QT interval prolongation: clinical assessment, risk factors and quantitative pharmacological considerations

Prolongation of the QT interval in the ECG is a critical finding that signifies an extended duration from the onset of ventricular depolarization to the end of ventricular repolarization. It can predispose patients to life-threatening arrhythmias, such as Torsades de Pointes (TdP). Long QT syndromes (LQTS) are defined by mutations in ion channel genes, particularly those encoding cardiac potassium and sodium channels and are characterized by a significant risk for sudden cardiac death if untreated. However, besides these clearly defined entities various medications have been implicated in causing QT interval prolongation. There is increasing evidence for a genetically determined risk for drug-induced QT prolongation. In addition, due to numerous clinical factors influencing the QT interval, QT prolongation increases the risk of TdP particularly in multi-morbid patients necessitating vigilant monitoring in at-risk populations. This review gives an overview of mechanisms and conditions which induce QT prolongation, the clinical assessment of QT interval duration, thereby highlighting quantitative variations in measurement techniques and heart-rate correction, as well as in demographic interpretation of normal values. The risk of cardiac arrhythmia is discussed, in both patients with congenital LQTS and acquired QT prolongation, along with influencing pharmacokinetic/pharmacodynamic, non-pharmacologic and genetic risk factors for TdP. Finally, clinical implications for individual patient management, including risk-adapted drug-prescription and use of ECG monitoring to mitigate the risks associated with QT prolongation, are summarized. Understanding the interplay between pharmacokinetics, pharmacodynamics, genetic predisposition and co-morbidities is essential for optimizing treatment in the context of prolonged QT intervals, preventing adverse cardiovascular events, and improving cardiac safety. Comprehensive drug labelling regarding exposure-QT relationships and available pharmacovigilance data are important sources of information enhancing patient safety.