Abstract
BackgroundAlthough atrial fibrillation ablation is increasingly used for rhythm control therapy, antiarrhythmic drugs (AADs) are commonly used, either alone or in combination with ablation. The effectiveness of AADs is highly variable. Previous work from our group suggests that alterations in atrial resting membrane potential (RMP) induced by low Pitx2 expression could explain the variable effect of flecainide.ObjectiveThe purpose of this study was to assess whether alterations in atrial/cardiac RMP modify the effectiveness of multiple clinically used AADs.MethodsThe sodium channel blocking effects of propafenone (300 nM, 1 μM), flecainide (1 μM), and dronedarone (5 μM, 10 μM) were measured in human stem cell–derived cardiac myocytes, HEK293 expressing human NaV1.5, primary murine atrial cardiac myocytes, and murine hearts with reduced Pitx2c.ResultsA more positive atrial RMP delayed INa recovery, slowed channel inactivation, and decreased peak action potential (AP) upstroke velocity. All 3 AADs displayed enhanced sodium channel block at more positive atrial RMPs. Dronedarone was the most sensitive to changes in atrial RMP. Dronedarone caused greater reductions in AP amplitude and peak AP upstroke velocity at more positive RMPs. Dronedarone evoked greater prolongation of the atrial effective refractory period and postrepolarization refractoriness in murine Langendorff-perfused Pitx2c+/– hearts, which have a more positive RMP compared to wild type.ConclusionAtrial RMP modifies the effectiveness of several clinically used AADs. Dronedarone is more sensitive to changes in atrial RMP than flecainide or propafenone. Identifying and modifying atrial RMP may offer a novel approach to enhancing the effectiveness of AADs or personalizing AAD selection.
Highlights
Rhythm control therapy is used in 10%–20% of patients with atrial fibrillation (AF) to improve AF-related symptoms, often involving antiarrhythmic drugs (AADs) as first-line therapy[1] or in combination with AF ablation.[2]
Dronedarone evoked greater prolongation of the atrial effective refractory period and postrepolarization refractoriness in murine Langendorff-perfused Pitx2c1/– hearts, which have a more positive resting membrane potential (RMP) compared to wild type
Dronedarone is more sensitive to changes in atrial RMP than flecainide or propafenone
Summary
Rhythm control therapy is used in 10%–20% of patients with atrial fibrillation (AF) to improve AF-related symptoms, often involving antiarrhythmic drugs (AADs) as first-line therapy[1] or in combination with AF ablation.[2] anticoagulation prevents most ischemic strokes in AF patients, the rates of stroke, heart failure, unplanned hospitalizations, and cardiovascular death remain high.[1,3] Data suggest that restoring and maintaining sinus rhythm in patients with recently diagnosed AF provides clinical benefit compared to symptom-directed, selective rhythm control therapy.[4] This clinical benefit was achieved using a treatment strategy comprising AADs and AF ablation.[4] These results enhance the need for widely accessible and effective rhythm control therapy. Previous work from our group suggests that alterations in atrial resting membrane potential (RMP) induced by low Pitx[2] expression could explain the variable effect of flecainide
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