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Mutations of Voltage-Gated Ionic Channels and Risk of Severe Cardiac Arrhythmias

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Acta Cardiol Sin 2019;35:99-110 Review Article doi: 10.6515/ACS.201903_35(2).20181028A Mutations of Voltage-Gated Ionic Channels and Risk of Severe Cardiac Arrhythmias Amir Dehghani-Samani,1 Samin Madreseh-Ghahfarokhi2 and Azam Dehghani-Samani3 Background: Arrhythmias as important malfunctions of heart are known as abnormal rhythm of heart. Several causes can make arrhythmias and most of them are related to generation and/or conduction of action potential in heart. Action potential in myocytes results from the sequential opening and closing of ion channel proteins that span the plasma membrane of individual myocytes. Action potential’s conduction through the heart is depended on electrical coupling between myocytes, which is mediated by gap junctions. Generation and conduction of action potentials are related to perfect action of ionic channels in heart. Objectives: This novel review comprehensively addressed the ionic mechanisms of the arrhythmogenic mutations in cardiac voltage-gated ionic channels including: CACNA1C, CACNA1D, KCNA5, KCND2, KCND3, KCNE1, KCNE2, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4A, SCN5A, SCN1B, SCN2B, SCN3B and SCN4B. Methods: Current study, for the first time, review and discuses about relation between cardiac arrhythmias and whole of important voltage gated ionic channels from different families, altogether and at the same time. Results: This review clears that mutations in voltage-gated ionic channels play important roles in generation of severe cardiac arrhythmias, and among them it is looked that mutations in voltage-gated potassium channels are more important. Conclusions: Most of induced arrhythmias due to voltage-gated ionic channels mutations result in action potentials prolongation and long QT syndromes. Study on ionic channel regulators can be considered as a subject for future research. Key Words: Arrhythmia · Ion channel · Ionic current INTRODUCTION atria no longer function as primer pumps for the ventri- cles.1 Related symptoms to cardiac arrhythmias are in- Cardiac arrhythmias, as important kinds of heart cluding: shortness of breath, weakness, lightheaded- malfunctions, are occurring due to abnormal rhythm of ness, dizziness and occasionally, chest pain in mild types the heart. For instance, sometimes the beat of the atria of arrhythmias, and fainting, loss of conscious, syncope is not coordinated with the beat of the ventricles, so the and finally death in severe types of arrhythmias. The causes of the cardiac arrhythmias are usually related to generation and/or conduction of action potentials (APs) Received: April 4, 2018 Accepted: October 28, 2018 in cardiac tissues, which are sharply related to perfect 1Department of Clinical Sciences, Faculty of Veterinary Medicine, action of ionic channels in heart.1 Shahrekord University, Shahrekord; 2Department of Clinical Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad; 3Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran. DIFFERENT TYPES OF ARRHYTHMIA Corresponding author: Dr. Amir Dehghani Samani, Department of Clinical Sciences, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran. Tel: +98-3814424427; Fax: +98-3814424427; E-mail: According to the specific cause and character, car- [email protected] diac arrhythmias can divide to different groups. In one 99 Acta Cardiol Sin 2019;35:99-110 Amir Dehghani-Samani et al. of the best divisions, they are divided into eight differ- sub-divisions and different characteristics of each type ent categories.1 Table 1 shows the causes, mechanisms, of arrhythmias. Table 1. Different groups of arrhythmias and their characteristics Characteristics, electrocardiogram Type of arrhythmia Subtypes Common cause (ECG), etc. Abnormal sinus rhythms1 Tachycardia1 Increased body temperature, Heart rate more than 100 beats/ stimulation of the heart by min, ECG: normal, except heart rate.1 sympathetic nerves, toxic conditions, etc.1 Bradycardia1 Large and strong heart, vagal Heart rate less than 60 beats/min, stimulation, etc.1 ECG: normal, except heart rate.1 Sinus arrhythmia1 Alter in strength of the sympathetic Range of increasing/decreasing in and parasympathetic signals to sinus heart rate during the stimulation is node, etc.1 more than normal range.1 Block of heart signals1 Sinoatrial block1 Impulse from sinus node is blocked Sudden cessation of P waves in ECG, before it enters to atrial muscle, etc.1 with resultant standstill of the atria.1 Atrioventricular block1 Decrease the rate of impulse Prolonged P-R or P-Q Interval (First conduction in atrioventricular bundle, degree), P wave with no QRS-T wave etc.1 (2nd degree), Dissociated P wave from QRS-T complexes (3rd degree).1 