Review Calcium Signaling Series Donald M. Bers, Guest Editor Calcium Signaling and Cardiac Arrhythmias Andrew P. Landstrom, Dobromir Dobrev, Xander H.T. Wehrens Abstract: There has been a significant progress in our understanding of the molecular mechanisms by which calcium (Ca2+) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular Downloaded from tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca2+-handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca2+ in normal cardiac function—in particular, excitation–contraction coupling and normal electric rhythms. The functional involvement of Ca2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused 2+ http://circres.ahajournals.org/ by mutations in Ca -handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes. (Circ Res. 2017;120:1969-1993. DOI: 10.1161/CIRCRESAHA.117.310083.) Key Words: arrhythmias, cardiac ■ atrial fibrillation ■ calcium channels ■ cardiomyopathy ■ ryanodine receptor calcium release channel 2+ by guest on June 11, 2017 he bivalent cation calcium (Ca ) represents one of the Overview of Excitation–Contraction Tmost ubiquitous signal transduction molecules known.1 Coupling in the Heart It mediates a diverse array of biological functions including Regular contraction of the heart requires the conversion of muscle contraction, cellular exocytosis, neuronal activity, and electric activation (excitation) into mechanical force (con- triggering of programmed cell death. Since the first observa- traction). This process, known as excitation–contraction (EC) tion by Ringer in 1883 that Ca2+ was required for cardiac con- coupling, requires coordinated movement of Ca2+ ions at the traction, the role of Ca2+ as a signaling ion in the heart has cardiomyocyte level (Figure 1A). Each action potential (AP), become increasingly appreciated.2 In addition, it has become triggered by influx of sodium (Na+) through the voltage-gated clear that abnormalities of Ca2+ homeostasis can play a key sodium channel (Nav1.5), thereby generating the INa current, role in the pathogenesis of common cardiovascular disorders, induces Ca2+ influx through voltage-activated L-type Ca2+ including cardiac arrhythmias. Human genetic studies of pa- 2+ channels (LTCCs, Cav1.2), creating the ICa,L current. This Ca tients with inherited arrhythmia syndromes have uncovered triggers a much larger Ca2+ release from the sarcoplasmic re- inherited mutations in various Ca2+ channels and Ca2+ trans- ticulum (SR), the principal intracellular Ca2+ storage organ- porters, directly implicating dysfunction of these proteins in elle.3 SR Ca2+ release is mediated by specialized Ca2+-release the disease mechanisms. Moreover, acquired modifications channels known as ryanodine receptor type-2 (RyR2).4 This of various Ca2+-handling proteins have been associated with process of Ca2+-sensitive RyR2-mediated SR release is known cardiac arrhythmias, including atrial fibrillation (AF) and ven- as Ca2+-induced Ca2+-release (CICR). The cytosolic Ca2+ binds tricular arrhythmias in failing hearts. In this review, we pro- to and activates cardiac troponin C (TnC), the Ca2+-sensing vide a comprehensive overview of the potential contributions protein of the contractile apparatus and initiates myofilament of Ca2+ in arrhythmia mechanisms and highlight various gaps contraction. During diastole, cardiac muscle relaxation occurs in knowledge and controversies in the field. when Ca2+ is removed from the cytosol either by sequestration From the Section of Cardiology, Department of Pediatrics (A.P.L.), Cardiovascular Research Institute (A.P.L., X.H.T.W.), and Departments of Molecular Physiology and Biophysics, Medicine (Cardiology), Center for Space Medicine (X.H.T.W.), Baylor College of Medicine, Houston, TX; and Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (D.D.). Correspondence to Xander H.T. Wehrens, MD, PhD, Baylor College of Medicine, One Baylor Plaza, BCM335, Houston, TX 77030. E-mail wehrens@ bcm.edu © 2017 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.117.310083 1969 1970 Circulation Research June 9, 2017 each extruded Ca2+ ion, thereby creating a depolarizing tran- Nonstandard