Free Fatty Acid Effects on the Atrial Myocardium: Membrane Ionic Currents Are Remodeled by the Disruption of T-Tubular Architecture.
BACKGROUND
Epicardial adiposity and plasma levels of free fatty acids (FFAs) are elevated in atrial fibrillation, heart failure and obesity, with potentially detrimental effects on myocardial function. As major components of epicardial fat, FFAs may be abnormally regulated, with a potential to detrimentally modulate electro-mechanical function. The cellular mechanisms underlying such effects of FFAs are unknown.


OBJECTIVE
To determine the mechanisms underlying electrophysiological effects of palmitic (PA), stearic (SA) and oleic (OA) FFAs on sheep atrial myocytes.


METHODS
We used electrophysiological techniques, numerical simulations, biochemistry and optical imaging to examine the effects of acutely (≤ 15 min), short-term (4-6 hour) or 24-hour application of individual FFAs (10 μM) on isolated ovine left atrial myocytes (LAMs).


RESULTS
Acute and short-term incubation in FFAs resulted in no differences in passive or active properties of isolated left atrial myocytes (LAMs). 24-hour application had differential effects depending on the FFA. PA did not affect cellular passive properties but shortened (p<0.05) action potential duration at 30% repolarization (APD30). APD50 and APD80 were unchanged. SA had no effect on resting membrane potential but reduced membrane capacitance by 15% (p<0.05), and abbreviated APD at all values measured (p≤0.001). OA did not significantly affect passive or active properties of LAMs. Measurement of the major voltage-gated ion channels in SA treated LAMs showed a ~60% reduction (p<0.01) of the L-type calcium current (ICa-L) and ~30% reduction (p<0.05) in the transient outward potassium current (ITO). A human atrial cell model recapitulated SA effects on APD. Optical imaging showed that SA incubated for 24 hours altered t-tubular structure in isolated cells (p<0.0001).


CONCLUSIONS
SA disrupts t-tubular architecture and remodels properties of membrane ionic currents in sheep atrial myocytes, with potential implications in arrhythmogenesis.
Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan Medical School, Ann Arbor, MI 48109, United States of America; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, United States of America.
Ryan P
RP
O'Connell
Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan Medical School, Ann Arbor, MI 48109, United States of America.
Hassan
H
Musa
Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan Medical School, Ann Arbor, MI 48109, United States of America.
Mario San Martin
MS
Gomez
Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan Medical School, Ann Arbor, MI 48109, United States of America.
Uma Mahesh
UM
Avula
Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan Medical School, Ann Arbor, MI 48109, United States of America; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, United States of America.
Todd J
TJ
Herron
Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan Medical School, Ann Arbor, MI 48109, United States of America.
Jerome
J
Kalifa
Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan Medical School, Ann Arbor, MI 48109, United States of America; Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, United States of America.
Justus M B
JM
Anumonwo
D000818:Animals; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D004594:Electrophysiology; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D006325:Heart Atria / Q000187:drug effects*; D015151:Immunoblotting; D017136:Ion Transport / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D012756:Sheep
D005230:Fatty Acids, Nonesterified