Incomplete Block impulse conduction in the Replicated increasing/decreasing in intraventri-cular block1 peripheral ventricular Purkinje system, height of QRS wave.1 etc.1 Premature contractions1 Premature atrial Mostly result from ectopic foci in P wave occurs soon, P-R interval is contractions1 heart due to local areas of ischemia; shortened.1 Atrioventricular nodal small calcified plaques and toxic P wave is missing; instead P wave is contractions1 irritation of the Atrioventriclar node, superimposed onto QRS-T complex.1 Premature ventricular Purkinje system or myocardium caused Prolonged QRS with high voltage, T contractions1 by infection, drugs, nicotine, or wave has electrical potential polarity caffeine, etc.1 exactly opposite to QRS.1 Paroxysmal tachycardia1 Atrial paroxysmal Mostly caused by re-entrant circus Inverted P wave is seen before tachycardia1 movement feedback pathways that each QRS-T complex.1 Ventricular paroxysmal set up local repeated self-re-excitation Series of ventricular premature beats tachycardia1 and this focus becomes the pacemaker occurring one after another without of the heart, etc.1 any normal beats interspersed.1 Ventricular fibrillation1 Results from cardiac impulses that have gone berserk within ECG is bizarre and ordinarily shows the ventricular muscle mass, stimulating first one portion of no tendency toward a regular the ventricular muscle, then another portion, then another, rhythm of any type.1 and eventually feeding back onto itself to re-excite the same ventricular muscle over and over, never stopping, etc.1 Atrial fibrillation1 Mechanism of atrial fibrillation is identical to that of Numerous small depolarization ventricular fibrillation, except that the process occurs only in waves exist. P waves are weak; the atrial muscle mass, etc.1 conversely, QRS-T complexes are normal.1 Atrial flutter1 Caused by circus movements in the atria. It causes a rapid rate P waves are strong, QRS-T complex of contraction of the atria, usually between 200 and 350 beats follows an atrial P wave only once per minute, etc.1 for every two to three beats of the atria.1 Cardiac arrest1 Results from cessation of all electrical control signals in the Stop of waves.1 heart, etc.1 Acta Cardiol Sin 2019;35:99-110 100 Genetic Disorders and Risk of Cardiac Arrhythmias NORMAL GENERATION OF ACTION POTENTIALS 1showsthedifferentphasesofAP’sgenerationinmyo- (APs) cytes schematically. Several factor regulate the genera- tion and conduction of APs including:1 changes in the The best introduced mechanism for AP in cardiac properties and/or in the functional expression of ionic cells, which is explained by scientists, indicates that AP channels, which are resulted from inherited mutations in myocytes results from the sequential opening and in the genes encoding these channels,1 or from cardiac closing of ion channels span in plasma membrane of in- diseases,1 which can change the AP’s waveforms, synch- dividual myocytes. Also differences in the expression and ronization, and/or propagation, thereby predisposing properties of these channels result in heterogeneities in the heart to potentially life-threatening arrhythmias.2 AP wave. Action potential’s conduction through the heart depends on electrical coupling between myocytes, which is mediated by gap junctions.1 The cardiac AP in VOLTAGE-GATED IONIC CHANNELS (VGICs) humans has five different phases (from 0 to 4). Depolar- ization from the pacemaker cells in Sino-Atrial node VGICs are an important and specific class of trans- brings the membrane potential to the threshold, open- membrane channels.1 The first identified VGIC that was ing the voltage-activated sodium channels, then the re- voltage-gated sodium channel or (VGSC) was isolated 3 sulting sodium current (INa) produces a positive feed- and purified from the eel electroplax. The first volt- back loop that causes further sodium channels to open age-gated potassium channel’s sequence was deduced (phase0).Innextstepearlyrapidrepolarizationresults from the Shaker mutant of Drosophila melanogaster.3 from the activation of the fast and slow transient out- Some functional VGICs are made up a protein with four ward potassium currents, Ito,f and Ito,s, and it is responsi- different subunits like voltage gated potassium chan- ble for phase 1 of the AP’s generation. This is followed nels (VGPCs), or one protein with four homologous do- by a prolonged plateau resulting from a balance between mains like VGSCs and voltage gated calcium channels the inward currents mediated by the L-type voltage- (VGCCs). Each one of the domains or subunits has six gated calcium channel (ICa,L) and sodium-calcium ex- trans-membrane segments (S1-6) and a pore loop; the changer (INCX),andtheoutwardcurrentsmediatedby S5, S6 and the pore loop were found to be responsible the delayed
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