Electrophysiology of Hypokalemia and Hyperkalemia.

Basic Science for the Clinical Electrophysiologist Electrophysiology of Hypokalemia and Hyperkalemia James N. Weiss, MD; Zhilin Qu, PhD; Kalyanam Shivkumar, MD, PhD P Downloaded from http://circep.ahajournals. org/ by guest on March 18, 2017 otassium (K + ) was first isolated as an element in 1807 by Sir Humphrey Davy when he electrolyzed potash (plant ashes soaked in pots of water), from which its name is derived. Despite the organic origin of its isolation, however, the role of K + in biology was not elucidated until the 20th century. In this article, we discuss the basic science underlying the effects of both hypo- and hyperkalemia on cardiac excitability and arrhythmias. As the major intracellular cation, K + is con- centrated 30- to 40-fold over its extracellular concentration by the activity of Na + -K + ATPase in the plasma membrane, which hydrolyzes ATP to pump 3 Na + ions out of the cell in exchange for 2 extracellular K + ions into the cell, generating an outward current in the process. Because most cells express time-independent K + ion channels in their plasma membrane, the high selective permeability to K + over other ions gener- ates a negative resting membrane potential (E m ) approaching the K + equilibrium potential (E K ) as determined by the Nernst equation (−95 mV for extracellular and intracellular [K + ] of 4.0 and 140 mmol/L, respectively). In excitable tissues such as the heart, the negative resting E m stabilizes working atrial and ventricular myocytes during diastole, preventing spontaneous action potentials (APs) from causing premature extrasystoles. For this reason, serum [K + ] is closely regulated physiologi- cally, with normal values ranging from 3.5 to 5.0 mmol/L. Outside of this range, lower and higher values of serum [K + ] have electrophysiological effects that commonly promote car- diac arrhythmias, not solely because of direct effects of K + , but also because the cellular balances of K + , Na + , and Ca 2+ are interlinked through Na + -K + ATPase and Na + -Ca 2+ exchange (Figure 1A). Thus, hypo- and hyperkalemia directly impact Na + and Ca 2+ and K + balances. In this article, we discuss how these relationships promote cardiac arrhythmias. First, we review how hypokalemia not only reduces repolarization reserve by suppressing K + conductances, but also significantly inhibits Na + -K + ATPase activity, causing intracellular Na + and Ca 2+ accumulation. Increased intracellular Ca 2+ loading acti- vates Ca 2+ -calmodulin kinase (CaMK) signaling to further reduce repolarization reserve by inducing late Na + and Ca 2+ currents. This positive feedback loop promotes early afterde- polarization (EAD)–mediated arrhythmias, especially when K + channel-blocking drugs are present, and delayed afterde- polarization (DAD)–mediated arrhythmias and automaticity. We then turn to hyperkalemia, both systemic and interstitial. We discuss how resting membrane depolarization by systemic hyperkalemia promotes conduction block and reentry and may also promote phase 2 reentry. Finally, we describe how inter- stitial hyperkalemia, a prominent feature of acute myocardial ischemia, contributes to injury currents causing electrocar- diographic ST-segment elevation and TQ-segment depres- sion that promote arrhythmias, including phase 2 reentry similar to Brugada and other early repolarization syndromes. Differences between responses of conduction system tissues and atrial and ventricular myocardium to changes in extracel- lular [K + ] are also noted. Hypokalemia Hypokalemia is most commonly encountered clinically as a complication of diuretic therapy 2 used to treat hypertension, heart failure, renal disease, and other conditions. Its direct electrophysiological effects include resting membrane hyper- polarization, Na + -K + ATPase inhibition, and suppression of K + channel conductances resulting in AP duration (APD) pro- longation, reduced repolarization reserve, EAD, DADs, and automaticity. Arrhythmia Mechanisms Reduced repolarization reserve predisposes the heart to EADs (Figure 1B) and EAD-mediated arrhythmias, includ- ing Torsades de pointes and polymorphic ventricular tachy- cardia (VT), which can degenerate to ventricular fibrillation (VF) causing sudden cardiac death (Figure 2). 1 Reductions in repolarization reserve prolong APD in a heterogeneous manner, both because ion channel expression is hetero- geneous throughout the atria and ventricles 3 and because EADs are intrinsically chaotic, occurring irregularly instead of reliably with every beat. 4 Because of the gap junction coupling in cardiac tissue that prevents adjacent myocytes from exhibiting markedly different APD, the chaotic behav- ior causes some regions to exhibit EADs synchronously, whereas other nearby regions do not. This dynamical pro- cess has been termed regional chaos synchronization and generates marked dispersion of repolarization because areas with long APD due to EADs are juxtaposed next to regions much shorter APD without EADs 4,5 (Figure 3). 6 Moreover, if His-Purkinje fibers or regions of myocardium with EADs reach the threshold for triggered activity, the resulting extra- systoles can propagate into recovered regions without EADs but may block when propagating into other regions with Received December 19, 2016; accepted February 6, 2017. From the UCLA Cardiovascular Research Laboratory and Cardiac Arrhythmia Center, Departments of Medicine (Cardiology) (J.N.W., Z.Q., K.S.), Physiology (J.N.W.), and Radiological Sciences (K.S.), David Geffen School of Medicine at UCLA, Los Angeles, CA. Correspondence to James N. Weiss, MD, UCLA Cardiovascular Research Laboratory, MRL 3645, David Geffen School of Medicine at UCLA, 675 Charles E, Young Dr S, Los Angeles, CA 90095. E-mail jweiss@mednet.ucla. edu (Circ Arrhythm Electrophysiol. 2017;10:e004667. DOI: 10.1161/CIRCEP.116.004667.) © 2017 American Heart Association, Inc. Circ Arrhythm Electrophysiol is available at http://circep.ahajournals. org DOI: 10.1161/CIRCEP.116. 004667