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Xiao-Dong Zhang, Zana A Coulibaly, Wei Chun Chen, Hannah A Ledford, Jeong Han Lee, Padmini Sirish, Gu Dai, Zhong Jian, Frank Chuang, Ingrid Brust-Mascher, Ebenezer N Yamoah, Ye Chen-Izu, Leighton T Izu, Nipavan Chiamvimonvat
Small-conductance Ca2+ -activated K+ (SK) channels regulate the excitability of cardiomyocytes by integrating intracellular Ca2+ and membrane potentials on a beat-to-beat basis. The inextricable interplay between activation of SK channels and Ca2+ dynamics suggests the pathology of one begets another. Yet, the exact mechanistic underpinning for the activation of cardiac SK channels remains unaddressed. Here, we investigated the intracellular Ca2+ microdomains necessary for SK channel activation. SK currents coupled with Ca2+ influx via L-type Ca2+ channels (LTCCs) continued to be elicited after application of caffeine, ryanodine or thapsigargin to deplete SR Ca2+ store, suggesting that LTCCs provide the immediate Ca2+ microdomain for the activation of SK channels in cardiomyocytes...
March 16, 2018: Scientific Reports
David J Tester, Leonie C H Wong, Pritha Chanana, Amie Jaye, Jared M Evans, David R FitzPatrick, Margaret J Evans, Peter Fleming, Iona Jeffrey, Marta C Cohen, Jacob Tfelt-Hansen, Michael A Simpson, Elijah R Behr, Michael J Ackerman
BACKGROUND: Sudden infant death syndrome (SIDS) is a leading cause of postneonatal mortality. Genetic heart diseases (GHDs) underlie some cases of SIDS. OBJECTIVES: This study aimed to determine the spectrum and prevalence of GHD-associated mutations as a potential monogenic basis for SIDS. METHODS: A cohort of 419 unrelated SIDS cases (257 male; average age 2.7 ± 1.9 months) underwent whole exome sequencing and a targeted analysis of 90 GHD-susceptibility genes...
March 20, 2018: Journal of the American College of Cardiology
Uma Mahesh R Avula, Jonathan J Hernandez, Masatoshi Yamazaki, Carmen R Valdivia, Antony Chu, Alvaro Rojas-Pena, Kuljeet Kaur, Roberto Ramos-Mondragón, Justus M Anumonwo, Stanley Nattel, Héctor H Valdivia, Jérôme Kalifa
BACKGROUND: The mechanisms underlying spontaneous atrial fibrillation (AF) associated with atrial ischemia/infarction are incompletely elucidated. Here, we investigate the mechanisms underlying spontaneous AF in an ovine model of left atrial myocardial infarction (LAMI). METHODS AND RESULTS: LAMI was created by ligating the atrial branch of the left anterior descending coronary artery. ECG loop recorders were implanted to monitor AF episodes. In 7 sheep, dantrolene-a ryanodine receptor blocker-was administered in vivo during the 8-day observation period (LAMI-D, 2...
March 2018: Circulation. Arrhythmia and Electrophysiology
Katsuhito Matsuki, Daiki Kato, Masashi Takemoto, Yoshiaki Suzuki, Hisao Yamamura, Susumu Ohya, Hiroshi Takeshima, Yuji Imaizumi
Physiological functions of type 3 ryanodine receptors (RyR3) in smooth muscle (SM) tissues are not well understood, in spite of their wide expression. However, the short isoform of RyR3 is known to be a dominant negative variant (DN-RyR3), which may negatively regulate functions of both RyR2 and full length (FL)-RyR3 by forming hetero-tetramers. Here, functional roles of RyR3 in the regulation of Ca2+ signaling in mesenteric artery SM cells (MASMCs) were examined using RyR3 homozygous knockout mice (RyR3-/- )...
