scholarly journals Computational Study to Identify the Effects of the KCNJ2 E299V Mutation in Cardiac Pumping Capacity

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Da Un Jeong ◽  
Jiyeong Lee ◽  
Ki Moo Lim
Keyword(s):  
Ventricular Fibrillation ◽  
Sinus Rhythm ◽  
Computational Study ◽  
Three Dimensional ◽  
Gene Mutations ◽  
Expression Level ◽  
Inward Rectification ◽  
Short Qt Syndrome ◽  
Ventricular Cells ◽  
Qt Syndrome

The KCNJ2 gene mutations induce short QT syndrome (SQT3) by directly increasing the IK1 current. There have been many studies on the electrophysiological effects of mutations such as the KCNJ2 D172N that cause the SQT3. However, the KCNJ2 E299V mutation is distinguished from other representative gene mutations that can induce the short QT syndrome (SQT3) in that it increased IK1 current by impairing the inward rectification of K+ channels. The studies of the electromechanical effects on myocardial cells and mechanisms of E299V mutations are limited. Therefore, we investigated the electrophysiological changes and the concomitant mechanical responses according to the expression levels of the KCNJ2 E299V mutation during sinus rhythm and ventricular fibrillation. We performed excitation-contraction coupling simulations using a human ventricular model with both electrophysiological and mechanical properties. In order to observe the electromechanical changes due to the expression of KCNJ2 E299V mutation, the simulations were performed under normal condition (WT), heterogeneous mutation condition (WT/E299V), and pure mutation condition (E299V). First, a single-cell simulation was performed in three types of ventricular cells (endocardial cell, midmyocardial cell, and epicardial cell) to confirm the electrophysiological changes and arrhythmogenesis caused by the KCNJ2 E299V mutation. In three-dimensional sinus rhythm simulations, we compared electrical changes and the corresponding changes in mechanical performance caused by the expression level of E299V mutation. Then, we observed the electromechanical properties of the E299V mutation during ventricular fibrillation using the three-dimensional reentry simulation. The KCNJ2 E299V mutation accelerated the opening of the IK1 channel and increased IK1 current, resulting in a decrease in action potential duration. Accordingly, the QT interval was reduced by 48% and 60% compared to the WT condition, for the WT/E299V and E299V conditions, respectively. During sustained reentry, the wavelength was reduced due to the KCNJ2 E299V mutation. Furthermore, there was almost no ventricular contraction in both WT/E299V and E299V conditions. We concluded that in both sinus rhythm and fibrillation, the KCNJ2 E299V mutation results in very low contractility regardless of the expression level of mutation and increases the risk of cardiac arrest and cardiac death.

Preclinical short QT syndrome models: studying the phenotype and drug-screening

EP Europace ◽  
2021 ◽  
Author(s):  
Xuehui Fan ◽  
Guoqiang Yang ◽  
Jacqueline Kowitz ◽  
Firat Duru ◽  
Ardan M Saguner ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Family History ◽  
Three Dimensional ◽  
Induced Pluripotent Stem Cell ◽  
Experimental Models ◽  
Short Qt Syndrome ◽  
Pathophysiological Mechanisms ◽  
History Of ◽  
Qt Syndrome ◽  
European Society Of Cardiology

Abstract Cardiovascular diseases are the main cause of sudden cardiac death (SCD) in developed and developing countries. Inherited cardiac channelopathies are linked to 5–10% of SCDs, mainly in the young. Short QT syndrome (SQTS) is a rare inherited channelopathy, which leads to both atrial and ventricular tachyarrhythmias, syncope, and even SCD. International European Society of Cardiology guidelines include as diagnostic criteria: (i) QTc ≤ 340 ms on electrocardiogram, (ii) QTc ≤ 360 ms plus one of the follwing, an affected short QT syndrome pathogenic gene mutation, or family history of SQTS, or aborted cardiac arrest, or family history of cardiac arrest in the young. However, further evaluation of the QTc ranges seems to be required, which might be possible by assembling large short QT cohorts and considering genetic screening of the newly described pathogenic mutations. Since the mechanisms underlying the arrhythmogenesis of SQTS is unclear, optimal therapy for SQTS is still lacking. The disease is rare, unclear genotype–phenotype correlations exist in a bevy of cases and the absence of an international short QT registry limit studies on the pathophysiological mechanisms of arrhythmogenesis and therapy of SQTS. This leads to the necessity of experimental models or platforms for studying SQTS. Here, we focus on reviewing preclinical SQTS models and platforms such as animal models, heterologous expression systems, human-induced pluripotent stem cell-derived cardiomyocyte models and computer models as well as three-dimensional engineered heart tissues. We discuss their usefulness for SQTS studies to examine genotype–phenotype associations, uncover disease mechanisms and test drugs. These models might be helpful for providing novel insights into the exact pathophysiological mechanisms of this channelopathy and may offer opportunities to improve the diagnosis and treatment of patients with SQT syndrome.

