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PMCOL 515 Ion channels and cardiac physiology

PMCOL 515 Ion channels and cardiac physiology. Congenital LQT Acquired (drug-induced) LQT Brugada syndrome SIDS and cardiac ion channels. Dr. Peter Light 6126A HRIF East (ADI) Peter.light@ualberta.ca. Searching for LQT…. What is Long QT?. Dispersion of refractoriness.

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PMCOL 515 Ion channels and cardiac physiology

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  1. PMCOL 515Ion channels and cardiac physiology Congenital LQT Acquired (drug-induced) LQT Brugada syndrome SIDS and cardiac ion channels Dr.Peter Light 6126A HRIF East (ADI) Peter.light@ualberta.ca

  2. Searching for LQT….

  3. What is Long QT?

  4. Dispersion of refractoriness Theaction potential length is critically important in preventing action potentials from travelling in the wrong direction.

  5. What is Long QT?

  6. What causes QRS complex inversion?

  7. Re-entrant arrhythmias Normal VF

  8. 1. Congenital LQT • KILLED BY AN ALARM CLOCKA GRIEVING mother says she has proof her daughter was killed by an alarm clock.DNA Tests have finally shown nurse Lisa Jane Browne, 27, suffered a rare condition which could have caused her heart to stop in shock when the alarm woke her in January 1998.A coroner recorded an open verdict saying the cause of Lisa's death was a mystery.But now Lisa's mum wants the inquest re-opened after discovering Lisa had Long QT Syndrome.Doreen Harley and her husband Terry - who have spent the past seven years trying to prove their daughter was ill - had a sample of Lisa's tissue sent to Sweden for analysis two years ago.She said: "It took 20 months to diagnose Lisa definitely had Long QT. We could never accept she died for no reason. "The syndrome, which affects around one in 7,000, is a disorder of the heart's electrical rhythm - leaving victims open to heart attacks which can be produced by sudden shocks. The family then found Lisa's sister Rachel had Long QT. She had a pacemaker fitted, which saved her when a shock triggered a heart attack.

  9. 1. Congenital LQT Caused by: Gain of function (GOF) or loss of function (LOF) mutations in cardiac ion channels that result in decreases in AP repolarization and QT prolongation. Nomenclature: LQT1 -10 Examples: LQT2 HERG K channel (LOF) LQT3 voltage gated Na channel (GOF)

  10. Acquired. Those affected do not present overt LQT and TdP unless taking certain drugs or drug-drug combinations. Subclinical. Those affected may have a normal or slightly prolonged QT interval and not present overt LQT and TdP BUT Are more sensitive to drug-induced LQT as the repolarization Reserve is reduced. 2. Acquired/drug-induced LQT

  11. Can lengthen AP duration too much!

  12. Drugs: Long QT and TdP

  13. Drugs: LQT and TdP

  14. Drugs that prolong QT..

  15. Drugs that prolong QT..cont

  16. Seldane • Seldane (terfenadine), an anti-histamine OTC hay fever drug was withdrawn from market in 1997. Why? The pro-drug Terfanadine metabolized to the active metabolite fexofenadine by hepatic CYP3A4 activity (cytochrome P450-3A4). If CYP3A4 activity is inhibited then terfenadine levels rise. Terfenadine is a very good inhibitor of IKr (HERG) current in the heart leading to TdP. Many antifungal and antibiotics inhibit CYP3A4. The active metabolite fexofenadine is now marketed as Allegra

  17. 3. Brugada syndrome The Brugada syndrome, first described as a new clinical entity by Drs. Pedro and Josep Brugada in 1992, is a form of sudden cardiac death that tragically takes the lives of young adults. It is an inherited syndrome (arrhythmia) that can lead to life threatening ventricular fibrillation. Caused by mutations in sodium channels that lead to loss of function. Normal LQT Brugada

  18. 4. SIDS andcardiac ion channels? • Can ion channel mutations in the heart lead to SCD in infants? • LQT like sodium channel mutations? • Many adult SCD events occur when sleeping…does this also occur in infants?

  19. 1. The papers…. 2. 3. chemtract

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