Parikh, Ashish
(2014)
Pharmacological interventions of arrhythmias.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Multiple mechanisms have been implicated in the genesis of early afterdepolarizations (EADs) leading to torsade de pointes (TdP) under long QT syndrome (LQTS). In atrial fibrillation (AF), recent studies have provided new insights into the molecular determinants of atrial structural remodeling pointing out to the importance of fibrosis, as both a cause and a therapeutic target. Physiological experiments combined with mathematical modeling have direct implications to the understanding the effect of drugs and to the treatment of cardiac arrhythmias.
Ranolazine (Ran) approved by the FDA in 2006 as an anti-anginal and anti-ischemic drug, is known to inhibit multiple ionic currents. Functionally, Ran has been shown to suppress EADs in drug-induced long QT type 2 (LQT2), however, its mode of action still remains unknown. Our studies indicated that Ran reduces the open probability (Po) of ryanodine receptors (RyR2), inhibits the SR Ca2+ overload and combined with its effect on late sodium current (INa,Late) suppressed EADs. Reactivation of the L-type Ca2+ channel (ICaL) has also been shown to play a major role in EAD formation under LQTS. In several pathological conditions, ICaL has a larger window current promoting Ca2+ overload and EADs. Dauricine (Dau), a Chinese herb has been shown to impart antiarrhythmic properties. Our experimental studies confirmed that Dau suppressed EADs primarily by reducing the ICaL via slowing down the kinetics. Further investigation suggested that a minor shift in voltage-dependent activation/inactivation parameters can also be utilized as a novel antiarrhythmic strategy.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
1 February 2014 |
| Date Type: |
Publication |
| Defense Date: |
27 June 2012 |
| Approval Date: |
1 February 2013 |
| Submission Date: |
24 July 2012 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
120 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
NA |
| Date Deposited: |
01 Feb 2014 06:00 |
| Last Modified: |
01 Feb 2018 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/13068 |
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