Tieyan
authors.initials: T
authors.lastname: Han
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Philipson
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Roos
mesh_terms: D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000473:pathology; D002302:Cardiac Output; D004195:Disease Models, Animal; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000473:pathology*; D006439:Hemodynamics; D007545:Isoproterenol / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009206:Myocardium / Q000166:cytology* / Q000473:pathology; D019831:Sodium-Calcium Exchanger / Q000096:biosynthesis* / Q000187:drug effects; D014463:Ultrasonography
chemical_list: D000318:Adrenergic beta-Agonists; D019831:Sodium-Calcium Exchanger; D007545:Isoproterenol
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