Altered Na+Currents in Atrial Fibrillation
Key result
Ranolazine decreases late INa by ~60% in AF myocytes compared to sinus rhythm.
- P<0.05
- n=102
Why the study?
It remains unclear whether Na+ currents are altered in permanent atrial fibrillation and how their inhibition affects arrhythmias and contractility.
Does ranolazine reduce late Na+ currents and proarrhythmic activity in isolated atrial myocytes from patients with atrial fibrillation?
Key Points
- To investigate alterations in sodium currents in permanent atrial fibrillation and assess whether sodium current inhibition using ranolazine reduces arrhythmias and improves contractility in human atrial myocardium.
- Obtained right atrial appendages from patients with permanent atrial fibrillation (n = 23) and individuals in sinus rhythm (n = 79).
- Performed patch-clamp electrophysiology on isolated atrial myocytes to measure peak and late sodium currents alongside Nav1.5 protein expression analysis.
- Assessed proarrhythmic activity and diastolic tension under ranolazine exposure (10 µmol/L) in atrial trabeculae challenged with high extracellular calcium, isoprenaline, or pacing rates from 0.5 to 3.0 Hz.
- Isolated atrial myocytes from patients with atrial fibrillation showed an approximately 16% reduction in peak sodium current density and 26% lower Nav1.5 expression (p < 0.05), contrasted by an approximately 26% increase in late sodium currents.
- Ranolazine (10 µmol/L) reduced late sodium currents by approximately 60% in atrial fibrillation myocytes (p < 0.05) compared to approximately 18% in sinus rhythm myocytes (p < 0.05).
- Ranolazine reversed proarrhythmic triggers induced by high extracellular calcium by 83% and isoprenaline by 100%, while significantly lowering pacing-induced diastolic tension across both rhythm groups.
Structured PICO
Does ranolazine reduce late Na+ currents and proarrhythmic activity in isolated atrial myocytes from patients with atrial fibrillation?
P
Population
Ex vivo study of right atrial appendages from 102 patients, including 23 with permanent atrial fibrillation and 79 in sinus rhythm.
I
Intervention
Ranolazine (10 µmol/l) applied in vitro
C
Comparator
Myocytes from patients in sinus rhythm (for disease comparison) and baseline conditions prior to ranolazine exposure (for intervention comparison)
O
Outcome
Changes in peak and late Na+ current (I(Na)) density, Nav1.5 expression, and the effects of ranolazine on proarrhythmic activity and diastolic tensionsurrogate
Main Result
Absolute Event Rate: 60% vs 18%
p-value: p=<0.05
Inhibition of late sodium currents with ranolazine exhibits antiarrhythmic effects and improves diastolic function in human atrial myocardium from patients with atrial fibrillation.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“In contrast, the implications of the study on direct proarrhythmic effects are much more difficult to appreciate. The authors suggest that enhanced I NaL might be an “additional mechanism for AF” by enhancing triggered activity in the atria (1). The question arises why the enhanced propensity to triggered activity due to increased I NaL does not result in proarrhythmic events occurring in the right atrial appendages.”
Implication
Ranolazine preferentially suppresses late INa in AF myocytes; hypothesis-generating only and should not change practice.
Abstract
Objectives We investigated changes in Na(+) currents (I(Na)) in permanent (or chronic) atrial fibrillation (AF) and the effects of I(Na) inhibition using ranolazine (Ran) on arrhythmias and contractility in human atrial myocardium. Background Electrical remodeling during AF is typically associated with alterations in Ca(2+) and K(+) currents. It remains unclear whether I(Na) is also altered. Methods Right atrial appendages from patients with AF (n = 23) and in sinus rhythm (SR) (n = 79) were studied. Results Patch-clamp experiments in isolated atrial myocytes showed significantly reduced peak I(Na) density ( approximately 16%) in AF compared with SR, which was accompanied by a 26% lower expression of Nav1.5 (p < 0.05). In contrast, late I(Na) was significantly increased in myocytes from AF atria by approximately 26%. Ran (10 mumol/l) decreased late I(Na) by approximately 60% (p < 0.05) in myocytes from patients with AF but only by approximately 18% (p < 0.05) in myocytes from SR atria. Proarrhythmic activity was elicited in atrial trabeculae exposed to high [Ca(2+)](o) or isoprenaline, which was significantly reversed by Ran (by 83% and 100%, respectively). Increasing pacing rates from 0.5 to 3.0 Hz led to an increase in diastolic tension that could be significantly decreased by Ran in atria from SR and AF patients. Conclusions Na(+) channels may contribute to arrhythmias and contractile remodeling in AF. Inhibition of I(Na) with Ran had antiarrhythmic effects and improved diastolic function. Thus, inhibition of late I(Na) may be a promising new treatment option for patients with atrial rhythm disturbances and diastolic dysfunction.
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Cite This Study
Sossalla et al. (2010) studied Permanent (or chronic) atrial fibrillation (n=102). Ranolazine vs. Sinus rhythm myocytes was evaluated on Reduction in late Na+ current (INa) (p=<0.05). Ranolazine decreased late INa by approximately 60% in atrial myocytes from patients with atrial fibrillation compared to only 18% in myocytes from sinus rhythm patients (p<0.05).