Metabolic stress, reactive oxygen species, and arrhythmia

Abstract

Cardiac arrhythmias can cause sudden cardiac death (SCD) and add to the current heart failure (HF) health crisis. Nevertheless, the pathological processes underlying arrhythmias are unclear. Arrhythmic conditions are associated with systemic and cardiac oxidative stress caused by reactive oxygen species (ROS). In excitable cardiac cells, ROS regulate both cellular metabolism and ion homeostasis. Increasing evidence suggests that elevated cellular ROS can cause alterations of the cardiac sodium channel (Na_v1.5), abnormal Ca²⁺ handling, changes of mitochondrial function, and gap junction remodeling, leading to arrhythmogenesis. This review summarizes our knowledge of the mechanisms by which ROS may cause arrhythmias and discusses potential therapeutic strategies to prevent arrhythmias by targeting ROS and its consequences. This article is part of a Special Issue entitled “Local Signaling in Myocytes”.

Introduction

The majority of sudden cardiac death (SCD) results from the occurrence of potentially lethal ventricular tachycardia (VT) or ventricular fibrillation (VF), only two of many types of arrhythmia. Arrhythmia is an irregular heart rhythm and is classified by rate as either tachycardia or bradycardia (resting heart rate > 100 beats/min or < 60 beats/min, respectively). Arrhythmias are also mechanistically classified as automatic, reentrant, and triggered. Reentry is favored by slow, inhomogeneous conduction. Types of arrhythmia include (1) premature beats; (2) supraventricular arrhythmias (e.g., atrial fibrillation (AF), atrial flutter, and paroxysmal supraventricular tachycardia); (3) ventricular arrhythmias (e.g., VT and VF); and (4) bradyarrhythmias.

SCD occurs in approximately 180,000–250,000 cases annually in the United States, and an estimated 4–5 million cases worldwide [1]. SCD occurs in hypertrophic cardiomyopathy, dilated cardiomyopathies, arrhythmogenic right ventricular dysplasia, myocardial infiltrative diseases, and other related disease states [2]. The prevalence of cardiovascular diseases potentially associated with lethal ventricular arrhythmia is estimated at approximately 13 million US individuals, which is about 5% of the middle-aged population [3].

Paroxysmal or persistent AF afflicts approximately 2.2 million Americans in addition to 4.5 million people in the European Union. AF is a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation with consequential deterioration of atrial mechanical function. It is the most common arrhythmia clinically encountered, accounting for over 30% of hospital admissions for cardiac rhythm disturbances [4] and is associated with increased risks for stroke, heart failure (HF), and death [5], [6]. The incidence of AF noticeably increases over the age of 60, afflicts 3–5% of the population 65 to 75 years old and occurs in up to 8% of those older than 80 years [7], [8], [9]. The prevalence of this arrhythmia has significantly increased recently, and the number of Americans with AF is expected to surpass 5 million by 2050 [10].

Despite the high prevalence and significance of arrhythmias, the mechanisms of arrhythmogenesis are not fully understood. Some molecular mechanisms known to contribute to arrhythmias include genetic alterations of ion channels leading to electrophysiological dysregulations and structural remodeling of the left ventricle (LV) in hypertrophy and HF [11], [12], [13], [14]. Increasing evidence suggests that altered cardiac ion homeostasis and structural remodeling are highly associated with elevated reactive oxygen species (ROS) and metabolic stress [15], [16]. In this review, we summarize possible mechanisms whereby the imbalanced cellular redox state may cause arrhythmogenesis by ROS-induced alterations of ion homeostasis and ion channel behavior.