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.
%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
}