Hypercontractile Cardiac Phenotype in Mice with Migraine-Associated Mutation in the Na⁺,K⁺-ATPase ₂-Isoform

Two alpha-isoforms of the Na+,K+-ATPase (alpha(1) and alpha(2)) are expressed in the cardiovascular system, and it is unclear which isoform is the preferential regulator of contractility. Mice heterozygous for the familial hemiplegic migraine type 2 (FHM2) associated mutation in the alpha(2)-isoform (G301R; alpha(2)+/(G301R) mice) have decreased expression of cardiac alpha(2)-isoform but elevated expression of the alpha(1)-isoform. We aimed to investigate the contribution of the alpha(2)-isoform function to the cardiac phenotype of alpha(2) (+/G301R) hearts. We hypothesized that alpha 2(+/G301R) hearts exhibit greater contractility due to reduced expression of cardiac alpha(2)-isoform. Variables for contractility and relaxation of isolated hearts were assessed in the Langendorff system without and in the presence of ouabain (1 mu M). Atrial pacing was performed to investigate rate-dependent changes. The alpha(+/G301R)(2) hearts displayed greater contractility than WT hearts during sinus rhythm, which was rate-dependent. The inotropic effect of ouabain was more augmented in alpha(+/G301R)(2) hearts than in WT hearts during sinus rhythm and atrial pacing. In conclusion, cardiac contractility was greater in alpha(+/G301R)(2) hearts than in WT hearts under resting conditions. The inotropic effect of ouabain was rate-independent and enhanced in alpha(2) (+/G301R) hearts, which was associated with increased systolic work.