Posts Tagged: sudden cardiac death

Heart–Brain Axis: Effects of Neurologic Injury on Cardiovascular Function

Heart–Brain Axis: Effects of Neurologic Injury on Cardiovascular Function

Pouya Tahsili-Fahadan, Romergryko G. Geocadin

Neural control of the cardiovascular system. Afferent and efferent pathways are shown in green and red lines, respectively. Some potential sites for therapeutic interventions are illustrated in the blue text boxes. The figure has been simplified to illustrate the major cortical, subcortical, and brain stem areas involved in control of the cardiovascular function. Most of the shown areas are interconnected. For anatomic details and physiological effects of the illustrated pathways, please refer to the text. [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]

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]

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]

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]

Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel

Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel

Arthur A.M. Wilde, Ramon Brugada

Schematic representation of the β-subunits of cardiac sodium channel (β1 [A], β2 [B], β3 [C], and β4 [D]), each containing 1 transmembrane segment. For each β-subunit, identified variants that have been linked to either syndrome (see color code below the schematic illustrations) are depicted. [Powerpoint File]