Pharmacogenomics and acquired long QT syndrome.
During the past decade pharmaceutical companies have been faced with the withdrawal of some of their marketed drugs because of rare, yet lethal, postmarketing reports associated with ventricular arrhythmias. The implicated drugs include antiarrhythmics, but also non-cardiac drugs, such as histamine blockers, antipsychotics, and antibiotics. These undesired effects involve prolongation of the QT interval, which may lead to characteristic ventricular tachyarrhythmias, known as torsades de pointes. These clinical symptoms of the acquired long QT syndrome (LQTS) are also found in an inherited form of the disease, called congenital LQTS. Nowadays, a number of environmental (non-genetic) and genetic risk factors for acquired LQTS have been described. Non-genetic factors include female gender, hypokalemia, and other heart diseases. The knowledge of genetic risk factors is emerging rapidly. During the last decade, mutations in several genes encoding ion channels have been shown to cause congenital LQTS. In acquired LQTS, a number of 'silent' mutation carriers in these LQTS genes have been identified, and functional polymorphisms in the same genes have been found that are associated with an increased vulnerability for the disease. Furthermore, there is also evidence that interindividual differences in drug metabolism, caused by functional polymorphisms in drug-metabolizing enzyme genes, may be a risk factor for acquired LQTS, especially if multiple drugs are involved. This review evaluates the current knowledge on these risk factors for acquired LQTS, with an emphasis on the genetic risk factors. It also assesses the potential to develop pharmacogenetic tests that will enable clinicians and pharmaceutical companies to identify at an early stage patients or individuals in the general population who are at risk of acquired LQTS.
Aerssens
Jeroen
J
Johnson & Johnson Pharmaceutical Research and Development, Department of Internal Medicine, Turnhoutseweg 30, B-2340 Beerse, Belgium. jaerssen@prdbe.jnj.com
Paulussen
Aimée D C
AD
D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000151:congenital / Q000235:genetics*; D010597:Pharmacogenetics; D011237:Predictive Value of Tests; D012307:Risk Factors; D016171:Torsades de Pointes / Q000139:chemically induced / Q000235:genetics; D018675:Toxicity Tests
D000889:Anti-Arrhythmia Agents