Posts Tagged: cardiac arrhythmias

Calcium Signaling and Cardiac Arrhythmias

Calcium Signaling and Cardiac Arrhythmias

Andrew P. Landstrom, Dobromir Dobrev, Xander H.T. Wehrens

Ryanodine receptor type-2 (RyR2) macromolecular complex. Cartoon representing RyR2 pore-forming subunits with accessory proteins that bind to and/or modulate channel function. CaM indicates calmodulin; CaMKII, Ca2+/calmodulin-dependent protein kinase II; CASQ2, calsequestrin-2; FKBP12.6, FK506-binding protein-12.6; JCTN, junctin; JPH2, juncophilin-2; PKA, protein kinase A; PM, plasma membrane; PP, protein phosphatase; SR, sarcoplasmic reticulum; TECRL, trans-2,3-enoyl-CoA reductase-like protein; and TRDN; triadin. [Powerpoint File]

Calcium Signaling and Cardiac Arrhythmias

Calcium Signaling and Cardiac Arrhythmias

Andrew P. Landstrom, Dobromir Dobrev, Xander H.T. Wehrens

Role of calcium-handling in excitation–contraction (EC) coupling. A, Schematic overview of key Ca2+-handling proteins involved in EC coupling. B, Schematic diagram of Ca2+ release unit and major components of the JMC (junctional membrane complex). The transverse tubule (TT) and sarcoplasmic reticulum (SR) membranes approximate to form the dyad. BIN1 indicates bridging integrator 1; Cav1.2, L-type Ca2+ channel; CAV3, caveolin-3; JPH2, juncophilin-2; NCX1, Na+/Ca2+ exchanger type-1; PM, plasma membrane; PMCA, plasmalemmal Ca2+-ATPase; RyR2, ryanodine receptor type-2; and SERCA2a, sarco/endoplasmic reticulum ATPase type-2a.* [Powerpoint File]

Genetics of Sudden Cardiac Death

Genetics of Sudden Cardiac Death

Connie R. Bezzina, Najim Lahrouchi, Silvia G. Priori

Schematic representation of a cardiomyocyte displaying the proteins involved in the pathogenesis of the primary electric disorders. A, potassium (IKr; B), calcium (ICaL), and (C) sodium (INa) channel structures and subunits are shown. CASQ2 indicates calsequentrin-2; PLN, cardiac phospholamban; RyR2, ryanodine receptor 2; SERCA2a, sarcoplasmic/endoplasmic reticulum calcium ATPase 2a; and SR, sarcoplasmic reticulum (Illustration credit: Ben Smith). [Powerpoint File]

Genetics of Sudden Cardiac Death

Genetics of Sudden Cardiac Death

Connie R. Bezzina, Najim Lahrouchi, Silvia G. Priori

Schematic representation of a cardiomyocyte exhibiting proteins involved in the pathogenesis of the inherited cardiomyopathies, including sarcomeric, cytoskeletal, desmosomal proteins, and nuclear envelope proteins. MLP indicates cysteine and glycine-rich protein 3 (also known as muscle LIM [Lin-11, Islet-1, Mec-3] protein) (Illustration credit: Ben Smith). [Powerpoint File]

Genetics of Sudden Cardiac Death

Genetics of Sudden Cardiac Death

Connie R. Bezzina, Najim Lahrouchi, Silvia G. Priori

Structure and mutational clusters of RyR2. A, Clusters with frequent mutations are depicted with their location along the protein. Clusters are represented by numbered red lines. Individual mutations outside the canonical clusters are depicted as yellow dots. B, Clusters are represented by boxes, with the amino acid (AA) range of the clusters and the percentage of published mutations for each cluster (AA numbering refers to the human RyR2 protein sequence). The numbers in A correspond to the clusters shown in B. SR indicates sarcoplasmic reticulum (Illustration credit: Ben Smith). [Powerpoint File]

Mechanisms of Sudden Cardiac Death: Oxidants and Metabolism

Mechanisms of Sudden Cardiac Death: Oxidants and Metabolism

Kai-Chien Yang, John W. Kyle, Jonathan C. Makielski, Samuel C. Dudley Jr

Oxidative phosphorylation and reactive oxygen species (ROS) production in mitochondria. The diagrams of the mitochondrial inner membrane show key components of the electron transport chain (ETC) above, and channels and transporters (below). Reducing equivalents nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) produced from the tricarboxylic acid (TCA) cycle feed electrons to the ETC along the mitochondrial inner membrane. The electrons flow through the ETC with the following sequence: complex I and II→coenzyme Q [Q]→complex III→cytochrome C [Cyt C]→complex IV→O2, during which coupled redox reactions drive H+ across the inner membrane, forming the proton gradient and the negative mitochondrial membrane potential (ΔΨm=−150 to −180 mV). The free energy stored in the proton gradient and ΔΨm then drive H+ through the mitochondrial ATP synthase (complex V), converting ADP to ATP. An estimated 0.1% to 1% of the electrons leak prematurely to O2 at complexes I, II, or III, resulting in the formation of superoxide (O2•−). Multiple important mitochondrial channels located on the inner membrane including mitochondrial KATP channels (mito-KATP), the mitochondrial Na+/Ca2+ exchanger (mito-NCX), the inner membrane anion channel (IMAC), the permeability transition pore (PTP), and the mitochondrial calcium uniporter (MCU) also contribute to the regulation of mitochondrial function, myocardial ROS, and cellular cation homeostasis. [Powerpoint File]