Abbreviations and Acronyms 2+ sient inward current (INCX). The rapid release of Ca from the AF atrial fibrillation SR into the cytosol, followed by rapid reuptake into the SR or AP action potential extrusion from the cell, creates a Ca2+ wave that runs through 2+ ARVC arrhythmogenic right ventricular cardiomyopathy the cardiomyocyte, and is known as the Ca transient. The 2+ CaM calmodulin amount of Ca released from the SR via RyR2 largely deter- 2+ CASQ2 calsequestrin-2 mines the Ca -transient amplitude, which correlates with the CaMKII Ca2+/calmodulin-dependent protein kinase II strength of systolic contraction. CICR Ca2+-induced Ca2+-release EC coupling occurs within specialized subcellular structures DCM dilated cardiomyopathy called junctional membrane complexes (JMCs), where LTCCs on transverse T-tubules—plasmalemmal invaginations that reach EC excitation–contraction deep into myocytes—are positioned in close proximity of the FKBP12.6 FK506-binding protein-12.6 RyR2 channels on the SR membranes (Figure 1B).5 The move- HRC histidine-rich Ca2+-binding protein ment of Ca2+ within these dyadic cleft domains is, in part, regu- iPSC induced pluripotent stem cells lated by JPH2 (junctophilin-2), a protein that provides a structural iPSC-CM iPSC-derived cardiomyocytes bridge between the plasmalemma and SR ensuring appropriate JCTN junctin proximity between the LTCC and RyR2 channels.6,7 JPH2 is also JMCs junctional membrane complexes necessary for BIN1 (bridging integrator 1) recruitment to develop Downloaded from JPH2 junctophilin-2 the T-tubule forming the dyad. There are important differences in LQTS long QT syndrome the organization of the JMC between atrial and ventricular cardio- LTCCs L-type Ca2+ channels myocytes.8 In ventricular myocytes, almost all Ca2+ release events NCX sodium-calcium exchanger type 1 (ie, sparks and transients/waves) are activated directly by LTCC PKA protein kinase A on T tubules, which leads to synchronized SR Ca2+ release and a http://circres.ahajournals.org/ SERCA2a SR Ca2+-ATPase type-2a rapid upstroke of the Ca2+ transient. In atrial cardiomyocytes, in SR sarcoplasmic reticulum which T tubules are relatively underdeveloped, the Ca2+ transient TnC troponin C begins with LTCC-triggered local SR Ca2+-release events at the TnI troponin I cell periphery that propagate slowly as Ca2+ waves toward the cell TnT troponin T center.9,10 In addition, atrial cardiomyocytes possess larger and TRDN triadin more heterogeneous axial tubules and much more Ca2+-buffering 11,12 RyR2 ryanodine receptor type-2 mitochondria than ventricular cardiomyocytes. Finally, anoth- 2+ WES whole-exome sequencing er class of Ca release channels known as inositol 1,4,5-trisphos- by guest on June 11, 2017 phate type 2 receptors may also contribute to CICR.13 into the SR by the SR Ca2+-ATPase type-2a (SERCA2a) or Regulation of Intracellular Calcium Handling out into the extracellular space by the Na+/Ca2+-exchanger The activity of Ca2+ channels and exchangers involved in EC type-1 (NCX). In addition, there is a minor contribution by coupling is regulated by several mechanisms and signaling the PMCA (plasmalemmal Ca2+-ATPase). Na+/Ca2+-exchanger pathways in response to changing demands for cardiac out- type-1 is electrogenic, as it imports 3 Na+ ions into the cell for put. For example, the fight-or-flight response activates the Figure 1. 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.* Landstrom et al Calcium Signaling and Cardiac Arrhythmias 1971 sympathetic portion of the autonomous nervous system with The LTCC, responsible for voltage-dependent Ca2+ entry downstream effects on Ca2+ signaling (recently reviewed).14 into the cells, consists of a macromolecular protein complex Activation of the β-adrenoceptor (βAR) causes a rise in the comprised of a pore-forming Cav1.2 (α subunit) and various intracellular concentration of the second messenger cAMP. auxillary subunits (α2, β, δ, and γ) that modulate channel Downstream effectors of cAMP include cAMP-dependent function (Figure 3). Similar to RyR2, the LTCC is regulated protein kinase A (PKA), which in turn can phosphorylate Ca2+ by protein kinases such as CaMKII