Molecular Pathophysiology of Congenital Long QT Syndrome

Abstract

Ion channels represent the molecular entities that give rise to the cardiac action potential, the fundamental cellular electrical event in the heart. The concerted function of these channels leads to normal cyclical excitation and resultant contraction of cardiac muscle. Research into cardiac ion channel regulation and mutations that underlie disease pathogenesis has greatly enhanced our knowledge of the causes and clinical management of cardiac arrhythmia. Here we review the molecular determinants, pathogenesis, and pharmacology of congenital Long QT Syndrome. We examine mechanisms of dysfunction associated with three critical cardiac currents that comprise the majority of congenital Long QT Syndrome cases: 1) I_Ks, the slow delayed rectifier current; 2) I_Kr, the rapid delayed rectifier current; and 3) I_Na, the voltage-dependent sodium current. Less common subtypes of congenital Long QT Syndrome affect other cardiac ionic currents that contribute to the dynamic nature of cardiac electrophysiology. Through the study of mutations that cause congenital Long QT Syndrome, the scientific community has advanced understanding of ion channel structure-function relationships, physiology, and pharmacological response to clinically employed and experimental pharmacological agents. Our understanding of congenital Long QT Syndrome continues to evolve rapidly and with great benefits: genotype-driven clinical management of the disease has improved patient care as precision medicine becomes even more a reality.

FIGURE 1.

ECG to cellular ionic currents. A: membrane depolarization and the rapid upstroke of the ventricular action potential give rise to the QRS complex. The duration of the QT-interval corresponds to the time to ventricular repolarization. The relatively stable membrane potential during the plateau phase of the action potential gives rise to a brief isoelectric period. Ventricular repolarization gives rise to the T-wave. B: time course of several ionic currents that underlie ventricular action potential morphology (currents not to scale). The rapidly activating and inactivating I_Na drives membrane depolarization. Two K⁺ currents, I_Ks and I_Kr, contribute most to the repolarizing current necessary to drive membrane potential back to rest.

FIGURE 2.

Schematic of a generic K⁺ and Na⁺ ion channel. Ion channels allow for selective permeation of ions through the plasma membrane down their electrochemical gradient. The classic K⁺ channel consists of four identical pore-forming subunits, whereas each Na⁺ channel is formed by a single polypeptide with four homologous domains.

FIGURE 3.

Molecular biology of I_Ks and regulation by PKA-mediated signaling. A: the I_Ks macromolecular complex, including KCNQ1, KCNE1, and associated scaffolding and signaling proteins. B and C: single pulse voltage-clamp recordings of KCNQ1 expressed alone or coexpressed with KCNE1 in Xenopus oocytes. D: dialysis with 200 μM cAMP and 0.2 μM okadaic acid (OA) increases I_Ks amplitude and slows deactivation when heterologously expressed in CHO cells. [From Chen et al. (78).]

FIGURE 4.

I_Ks dysfunction leading to congenital LQTS. A: ECG from a LQT1 patient demonstrates a characteristic broad-based T wave (unpublished data). B: simulated action potential (top) and I_Ks (bottom) in WT (black) and heterozygous LQT1 (gray) conditions, demonstrating the effect of 50% reduction in I_Ks. C: single pulse voltage-clamp I_Ks recording in Xenopus oocytes demonstrating loss of channel function in an I_Ks-associated LQTS mutation. D: topology of KCNQ1 and KCNE1 in the plasma membrane. Several examples of LQT1- and LQT5-associated mutations are highlighted in blue and teal, respectively. These mutations represent a variety of mechanisms of loss-of-function including disruption of permeation (yellow-filled square), gating (yellow-filled circle), trafficking (yellow-filled triangle), PKA-mediated signaling (yellow-filled star), KCNQ1-KCNE1 interaction (white-filled square), PIP₂ affinity (white-filled circle), and calmodulin affinity (white-filled triangle).

FIGURE 5.

hERG structure and electrophysiology. A: schematic of the I_Kr channel complex. Four hERG1 subunits tetramerize to comprise the pore-forming alpha subunit of I_Kr. hERG1 contains a voltage-sensing domain (purple), including the S4 helix which contains positively charged gating residues, and a pore domain (gray). KCNE2, an accessory subunit of the I_Kr channel complex, consists of a single transmembrane helix (blue). B: voltage-clamp protocol (top panel) and heterologously expressed hERG1 ionic currents (bottom panel) recorded from a Xenopus oocyte. Currents were recorded at potentials that ranged from −70 to +50 mV; deactivating (“tail”) currents were measured at −70 mV. C: current-voltage (I-V) relationship for hERG1 currents measured at the end of test pulses, as indicated by red circle in B. D: voltage dependence of hERG1 current activation. The peak of tail currents measured at −70 mV (indicated by blue square in B) were normalized to the largest value and plotted as a function of the test potential. E: voltage dependence of hERG1 inactivation. Channel availability is decreased at positive potentials, resulting in a decreased magnitude of peak outward currents and the bell-shaped I-V relationship depicted in C. [B–E from Sanguinetti (356), with permission of Springer.]

FIGURE 6.

I_Kr dysfunction leading to congenital LQTS. A: ECG from a LQT2 patient demonstrates a characteristic “notched,” or bifid, T wave with QTc prolongation (unpublished data). B: simulated action potential (top) and I_Kr (bottom) in WT (black) and heterozygous LQT2 (gray) conditions, demonstrating the effect of 50% reduction in I_Kr.

FIGURE 7.

Topology of hERG and KCNE1 in the plasma membrane, representative LQT2- and LQT6-associated mutations highlighted. Different mechanisms of loss of function in hERG or KCNE2, including gating (yellow-filled circle), K⁺ permeation (black-filled square), trafficking (white-filled triangle), or combined defects (green-filled star) are categorized.

FIGURE 8.

Physiology and molecular biology of I_Na. A: consecutive recordings of single Na⁺ channels recorded under cell-attached conditions in HEK293 cells transfected with Na_v1.5 cDNA (unpublished data). B: WT Na⁺ currents recorded under whole cell patch-clamp conditions and obtained by depolarizations from −120 to −30 mV (unpublished data). At high gain (inset), whole cell currents return nearly to 0 nA. C: voltage dependence of activation (red-filled square) and inactivation (blue-filled circle) (unpublished data). D: topology of Na_v1.5 in the plasma membrane with accessory proteins implicated in LQTS.

FIGURE 9.

I_Na dysfunction leading to congenital LQTS. A: topology of Na_v1.5 in the plasma membrane. Several representative LQT3-associated mutations were selected because there is strong evidence that they induce I_NaL by channel bursting (red-filled triangle) or by late reopening (red-filled circle), or prolong the action potential without I_NaL (red-filled square). B: ECG from a LQT3 patient (unpublished data). C: simulated action potential (top) and I_Na (bottom) in WT (green) and heterozygous LQT3 (purple) conditions. I_Na peak current was truncated to enhance view of I_NaL. D: representative current recordings from WT (purple) and F1473C (orange) Na_v1.5 expressed in HEK293 cells at low and high gain (inset) elicited by depolarization to −10 mV (35). E: steady-state channel availability for WT (green triangle) and F1473C (purple square). [D and E from Bankston et al. (35).]

FIGURE 10.

Representative recordings at low and high (insets) gain of F1473C inhibition by 50 μM mexiletine (A), 50 μM ranolazine (B), and 10 μM flecainide (C). D: mexiletine, ranolazine, and flecainide inhibit I_Na with preference for I_NaL. [From Bankston et al. (35).]