Background— In the failing human heart, altered Ca²⁺ homeostasis causes contractile dysfunction. Because Ca²⁺ and Na⁺ 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, 37°C), isometric force was similar in NF (n=6) and failing (n=12) myocardium (6.4±1.2 versus 7.2±1.9 mN/mm²), but [Na⁺]_i and diastolic force were greater in failing (22.1±2.6 mmol/L and 15.6±3.2 mN/mm²) than in NF (15.9±3.1 mmol/L and 3.50±0.55 mN/mm²; 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.