Rate dependence of [Na+]i and contractility in nonfailing and failing human myocardium

Background-In the failing human heart, altered Ca2+ homeostasis causes contractile dysfunction. Because Ca2+ and Na2+ homeostasis are intimately linked through the Na+/Ca2+ exchanger, we compared the regulation of [Na+](i) in nonfailing (NF) and failing human myocardium. Methods and Results-[Na+](i) was measured in SBFI-loaded muscle strips. At slow pacing rates (0.25 Hz, 37degreesC), isometric force was similar in NF (n=6) and failing (n=12) myocardium (6.4+/-1.2 versus 7.2+/-1.9 mN/mm(2)), but [Na+](i) and diastolic force were greater in failing (22.+/-2.6 mmol/L and 15.6+/-3.2 mN/mm(2)) than in NF (15.9+/-3.1 mmol/L and 3.50+/-0.55 mN/mm(2); P<0.05) myocardium. In NF hearts, increasing stimulation rates resulted in a parallel increase in force and [Na+](i) without changes in diastolic tension. At 2.0 Hz, force increased to 136+/-17% of the basal value (P<0.05), and [Na+](i) to 20.5+/-4.2 mmol/L (P<0.05). In contrast, in failing myocardium, force declined to 45+/-3%, whereas [Na+](i) increased to 27.4+/-3.2 mmol/L (both P<0.05), in association with significant elevations in diastolic tension. [Na+](i) was higher in failing than in NF myocardium at every stimulation rate. [Na+](i) predicted in myocytes from Na-pipette(+)-contraction relations was 8.0 mmol/L in NF (n=9) and 12.1 mmol/L in failing (n=57; P<0.05) myocardium at 0.25 Hz. Reverse-mode Na+/Ca2+ exchange induced significant Ca2+ influx in failing but not NF myocytes, compatible with higher [Na+](i), in failing myocytes. Conclusions-Na-i(+) homeostasis is altered in failing human myocardium. At slow heart rates, the higher [Na+](i) in failing myocardium appears to enhance Ca2+ influx through Na+/Ca2+ exchange and maintain sarcoplasmic reticulum Ca2+ load and force development. At faster rates, failing myocytes with high [Na+](i) cannot further increase sarcoplasmic reticulum Ca2+ load and are prone to diastolic Ca2+ overload.