Mechanisms of Sudden Cardiac Death: Oxidants and Metabolism

Mechanisms of Sudden Cardiac Death: Oxidants and Metabolism

Kai-Chien Yang, John W. Kyle, Jonathan C. Makielski, Samuel C. Dudley Jr

Effects of metabolic stresses on cardiac ion channel/transporter function. Schematic illustration of the impact of acute (ischemia/hypoxia) and chronic (heart failure and diabetes mellitus) metabolic stresses on cardiac ion channel/transporter function and the electrophysiological consequences. Acidosis during acute ischemia leads to opening of sarcKATP channels, increased activity of Na+/H+ exchanger (NHE), and increased late Na+-current (INa). ATP depletion during ischemia contributes to the opening of sarcKATP channels, as well as impairs the function of Na/K ATPase. Other electrophysiological effects from ischemia include the reduction of peak INa, increased connexin (Cx) conduction, and reduced ryanodine receptor 2 (RyR2) activity. Reduced RyR2 activity during acute ischemia is rapidly reversed on reperfusion, contributing to the spontaneous waves of Ca2+ release and delayed afterdepolarizations (DADs). A few examples of electrophysiological impact from chronic metabolic stresses associated with heart failure and diabetes mellitus are also illustrated: heart failure reduces peak INa and multiple Kv (Ito, IK) currents. Diabetes mellitus is also associated with reduction in Kv currents. The increase in sarcKATP currents lead to action potential duration (APD) shortening, whereas reduced Kv currents and increased late INa lead to prolonged APD and early afterdepolarizations (EADs). Finally, reduced Na/K ATPase activity, increased RyR2 activity, and increased gap junction conduction during ischemia predispose to arrhythmogenic DADs. [Powerpoint File]

Ion Channel Macromolecular Complexes in Cardiomyocytes: Roles in Sudden Cardiac Death

Ion Channel Macromolecular Complexes in Cardiomyocytes: Roles in Sudden Cardiac Death

Hugues Abriel, Jean-Sébastien Rougier, José Jalife

Scheme showing the protein composition of the 3 CaV1.2-macromolecular complexes (dyad, extradyad, and extra t-tubule). (1) The extra t-tubule; CaV1.2 channels, and caveolin-3 (Cav-3); (2) the extradyad: CaV1.2 channels, bridging integrator 1/amphiphysin 2 (Bin1), dysferlin, β2-adrenergic receptor (β2-AR), ahnak1, and calcineurin; and (3) the dyad: CaV1.2 channels, type 2 ryanodine receptor (RyR2), sorcin, and junctophilin 2 (JPH2). Illustration credit: Ben Smith. [Powerpoint File]

Ion Channel Macromolecular Complexes in Cardiomyocytes: Roles in Sudden Cardiac Death

Ion Channel Macromolecular Complexes in Cardiomyocytes: Roles in Sudden Cardiac Death

Hugues Abriel, Jean-Sébastien Rougier, José Jalife

Cav1.2 channel subunits (Cavα1, Cavβ, Cavα2-δ, and Cavγ) and their major interacting proteins. Ahnak1, Nedd4-1(Neural precursor cell Expressed, Developmentally Downregulated 4-1), RGK (Rem, Rem2, Rad, and Gem/Kir), caveolin-3 (Cav-3), protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and ubiquitin carboxyl-terminal hydrolase 2 isoform 45 (USP2-45). Illustration credit: Ben Smith. [Poweproint File]

Cardiac Innervation and Sudden Cardiac Death

Cardiac Innervation and Sudden Cardiac Death

Keiichi Fukuda, Hideaki Kanazawa, Yoshiyasu Aizawa, Jeffrey L. Ardell, Kalyanam Shivkumar

Regulation of cardiac innervation patterning and sudden cardiac death (SCD). Left, Overexpression or lack of semaphorin 3A (sema3A) in endocardium causes unbalanced patterning of sympathetic nerves, which alters the potential for lethal arrhythmia. Appropriate sema3A-mediated sympathetic innervation is crucial for maintenance of arrhythmia-free heart. Middle, Upregulation of secreted nerve growth factor (NGF) from cardiomyocytes in diseased heart may cause lethal arrhythmia and SCD. Right, Downregulation of NGF in diabetic heart induces denervation of cardiac sensory nerve, which leads to silent ischemia and lethal arrhythmia. SG indicates stellate ganglia. Details of these pathways are referenced in the text. [Powerpoint File]

