Myocardial function with reduced expression of the sodium-calcium exchanger

J Card Fail. 2010 Sep;16(9):786-96. doi: 10.1016/j.cardfail.2010.03.012. Epub 2010 May 14.

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.

Methods and 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / administration & dosage
  • Adrenergic beta-Agonists / therapeutic use
  • Analysis of Variance
  • Animals
  • Aorta / pathology
  • Cardiac Output
  • Disease Models, Animal
  • Heart Failure / diagnostic imaging
  • Heart Failure / pathology*
  • Hemodynamics
  • Isoproterenol / administration & dosage
  • Isoproterenol / therapeutic use
  • Mice
  • Mice, Knockout
  • Models, Cardiovascular
  • Myocardium / cytology*
  • Myocardium / pathology
  • Sodium-Calcium Exchanger / biosynthesis*
  • Sodium-Calcium Exchanger / drug effects
  • Ultrasonography

Substances

  • Adrenergic beta-Agonists
  • Sodium-Calcium Exchanger
  • Isoproterenol