The long QT syndrome (LQTS) is an inherited or acquired disorder characterized by delayed ventricular repolarization that predisposes affected individuals to fatal cardiac arrhythmias. At least 10 different forms of the long-QT syndrome have been described. In approximately 45% of genotyped patients, the underlying causes are mutations in the KCNQ1 gene(also known as KVLQT1 or Kv7.1), which encodes the pore-forming alpha subunits of the slow delayed outward potassium I_Ks current. This form of the long- QT syndrome is designated as long-QT syndrome type 1 (LQT1). One obstacle towards a better treatment of LQTS patients is the lack of an in vitro system for the analysis of LQT-associated mutations. The generation of human induced pluripotent stem cells (iPSCs) has opened exciting new prospects for studying pathogenesis of cardiovascular diseases at the cellular level in the context of patients' own genetic background. We screened a family affected by long-QT syndrome type 1 and identified an autosomal dominant missense mutation (R190Q) in the KCNQ1 gene. Dermal fibroblasts were obtained from two family members and two healthy controls and infected with retroviral vectors to generate pluripotent stem cells. With the use of a specific protocol, cardiomyocytes harboring the disease-causing mutation were generated. Electrophysiological experiments revealed that among the differentiated cells, atrial, ventricular and nodal phenotypes could be identified. LQT1 cells maintained the diseased genotype and showed a marked prolongation of action potentials compared to cells from control individuals. In LQT1 cells the I_Ks current was reduced to almost 75%, while I_Kr and I_to currents were unchanged. QT-interval prolongating drugs demonstrated a marked susceptibility to tachyarrhythmia of diseased myocytes. Moreover, we showed that myocytes derived from patients with LQT1 had an increased susceptibility to catecholamine-induced tachyarrhythmia and that betablockade attenuated this phenotype. This study demonstrates for the first time that cardiac cells generated from human iPSCs can be used to model the specific pathology seen in a genetically inherited cardiac disease.

¹Moretti et al. N Engl J Med. (2010), 363:1397–409.