Electrophysiology of Hypokalemia and Hyperkalemia

Potassium (K+) was first isolated as an element in 1807 by Sir Humphrey Davy when he electrolyzed potash (plant ashes soaked in pots of water), for which its name is derived. Despite the organic origin of its isolation, however, K+’s role 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 concentrated 30–40 fold over its extracellular concentration by the activity of Na+-K+ ATPase in the plasma membrane, which hydrolyzes ATP to pump three 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 generates a negative resting membrane potential (Em) approaching the K+ equilibrium potential (EK) 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 Em stabilizes working atrial and ventricular myocytes during diastole, preventing spontaneous action potentials (AP’s) from causing premature extrasystoles. For this reason, serum [K+] is closely regulated physiologically, 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 cardiac arrhythmias, not solely because of direct effects of K+, but also because the cellular balances of K+, Na+ and Ca2+ are interlinked through Na+-K+ ATPase and Na+-Ca2+ exchange (Fig. 1A). Thus, hypo- and hyperkalemia directly impact Na+ and Ca2+ as well as 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 Ca2+ accumulation. Increased intracellular Ca2+ loading activates Ca2+-calmodulin kinase (CaMK) signaling to further reduce repolarization reserve by inducing late Na+ and Ca2+ currents. This positive feedback loop promotes early afterdepolarization (EAD)-mediated arrhythmias, especially when K+ channel-blocking drugs are present, as well as delayed afterdepolarization (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 interstitial hyperkalemia, a prominent feature of acute myocardial ischemia, contributes to injury currents causing electrocardiographic ST segment elevation and TQ segment depression 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 extracellular [K+] are also noted. Open in a separate window Figure 1 A. Interconnectedness of K+, Na+ and Ca2+ balances in the cardiac myocyte. Outward K+ loss through K+ channels (left) is recovered by the Na+-K+ ATPase removing 3 Na+ ions in exchange for 2 K+ ions. Some Na+ ions enter the cell via Na+ channels, but most via Na+-Ca2+ exchange (NCX) during diastole, which exchanges 1 Ca2+ ion for 3 Na+ ions. In the steady state, the Ca2+ removed by NCX balances the Ca2+ entering the cell via Ca2+ channels. Most Ca2+ in the cell recycles between the sarcoplasmic reticulum (SR) and cytoplasm, with uptake by sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) and release through ryanodine receptors (RyR). Cytoplasmic free Ca2+ activates CaMK, which regulates the properties of Na+, Ca2+ and K+ channels, and RyR in the SR (dotted arrows). B. Effects of hypokalemia on the AP. Superimposed AP recordings from an isolated rabbit ventricular myocyte with [K+]o=5.4 mmol/l (black trace) versus [K+]o= 2.7 mmol/l (red trace), showing hyperpolarized Em and EADs, the latter suppressed by the CaMK blocker KN-93 (green trace), but not by inactive KN-92 (blue trace). Modified from Pezhouman et al2 with permission.