March 14, 2018: American Journal of Physiology. Cell Physiology
Tian Li, Yafeng Shen, Li Su, Xiaoyan Fan, Fangxing Lin, Xuting Ye, Dianer Ding, Ying Tang, Yang Yongji, Changhai Lei, Shi Hu
Post-ischemic heart failure is a major cause of death worldwide. Reperfusion of infarcted heart tissue after myocardial infarction has been an important medical intervention to improve outcomes. However, disturbances in Ca2+ and redox homeostasis at the cellular level caused by ischemia/reperfusion remain major clinical challenges. In this study, we investigated the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of a Type-2 ryanodine receptor (RyR2) degradation-associated gene, Presenilin 1 (PSEN1), to combat post-ischemic heart failure...
March 9, 2018: Journal of Drug Targeting
Elisa Bovo, Stefan R Mazurek, Aleksey V Zima
Defective Ca2+ regulation plays a key role in the blunted force-frequency response in heart failure (HF). Since HF is commonly associated with oxidative stress, we studied whether oxidation of ryanodine receptor (RyR2) contributes to this defect. In control ventricular myocytes, oxidative stress induced formation of disulfide bonds between RyR2 subunits: intersubunit cross-linking (XL). Western blot analysis and Ca2+ imaging revealed a strong positive correlation between RyR2 XL and sarcoplasmic reticulum (SR) Ca2+ leak...
March 2, 2018: Pflügers Archiv: European Journal of Physiology
C M Mak, S Pl Chen, N S Mok, W K Siu, H Hc Lee, C K Ching, P T Tsui, N C Fong, Y P Yuen, W T Poon, C Y Law, Y K Chong, Y W Chan, T C Yung, K Yy Fan, C W Lam
INTRODUCTION: Hereditary channelopathies and cardiomyopathies are potentially lethal and are clinically and genetically heterogeneous, involving at least 90 genes. Genetic testing can provide an accurate diagnosis, guide treatment, and enable cascade screening. The genetic basis among the Hong Kong Chinese population is largely unknown. We aimed to report on 28 unrelated patients with positive genetic findings detected from January 2006 to December 2015. METHODS: Sanger sequencing was performed for 28 unrelated patients with a clinical diagnosis of channelopathies or cardiomyopathies, testing for the following genes: KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A, for long QT syndrome; SCN5A for Brugada syndrome; RYR2 for catecholaminergic polymorphic ventricular tachycardia; MYH7 and MYBPC3 for hypertrophic cardiomyopathy; LMNA for dilated cardiomyopathy; and PKP2 and DSP for arrhythmogenic right ventricular dysplasia/cardiomyopathy...
March 2, 2018: Hong Kong Medical Journal, Xianggang Yi Xue za Zhi
Jozef Klučka, Tomáš Juřenčák, Petr Štourač, Pavel Vít, Vladimíra Foralová, Iva Synková
Out-of-hospital cardiac arrest in pediatric population is rare and predominantly has respiratory aetiology. Authors present the relatively unique case of out-of hospital cardiac arrest in 5-years old pediatric patient due to ventricular fibrillation (VF) as the initial rhythm during the advanced life support. The patient was resuscitated by his parents and the initial rhythm was VF. After defibrillation the patient was admitted to the pediatric intensive care were another two episodes of VF was detected and treated...
February 28, 2018: Pediatric Emergency Care
Jing Xiong, Xijun Liu, Yunyun Gong, Peng Zhang, Sujing Qiang, Qian Zhao, Rong Guo, Yunyun Qian, Lipeng Wang, Li Zhu, Ruiwu Wang, Zhiyuan Hao, Han Wen, Jingying Zhang, Kai Tang, Wang-Fu Zang, Zhiguang Yuchi, Haijun Chen, S R Wayne Chen, Wenjun Zheng, Shi-Qiang Wang, Ya-Wei Xu, Zheng Liu
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a condition that is characterized by an abnormal heart rhythm in response to physical or emotional stress. The majority CPVT patients carry mutations in the RYR2 gene that encodes the calcium release channel/ryanodine receptor (RyR2) in cardiomyocytes. The pathogenic mechanisms that account for the clinical phenotypes of CPVT are still elusive. We have identified a de novo mutation, A165D, from a CPVT patient. We found that CPVT phenotypes are recapitulated in A165D knock-in mice...
