Molecular Pathophysiology of Congenital Long QT Syndrome.

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) IKs, the slow delayed rectifier current; 2) IKr, the rapid delayed rectifier current; and 3) INa, 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.

A computational model of Purkinje fibre single cell electrophysiology: implications for the long QT syndrome.

Computer modelling has emerged as a particularly useful tool in understanding the physiology and pathophysiology of cardiac tissues. Models of ventricular, atrial and nodal tissue have evolved and include detailed ion channel kinetics and intercellular Ca(2+) handling. Purkinje fibre cells play a central role in the electrophysiology of the heart and in the genesis of cardiac arrhythmias. In this study, a new computational model has been constructed that incorporates the major membrane currents that have been isolated in recent experiments using Purkinje fibre cells. The model, which integrates mathematical models of human ion channels based on detailed biophysical studies of their kinetic and voltage-dependent properties, recapitulates distinct electrophysiological characteristics unique to Purkinje fibre cells compared to neighbouring ventricular myocytes. These characteristics include automaticity, hyperpolarized voltage range of the action potential plateau potential, and prolonged action potential duration. Simulations of selective ion channel blockade reproduce responses to pharmacological challenges characteristic of isolated Purkinje fibres in vitro, and importantly, the model predicts that Purkinje fibre cells are prone to severe arrhythmogenic activity in patients harbouring long QT syndrome 3 but much less so for other common forms of long QT. This new Purkinje cellular model can be a useful tool to study tissue-specific drug interactions and the effects of disease-related ion channel dysfunction on the cardiac conduction system.

Simulation and prediction of functional block in the presence of structural and ionic heterogeneity.

Inhomogeneities in myocardial structure and action potential duration (APD) lead to dispersion of APD throughout the heart. APD gradients in the range of 20-125 ms/cm have been reported to produce functional block. In this study, a multicellular fiber model was used to examine the effect of structural and ionic inhomogeneities on the likelihood of premature stimuli to produce functional block. With the use of both the Fenton-Karma and Luo-Rudy phase II membrane models, functional block is found to occur in tissue with a maximum gradient <45 ms/cm and depends on the spatial extent. In general, the narrower the extent the larger the magnitude needed for block. A simple relationship for predicting block is presented that only requires information about the conduction velocity (CV) restitution properties of the tissue and the APD gradients. Analysis reveals that the effects of a steep CV restitution slope may be beneficial in overcoming intrinsic cellular heterogeneity for a single premature beat.