Long QT syndrome (LQTS) is a genetic disease characterized by prolonged QT interval and a high incidence of sudden cardiac death (SCD). Despite recent advances in our understanding of the genetic and molecular abnormalities underlying LQTS, the mechanistic relationship between such abnormalities and SCD is not well understood. In patients with LQTS, episodes of syncope and SCD are caused by torsade de pointes (TdP), where afterdepolarizations are believed to play a critically important role. Abnormal management (i.e. handling) of intracellular calcium has been implicated as an important mechanism of afterdepolarizations, including afterdepolarizations that are enhanced by Calcium/calmodulin-dependent protein kinase II (CaM kinase). We hypothesize that heterogeneities of calcium handling are present normally and are enhanced by electrophysiological changes that occur in LQTS. As a result, regional """"""""hot spots"""""""" of abnormal calcium handling develop that are prone to the formation of early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs). It is further hypothesized that the location and timing of afterdepolarizations and their interaction with transmural repolarization gradients can critically influence the initiation of TdP.
The specific aims of his proposal are to: 1) Determine the regional differences (i.e. heterogeneities) of intracellular calcium handling and action potential duration across the ventricular transmural wall that occur normally and in models of LQTS (i.e. LOT1, LQT2, LQT3). 2): Determine the cellular/molecular mechanisms of calcium handling heterogeneities that occur normally by measuring the level of calcium regulatory protein expression under control conditions. 3) Determine the cellular/molecular mechanisms of enhanced heterogeneities of (i.e. abnormal) intracellular calcium handling and afterdepolarization in models of acquired LQTS, where calcium release from the sarcoplasmic reticulum and CaM klnase are important mechanisms. 4) Determine the mechanistic relationship between the regional occurrence of EADs, repolarization gradients, and episodes of TdP in all three models of acquired LQTS, with an emphasis on the mechanisms of initiation by pauses in cycle length. New optical mapping techniques developed and validated by the PI to measure transmembrane potential and intracellular calcium simultaneously from 256 sites across intact heart preparations will be used. A major advantage of this experimental system is that multiple cellular parameters can be measured during arrhythmia initiation, providing the unique ability to bridge cellular and molecular abnormalities with arrhythmias that are a consequence. The long term objectives of this study are to determine the mechanistic relationship between abnormal intracellular calcium handling and arrhythmias associated with LQTS (i.e. TdP).
| Laurita, Kenneth R; Rosenbaum, David S (2008) Cellular mechanisms of arrhythmogenic cardiac alternans. Prog Biophys Mol Biol 97:332-47 |
| Deschenes, Isabelle; Laurita, Kenneth R (2007) How can a single mutation cause such arrhythmic havoc? Heart Rhythm 4:198-9 |
| Hirose, Masamichi; Laurita, Kenneth R (2007) Calcium-mediated triggered activity is an underlying cellular mechanism of ectopy originating from the pulmonary vein in dogs. Am J Physiol Heart Circ Physiol 292:H1861-7 |
| Katra, Rodolphe P; Oya, Toshiyuki; Hoeker, Gregory S et al. (2007) Ryanodine receptor dysfunction and triggered activity in the heart. Am J Physiol Heart Circ Physiol 292:H2144-51 |
| Mills, William R; Mal, Niladri; Kiedrowski, Matthew J et al. (2007) Stem cell therapy enhances electrical viability in myocardial infarction. J Mol Cell Cardiol 42:304-14 |
| Fouts, Kristen; Fernandes, Brian; Mal, Niladri et al. (2006) Electrophysiological consequence of skeletal myoblast transplantation in normal and infarcted canine myocardium. Heart Rhythm 3:452-61 |
| Mills, William R; Mal, Niladri; Forudi, Farhad et al. (2006) Optical mapping of late myocardial infarction in rats. Am J Physiol Heart Circ Physiol 290:H1298-306 |
| Wan, Xiaoping; Laurita, Kenneth R; Pruvot, Etienne J et al. (2005) Molecular correlates of repolarization alternans in cardiac myocytes. J Mol Cell Cardiol 39:419-28 |
| Liu, Jinqiu; Laurita, Kenneth R (2005) The mechanism of pause-induced torsade de pointes in long QT syndrome. J Cardiovasc Electrophysiol 16:981-7 |
| Laurita, Kenneth R; Katra, Rodolphe P (2005) Delayed after depolarization-mediated triggered activity associated with slow calcium sequestration near the endocardium. J Cardiovasc Electrophysiol 16:418-24 |
Showing the most recent 10 out of 16 publications
