GENE-EXPRESSION OF THE CARDIAC NA+-CA2+ EXCHANGER IN END-STAGE HUMAN HEART-FAILURE

The regulation of cytosolic Ca2+ concentration during excitation-contraction coupling is altered in the failing human heart. Previous studies have focused on disturbances in Cazt release and reuptake from the sarcoplasmic reticulum (SR), whereas functional studies of the cardiac Na+-Ca2+ exchanger, another important determinant of myocyte homeostasis, are lacking for the failing human heart. Using a cardiac Na+-Ca2+ exchanger cDNA recently cloned from a guinea pig cDNA library, we investigated the gene expression of the cardiac Na+-Ca2+ exchanger in relation to the SR Ca2+ ATPase. Expression of both genes was quantified in left ventricular myocardium from 24 failing human cardiac explants and 7 control heart samples in relation to beta-myosin heavy chain mRNA by slot blot analysis. Compared with patients with nonfailing hearts, patients with dilated cardiomyopathy (DCM, n=13) showed a 55% increase in Na+-Ca2+ exchanger mRNA levels (P<.05 versus control value) and a 41% increase in patients with coronary artery disease (CAD, n=11). In the same hearts, SR Ca2+-ATPase mRNA levels were decreased by 50% in DCM and by 45% in CAD (P<.05 for both versus control value). There was a positive correlation between Na+-Ca2+ exchanger and SR Ca2+-ATPase mRNA levels both in normal and failing human hearts, albeit with different slopes and intercepts of the regression line. The Na+-Ca+ exchanger protein levels as assessed by Western blot analysis and normalized to P-myosin heavy chain protein were increased in DCM and CAD (P<.05 and P<.01 versus control value, respectively), whereas SR Ca2+-ATPase protein levels were reduced (P<.05 for both groups versus control values). Thus, the Na+-Ca2+ exchanger gene expression is enhanced in failing human hearts and may, in part, compensate for the depressed SR function with regard to diastolic Ca2+ removal.