February 22, 2018: Journal of Molecular and Cellular Cardiology
Kenji Suita, Takayuki Fujita, Wenqian Cai, Yuko Hidaka, Huiling Jin, Rajesh Prajapati, Masanari Umemura, Utako Yokoyama, Motohiko Sato, Björn C Knollmann, Satoshi Okumura, Yoshihiro Ishikawa
Sympathetic activation causes clinically important arrhythmias including atrial fibrillation (AF) and ventricular tachyarrhythmia. Although the usefulness of β-adrenergic receptor blockade therapy is widely accepted, its multiple critical side effects often prevent its initiation or continuation. The aim of this study is to determine the advantages of vidarabine, an adenylyl cyclase (AC)-targeted anti-sympathetic agent, as an alternative treatment for arrhythmia. We found that vidarabine, which we identified as a cardiac AC inhibitor, consistently shortens AF duration and reduces the incidence of sympathetic activation-induced ventricular arrhythmias...
February 16, 2018: Pflügers Archiv: European Journal of Physiology
Peter J Schwartz, Maria-Christina Kotta
No abstract text is available yet for this article.
February 2018: Circ Genom Precis Med
Jamie D Kapplinger, Krishna N Pundi, Nicholas B Larson, Thomas E Callis, David J Tester, Hennie Bikker, Arthur A M Wilde, Michael J Ackerman
BACKGROUND: Pathogenic RYR2 variants account for ≈60% of clinically definite cases of catecholaminergic polymorphic ventricular tachycardia. However, the rate of rare benign RYR2 variants identified in the general population remains a challenge for genetic test interpretation. Therefore, we examined the results of the RYR2 genetic test among patients referred for commercial genetic testing and examined factors impacting variant interpretability. METHODS: Frequency and location comparisons were made for RYR2 variants identified among 1355 total patients of varying clinical certainty and 60 706 Exome Aggregation Consortium controls...
February 2018: Circ Genom Precis Med
Seung Min Baek, Hyun Chung, Mi Kyoung Song, Eun Jung Bae, Gi Beom Kim, Chung Il Noh
BACKGROUND AND OBJECTIVES: Multifocal atrial tachycardia (MAT), in general, has a favorable outcome. However, there are insufficient data regarding MAT in a pediatric population. This study sought to determine the clinical course of MAT and identify potential prognostic factors. METHODS: The medical records of MAT patients from 1997-2015 were reviewed. The arrhythmia control rate and factors for unfavorable outcomes were assessed and compared to those in the literature...
February 2018: Korean Circulation Journal
Gina Sánchez, Felipe Araneda, Juan Pedro Peña, José Pablo Finkelstein, Jaime A Riquelme, Luis Montecinos, Genaro Barrientos, Paola Llanos, Zully Pedrozo, Matilde Said, Ricardo Bull, Paulina Donoso
Ventricular arrhythmias are a common cause of sudden cardiac death, and their occurrence is higher in obese subjects. Abnormal gating of ryanodine receptors (RyR2), the calcium release channels of the sarcoplasmic reticulum, can produce ventricular arrhythmias. Since obesity promotes oxidative stress and RyR2 are redox-sensitive channels, we investigated whether the RyR2 activity was altered in obese mice. Mice fed a high fat diet (HFD) became obese after eight weeks and exhibited a significant increase in the occurrence of ventricular arrhythmias...
February 10, 2018: International Journal of Molecular Sciences
Kazuaki Miyata, Seiko Ohno, Hideki Itoh, Minoru Horie
Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal inherited disease characterized by ventricular arrhythmias induced by physical exercise or emotional stress. The major cause of CPVT is mutations in RYR2, which encodes the cardiac ryanodine receptor channel. Recent advances in sequencing technology have yielded incidental findings of RYR2 variants in other cardiac diseases. Analyzing the characteristics of RYR2 variants related to CPVT will be useful for differentiation from those related to other cardiac diseases...
