Ion Channel Remodeling in Cardiac Arrhythmias – Introduction

Masayasu Hiraoka

Department of Cardiovascular Diseases, Medical Research Institute,
Tokyo Medical and Dental University, Tokyo, Japan

Correspondence: Masayasu Hiraoka, Department of Cardiovascular Diseases, Medical Research Institute,
Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Tokyo, Japan.
E-mail: hiraoka.card@mri.tmd.ac.jp, phone +81-3-5803-5829, fax +81-3-5684-6295

1.  Introduction

Cardiac arrhythmias develop on the basis of altered functions of various ion channels and their disorganized activities. In addition, changes in cell and tissue architectures are involved in their genesis. Recently, attention has been paid to ion channel remodeling as a major substrate for arrhythmias in various pathological conditions, where cardiac arrhythmias are prone to develop in high incidence, frequent recurrences and resistant to therapeutic means. Pathological conditions where remodeling of ion channels take place include hypertrophy, heart failure, tachycardias, cardiomyopathy, diabete mellitus etc. Ion channel remodeling induces altered channel expression, distribution and function of diseased hearts. Therefore, remodeling can modulate membrane potentials of cells, excitability, conduction of impulses and Ca²⁺ transporting functions as well as sensitivity to drugs. All these factors either in single or in combination contribute to the genesis of arrhythmias in diseased hearts.

2.  Overview of the Previous Works on Ion Channel Remodeling

The most notable and consistent change in action potentials in cardiac hypertrophy, failure, cardiomyopathy and in some forms of diabetic hearts is a lengthening of action potential duration (APD). As to the ionic basis for the APD lengthening, a decreased transient outward K⁺ current (I_to) has been implicated as a major factor and several reports have also demonstrated reduced expression of the candidate genes for I_to, such as Kv4.2/4.3. In addition, reduction in the inward rectifier K⁺ current (I_k1) and delayed rectifier K⁺ currents (I_kr and I_ks) are observed, but these changes are not constantly seen in every experiments, but may vary depending on the types of animal models, stages and severity of the heart diseases [Hart 1994; Tomaselli and Marban 1999].

The changes in the L-type Ca²⁺ channels (I_Ca.L) are variable with either no changes, decreased or increased activities compared to control heart depending on the models, stages and severity of the cardiac conditions, while the lengthening of APD is consistently observed. Variable changes in the I_Ca.L channel messages are also reported, indicating that changes in I_Ca.L do not play a major role for the APD lengthening. At advanced stages of hypertrophy and heart failure, decreased functions of I_Ca.L are generally observed associated with abnormal intracellular Ca²⁺ transient. These changes are responsible for decreased cardiac functions in advanced stages of hypertrophy and heart failure. The Na⁺ - Ca²⁺ exchangers are increased in heart failure and the activity of Ca²⁺ pump is decreased, which also contribute to reduced contractility. The T-type Ca²⁺ channels are increased in hypertrophy and failure in some studies.

The pacemaker current, I_f, and the messages for its candidate genes, HCN2 and HCN4, appear in the ventricular myocytes from hypertrophy heart, indicating a possible contribution of the phase 4 pacemaker activity in arrhythmogenesis [Cerbai et al 1995]. Some report indicates increased Cl^- current in hypertrophy but its nature and functional significance are not known. We examined the time course of changes in the messages of HCN2, HCN4, and ClC3, a candidate gene for voltage dependnent Cl^- channels, in hypertrophy models with rat abdominal-aortic banding [Hiramatsu et al 2002]. All three messages decreased after 2-4 weeks and increased after 8 weeks of aortic banding, while increased heart weight fully developed at 2 weeks and no further increase, suggesting different signaling mechanisms are involved in the process of hypertrophy and ion channel remodeling in vivo.

The gap junction channels playing a major role for impulse propagation, are also changed in their distribution and function in hypertrophy, which may play an important role for altered conduction velocity and patterns. On the basis of ion channel remodeling, increased ectopic impulse formation either due to slow diastolic depolarization or appearances in early and delayed afterdepolarizations is expected in these hearts [Cerbai et al 1995; Vermeulen et al 1998]. In addition, altered conduction properties due to remodeling in the gap junction channels and a possible increase in disparity of repolarization due to the APD lengthening, which may develop in variable degrees with regional differences, contribute to the development of reentry.

References

Hart G. Cellular electrophysiology in cardiac hypertrophy and failure. Cardiovascular Research 1994;28:933-946.

Tomaselli GF, Marban E. Electrophysiological remodeling in hypertrophy and heart failure. Cardiovascular Research 1999;42:270-283.

Cerbai E, Barberi M, Porciatti F, Mugelli A. Ionic channels in hypertrophy and heart failure: relevance for arrhythmogenesis. New Trends in Arrhythmias 1995;9:135-139.

Hiramatsu M, Furukawa T, Sawanobori T, Hiraoka M. Ion channel remodeling in cardiac hypertrophy is prevented by blood pressure reduction without affecting heart weight increase in rats with abdominal aortic-banding. Journal of Cardiovascular Pharmacology 2002;39:866-874.

Vermeulen JT. Mechanism of arrhythmias in heart failure. Journal of Cardiovascular Electrophysiology 1998;9:208-221.