Lasting alterations of the sodium current by short-term hyperlipidemia as a mechanism for initiation of cardiac remodeling.
Clinical and animal studies indicate that increased fatty acid delivery to lean tissues induces cardiac electrical remodeling and alterations of cellular calcium homeostasis. Since this may represent a mechanism initiating cardiac dysfunction during establishment of insulin resistance and diabetes or anaerobic cardiac metabolism (ischemia), we sought to determine if short-term exposure to high plasma concentration of fatty acid in vivo was sufficient to alter the cardiac sodium current (INa) in dog ventricular myocytes. Our results show that delivery of triglycerides and nonesterified fatty acids by infusion of Intralipid + heparin (IH) for 8 h increased the amplitude of INa by 43% and shifted its activation threshold by -5 mV, closer to the resting membrane potential. Steady-state inactivation (availability) of the channels was reduced by IH with no changes in recovery from inactivation. As a consequence, INa "window" current, a strong determinant of intracellular Na+ and Ca2+ concentrations, was significantly increased. The results indicate that increased circulating fatty acids alter INa gating in manners consistent with an increased cardiac excitability and augmentation of intracellular calcium. Moreover, these changes could still be measured after the dogs were left to recover for 12 h after IH perfusion, suggesting lasting changes in INa. Our results indicate that fatty acids rapidly induce cardiac remodeling and suggest that this process may be involved in the development of cardiac dysfunctions associated to insulin resistance and diabetes.
Department of Physiology and Biophysics, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Quebec, Canada; and.
M
M
Biet
N
N
Morin
O
O
Benrezzak
F
F
Naimi
S
S
Bellanger
J P
JP
Baillargeon
L
L
Chouinard
N
N
Gallo-Payet
A C
AC
Carpentier
R
R
Dumaine
D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004285:Dogs; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism; D005260:Female; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D006949:Hyperlipidemias / Q000378:metabolism* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D020257:Ventricular Remodeling; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
D005227:Fatty Acids; D014280:Triglycerides; D061566:Voltage-Gated Sodium Channels; D012964:Sodium; D002118:Calcium
dog; insulin; patch clamp; sodium channels