Ion channel dysfunction and diseases of the heart

Transcription

1 Basisvorlesung (BVO) Zelluläre Signaltransduktion- Krankheitsbilder Sommersemester PhD- Programm Molecular Signal Transduction Ion channel dysfunction and diseases of the heart H. Todt Dpt. of Neurophysiology/Neuropharmacology

2 Ventricular Fibrillation in the Electrocardiogram

3 Clinical Relevance of Sudden Cardiac Death Arzneimittelbrief 35/ deaths per week and million people 10x more deaths than by traffic accidents 50% of deaths due to cardiovascular disease Risk of sudden cardiac death after myocardial infarction: 2-3 % / year Heart failure: 5-10%/year After aborted sudden cardiac death + sustained ventricular arrhythmias: 15-25% / year

4 At least 50% of all SCDs due to CHD occurs as first clinical event or among subgroups of patients thought to be at relatively low risk for SCD.

5 Integrative Investigation of Cardiac Ion Channel Dysfunction MOUSE

6 Currents Genes Channels

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9 Membrane topology of the voltagegated Na channel

10 Multiple interacting proteins at the intracellular surface of the channel

11 Current Clamp Ohm s law: I=G*E E=I/G

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13 The Action Potential as Determinant of Excitability recovery from inactivation +40mV -40mV -80mV -50mV -80mV

14 The Action Potential Controls Impulse Propagation in Excitable Tissue

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16 The Action Potential as Electrical Control of the Pumping Function of the Heart

17 AP duration varies inversely with heart rate

18 Reverse rate-dependent effect of K channel blockers

19 I Kr = Human ether-a-gogo K + channel = HERG

20 Arrhythmias Can Be Produced by Electrical Dysfunction of Single Cells Some Drugs Prolong the Duration of the Action Potential and Elicit Arrhythmias LQT

21 Triangulation Hypothesis of Early Afterdepolarizations

22 Genetic Long-QT Syndrome: 1:2000 LQT1-3 also implicated in sudden infant death syndrome

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24 Prolongation of the Action Potential by Non-Inactivating Na Channels

25 Arrhythmias can be generated by the interaction of cells

26 Circus movement in an electrically inhomogeneous area

27 Atrial Fibrillation

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29 Circus movement in an electrically inhomogeneous area

30 Heterogeneity of Repolarization as Arrhythmogenic Substrate

31 Arrhythmias Can Be Produced by Electrical Dysfunction of Single Cells Some Drugs Prolong the Duration of the Action Potential and Elicit Arrhythmias LQT

32 The Brugada Syndrome autosomal dominant % of adult population Worldwide 4 12% of all sudden deaths at least 20% of sudden deaths in structurally normal hearts Manifestation during adulthood typical ECG (normalized by ß-stimulation, accentuated by Na channel blockers) risk for recurrence in patients presenting with aborted SCD: 70%

33 Circ J 2012; 76:

34 EKG Morphology in the Brugada Syndrome

35 Genesis of Arrhythmias in the Brugada Syndrome I to is unopposed by I Na

36 Genesis of the EKG Morphology in the Brugada Syndrome Meregelli et al., Cardiovascular Research 67 (2005)

37 Channelopathies: Sources of Phenotypic Variability Intrinsic modifiers Transcriptional modifiers Translational modifiers Trafficking to cell membrane Post-translational modifiers PKA and PKC ROS Alterations in metabolism Degradation pathways Liu, M. et al. Nat. Rev. Cardiol. advance online publication 24 June 2014 ; doi: /nrcardio Extrinsic modifiers Other cardiac ion channels Regulation of the channel complex Genetic and genomic background

38 Some Limitations of the Mouse as substitute for Man in the Study of Electrogenic Cardiac Disease High heart rate (~ 600 beats/min) Small degree of modulation of heart rate Different mechanism of repolarization Small tissue volume

39 The Mouse as Model for Cardiac Arrhythmias

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41 Species-dependent Differences in Heart Rate Maximum Heart Rate Reserve Kass DA et al., Circ Res. 1998;82: