Dominant frequency increase rate predicts transition from paroxysmal to long-term persistent atrial fibrillation.
BACKGROUND
Little is known about the mechanisms underlying the transition from paroxysmal to persistent atrial fibrillation (AF). In an ovine model of long-standing persistent AF we tested the hypothesis that the rate of electric and structural remodeling, assessed by dominant frequency (DF) changes, determines the time at which AF becomes persistent.


RESULTS
Self-sustained AF was induced by atrial tachypacing. Seven sheep were euthanized 11.5±2.3 days after the transition to persistent AF and without reversal to sinus rhythm; 7 sheep were euthanized after 341.3±16.7 days of long-standing persistent AF. Seven sham-operated animals were in sinus rhythm for 1 year. DF was monitored continuously in each group. Real-time polymerase chain reaction, Western blotting, patch clamping, and histological analyses were used to determine the changes in functional ion channel expression and structural remodeling. Atrial dilatation, mitral valve regurgitation, myocyte hypertrophy, and atrial fibrosis occurred progressively and became statistically significant after the transition to persistent AF, with no evidence for left ventricular dysfunction. DF increased progressively during the paroxysmal-to-persistent AF transition and stabilized when AF became persistent. Importantly, the rate of DF increase correlated strongly with the time to persistent AF. Significant action potential duration abbreviation, secondary to functional ion channel protein expression changes (CaV1.2, NaV1.5, and KV4.2 decrease; Kir2.3 increase), was already present at the transition and persisted for 1 year of follow up.


CONCLUSIONS
In the sheep model of long-standing persistent AF, the rate of DF increase predicts the time at which AF stabilizes and becomes persistent, reflecting changes in action potential duration and densities of sodium, L-type calcium, and inward rectifier currents.
Department of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI (R.P.M., K.K., E.H., R.J.R., B.C.W., D.F.-R., S.R.E., Y.T., D.P.-B., M.Z., R.P.O., H.M., G.G.-S., U.M.R.A., S.V.P., O.B., J.J.); Department of Surgery, University of Rochester, Rochester, NY (M.F.S.); and Department of Engineering, Norfolk State University, Norfolk, VA (S.B., M.D.).
Raphael P
RP
Martins
Kuljeet
K
Kaur
Elliot
E
Hwang
Rafael J
RJ
Ramirez
B Cicero
BC
Willis
David
D
Filgueiras-Rama
Steven R
SR
Ennis
Yoshio
Y
Takemoto
Daniela
D
Ponce-Balbuena
Manuel
M
Zarzoso
Ryan P
RP
O'Connell
Hassan
H
Musa
Guadalupe
G
Guerrero-Serna
Uma Mahesh R
UM
Avula
Michael F
MF
Swartz
Sandesh
S
Bhushal
Makarand
M
Deo
Sandeep V
SV
Pandit
Omer
O
Berenfeld
José
J
Jalife
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D018450:Disease Progression; D022062:Electrophysiologic Techniques, Cardiac; D006339:Heart Rate / Q000502:physiology*; D006984:Hypertrophy; D032383:Myocytes, Cardiac / Q000473:pathology; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology*; D012756:Sheep; D012849:Sinoatrial Node / Q000503:physiopathology*; D015222:Sodium Channels / Q000502:physiology*; D013997:Time Factors
D020746:Calcium Channels, L-Type; D024661:Potassium Channels, Inwardly Rectifying; D015222:Sodium Channels
atrial fibrillation; electrophysiological; fibrosis; ion channels; refractory period