Failing human hearts demonstrated increased sensitivity to ouabain, associated with a 42% reduction (95% CI 26-56%) in Na/K-ATPase concentration compared to non-failing hearts.
Effect estimate: 42% reduction (95% CI 26-56)
Absolute Event Rate: 293% vs 507%
p-value: p=<0.001
OBJECTIVE: The aim was to determine whether failing human hearts have increased sensitivity to the inotropic and toxic effects of ouabain, and to examine alterations in Na/K-ATPase that might explain the observed higher ouabain sensitivity. METHODS: For contractility studies, a total of 57 trabeculae were isolated from two non-failing (death from head injury) and 10 terminally failing, explanted human hearts. After the experiment, each trabecula was inspected under the light microscope for morphological alterations consistent with heart failure. Samples for biochemical and molecular studies were obtained from five non-failing and 13 failing hearts. Total Na/K-ATPase was measured in desoxycholate treated homogenates and expressed per unit of tissue wet or dry weight, DNA, protein, or myosin. Interference from residual bound digoxin due to previous therapy was excluded. The expression of the three alpha isoforms was studied at both the mRNA level using northern blots and the protein level by analysis of dissociation kinetics of the 3Houabain-enzyme complex. RESULTS: Trabeculae showing morphological alterations and decreased contractility were sensitive to lower concentrations of ouabain (3-100 nM) than control trabeculae (100-1000 nM); the inotropic EC50 and the minimum toxic concentration were both reduced. 3HOuabain binding was significantly lower (p << 0.001) in failing than in non-failing hearts, at 293(SD 74) v 507(48) pmol.g-1 wet weight. No significant change was observed in maximum ATPase turnover rate, or in sensitivities to Na+, K+, vanadate, and dihydro-ouabain. All three alpha isoforms were expressed at the mRNA level in both normal and failing hearts. CONCLUSIONS: This study shows conclusively, for the first time, that failing human hearts are more sensitive to ouabain. This may be at least partly due to a mean reduction of 42% (95% confidence interval, 26 to 56%) in the concentration of Na/K-ATPase (decrease in Na,K pump reserve), but not to an alteration in its catalytic properties or in its isoform composition.
Shamraj et al. (Wed,) conducted a other in Heart failure (n=18). Heart failure vs. Non-failing hearts was evaluated on [3H]Ouabain binding (pmol/g wet weight) (42% reduction, 95% CI 26-56, p=<0.001). Failing human hearts demonstrated increased sensitivity to ouabain, associated with a 42% reduction (95% CI 26-56%) in Na/K-ATPase concentration compared to non-failing hearts.