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https://www.readbyqxmd.com/read/28445755/mapping-ryanodine-binding-sites-in-the-pore-cavity-of-ryanodine-receptors
#1
Van A Ngo, Laura L Perissinotti, Williams Miranda, S R Wayne Chen, Sergei Y Noskov
Ryanodine (Ryd) irreversibly targets ryanodine receptors (RyRs), a family of intracellular calcium release channels essential for many cellular processes ranging from muscle contraction to learning and memory. Little is known of the atomistic details about how Ryd binds to RyRs. In this study, we used all-atom molecular dynamics simulations with both enhanced and bidirectional sampling to gain direct insights into how Ryd interacts with major residues in RyRs that were experimentally determined to be critical for its binding...
April 25, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28428008/force-development-and-intracellular-ca-2-in-intact-cardiac-muscles-from-gravin-mutant-mice
#2
Zhitao Li, Sonal Singh, Santosh V Suryavanshi, Wengang Ding, Xiaoxu Shen, Cori S Wijaya, Wei Dong Gao, Bradley K McConnell
Gravin (AKAP12) is an A-kinase-anchoring-protein that scaffolds protein kinase A (PKA), β2-adrenergic receptor (β2-AR), protein phosphatase 2B and protein kinase C. Gravin facilitates β2-AR-dependent signal transduction through PKA to modulate cardiac excitation-contraction coupling and its removal positively affects cardiac contraction. Trabeculae from the right ventricles of gravin mutant (gravin-t/t) mice were employed for force determination. Simultaneously, corresponding intracellular Ca(2+) transient ([Ca(2+)]i) were measured...
April 17, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28422759/ryr2r420q-catecholaminergic-polymorphic-ventricular-tachycardia-mutation-induces-bradycardia-by-disturbing-the-coupled-clock-pacemaker-mechanism
#3
Yue Yi Wang, Pietro Mesirca, Elena Marqués-Sulé, Alexandra Zahradnikova, Olivier Villejoubert, Pilar D'Ocon, Cristina Ruiz, Diana Domingo, Esther Zorio, Matteo E Mangoni, Jean-Pierre Benitah, Ana María Gómez
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal genetic arrhythmia that manifests syncope or sudden death in children and young adults under stress conditions. CPVT patients often present bradycardia and sino-atrial node (SAN) dysfunction. However, the mechanism remains unclear. We analyzed SAN function in two CPVT families and in a novel knock-in (KI) mouse model carrying the RyR2R420Q mutation. Humans and KI mice presented slower resting heart rate. Accordingly, the rate of spontaneous intracellular Ca2+ ([Ca2+]i) transients was slower in KI mouse SAN preparations than in WT, without any significant alteration in the "funny" current (If )...
April 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28405885/sudden-death-due-to-catecholaminergic-polymorphic-ventricular-tachycardia-following-negative-stress-test-outcome-genetics-and-clinical-implications
#4
Cristian D'Ovidio, Aldo Carnevale, Vincenzo M Grassi, Enrica Rosato, Bernat Del Olmo, Monica Coll, Oscar Campuzano, Anna Iglesias, Ramon Brugada, Antonio Oliva
This paper discusses the case of a young boy who died suddenly during a football match. The victim's personal and family medical histories were negative for cardiac events. He had undergone a cardiological investigation some months before his death, enabling him to participate in competitive sports. Only post-mortem molecular analysis allowed for a clearer determination of the most plausible cause of death, which was identified as inherited arrhythmogenic heart disease, known as catecholaminergic polymorphic ventricular tachycardia...
April 13, 2017: Forensic Science, Medicine, and Pathology
https://www.readbyqxmd.com/read/28404607/interpreting-incidentally-identified-variants-in-genes-associated-with-catecholaminergic-polymorphic-ventricular-tachycardia-in-a-large-cohort-of-clinical-whole-exome-genetic-test-referrals
#5
Andrew P Landstrom, Andrew L Dailey-Schwartz, Jill A Rosenfeld, Yaping Yang, Margaret J McLean, Christina Y Miyake, Santiago O Valdes, Yuxin Fan, Hugh D Allen, Daniel J Penny, Jeffrey J Kim
BACKGROUND: The rapid expansion of genetic testing has led to increased utilization of clinical whole-exome sequencing (WES). Clinicians and genetic researchers are being faced with assessing risk of disease vulnerability from incidentally identified genetic variants which is typified by variants found in genes associated with sudden death-predisposing catecholaminergic polymorphic ventricular tachycardia (CPVT). We sought to determine whether incidentally identified variants in genes associated with CPVT from WES clinical testing represent disease-associated biomarkers...
