Posts in Category: Arrhythmias

Current Interventional and Surgical Management of Congenital Heart Disease: Specific Focus on Valvular Disease and Cardiac Arrhythmias

Current Interventional and Surgical Management of Congenital Heart Disease: Specific Focus on Valvular Disease and Cardiac Arrhythmias

Kimberly A. Holst, Sameh M. Said, Timothy J. Nelson, Bryan C. Cannon, Joseph A. Dearani

Schematic representation of the possible lines of ablation to treat macro reentrant atrial tachycardia in the presence of various atrial anomalies associated with complex congenital heart disease. avn indicates atrioventricular node; CS, coronary sinus; FO, foramen ovale; HV, hepatic vein; IVC, inferior vena cava; LAA, left atrial appendage; LSVC, left superior vena cava; MV, mitral valve; PV, pulmonary valve; RAA, right atrial appendage; RSVC, right superior vena cava; TAPVR, total anomalous pulmonary venous return; and TV, tricuspid valve. Reproduced from Mavroudis et al53 with permission of the publisher. Copyright ©2008, The Society of Thoracic Surgeons. [Powerpoint File]

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Frank Lezoualc’h, Loubina Fazal, Marion Laudette, Caroline Conte

Mechanism of exchange protein directly activated by cAMP (EPAC) activation. cAMP is produced from ATP by adenylyl cyclase (AC) in response to Gαs-coupled G protein–coupled receptors (GPCRs) stimulation and activates its classical downstream effector, cAMP-dependent protein kinase A (PKA). Phosphodiesterases (PDE) degrade cAMP and thereby regulate the duration and intensity of cAMP signaling. EPAC function in a PKA-independent manner and represents a novel mechanism for governing signaling specificity within the cAMP cascade. Binding of cAMP to the high-affinity cyclic nucleotide–binding domain (CNBD-B) of EPAC induces marked conformational changes in the protein, which leads to exposure of the catalytic region for binding of Rap GTPase to catalyze the exchange of GDP for GTP. Rap-GTPase–activating proteins (Rap-GAPs) enhance the intrinsic GTP hydrolysis activity of Rap leading to GTPase inactivation. [Powerpoint File]

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Frank Lezoualc’h, Loubina Fazal, Marion Laudette, Caroline Conte

Overview of key exchange protein directly activated by cAMP (EPAC) functions in the vasculature. In vascular endothelial cells, EPAC1 enhances endothelial barrier (EB) function through various mechanisms. The A-kinase anchoring protein 9 (AKAP9) interacts with EPAC1 to promote microtubule growth thereby contributing to the EPAC1-induced enhancement of EB function. The complex EPAC1–PDE4D at vascular endothelial (VE)-cadherin–bearing cell–cell contacts and the interaction of EPAC1 with Ezrin/radixin/moesin (ERM) molecules stabilize EB function. EPAC1 enhances EB function by modulating Rac (via the Rac-GEFs, Tiam and Vav) and RhoA activity and cortical actin rearrangement. In addition, EPAC1–Rap1 pathway interacts with the Rap1 effectors, Radil and Rasip1 to increase barrier stability. EPAC1, via c-Jun and CCAAT/enhancer-binding protein transcription factors, promotes induction of suppressor of cytokine signaling 3 (SOCS-3), which blocks the proinflammatory action of IL-6. EPAC1 decreases vascular smooth muscle cell (VSMC) proliferation through the inhibition of Early growth response 1 (Egr1) and other factors such as cyclin D1 and S-phase kinase-associated protein-2 (Skp2). EPAC-dependent vasorelaxation involves several mechanisms. Activation of EPAC1–Rap1 signaling inhibits RhoA activity thereby inducing dephosphorylation of myosin light chain (MLC; via MLC phosphatase [MLCP]) and vasorelaxation. EPAC1 also stimulates the ryanodine receptor (RyR) and the subsequent release of Ca2+ from the sarcoplasmic reticulum activates cell surface Ca2+-sensitive large-conductance K+ (BKCa) channels, causing membrane hyperpolarization, closure of voltage-gated Ca2+ channels and a decrease of intracellular Ca2+ concentration ([Ca2+]i), which induces VSMC relaxation. Moreover, EPAC1 induces endothelial-dependent relaxation via activation of endothelial nitric oxide (NO) synthase and NO release. [Powerpoint File]

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Frank Lezoualc’h, Loubina Fazal, Marion Laudette, Caroline Conte