Cardiac Innervation and Sudden Cardiac Death

Cardiac Innervation and Sudden Cardiac Death

Keiichi Fukuda, Hideaki Kanazawa, Yoshiyasu Aizawa, Jeffrey L. Ardell, Kalyanam Shivkumar

Systemic autonomic interactions and crosstalk between cardiomyocyte and sympathetic nerve terminal via humoral factors in diseased heart. This figure shows that central and peripheral mechanism of the heart and brain interaction including the cardiac autonomic efferent (sympathetic and parasympathetic) and afferent (sensory) nerves. Representative promising interventional therapies are also described in the figure. In addition, alteration of cardiac sympathetic nerves occurs in postganglionic fiber. Failing cardiomyocytes induces nerve growth factor (NGF) via endothelin-1 (ET-1)–mediated pathway and leukemia inhibitory factor (LIF). NGF and LIF lead to hyperinnervation (anatomic modulation) and rejuvenation/cholinergic differentiation (functional modulation), respectively. This phenomenon shows the expression of catecholaminergic markers such as tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH) reduced and of cholinergic (choline transporter [CHT], choline acetyltransferase [ChAT]) and juvenile (polysialylated neural cell adhesion molecule [PSA-NCAM]) increased. Ach indicates acetylcholine; BP, blood pressure, CG, intrinsic cardiac ganglia; DRG, dorsal root ganglia; NE, norepinephrine; NTS, solitary tract; PVN, paraventricular nucleus; ROS, reactive oxygen species; RVLM, rostral ventrolateral medulla; SG, stellate ganglia; and TrkA, tropomyosin-related kinase A. [Powerpoint File]

Mathematical Approaches to Understanding and Imaging Atrial Fibrillation: Significance for Mechanisms and Management

Mathematical Approaches to Understanding and Imaging Atrial Fibrillation: Significance for Mechanisms and Management

Natalia A. Trayanova

Geometric models of the atria. A, Volume image of the sheep atria acquired by serial surface imaging (resolution, 50 μm), with a representative slice. Subdivision of atria into different regions as represented by the different colors: right atrium (RA), green; left atrium (LA), blue; Bachman bundle (BB), red; and posterior LA (PLA), yellow. LAA indicates LA appendage; LSPV, left superior pulmonary vein; RAA, RA appendage; and RSPV, right superior pulmonary vein. Images reproduced from Zhao et al50,51 with permission of the publisher. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. B, A model of the fibrotic human atria generated from a patient late gadolinium enhancement (LGE) MRI scan (top left) after segmentation (top right) into normal and fibrotic tissue (fibrotic lesions in red). Reproduced with permission from McDowell et al. [Powerpoint File]

Atrial Fibrillation Therapy Now and in the Future: Drugs, Biologicals, and Ablation

Atrial Fibrillation Therapy Now and in the Future: Drugs, Biologicals, and Ablation

Christopher E. Woods, Jeffrey Olgin

Emerging imaging modalities for atrial fibrillation (AF). A, MRI-based fibrosis imaging of the atria showing the University of Utah Atrial Fibrillation LGE-MRI–based staging system in human. Green areas indicate areas of fibrosis (adapted from Vergara et al72 with permission of the publisher). B, Left atrial rotor with counterclockwise activation in human mapped computationally using the proprietary focal impulse and rotor modulation mapping system (RhythmView, Topera Medical, Lexington, MA; adapted from Narayan et al17 with permission of the publisher). C, Phase mapping of posterior human left atrium during paroxysmal AF showing 2 successive rotations of a rotor near the right pulmonary vein ostia using 252-electrode vest was applied to the patient’s torso for body-surface mapping. The core of the rotor is depicted with a white star. The phases of the voltage propagation period are color coded with blue representing the depolarizing period and green representing the end of the repolarization (adapted from Haissaguerre et al77 with permission of the publisher). D, Endoscopic optical mapping of pulmonary vein (top left) and left ventricle (top right) in swine-isolated heart with a balloon tipped catheter via transeptal approach. Propagation map at successive time points from ventricular image for 1 beat shown below (C.E. Woods, MD, PhD, unpublished data, 2013; courtesy of AUST Development, LLC). Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. [Powerpoint File]

Emerging Directions in the Genetics of Atrial Fibrillation

Emerging Directions in the Genetics of Atrial Fibrillation

Nathan R. Tucker, Patrick T. Ellinor

Known genetic pathways for atrial fibrillation (AF) pathogenesis. Schematic of known AF-related genes derived from previous studies. Genes listed include those where coding variation was identified in familial AF and candidate gene screens, as well as the genes suggested to be implicated in AF based on genome-wide association studies (GWAS). Names listed in red indicate those identified by familial studies and candidate gene screens, whereas those listed in gray are gene targets implicated by GWAS. [Powerpoint File]