%0 Journal Article %1 Pies_2002_447 %A Pieske, Burkert %A Maier, Lars S %A Piacentino, Valentino %A Weisser, Jutta %A Hasenfuss, Gerd %A Houser, Steven %D 2002 %J Circulation %K 12135944 ATPase, Acids, Aged, Benzofurans, Calcium, Calcium-Binding Cardiac Cells, Conductivity, Congestive, Contraction, Culture Cultured, Dyes, Electric Failure, Fluorescent Gov't, Heart Heart, Homeostasis, Humans, In Ion Kinetics, Low, Middle Myocardial Myocardium, Non-U.S. Ouabain, Output, P.H.S., Phthalic Proteins, Reference Research Rest, Reticulum, Sarcoplasmic Sodium, Stimulation, Support, Techniques, Transport, U.S. Values, Vitro, {C}a$^{2+}$-Transporting %N 4 %P 447--453 %T Rate dependence of Na$^+$i and contractility in nonfailing and failing human myocardium. %U http://circ.ahajournals.org/cgi/content/short/106/4/447 %V 106 %X BACKGROUND: In the failing human heart, altered Ca$^2+$ homeostasis causes contractile dysfunction. Because Ca$^2+$ and Na$^+$ homeostasis are intimately linked through the Na$^+$/Ca$^2+$ 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 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$^+$/Ca$^2+$ exchange induced significant Ca$^2+$ 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 Ca$^2+$ influx through Na$^+$/Ca$^2+$ 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 Ca$^2+$ load and are prone to diastolic Ca$^2+$ overload.

@article{Pies_2002_447, abstract = {BACKGROUND: In the failing human heart, altered {C}a$^{2+}$ homeostasis causes contractile dysfunction. Because {C}a$^{2+}$ and {N}a$^{+}$ homeostasis are intimately linked through the {N}a$^{+}$/{C}a$^{2+}$ exchanger, we compared the regulation of [{N}a$^{+}$]i in nonfailing (NF) and failing human myocardium. METHODS {AND} RESULTS: [{N}a$^{+}$]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 [{N}a$^{+}$]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 [{N}a$^{+}$]i without changes in diastolic tension. At 2.0 Hz, force increased to 136+/-17\% of the basal value (P<0.05), and [{N}a$^{+}$]i to 20.5+/-4.2 mmol/L (P<0.05). In contrast, in failing myocardium, force declined to 45+/-3\%, whereas [{N}a$^{+}$]i increased to 27.4+/-3.2 mmol/L (both P<0.05), in association with significant elevations in diastolic tension. [{N}a$^{+}$]i was higher in failing than in NF myocardium at every stimulation rate. [{N}a$^{+}$]i predicted in myocytes from {N}a$^{+}$ (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 {N}a$^{+}$/{C}a$^{2+}$ exchange induced significant {C}a$^{2+}$ influx in failing but not NF myocytes, compatible with higher [{N}a$^{+}$]i in failing myocytes. CONCLUSIONS: {N}a$^{+}$i homeostasis is altered in failing human myocardium. At slow heart rates, the higher [{N}a$^{+}$]i in failing myocardium appears to enhance {C}a$^{2+}$ influx through {N}a$^{+}$/{C}a$^{2+}$ exchange and maintain sarcoplasmic reticulum {C}a$^{2+}$ load and force development. At faster rates, failing myocytes with high [{N}a$^{+}$]i cannot further increase sarcoplasmic reticulum {C}a$^{2+}$ load and are prone to diastolic {C}a$^{2+}$ overload.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Pieske, Burkert and Maier, Lars S and Piacentino, Valentino and Weisser, Jutta and Hasenfuss, Gerd and Houser, Steven}, biburl = {https://www.bibsonomy.org/bibtex/239a1fd0da54ff7966f65f2dd9b9f7731/hake}, description = {The whole bibliography file I use.}, file = {Pies_2002_447.pdf:Pies_2002_447.pdf:PDF}, interhash = {89d2f9025dc08a128247115f5a5355bb}, intrahash = {39a1fd0da54ff7966f65f2dd9b9f7731}, journal = {Circulation}, key = 206, keywords = {12135944 ATPase, Acids, Aged, Benzofurans, Calcium, Calcium-Binding Cardiac Cells, Conductivity, Congestive, Contraction, Culture Cultured, Dyes, Electric Failure, Fluorescent Gov't, Heart Heart, Homeostasis, Humans, In Ion Kinetics, Low, Middle Myocardial Myocardium, Non-U.S. Ouabain, Output, P.H.S., Phthalic Proteins, Reference Research Rest, Reticulum, Sarcoplasmic Sodium, Stimulation, Support, Techniques, Transport, U.S. Values, Vitro, {C}a$^{2+}$-Transporting}, month = Jul, number = 4, pages = {447--453}, pmid = {12135944}, timestamp = {2009-06-03T11:21:25.000+0200}, title = {Rate dependence of [{N}a$^{+}$]i and contractility in nonfailing and failing human myocardium.}, url = {http://circ.ahajournals.org/cgi/content/short/106/4/447}, volume = 106, year = 2002 }