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 Na+ homeostasis are intimately linked through the Na+/Ca2+ exchanger, we compared the regulation of [Na+]i in nonfailing (NF) and failing human myocardium.


RESULTS
[Na+]i was measured in SBFI-loaded muscle strips. At slow pacing rates (0.25 Hz, 37 degrees 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 Ca(2+) 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.
Pieske
Burkert
B
Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Germany. pieske@med.uni-goettingen.de
Maier
Lars S
LS
Piacentino
Valentino
V
Weisser
Jutta
J
Hasenfuss
Gerd
G
Houser
Steven
S
D001572:Benzofurans / Q000032:analysis; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D046508:Culture Techniques; D004553:Electric Conductivity; D004558:Electric Stimulation; D005456:Fluorescent Dyes / Q000032:analysis; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology*; D006706:Homeostasis; D006801:Humans; D017136:Ion Transport; D007700:Kinetics; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry*; D010042:Ouabain / Q000494:pharmacology; D010795:Phthalic Acids / Q000032:analysis; D012964:Sodium / Q000032:analysis*
D001572:Benzofurans; D005456:Fluorescent Dyes; D010795:Phthalic Acids; C103805:sodium binding benzofuran isophthalate acetoxymethyl ester; D010042:Ouabain; D012964:Sodium; D002118:Calcium