Distinct phenotype patterns of Ca2+ handling proteins in end-stage failing human hearts

Downregulation of SR Ca2+-ATPase (SERCA2a) and upregulation of Na+/Ca2+-exchanger (NCX1) is regarded to be relevant for altered systolic and diastolic performance of the failing human heart. We tested the hypothesis that large variations in the degree of altered expression of these proteins exist between failing hearts, determining the extent of impaired contractile function. Furthermore, we evaluated whether differences in protein expression can also be observed in different regions of individual hearts. We observed a blunted force-frequency response and a significant downregulation of SERCA2a in end-stage failing human myocardium. However, there was a wide variation in force-frequency behavior (with some failing hearts showing even a preserved positive force-frequency relation) and a wide variation in SERCA2a protein expression in these hearts. There was a close correlation between the degree of altered force-frequency response and reduced SERCA2a expression. Furthermore, average diastolic contractile behavior was significantly disturbed in end-stage failing myocardium, but NCX1 protein was significantly upregulated. Again, there was a wide variation in distolic force-frequency behavior and the degree of increased NCX1 expression, but a significant inverse correlation between the extent of diastolic dysfunction and NCX1 upregulation existed. In individual failing hearts, a transmural gradient within the left ventricular free wall existed for the expression of both SERCA2a and atrial natriuretic peptide (ANP), but not for NCX1. In conclusion, average force-frequency behavior is blunted in human heart failure: associated with reduced expression of SERCA2a and increased expression of NCX1. However, large variations in the degree of altered expression of these proteins determine the extent of systolic and diastolic dysfunction of individual hearts. Furthermore, transmural gradients for SERCA2a, but not for NCX1 were observed within the same hearts, making a coordinate regulation of these proteins unlikely.