LQT3 Final Presentation
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LQT3 is caused by a mutation that affects the inactivation gate of the cardiac sodium channel, resulting in a sustained inward sodium current. This prolongs the cardiac action potential and QT interval. Symptoms include arrhythmia and loss of consciousness. The mutation results in faster inactivation time constants for the sodium channel and an inability of the inactivation gates to remain closed, leading to a "bursting mode" current. Computer models of the mutation replicate these effects on channel kinetics and the prolonged action potential.
LQT3 Final Presentation
- 1. LQT Syndrome 3 GROUP 4 Matthew Argentieri Michelle Hung Susan Mathew Sweta Roy Yarden Segal Dikesh Shrestha
- 2. Background • LQT3 is an autosomal dominant disease. – This mutation affects the inactivation gate of the sodium channel and causes a gain of function of sodium current. – Primary LQT3 mutation is ΔKPQ • ΔKPQ is the deletion of lysine, proline, and glutamine between domains III and IV.
- 3. Background
- 4. Symptoms • Arrhythmia • Partial or total loss of consciousness • Abdominal pain and GI complications • Clinical features – Long ST segments with a late appearing T wave – Has QT >490+/- 40 ms
- 5. Factors • There was no voltage shift, no change in channel conductance, and no change in ionic concentrations. • Changes in gate kinetics (time constants) and a new sustained inward current were the only factors discerning LQT3 from wild-type cells.
- 6. Time Constants • Activation gate unaffected • The time constants for the inactivation gates (fast and slow) changed. – Wild Type • τ fast : 1.47 +/- 0.11 ms • τ slow: 8.59 +/- 0.71 ms – Mutant • τ fast : 0.98 +/- 0.07 ms • τ slow: 5.40 +/- 0.55 ms
- 7. Approach • Multiplied time constants by a scaling factor – τfast : 66.67% (2/3) – τslow : 62.86% (540/859) • Altered steady-state inactivation curves (minimum probability of inactivation) – Fast : 1% – Slow: 3%
- 8. Modified Steady State Curves BLUE CURVE: Modified fast inactivation steady state curve – levels out at 1% probability of being open (i.e. never reaches 0%) RED CURVE: Modified slow inactivation steady state curve – levels out at 3% probability of being open (i.e. never reaches 0%)
- 9. MATLAB CODE h_ss(index) = alpha_h/(alpha_h+beta_h); if h_ss(index) <=0.01 h_ss(index) = 0.01; end j_ss(index) = alpha_j/(alpha_j+beta_j); if j_ss(index) <=0.03 j_ss(index) = 0.03; end tau_h = 1.0/(alpha_h+beta_h)*(2/3); tau_j = 1.0/(alpha_j+beta_j)*(540/859);
- 10. Preview of the GUI
- 11. Preview of the GUI ΔKPQ Mutant Cardiomyocyte Action Potential Normal Cardiomyocyte Action Potential
- 12. Conclusions • Action potential duration is elongated due to longer repolarization – Increased time of repolarization due to sustained inward sodium current – Diastolic Interval is reduced • Time constants for LQT3 are smaller and cause faster inactivation • Inactivation gates fail to remain inactivated – Leads to bursting mode current
- 13. THANK YOU! Visit our educational website at: http://mysbfiles.stonybrook.edu/~margentieri
- 14. References • Baars, H. F., Smagt, J. J., & Doevendans, P. (2010). Clinical cardiogenetics. (1st ed., p. 149). Springer. • Bankston, J., & Kass, R. (2010). Molecular determinants of local anesthetic action of beta-blocking drugs: Implications for therapeutic management of long qt syndrome variant 3. NIH Public Access • Beinart, R., Michailidis, A., Gurevitz, O., & Gilkson, M. (2009). Is flecainide dangerous in long QT-3 patients? Journal compilation, 32, 143-145. • Brisbane, J. (2006 (Updated 2009)). Acce review summary: The long qt-syndrome (lqts). Office of Population Health Genomics, Government of Western Australia, Department of Health. • Moss, A., Windle , J., Hall, W., Zareba, W., Robinson, J., McNitt , S., Severski, P, Rosero, S, et al. (2005). Safety and efficacy of flecainide in subjects with long QT-3 syndrome (ΔKPQ mutation): A randomized, double-blind, placebo-controlled clinical trial. Annals of Noninvasive Electrocardiology, 10(4), 59-66. • Ruan, Y., Liu, N., Napolitano, C., & Priori, S. (2008). Therapeutic strategies for Long-QT syndrome: Does the molecular substrate matter?. Circ Arrhythm Electrophysiol, 1, 290- 297. • Schwartz, P., Priori, S., Locati, E., Napolitano, C., Cantù, F., Towbin, J., Keating, M., & Hammoude, H, et al. (1995). Long QT syndrome patients with mutations of the • SCN5A and HERG genes have differential responses to Na channel blockade and • to increases in heart rate. Circulation, (92), 3381-3386. • Sovari, A. (2012, January 10). Long QT syndrome. Retrieved from http://emedicine.medscape.com/article/157826-overview • Wang , H., Zheng, Y., Yang, Z., Li , C., & Liu, Y. (2003). Effect of mexiletine on long • QT syndrome model. Chinese Pharmacological Society, 4, 316-320.
Editor's Notes
- #3: LQT3 is an autosomal dominant disease. It is caused by a mutation in the chromosome 3p21-24 for the gene CN5A that codes for the alpha helix of the voltage gated sodium channel. This mutation results in the inactivation gate of the sodium channel to not work properly. It slows down the inactivation gate, so it cannot close, therefore ventricular repolarization is prolonged. This causes the sodium inward current to increase.
- #7: Bennet et. al