We propose a Specialized Center of Research in Sudden Death at the University of Utah to investigate the relationship between abnormalities of repolarization and arrhythmic death. The investigative group is composed of 17 investigators and 8 consultants. Four Research Projects and four Core support laboratories are proposed. The first research project, lonic Mechanisms of Repolarization in Human Ventricular Myocytes, directed by MC Sanguinetti, centers on K+ and other repolarizing currents. Voltage clamp techniques are applied to isolated human myocytes to determine which currents are present, to fully characterize them and to determine how they influence normal and abnormal repolarization processes. In Project 2, Molecular and Physiologic Mechanisms of the Long QT Syndrome, MT Keating and colleagues investigate the molecular genetics and the cardiac electrophysiology of this inherited form of arrhythmia in man and in human myocardium. JW Mason and coworkers plan studies of repolarization changes that occur immediately preceding sudden death due to ischemia in the third project, Repolarization Changes Associated with Ventricular Arrhythmias and Sudden Death. In Project 4, Electrocardiographic Measures of Ventricular Repolarization, techniques for non-invasive measurement of regional cardiac repolarization and disparity of repolarization are developed by LS Green, RL Lux and colleagues for diagnosis and prognostication in man. The Administrative Core, led by Mason, will provide assistance to all investigators in budget management and intercommunication. Core 2, the Cell Processing Laboratory directed by WH Barry and GA Peeters, will prepare isolated human ventricular myocytes for Projects 1 and 2, maintain and culture frog oocytes for Project 1, and transform and maintain peripheral blood lymphocytes from patients with LQT for DNA analysis in Project 2. Core 3, the Repolarization Signal Processing Laboratory led by Lux, will provide electrocardiographic signal processing and interpretation capabilities to Projects 2, 3 and 4. TE Moon directs the fourth Core laboratory, Clinical Data Management and Biostatistics, which will assist Project 2, 3 and 4 investigators in collection, statistical analysis and interpretation of clinical data obtained from patients. This SCOR proposal is sharply focussed on a single facet of the problem of sudden death. It combines basic science with whole-organ physiology and complex clinical medicine. It is likely to produce insight into the pathophysiology of sudden death and lead to improvements in therapy while establishing a framework for future fundamental discoveries.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
1P50HL052338-01
Application #
2229665
Study Section
Special Emphasis Panel (ZHL1-CSR-J (S1))
Project Start
1995-02-01
Project End
1999-12-31
Budget Start
1995-02-01
Budget End
1995-12-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Lux, Robert L; Pope 3rd, C Arden (2009) Air pollution effects on ventricular repolarization. Res Rep Health Eff Inst :3-20; discussion 21-8
Segerson, Nathan M; Litwin, Sheldon E; Daccarett, Marcos et al. (2008) Scatter in repolarization timing predicts clinical events in post-myocardial infarction patients. Heart Rhythm 5:208-14
Valencik, Maria L; Zhang, Dongfang; Punske, Bonnie et al. (2006) Integrin activation in the heart: a link between electrical and contractile dysfunction? Circ Res 99:1403-10
Lux, Robert L; Gettes, Leonard S; Mason, Jay W (2006) Understanding proarrhythmic potential in therapeutic drug development: alternate strategies for measuring and tracking repolarization. J Electrocardiol 39:S161-4
Spitzer, Kenneth W; Pollard, Andrew E; Yang, Lin et al. (2006) Cell-to-cell electrical interactions during early and late repolarization. J Cardiovasc Electrophysiol 17 Suppl 1:S8-S14
Splawski, Igor; Yoo, Dana S; Stotz, Stephanie C et al. (2006) CACNA1H mutations in autism spectrum disorders. J Biol Chem 281:22085-91
Shusterman, Vladimir; Goldberg, Anna; London, Barry (2006) Upsurge in T-wave alternans and nonalternating repolarization instability precedes spontaneous initiation of ventricular tachyarrhythmias in humans. Circulation 113:2880-7
Skaluba, Stanislaw J; Bray, Bruce E; Litwin, Sheldon E (2005) Close coupling of systolic and diastolic function: combined assessment provides superior prediction of exercise capacity. J Card Fail 11:516-22
Chen, Tiehua; Inoue, Masashi; Sheets, Michael F (2005) Reduced voltage dependence of inactivation in the SCN5A sodium channel mutation delF1617. Am J Physiol Heart Circ Physiol 288:H2666-76

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