Elsevier

Heart Rhythm

Volume 13, Issue 3, March 2016, Pages 781-788
Heart Rhythm

Electrolyte disturbances differentially regulate sinoatrial node and pulmonary vein electrical activity: A contribution to hypokalemia- or hyponatremia-induced atrial fibrillation

https://doi.org/10.1016/j.hrthm.2015.12.005Get rights and content

Background

Hypokalemia and hyponatremia increase the occurrence of atrial fibrillation. Sinoatrial nodes (SANs) and pulmonary veins (PVs) play a critical role in the pathophysiology of atrial fibrillation.

Objective

The purpose of this study was to evaluate whether electrolyte disturbances with low concentrations of potassium ([K+]) or sodium ([Na+]) modulate SAN and PV electrical activity and arrhythmogenesis, and to investigate potential underlying mechanisms.

Methods

Conventional microelectrodes were used to record electrical activity in rabbit SAN and PV tissue preparations before and after perfusion with different low [K+] or [Na+], interacting with the Na+–Ca2+ exchanger inhibitor KB-R7943 (10 μΜ).

Results

Low [K+] (3.5, 3, 2.5, and 2 mM) decreased beating rates in PV cardiomyocytes with genesis of delayed afterdepolarizations (DADs), burst firing, and increased diastolic tension. Low [K+] (3.5, 3, 2.5, and 2 mM) also decreased SAN beating rates, with genesis of DADs. Low [Na+] increased PV diastolic tension, DADs, and burst firing, which was attenuated in the co-superfusion with low [K+] (2 mM). In contrast, low [Na+] had little effect on SAN electrical activities. KB-R7943 (10 μΜ) reduced the occurrences of low [K+] (2 mM)– or low [Na+] (110 mM)–induced DAD and burst firing in both PVs and SANs.

Conclusion

Low [K+] and low [Na+] differentially modulate SAN and PV electrical properties. Low [K+]– or low [Na+]–induced slowing of SAN beating rate and genesis of PV burst firing may contribute to the high occurrence of atrial fibrillation during hypokalemia or hyponatremia.

Introduction

Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with higher risk of stroke, heart failure, cardiac mortality, and overall mortality.1, 2 Clinical studies have shown that lower serum concentrations of potassium ([K+] <3.5 mM) are associated with a higher risk of AF.3 Diuretic therapy is the most common cause of K+ deficiency,4 which also commonly occurs during hemodialysis treatment sessions.5, 6 Low [K+] levels cause cellular hyperpolarity, which may increase cardiac arrhythmogenesis.7 Hypokalemia-induced hyperexcitability is clinically manifested by an increase in supraventricular and ventricular ectopy.8 Similarly, hyponatremia (serum sodium ([Na+]) level <135 mM)9 is common in renal disease or heart failure10, 11 and can predispose patients to the development of AF.12, 13 Patients with AF have been found to have significantly lower serum [Na+] than patients without AF, and acute reductions in serum [Na+] may cause paroxysmal AF episodes.14 Hyponatremia due to water retention increases atrial stretch, which can increase vulnerability to atrial arrhythmia.15, 16 However, the mechanisms by which hyponatremia and hypokalemia increase AF have yet to be elucidated.

Pulmonary veins (PVs) play a critical role in the pathophysiology of AF. Previous studies have shown that PVs behave high arrhythmogenicity due to enhanced triggered and spontaneous activities.17 Hypokalemia increases the occurrence of supraventricular ectopic beats, which suggests that hypokalemia may modulate PV arrhythmogenesis to facilitate the occurrence of paroxysmal AF.18 Moreover, hypokalemia has been shown to regulate sinoatrial node (SAN) electrical activity with a decrease in automaticity.19 Sick sinus syndrome plays a critical role in the genesis of AF,20, 21 and SAN dysfunction can enhance PV arrhythmogenesis, which may contribute to the high incidence of AF in sick sinus syndrome.22 Therefore, hypokalemia or hyponatremia may change SAN and PV electrical activity and facilitate the genesis of AF. In this study, we investigated the effects of lower [K+] or [Na+] on the electrophysiologic characteristics of SANs and PVs, and evaluated the potential underlying mechanisms.

