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, the slow delayed rectifier current; 2) I, the rapid delayed rectifier current; and 3) I, 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.

Functional phenotype variations of two novel KV7.1 mutations identified in patients with Long QT syndrome

“…QT C is a measure of ventricular repolarization, and prolonged repolarization of the ventricles may lead to tachycardia of the torsades de pointes type. Ultimately, it may degenerate into sudden cardiac death . LQTS is a heterogeneous disease, currently associated with mutations in 15 genes subdividing the syndrome in LQT1‐15 .…”

SUMOylation determines the voltage required to activate cardiac I Ks channels

“…Thus, I Ks varies in magnitude and timing subject to neuronal and hormonal influences (1). Abnormal changes in I Ks function, due to inherited mutations in KCNQ1 or KCNE1, or suppression of the current by medications, can produce long QT syndrome (LQTS) and life-threatening cardiac arrhythmias (2). KCNQ1 (also called K V 7.1 and previously K V LQT) is a classical voltage-gated potassium α-subunit with six transmembrane segments and a single pore-forming P loop.…”

“…Compared with channels formed by KCNQ1 subunits alone, KCNE1 produces a right shift in the half-maximal voltage required to activate the channel (V 1/2 ), slows the kinetics of activation and deactivation, increases the channel unitary conductance, alters the ion selectivity of the conduction pore and, modifies its pharmacology (3)(4)(5)(6)(7)(8). KCNE1 also endows I Ks channel with a high affinity for PIP 2 (9) and allows responsiveness to PKA-mediated phosphorylation following β-adrenergic stimulation (10). Here, we demonstrate that the V 1/2 inherent to native cardiac I Ks channels results from, and is modified by, KCNE1-dependent SUMOylation of KCNQ1.…”

Update on long QT syndrome

“…In LQTS, prolongation of the ventricular cardiac potential can be caused by genetic defects resulting in decrease of repolarizing potassium currents ( I Ks , I Kr , and I K1 ) or enhancement of depolarizing sodium and calcium currents ( I Na and I Ca,L ) …”