Abstract 15529: Transgenic Short QT Syndrome Type 1 Rabbits (HERG-N588K) Mimic the Human Phenotype with Shortened Cardiac Repolarization, Ventricular Fibrillation, and Sudden Death

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Katja E Odening ◽  
Gerlind Franke ◽  
Raphaela Rieke ◽  
Anna Topf Aguiar de Medeiros ◽  
Ilona Bodi ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
High Rate ◽  
Monophasic Action Potential ◽  
K Channel ◽  
Cardiac Repolarization ◽  
Detailed Knowledge ◽  
Short Qt Syndrome ◽  
Gain Of Function ◽  
Human Phenotype ◽  
Qt Syndrome

Introduction and Hypothesis: Short QT syndrome is an inherited ion channelopathy with an accelerated cardiac repolarization due to gain-of-function mutations in K+ channel genes. Patients are prone to ventricular tachycardia and sudden cardiac death (SCD). Detailed knowledge about mechanisms of arrhythmogenesis is lacking. We aimed at generating transgenic SQT1 rabbits as novel tool to investigate these mechanisms. Methods: FLAG-HA-tagged HERG-N588K cDNA and the b-MyHC promoter were integrated into a pBSII SK vector and microinjected into rabbit oocytes. SQT1 rabbits and their wildtype (WT) littermates were subjected to in vivo ECG and ex vivo monophasic action potential (AP) measurements. Electrical remodeling was investigated using real-time PCR. Results: We successfully generated 3 transgenic SQT1 founder rabbits. One of the founders died suddenly at the age of 60 days. In SQT1 rabbits (F1) not subjected to any experiments 3/11 died around day 40 vs. 0/8 WT rabbits (p<0.05). SQT1 founder rabbits and their offspring demonstrated a shortened QT interval compared to WT (QT, ms, SQT1, n=44, 147.8±1.7 vs. WT, n=24, 166.4±2.9, p<0.0001, heart-rate corrected QTi, %, 91.6±0.7 vs. 98.1±1.1, p<0.0001) with no gender differences among SQT1 rabbits. Moreover, in SQT1, AP duration was shortened in all segments of LV base, mid, and apex (LV base-lat, APD90, ms, SQT1, n=7, 118.6±5.1 vs. WT, n=9, 154.4±2.2, p<0.0001; APD75, 93.1±6.8 vs. 127.1±1.9, p<0.0001). Ventricular fibrillation (VF) occurred more often during AP measurements in SQT1 than in WT rabbits (SQT1, 5/13 vs. WT, 0/8, p<0.05). FLAG-HA-HERG-N588K channels expressed in HEK cells demonstrated increased IKr steady currents and impaired inactivation indicative of a gain-of-function. Remodeling of ion channels and Ca2+ handling proteins occurred in SQT1 rabbits with a downregulation of L-type Ca2+ channel mRNA in LV septum-mid (SQT1, n=4, 0.84±0.1 vs. WT, n=6, 1.03±0.1, p<0.05) and of RyR2 in LV septum-apex (0.85±0.1 vs. 1.08±0.1, p<0.05). Conclusion: These first transgenic SQT1 rabbits over-expressing a HERG-N588K gain-of-function mutation mimic the human phenotype with shortening of QT and APD, a high rate of VF and SCD. These models are thus a useful tool to explore arrhythmogenic mechanisms in SQTS.

scholarly journals A novel gain-of-function KCNJ2 mutation associated with short-QT syndrome impairs inward rectification of Kir2.1 currents

2011 ◽  
Vol 93 (4) ◽  
pp. 666-673 ◽  
Author(s):  
T. Hattori ◽  
T. Makiyama ◽  
M. Akao ◽  
E. Ehara ◽  
S. Ohno ◽  
...  
Keyword(s):  
Inward Rectification ◽  
Short Qt Syndrome ◽  
Gain Of Function ◽  
Qt Syndrome

Abstract 16213: Short QT Syndrome Case Study

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Lawrenshey Charles ◽  
Abdullah Al-Abcha ◽  
Tyler Kemnic ◽  
Zulfiqar Qutrio Baloch
Keyword(s):  
Atrial Fibrillation ◽  
Heart Rate ◽  
Sudden Cardiac Death ◽  
Sinus Rhythm ◽  
Cardiac Death ◽  
Normal Sinus Rhythm ◽  
Short Qt Syndrome ◽  
Icd Implantation ◽  
Normal Sinus ◽  
Qt Syndrome

Introduction: Short QT syndrome (SQTS) is a very rare genetic disease of the electrical system of the heart which is associated with an increase risk of abnormal cardiac rhythms and sudden cardiac death. First described in 2000 with the first genetic mutation associated with SQTS described in 2004. We present a case of Short QT syndrome in a 53 year old male. Case: A 53 year old male with a PMH of HTN, alcohol abuse, and tobacco dependence presented to the ED with palpitations. Patient endorsed that he was in his usual state of health the day prior to arrival. He went to bed after drinking alcohol and woke up suddenly pale and diaphoretic with dyspnea and a persistent feeling of impending doom. On arrival to the ED, he was tachypneic (26 breaths/min) with a heart rate of 163 bpm and a blood pressure of 100/80 mmHg. EKG showed atrial fibrillation with RVR. The patient converted to normal sinus rhythm after one dose of IV Cardizem 10 mg was administered for rate control. The next day he had multiple episodes of Torsades de Pointe and monomorphic ventricular tachycardia treated with synchronized cardioversion, 2g of magnesium, IV amiodarone and lidocaine drip. He was transferred to the ICU for further evaluation and monitoring. Repeat EKG showed normal sinus rhythm at 75 bpm and short QT (QT= 328). TTE showed normal biventricular size and function (LVEF 60-65%) with no valvular abnormalities. Dual chamber Implantable Cardioverter Defibrillator (ICD) was placed and outpatient genetic testing was scheduled. Discussion: SQTS is very rare with roughly 70 cases identified worldwide since the condition was discovered in 2000. It is a congenital channelopathy related to potassium channels and represented by a normal heart rate with accelerated cardiac repolarization. Normal QT range is 350-440 msec while SQTS range is 210-340 msec. Mutations in the KCNH2, KCNJ2, or KCNQ1 genes lead to enhanced flow of potassium ions across the membrane of cardiac muscle cells. Patients can present at any age with palpitations, syncope, atrial fibrillation, and sudden cardiac death. The cornerstone to diagnosing SQTS is an electrocardiogram. Patients with SQTS can be managed with ICD implantation, quinidine (especially with KCNH2 mutation), and sotalol (with other mutations other than KCNH2).

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