April 2017: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/28389603/the-impact-of-ryr2-potentiation-on-myocardial-function
#6
Elena Lascano, Jorge A Negroni, Martin Vila Petroff, Alicia Mattiazzi
This perspective attempts to shed light on an old and not yet solved controversy in cardiac physiology, i.e. the impact of increasing RyR2 open probability on myocardial function. Based on an already proved myocyte model, it is shown that increasing RyR2 open probability results in a purely short-lived increase in Ca(2+) transient amplitude, and therefore it does not increase cardiac contractility. However, potentiation of RyR2 activity permanently enhances fractional Ca(2+) release, shifting the intracellular Ca(2+) transient vs SR Ca(2+) content curve to a new state of higher efficiency...
April 7, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28374413/beneficial-effects-of-leptin-treatment-in-a-setting-of-cardiac-dysfunction-induced-by-transverse-aortic-constriction-in-mouse
#7
Nieves Gómez-Hurtado, Alejandro Domínguez-Rodríguez, Philippe Mateo, Maria Fernandez-Velasco, Almudena Val-Blasco, Rafael Aizpún, Jessica Sabourin, Ana Maria Gómez, Jean-Pierre Benitah, Carmen Delgado
KEY POINTS: Leptin, is a 16 kDa pleiotropic peptide, primary secreted by adipocytes, but also produced by other tissues including the heart. Controversy exists regarding the adverse and beneficial effects of Leptin on the heart We analysed the effect of a non-hypertensive dose of leptin on cardiac function, [Ca(2+) ]i handling and cellular electrophysiology, which participate in the genesis of pump failure and related arrhythmias both in control mice and in mice subjected to chronic pressure-overload by transverse aorta constriction We find that Leptin activates mechanisms that contribute to cardiac dysfunction in physiological conditions...
April 4, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28370799/through-modulation-of-cardiac-ca-2-handling-ucp2-affects-cardiac-electrophysiology-and-influences-the-susceptibility-for-ca-2-mediated-arrhythmias
#8
Robert Larbig, Sara Reda, Vera Paar, Andrea Trost, Johannes Leitner, Stephanie Weichselbaumer, Karolina A Motloch, Bernhard Wernly, Andreas Arrer, Benjamin Strauss, Michael Lichtenauer, Herbert A Reitsamer, Lars Eckardt, Guiscard Seebohm, Uta C Hoppe, Lukas J Motloch
Introduction UCP2 belongs to a superfamily of mitochondrial ion transporters. Due to its beneficial influence on production of reactive oxygen species it is suggested to reduce cardiac ischemic reperfusion injury. Recent studies uncovered its ability to regulate mitochondrial Ca(2+) -uptake and therefore to influence cardiac cytosolic Ca(2+) -handling, indicating compensatory pathways to avoid toxic Ca(2+) -overload in UCP2 knock-out mice (UCP2(-/-) ). However, the specific mechanisms and their impact on cardiac electrophysiology remain speculative...
March 31, 2017: Experimental Physiology
https://www.readbyqxmd.com/read/28369767/multiple-targets-for-flecainide-action-implications-for-cardiac-arrhythmogenesis
#9
REVIEW
Samantha C Salvage, Karthik H Chandrasekharan, Kamalan Jeevaratnam, Angela F Dulhunty, Andrew J Thompson, Antony P Jackson, Christopher L-H Huang
Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia, arrhythmic long QT syndromes (LQTS), as well as the Ca(2+) -mediated, catecholaminergic polymorphic ventricular, tachycardia (CPVT). However, flecainide can also exert pro-arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada Syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting, levels of cellular organisation...
April 3, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28359509/autosomal-recessive-cardiomyopathy-presenting-as-acute-myocarditis
#10
Serkan Belkaya, Amy R Kontorovich, Minji Byun, Sonia Mulero-Navarro, Fanny Bajolle, Aurelie Cobat, Rebecca Josowitz, Yuval Itan, Raphaelle Quint, Lazaro Lorenzo, Soraya Boucherit, Cecile Stoven, Sylvie Di Filippo, Laurent Abel, Shen-Ying Zhang, Damien Bonnet, Bruce D Gelb, Jean-Laurent Casanova
BACKGROUND: Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon (IFN)-α/β immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3, a potent inducer of IFNs, were proposed to underlie AVM...
