The opening of cardiac sodium channels initiates action potentials in most cardiac cells. Despite this critical role in cardiac physiology, variatio in the underlying genes (notably SCN5A, which encodes the major sodium channel in heart) is surprisingly common, with a striking diversity of human phenotypes. Loss of sodium channel function predisposes to sudden death due to ventricular fibrillation: this is seen with sodium channel blockers in patients convalescing from acute myocardial infarction and with mutations that reduce cell surface channel expression. To date, major insights into channel function have come from studies of the relationship between rare genetic variants and unusual human phenotypes. In addition, more recent work has implicated common variants in genes underlying cardiac sodium channel function (including not only SCN5A but also SCN10A not previously implicated in cardiac function) as modulators of the normal electrocardiogram as well as of arrhythmia susceptibility. This resubmission proposal tests the general hypothesis that variation in channel function or expression generates an arrhythmia-prone substrate that becomes manifest in the presence of modulators such as drugs, myocardial ischemia, concomitant heart disease, or common genetic variation.
Specific aim (1) will use pharmacological and genetic probes to dissect the role of SCN10A in cardiac sodium channel physiology.
Specific aim (2) will examine the effects of common variants in SCN5A on sodium current in mice with wild-type and mutant human cardiac sodium channels. Variation in cardiac sodium channel physiology has been associated with increased propensity to sudden death, a continuing public health problem. The mechanisms are being attacked at the in vitro level, using heterologous expression, but the way in which these changes impact whole-heart function has not previously been addressed in detail and this is the major goal of the present experiments. Understanding mechanisms underlying arrhythmia susceptibility may lead to improved preventive treatments.

Public Health Relevance

Serious heart rhythm abnormalities are common causes of death and disability in the United States and worldwide. This research focuses on how genetic variation in key molecules controlling normal heart behavior makes people more or less susceptible to serious heart rhythm abnormalities.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL049989-18A1
Application #
8399224
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Wang, Lan-Hsiang
Project Start
1994-08-01
Project End
2016-06-30
Budget Start
2012-07-03
Budget End
2013-06-30
Support Year
18
Fiscal Year
2012
Total Cost
$396,513
Indirect Cost
$142,338
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Stroud, Dina Myers; Yang, Tao; Bersell, Kevin et al. (2016) Contrasting Nav1.8 Activity in Scn10a-/- Ventricular Myocytes and the Intact Heart. J Am Heart Assoc 5:
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Roden, Dan M (2016) Pharmacogenetics of Potassium Channel Blockers. Card Electrophysiol Clin 8:385-93
Wrobel, Eva; Rothenberg, Ina; Krisp, Christoph et al. (2016) KCNE1 induces fenestration in the Kv7.1/KCNE1 channel complex that allows for highly specific pharmacological targeting. Nat Commun 7:12795
Yang, Tao; Chun, Young Wook; Stroud, Dina M et al. (2014) Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current. Circulation 130:224-34
Roden, Dan M (2014) Personalized medicine to treat arrhythmias. Curr Opin Pharmacol 15:61-7
Weeke, Peter; Roden, Dan M (2014) Applied pharmacogenomics in cardiovascular medicine. Annu Rev Med 65:81-94
Roden, Dan M (2014) Pharmacology and Toxicology of Nav1.5-Class 1 anti-arrhythmic drugs. Card Electrophysiol Clin 6:695-704
Roden, Dan M (2014) The Brugada ECG and schizophrenia. Circ Arrhythm Electrophysiol 7:365-7

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