Published online before print July 1, 2002, doi: 10.1161/01.CIR.0000023042.50192.F4
(Circulation. 2002;106:447.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Rate Dependence of [Na+]i and Contractility in Nonfailing and Failing Human Myocardium
From Abteilung Kardiologie und Pneumologie (B.P., L.S.M., J.W., G.H.), Georg-August-Universität Göttingen, Germany, and Department of Physiology (V.P., J.W., S.H.), Temple University, Philadelphia, Pa.
Correspondence to PD Dr Burkert Pieske, Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany. E-mail pieske{at}med.uni-goettingen.de
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.
Key Words: heart failure • contractility • sodium • calcium • diastole
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