April 4, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/28356340/analysis-of-cardiac-myocyte-maturation-using-casaav-a-platform-for-rapid-dissection-of-cardiac-myocyte-gene-function-in-vivo
#11
Yuxuan Guo, Nathan J VanDusen, Lina Zhang, Weiliang Gu, Isha Sethi, Silvia Guatimosim, Qing Ma, Blake D Jardin, Yulan Ai, Donghui Zhang, Biyi Chen, Ang Guo, Guo-Cheng Yuan, Long-Sheng Song, William T Pu
Rationale: Loss-of-function studies in cardiac myocytes (CMs) are currently limited by the need for appropriate conditional knockout alleles. The factors that regulate CM maturation are poorly understood. Prior studies on CM maturation have been confounded by heart dysfunction caused by whole organ gene inactivation. Objective: To develop a new technical platform to rapidly characterize cell-autonomous gene function in postnatal murine CMs and apply it to identify genes that regulate T-tubules, a hallmark of mature cardiac myocytes...
March 29, 2017: Circulation Research
https://www.readbyqxmd.com/read/28349937/biodegradable-polymeric-nanocapsules-prevent-cardiotoxicity-of-anti-trypanosomal-lychnopholide
#12
Renata Tupinambá Branquinho, Jérôme Roy, Charlotte Farah, Giani Martins Garcia, Franck Aimond, Jean-Yves Le Guennec, Dênia Antunes Saude-Guimarães, Andrea Grabe-Guimaraes, Vanessa Carla Furtado Mosqueira, Marta de Lana, Sylvain Richard
Chagas disease is a neglected parasitic disease caused by the protozoan Trypanosoma cruzi. New antitrypanosomal options are desirable to prevent complications, including a high rate of cardiomyopathy. Recently, a natural substance, lychnopholide, has shown therapeutic potential, especially when encapsulated in biodegradable polymeric nanocapsules. However, little is known regarding possible adverse effects of lychnopholide. Here we show that repeated-dose intravenous administration of free lychnopholide (2...
March 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28332202/calcium-signalling-silencing-in-atrial-fibrillation
#13
Maura Greiser
Sub-cellular calcium signalling silencing is a novel and distinct cellular and molecular adaptive response to rapid cardiac activation. Calcium signalling silencing develops during short-term sustained rapid atrial activation as seen clinically during paroxysmal atrial fibrillation (AF). It is the first 'anti-arrhythmic' adaptive response in the setting of AF and appears to counteract the maladaptive changes that lead to intracellular Ca(2+) signalling instability and Ca(2+) based arrhythmogenicity. Calcium signalling silencing results in a failed propagation of the [Ca(2+) ]i signal to the myocyte centre in both patients with AF and in a rabbit model...
March 22, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28316073/arrhythmic-effects-of-epac-mediated-ryanodine-receptor-activation-in-langendorff-perfused-murine-hearts-are-associated-with-reduced-conduction-velocity
#14
Mengye Li, Sandeep Hothi, Samantha C Salvage, Kamalan Jeevaratnam, Andrew A Grace, Christopher L-H Huang
Recent papers have attributed arrhythmic substrate in murine RyR2-P2328S hearts to reduced action potential (AP) conduction velocities (CV), reflecting acute functional inhibition and/or reduced expression of sodium channels. We explored for acute effects of direct Epac (exchange protein directly activated by cAMP)-mediated ryanodine receptor-2 (RyR2) activation on arrhythmic substrate and CV. Monophasic action potential recordings demonstrated that initial steady (8-Hz) extrinsic pacing elicited ventricular tachycardia (VT) in 0 of 18 Langendorff-perfused wild-type mouse ventricles before pharmacological intervention...
March 18, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/28237968/nationwide-experience-of-catecholaminergic-polymorphic-ventricular-tachycardia-caused-by-ryr2-mutations
#15
Anders Krogh Broendberg, Jens Cosedis Nielsen, Jesper Bjerre, Lisbeth Noerum Pedersen, Jens Kristensen, Finn Lund Henriksen, Henning Bundgaard, Henrik Kjaerulf Jensen
OBJECTIVE: The aim of this study was to characterise disease penetrance, course of disease and use of antiarrhythmic medication and implantable cardioverter-defibrillator (ICD) therapy in a Danish nationwide cohort of patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) due to mutations in the ryanodine receptor-2 (RyR2) gene. METHODS: The study population was identified through the national hereditary heart disease database (Progeny). The study population was divided into three groups: probands, symptomatic and asymptomatic relatives...
