Review Non-Coding RNAs in the Cardiac Action Potential and Their Impact on Arrhythmogenic Cardiac Diseases Estefania Lozano-Velasco 1,2 , Amelia Aranega 1,2 and Diego Franco 1,2, *   Citation: Lozano-Velasco, E.; Aranega, A.; Franco, D. Non-Coding RNAs in the Cardiac Action Potential and Their Impact on Arrhythmogenic Cardiac Diseases. Hearts 2021, 2, 307–330. https://doi.org/10.3390/ hearts2030026 Academic Editors: Francesco Onorati and Matthias Thielmann Received: 28 February 2021 Accepted: 25 June 2021 Published: 30 June 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; evelasco@ujaen.es (E.L.-V.); aaranega@ujaen.es (A.A.) 2 Fundación Medina, 18016 Granada, Spain * Correspondence: dfranco@ujaen.es Abstract: Cardiac arrhythmias are prevalent among humans across all age ranges, affecting millions of people worldwide. While cardiac arrhythmias vary widely in their clinical presentation, they possess shared complex electrophysiologic properties at cellular level that have not been fully studied. Over the last decade, our current understanding of the functional roles of non-coding RNAs have progressively increased. microRNAs represent the most studied type of small ncRNAs and it has been demonstrated that miRNAs play essential roles in multiple biological contexts, including normal development and diseases. In this review, we provide a comprehensive analysis of the functional contribution of non-coding RNAs, primarily microRNAs, to the normal configuration of the cardiac action potential, as well as their association to distinct types of arrhythmogenic cardiac diseases. Keywords: cardiac arrhythmia; microRNAs; lncRNAs; cardiac action potential 1. The Electrical Components of the Adult Heart The adult heart is a four-chambered organ that propels oxygenated blood to the entire body. It is composed of atrial and ventricular chambers, each of them with distinct left and right components, that are connected between them through the atrioventricular valves [1]. Oxygenated blood enters the heart through the pulmonary veins into the left atrium, passes through the atrioventricular mitral valve to the left ventricle and then is expelled to the aorta. Systemic blood is collected into the right atrium through the caval veins, enters the right ventricle along the atrioventricular tricuspid valve, and is subsequently expelled throughout the pulmonary artery into the lungs, before re-entering the heart through the pulmonary veins completing thus a new circulatory cycle [1]. Rhythmic contraction of the heart, leading to alternative systole and diastole contrac- tion phases is controlled by the cardiac conduction system (CCS). The CCS is formed by slow and fast conduction pathways. The slow components are two distinct low conduct- ing and self-firing nodes, the sinoatrial and the atrioventricular node, respectively. The sinoatrial node is located at the junction between the right superior caval vein entrance and the atrial chamber myocardium and is the main pacemaker of the heart [2]. The atrioventricular node is located at the top of the interventricular septum just at the junction between atrial and ventricular myocardium. The fast conducting components of the cardiac conduction system are exclusively located in the ventricular chambers, and are composed by the bundle of His, the left and right bundle branches, and the Purkinje fiber network [2]. At cellular level, the electrical activity of the myocardial cells is governed by an exquisite balance of inward and outward ion currents that configure the cardiac action potential. The cardiac action potential can be divided in at least four different phases. The first phase is initiated with a rapid upstroke of inward sodium currents, leading to the depolarization phase. Subsequently, the repolarization phase is initiated with fine-tuned balance of outward potassium currents, leading to phases two (I TO currents) and three (I K currents) of the cardiac action potential to finally reach the fourth phase of resting Hearts 2021, 2, 307–330. https://doi.org/10.3390/hearts2030026 https://www.mdpi.com/journal/hearts