This proposal details a comprehensive 5-year training program for my career development in cardiovascular research. This plan is designed to provide the additional scientific and technical training that will prepare me for an independent career in academic research. With the support provided by this grant, I will seek additional formal training in ion channel biophysics and the mathematical sciences and further my technical expertise with patch clamp techniques and in vitro analysis of cellular electrophysiology. Sudden cardiac death claims the lives of 350,000 Americans each year (equivalent to 1000 people a day or one person every two minutes). Many of these events occur as a consequence of inherited arrhythmias that cause dysfunction of ion channels, or """"""""channelopathies."""""""" The central hypothesis of this proposal is that the cardiac specialized conduction system, comprised of Purkinje fiber (PF) cells, plays a central role in the formation and maintenance of these deadly arrhythmias. In this proposal, the Purkinje system will be studied in a combined in vitro and computational approach in order to examine a novel paradigm: whether differences in tissue type and their interplay modulate the cellular effect of heritable channelopathies. The findings promise to have important implications in the pharmacologic management of affected patients. The insight gained may also enhance our understanding of channel dysfunction in more widespread cardiovascular conditions, such as heart failure and ischemia.
My aims are: 1. To investigate how changes in cell type regulate channel dysfunction in single/isolated Purkinje fiber (PF) cells and ventricular myocyte (VM) cells. 2. To study the cellular triggers of arrhythmi in channelopathy using an experimental mouse model, alongside the corresponding computational model. 3. To utilize multidimensional simulation to determine the impact of mutations in the Purkinje fiber system and interplay with the ventricle, establishing a link between genetic lesion and arrhythmia on the whole organ level.
Sudden cardiac death claims the lives of 325,000 Americans each year, equivalent to almost 1000 people a day or one person every two minutes;up to 20% of these deaths occur in patients without established heart disease. Normally, electrical activity of the heart proceeds from the endogenous pacemaker of the heart through a complex network of specialized conduction tissue, which electrically stimulates the much larger mass of heart muscle, causing it to contract and pump blood. In many cases of sudden cardiac death, inherited mutations in key proteins encoding ion channels disrupt the electrical function of the heart. These mutations likely exert a more severe effect on the specialized conduction system or wiring of the heart, relative to the muscle itself. In this project, the goal is to determine he tissue-specific effect of these dangerous mutations, which can hopefully lead to more effective therapies for affected patients.
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|Lorberbaum, Tal; Sampson, Kevin J; Chang, Jeremy B et al. (2016) Coupling Data Mining and Laboratory Experiments to Discover Drug Interactions Causing QT Prolongation. J Am Coll Cardiol 68:1756-1764|
|Biviano, Angelo B; Ciaccio, Edward J; Knotts, Robert et al. (2015) Atrial electrogram discordance during baseline vs reinduced atrial fibrillation: Potential ramifications for ablation procedures. Heart Rhythm 12:1448-55|
|Gramatikov, Boris; Iyer, Vivek (2015) Intra-QRS spectral changes accompany ST segment changes during episodes of myocardial ischemia. J Electrocardiol 48:115-22|
|Bohnen, Michael S; Iyer, Vivek; Sampson, Kevin J et al. (2015) Novel mechanism of transient outward potassium channel current regulation in the heart: implications for cardiac electrophysiology in health and disease. Circ Res 116:1633-5|
|Iyer, Vivek; Roman-Campos, Danilo; Sampson, Kevin J et al. (2015) Purkinje Cells as Sources of Arrhythmias in Long QT Syndrome Type 3. Sci Rep 5:13287|
|Iyer, Vivek; Garan, Arthur Reshad; Mancini, Donna et al. (2014) Ablation of ventricular tachycardia originating from the papillary muscle of the left ventricle early after heart transplantation. Circ Heart Fail 7:223-4|
|Iyer, Vivek; Sampson, Kevin J; Kass, Robert S (2014) Modeling tissue- and mutation- specific electrophysiological effects in the long QT syndrome: role of the Purkinje fiber. PLoS One 9:e97720|
|Garan, Arthur R; Iyer, Vivek; Whang, William et al. (2014) Catheter ablation for ventricular tachyarrhythmias in patients supported by continuous-flow left ventricular assist devices. ASAIO J 60:311-6|