February 25, 2017: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/28202948/identification-of-pathogenic-variants-in-genes-related-to-channelopathy-and-cardiomyopathy-in-korean-sudden-cardiac-arrest-survivors
#16
Ju Sun Song, Jong-Sun Kang, Young-Eun Kim, Seung-Jung Park, Kyoung-Min Park, June Huh, June Soo Kim, Hana Cho, Chang-Seok Ki, Young Keun On
Pathogenic variants in genes related to channelopathy and cardiomyopathy are the most common cause of sudden unexplained cardiac death. However, few reports have investigated the frequency and/or spectrum of pathogenic variants in these genes in Korean sudden cardiac arrest survivors. This study aimed to investigate the causative genetic variants of cardiac-associated genes in Korean sudden cardiac arrest survivors. We performed exome sequencing followed by filtering and validation of variants in 100 genes related to channelopathy and cardiomyopathy in 19 Korean patients who survived sudden cardiac arrest...
February 16, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28181690/calcium-mediated-cellular-triggered-activity-in-atrial-fibrillation
#17
Dobromir Dobrev, Xander H T Wehrens
Although atrial fibrillation (AF) is the most commonly encountered cardiac arrhythmia, the basic mechanisms underlying this disorder remain incompletely understood. During the past decade or so, it has become clear that alterations in intracellular Ca(2+) handling may play a role in the pathogenesis of AF. Studies in small and large animal models, as well as atrial samples from patients with different forms of AF have implicated ryanodine receptor type 2 (RyR2) dysfunction and enhanced spontaneous Ca(2+) release events from the sarcoplasmic reticulum (SR) as a potential cause of proarrhythmic cellular ectopic (triggered) activity in AF...
February 9, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28179314/dna-methylation-in-breast-tumor-from-high-risk-women-in-the-breast-cancer-family-registry
#18
Hui-Chen Wu, Melissa C Southey, Hanina Hibshoosh, Regina M Santella, Mary Beth Terry
To examine DNA methylation profiles in breast tumors of women with a strong breast cancer family history, we measured methylation by bisulfite sequencing in 40 genes in 40 breast tumor tissues from women in the Breast Cancer Family Registry. We selected candidate genes from analysis of the Cancer Genome Atlas project (TCGA) breast data. Compared to TCGA breast cancer, BCFR cases are younger and more likely to be ER-negative. Overall, we found that many of the methylation differences between BCFR tumor and normal adjacent tissues were smaller than that in TCGA samples...
2017: Anticancer Research
https://www.readbyqxmd.com/read/28179209/administration-of-anabolic-steroid-during-adolescence-induces-long-term-cardiac-hypertrophy-and-increases-susceptibility-to-ischemia-reperfusion-injury-in-adult-wistar-rats
#19
Fernando de Azevedo Cruz Seara, Raiana Andrade Quintanilha Barbosa, Dahienne Ferreira de Oliveira, Diorney Luiz Souza Gran da Silva, Adriana Bastos Carvalho, Andrea Claudia Freitas Ferreira, José Hamilton Matheus Nascimento, Emerson Lopes Olivares
Chronic administration of anabolic androgenic steroids (AAS) in adult rats results in cardiac hypertrophy and increased susceptibility to myocardial ischemia/reperfusion (IR) injury. Molecular analyses demonstrated that hyperactivation of type 1 angiotensin II (AT1) receptor mediates cardiac hypertrophy induced by AAS and also induces down-regulation of myocardial ATP-sensitive potassium channel (KATP), resulting in loss of exercise-induced cardioprotection. Exposure to AAS during adolescence promoted long-term cardiovascular dysfunctions, such as dysautonomia...
February 5, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28164397/four-main-active-ingredients-derived-from-a-traditional-chinese-medicine-guanxin-shutong-capsule-cause-cardioprotection-during-myocardial-ischemia-injury-calcium-overload-suppression
#20
Feng Liu, Zhuang-Zhuang Huang, Yu-Hong Sun, Ting Li, Dong-Hua Yang, Gang Xu, Ying-Ying Su, Tao Zhang
Guanxin Shutong capsule is a traditional Chinese medicine for the treatment of myocardial ischemia (MI). Previous studies have shown that the formula has four main active ingredients (FMAI), protocatechuic acid, cryptotanshinone, borneol, and eugenol. However, the mechanisms of action of these FMAI against MI injury are still not well known. The aim of the present study was to evaluate the protective effects of the FMAI on MI in vitro and in vivo. In vitro, rat neonatal cardiomyocytes were isolated, the cell viability and apoptosis rate were, respectively, measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method and fluorescence activating cell sorter, and the intracellular calcium concentration ([Ca(2+) ]i ) and CaM and CaMKII δ mRNA as well as protein levels were determined...
February 6, 2017: Phytotherapy Research: PTR
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