Exchange protein directly activated by cAMP (EPAC) signaling in cardiac remodeling. EPAC1–Rap2 pathway contributes to the hypertrophic effect of β1-adrenergic receptors (β1-AR) via the activation of phospholipase Cε (PLCε) and subsequent production of inositide 1,4,5 trisphosphate (IP3). Acetylation of histones promotes gene expression. The level of histone acetylation (Ac) is modulated by counteracting enzymes called histone acetyltransferases and histone deacetylases (HDACs) that incorporate and remove acetyl groups, respectively. Binding of IP3 to its perinuclear receptor (IP3-R) increases intranuclear Ca2+, which activates Ca2+/calmodulin kinase II (CaMKII) thereby inducing the nuclear export of HDACs and relieving the repression on the transcription factor myocyte enhancer factor (MEF-2). β-Arrestin (β-arr) and phosphodiesterases (PDE) regulate EPAC1 hypertrophic signaling, which also involves calcineurin (CaN) and nuclear factor of activated T cells (NFAT). In addition, EPAC proteins also stimulate ryanodine receptor (RyR) phosphorylation via CaMKII, and subsequent Ca2+ leak from the sarcoplasmic reticulum (SR) may trigger arrhythmia. EPAC1-induced hyperphosphorylation of phospholamban (PLB) may contribute to the development of arrhythmia and heart failure. SERCA indicates SR Ca2+ATPase. [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]

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]

Role of Sodium and Calcium Dysregulation in Tachyarrhythmias in Sudden Cardiac Death

Role of Sodium and Calcium Dysregulation in Tachyarrhythmias in Sudden Cardiac Death

Stefan Wagner, Lars S. Maier, Donald M. Bers

Schematic diagram of cellular Ca fluxes during excitation–contraction coupling. Ca entry via L-type Ca channels triggers Ca-induced Ca release from the sarcoplasmic reticulum (SR), which results in myofilament activation. For relaxation, cytosolic Ca is transported into the SR via SR Ca-ATPase (SERCA2a) and into the extracellular space via sarcolemmal Na/Ca exchanger. Reprinted from Bers6 with permission of the publisher. Copyright ©2000, Wolters Kluwer Health. [Poweroint File]

Role of Sodium and Calcium Dysregulation in Tachyarrhythmias in Sudden Cardiac Death

Role of Sodium and Calcium Dysregulation in Tachyarrhythmias in Sudden Cardiac Death

Stefan Wagner, Lars S. Maier, Donald M. Bers

Proarrhythmogenic mechanisms of enhanced late INa. In systole (upper panel), enhanced late INa leads to action potential (AP) prolongation (1). The longer AP plateau phase increases the likelihood of ICa reactivation (2), which may lead to early afterdepolarizations (EAD, 3). Lower panel, The increased amount of Na influx also results in increased intracellular Na (1), which impairs Ca elimination (2) by the Na/Ca exchanger (either less forward or even increased reverse mode activity). In diastole, the increased intracellular Ca facilitates SR Ca leak (3), which could lead to transient inward current (ITi) by the Na/Ca exchanger (4). The latter can result in delayed afterdepolarizations (DAD, 5). [Poweroint 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]

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]

Finding the Rhythm of Sudden Cardiac Death: New Opportunities Using Induced Pluripotent Stem Cell–Derived Cardiomyocytes

Finding the Rhythm of Sudden Cardiac Death: New Opportunities Using Induced Pluripotent Stem Cell–Derived Cardiomyocytes

Karim Sallam*, Yingxin Li*, Philip T. Sager, Steven R. Houser, Joseph C. Wu

Potential role for iPSC-CMs in evaluation of patients with known or at risk for arrhythmic disorders. Clinical genetic testing attempts to identify a rare variant in genes commonly associated with arrhythmic disorders. When a known variant is identified, this may aid the clinical diagnosis and genetic screening can be offered to family members to identify those at risk for developing the disorder. If a variant of uncertain significance (VUS) is identified, genome-edited lines with VUS can be developed, and cellular EP testing can be done on the resultant iPSC-CMs to detect electrophysiological abnormalities and compare them to proband iPSC-CMs. This may help re-characterize the VUS as possibly disease causing and place it in a similar category as a known variant. In cases where EP testing of the VUS is negative or inconclusive or no variants are identified on genetic testing, one can ignore the genetic component and use iPSC-CMs as the cellular functional testing platform (EP study in a dish). iPSC-CMs from the proband would be created and undergo comprehensive EP testing; abnormalities thus identified may be used to aid in the diagnosis and management of the patient. Furthermore, family members could be offered the opportunity to have iPSC-CMs generated and screened for their arrhythmic predisposition. Much like genetic testing, iPSC-CM testing may not identify all arrhythmic abnormalities, and those patients are left to rely on clinical testing and screening (Illustration credit: Ben Smith). [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

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]