Xanthine oxidase inhibition preserves left ventricular systolic but not diastolic function in cardiac volume overload

Academic Article

Abstract

  • Xanthine oxidase (XO) is increased in human and rat left ventricular (LV) myocytes with volume overload (VO) of mitral regurgitation and aortocaval fistula (ACF). In the setting of increased ATP demand, XO-mediated ROS can decrease mitochondrial respiration and contractile function. Thus, we tested the hypothesis that XO inhibition improves cardiomyocyte bioenergetics and LV function in chronic ACF in the rat. Sprague-Dawley rats were randomized to either sham or ACF ± allopurinol (100 mg·kg-1·day-1, n ≥7 rats/group). Echocardiography at 8 wk demonstrated a similar 37% increase in LV end-diastolic dimension (P < 0.001), a twofold increase in LV end-diastolic pressure/wall stress (P < 0.05), and a twofold increase in lung weight (P < 0.05) in treated and untreated ACF groups versus the sham group. LV ejection fraction, velocity of circumferential shortening, maximal systolic elastance, and contractile efficiency were significantly depressed in ACF and significantly improved in ACF + allopurinol rats, all of which occurred in the absence of changes in the maximum O2 consumption rate measured in isolated cardiomyocytes using the extracellular flux analyzer. However, the improvement in contractile function is not paralleled by any attenuation in LV dilatation, LV end-diastolic pressure/wall stress, and lung weight. In conclusion, allopurinol improves LV contractile function and efficiency possibly by diminishing the known XO-mediated ROS effects on myofilament Ca2+ sensitivity. However, LV remodeling and diastolic properties are not improved, which may explain the failure of XO inhibition to improve symptoms and hospitalizations in patients with severe heart failure.
  • Digital Object Identifier (doi)

    Author List

  • Gladden JD; Zelickson BR; Guichard JL; Ahmed MI; Yancey DM; Ballinger S; Shanmugam M; Babu GJ; Johnson MS; Darley-Usmar V
  • Volume

  • 305
  • Issue

  • 10