February 9, 2018: Internal Medicine
Shigehiko Nishimura, Takeshi Yamamoto, Yoshihide Nakamura, Michiaki Kohno, Yoriomi Hamada, Yoko Sufu, Go Fukui, Takuma Nanno, Hironori Ishiguchi, Takayoshi Kato, Xiaojuan Xu, Makoto Ono, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
BACKGROUND: Ryanodine receptor (RyR2) is known to be a causal gene of catecholaminergic polymorphic ventricular tachycardia (CPVT) as an important inherited disease. Some of the human CPVT-associated mutations were found in a domain (4026-4172), which has EF hand motifs; so-called calmodulin (CaM)-like domain (CaMLD). OBJECTIVE: To investigate the underlying mechanism by which CPVT is induced with mutation at CaMLD. METHODS: We newly generated N4103K/+ knock-in (KI) mice model...
February 7, 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
Shinichi Okuda, Yoko Sufu-Shimizu, Takayoshi Kato, Masakazu Fukuda, Shigehiko Nishimura, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Sachio Morimoto, Masafumi Yano
AIMS: Cardiac Troponin T (TnT) mutation-linked familial hypertrophic cardiomyopathy (FHC) is known to cause sudden cardiac death at a young age. Here, we investigated the role of the Ca2+ release channel of the cardiac sarcoplasmic reticulum (SR), ryanodine receptor (RyR2), in the pathogenic mechanism of lethal arrhythmia in FHC-related TnT-mutated transgenic mice (TG; TnT-delta160E). METHODS AND RESULTS: In TG cardiomyocytes, the Ca2+ spark frequency (SpF) was much higher than that in non-TG cardiomyocytes...
January 31, 2018: Biochemical and Biophysical Research Communications
Alexander Kondrashov, Minh Duc Hoang, James Smith, Jamie Bhagwan, Gary Duncan, Diogo Mosqueira, Maria Munoz, Nguyen T N Vo, Chris Denning
Modelling disease with hPSCs is hindered because the impact on cell phenotype from genetic variability between individuals can be greater than from the pathogenic mutation. While 'footprint-free' Cas9/CRISPR editing solves this issue, existing approaches are inefficient or lengthy. Here, a simplified PiggyBac strategy shortened hPSC editing by 2 weeks and required one round of clonal expansion and genotyping rather than two, with similar efficiencies to the longer conventional process. Success was shown across 4 cardiac-associated loci (ADRB2, GRK5, RYR2, ACTC1) by genomic cleavage and editing efficiencies of 8-93% and 8-67%, respectively, including mono- and/or bi-allelic events...
February 5, 2018: Stem Cells and Development
Florian Hiess, Pascal Detampel, Carme Nolla-Colomer, Alex Vallmitjana, Anutosh Ganguly, Matthias Amrein, Henk E D J Ter Keurs, Raul Benítez, Leif Hove-Madsen, S R Wayne Chen
Cardiac ryanodine receptors (RyR2s) are Ca2+ release channels clustering in the sarcoplasmic reticulum membrane. These clusters are believed to be the elementary units of Ca2+ release. The distribution of these Ca2+ release units plays a critical role in determining the spatio-temporal profile and stability of sarcoplasmic reticulum Ca2+ release. RyR2 clusters located in the interior of cardiomyocytes are arranged in highly ordered arrays. However, little is known about the distribution and function of RyR2 clusters in the periphery of cardiomyocytes...
January 23, 2018: Biophysical Journal
Advithi Rangaraju, Shuba Krishnan, G Aparna, Satish Sankaran, Ashraf U Mannan, B Hygriv Rao
Electrical storm (ES) is a life threatening clinical situation. Though a few clinical pointers exist, the occurrence of ES in a patient with remote myocardial infarction (MI) is generally unpredictable. Genetic markers for this entity have not been studied. In the present study, we carried out genetic screening in patients with remote myocardial infarction presenting with ES by next generation sequencing and identified 25 rare variants in 19 genes predominantly in RYR2, SCN5A, KCNJ11, KCNE1 and KCNH2, CACNA1B, CACNA1C, CACNA1D and desmosomal genes - DSP and DSG2 that could potentially be implicated in electrical storm...
January 30, 2018: Indian Pacing and Electrophysiology Journal
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