Ion channel dysfunction and

diseases of the heart

H. Todt

Dpt. of

Neurophysiology/Neuropharmacology

Basisvorlesung (BVO) “Zelluläre Signaltransduktion- Krankheitsbilder“ Sommersemester 2015

902.384

PhD- Programm „Molecular Signal Transduction

Ventricular Fibrillation in the Electrocardiogram

Clinical Relevance of Sudden Cardiac

Death

• 20-30 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% / yearArzneimittelbrief 35/8

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.

MOUSE

Integrative Investigation of Cardiac Ion Channel Dysfunction

Currents – Genes –

Channels

Membrane topology of the voltage-

gated Na channel

Multiple interacting proteins at the

intracellular surface of the channel

Ohm´s law:

I=G*E

E=I/G

Current Clamp

The Action Potential as Determinant of Excitability

recovery

from

inactivation

-80mV-50mV

+40mV

-40mV

-80mV

The Action Potential

Controls

Impulse Propagation in

Excitable Tissue

The Action Potential as Electrical Control of the Pumping Function

of the Heart

AP duration varies inversely with heart rate

„Reverse“ rate-dependent effect of K channel blockers

IKr= Human ether-a-gogo K+ channel = HERG

Some Drugs Prolong the Duration of the Action Potential and

Elicit Arrhythmias

„LQT“

Arrhythmias Can Be Produced by Electrical Dysfunction of

Single Cells

„Triangulation Hypothesis“ of Early Afterdepolarizations

LQT1-3 also implicated in sudden infant death syndrome

Genetic Long-QT Syndrome: 1:2000

Prolongation of the Action Potential by Non-Inactivating

Na Channels

Arrhythmias can be generated by the

interaction of cells

Circus movement in an electrically inhomogeneous area

Atrial Fibrillation

Circus movement in an electrically inhomogeneous area

Heterogeneity of Repolarization as Arrhythmogenic Substrate

Some Drugs Prolong the Duration of the Action Potential and

Elicit Arrhythmias

„LQT“

Arrhythmias Can Be Produced by Electrical Dysfunction of

Single Cells

The Brugada Syndrome

• autosomal dominant

• 0.05-0.6 % 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 abortedSCD: 70%

Circ J 2012; 76: 2713 – 2722

EKG Morphology in the Brugada Syndrome

Genesis of Arrhythmias in the Brugada Syndrome

Ito is unopposed by INa

Genesis of the EKG Morphology in the Brugada Syndrome

Meregelli et al., Cardiovascular Research 67 (2005) 367 – 378

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

Extrinsic modifiers

Other cardiac ion channels

Regulation of the channel complex

Genetic and genomic background

Liu, M. et al. Nat. Rev. Cardiol.

advance online publication 24 June

2014

; doi:10.1038/nrcardio.2014.85

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

The Mouse as Model for Cardiac Arrhythmias

Maximum Heart Rate Reserve

Species-dependent Differences in Heart Rate

Kass DA et al., Circ Res. 1998;82:519-522