Affiliation:
1. From the Department of Pharmacology, University of California, Davis, Davis, CA (E.G., D.M.B.); Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI (S.V.P., J.J.); the Division of Experimental Cardiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (N.V., D.D.); and the Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (A.J.W.).
Abstract
Rationale:
Understanding atrial fibrillation (AF) requires integrated understanding of ionic currents and Ca
2+
transport in remodeled human atrium, but appropriate models are limited.
Objective:
To study AF, we developed a new human atrial action potential (AP) model, derived from atrial experimental results and our human ventricular myocyte model.
Methods and Results:
Atria versus ventricles have lower I
K1
, resulting in more depolarized resting membrane potential (≈7 mV). We used higher I
to,fast
density in atrium, removed I
to,slow
, and included an atrial-specific I
Kur
. I
NCX
and I
NaK
densities were reduced in atrial versus ventricular myocytes according to experimental results. SERCA function was altered to reproduce human atrial myocyte Ca
2+
transients. To simulate chronic AF, we reduced I
CaL
, I
to
, I
Kur
and SERCA, and increased I
K1
,I
Ks
and I
NCX
. We also investigated the link between Kv1.5 channelopathy, [Ca
2+
]
i
, and AF. The sinus rhythm model showed a typical human atrial AP morphology. Consistent with experiments, the model showed shorter APs and reduced AP duration shortening at increasing pacing frequencies in AF or when I
CaL
was partially blocked, suggesting a crucial role of Ca
2+
and Na
+
in this effect. This also explained blunted Ca
2+
transient and rate-adaptation of [Ca
2+
]
i
and [Na
+
]
i
in chronic AF. Moreover, increasing [Na
+
]
i
and altered I
NaK
and I
NCX
causes rate-dependent atrial AP shortening. Blocking I
Kur
to mimic Kv1.5 loss-of-function increased [Ca
2+
]
i
and caused early afterdepolarizations under adrenergic stress, as observed experimentally.
Conclusions:
Our study provides a novel tool and insights into ionic bases of atrioventricular AP differences, and shows how Na
+
and Ca
2+
homeostases critically mediate abnormal repolarization in AF.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
298 articles.
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