Section snippets

Animal and tissue preparation

This study was approved by the local ethics review board of our hospital (IACUC-102-003) and conformed to the Institutional Guidelines for the Care and Use of Laboratory Animals and the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (NIH Publication No. 85-23, revised 1996). As described previously, 10 male New Zealand white rabbits (weight 2–3 kg) were euthanized by intravenous injection of sodium pentobarbital (100 mg/kg).23 The

Effects of low [K+] on SAN and PV electrical activity and diastolic tension

Compared to baseline ([K+] of 4 mM), a low [K+] (3.5, 3, 2.5, and 2 mM) decreased PV beating rates but increased diastolic tension in 9 PVs (Figure 1). A low [K+] of 2.5 mM significantly increased the occurrence of DAD and burst firing (0% vs 55%, P <.05) with a rate up to 6.5 Hz (4.0 ± 0.6 Hz at 2.5 mM, and 4.8 ± 0.7 Hz at 2 mM), but it insignificantly induced the occurrence of EAD (0% vs 22%, P >.05) in 9 PVs (Figure 2A). In addition, burst firings (n = 5) were followed by a pause or

Discussion

Electrolytes play a pivotal role in the genesis of APs, and disturbances in ion homeostasis are common with cardiac arrhythmia. Electrical activity of the heart is composed of transmembrane ionic movement, and electrolytes disturbance can contribute to an increased susceptibility to AF. In this study, we found that a low [K+] decreased the beating rate and induced triggered activity in the PVs and SANs. Previous study has also shown that hypokalemia significantly slows SAN upstroke and reduces

Conclusion

Hypokalemia and hyponatremia differentially modulate SAN and PV electrical properties. The slowing of SAN beating rate and the increase in PV burst firings with low [K+] or low [Na+] contribute to the high occurrence of AF during hypokalemia or hyponatremia.

References (43)

  • S. Sicouri et al.

    Antiarrhythmic effects of ranolazine in canine pulmonary vein sleeve preparations

    Heart Rhythm

    (2008)
  • P.A. Wolf et al.

    Atrial fibrillation as an independent risk factor for stroke: the Framingham Study

    Stroke

    (1991)
  • T.J. Wang et al.

    Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study

    Circulation

    (2003)
  • H. Zebe

    Atrial fibrillation in dialysis patients

    Nephrol Dial Transplant

    (2000)
  • M. Schulman et al.

    Hypokalemia and cardiovascular disease

    Am J Cardiol

    (1990)
  • N. El-Sherif et al.

    Electrolyte disorders and arrhythmogenesis

    Cardiol J

    (2011)
  • G. Spasovski et al.

    Clinical practice guideline on diagnosis and treatment of hyponatraemia

    Nephrol Dial Transplant

    (2014)
  • T. Takasu et al.

    Mechanisms of hyponatremia in chronic congestive heart failure

    Ann Intern Med

    (1961)
  • T. Horio et al.

    Chronic kidney disease as an independent risk factor for new-onset atrial fibrillation in hypertensive patients

    J Hypertens

    (2010)
  • J.G. Smith et al.

    Genetic polymorphisms confer risk of atrial fibrillation in patients with heart failure: a population-based study

    Eur J Heart Fail

    (2013)
  • C. Can et al.

    The relationship between serum sodium concentration and atrial fibrillation among adult patients in emergency department settings

    J Acad Emerg Med

    (2014)
  • Cited by (0)

    Drs. Lu and Cheng contributed equally to this manuscript. This study was supported by Grants NSC101-2314-B-040-017-MY2, NSC102-2314-B-016-029-MY2, NSC102-2325-B-010-005, NSC102-2628-B-038-002-MY3, and 103-2314-B-281-005-MY2 from the National Science Council of Taiwan; Grants CGH-MR-A10219, CGH-MR-A10221, CGH-MR-A10222, and CGH-MR-103-05 from Cathay General Hospital; and Grants 103swf05 and 103-wf-eva-02 from Wan Fang Hospital, Taipei Medical University.

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