The mechanism of the cardiac arrhythmias

Norbert Jost, PhD

Department of Pharmacology & Pharmacotherapy, University of Szeged

Division for Cardiovascular Pharmacology, Hungarian Academy of Sciences

Szeged, Hungary

„When the pulse strikes out in long beats and

smoothly for a long time and then the beats of

the pulse become smaller and hard on their own

account, then a quick death will occur and no

cure can be effected.”

Huang Ti Nei Ching Su Wen, China ~ 240 B.C.

Nomotop activity

Treshold potential Spontaneous diastolic

depolarization

Maximal diastolic

potential

Patologic depolarization !!!!!!!!!!!

General schema representing aritmia

mechanisms and the role of remodeling

Cardiac

arrhythmia

Disorder of the automaticity I.

Abnormal automaticity

EAD = Early AfterDepolarization

OK: Extrem repolarization lengthening

a, hypokalaemia

b, extrem bradicardia

c, genetic mallfunction

d, K-channel blockers

(ex. terfenadine, erythromycin, sotalol)

Treatment

a, serum K+ elevation

b, magnesium (Mg2+)

c, drugs that facilitate repolarization

(ex. mexiletine, verapamil)

early afterdepolarization

The demonstration of the arrhythmogen effect of the early

afterdepolarization (EAD) in canine heart preparations

Control

Purkinje fibre

Ventricular muscle

Ventricular muscle

Purkinje fibre

Disorder of the automaticity II.

OK: CALCIUM OVERLOAD

a, ischaemia

b, digitalis intoxication

Treatment

decrease of the intracellular calcium level

a) b-receptor blockers (propanolol)

b) calcium antagonists (verapamil)

c) Na-channel blockers (difedan,

lidocaine)

Abnormal automaticity

DAD = Delayed AfterDepolarization

delayed afterdepolarization

Principal mechanisms for arrhythmogenesis

Symmetrical injury of impulse conduction in heart

muscle I.

Asymmetrical injury impulse conduction in heart muscle

II.

The re-entry arrhythmias

Antiarrhythmic mechanisms

Proarrhythmic mechanisms

A B

C D

E F

1 2

1 2

1 2

1 2

1 2

1 2

CAST (1989)

Aim: To test the hypothesis how supression of ventricular extrasystoles by pure

CLASS I drugs flecainide and encainide which decrease impulse conduction can

improve arrhythmia related postinfarction mortality

Cardiac Arrhythmia Suppresion Trial

Flecainide Encainide

N Engl J Med, 321, 406-412, 1989.

Selective fast INa block

Flecainide, Encainide, Propafenone

Rate dependent block of the impulse propagation by inhibition of

the fast INa in the damaged tissue during sustained arrhythmia

but proarrhytmia due to:

Inhibition of the impulse propagation in the damaged

tissue during asymptomatic (arrhythmia free) periods

SWORD (1995)

Survival With ORal D-sotalol

d-sotalol

Aim: To test the hypothesis how a pure CLASS III drug - d-sotalol - which

drug prolongs ventricular repolarization can improve arrhythmia related

postinfartion mortaly

Sotalol, Dofetilide, Ibutilide

Lenghten both atrial and ventricular APD (ERP)

Selective IKr (HERG) BLOCK

but proarrhythmia due to:

Reverse rate dependent APD prolongation

Increased dispersion of repolarization (substrate)

EAD provocation (trigger)

Torsades de pointes ventricular tachycardia

The risk of the sudden cardiac death increases

EAD

ES

Proarrhythmia is a new or more frequent occurrence of pre-existing arrhythmias,

paradoxically precipitated by antiarrhythmic therapy, which means it is a side effect

associated with the administration of some existing antiarrhythmic drugs, as well as

drugs for other indications. In other words, it is a tendency of antiarrhythmic drugs

to facilitate emergence of new arrhythmias.

Proarrhythmia -definition

Withdrawn drugs

Terfenadine

Astemizole

Grepafloxacin

Cisapride

None approval or suspended development

several

Torsades de pointes

„QT interval prolongation, with the potential for fatal arrhythmias, has been the single most common

cause of withdrawal or relabeling of marketed drugs in the last decade” (Roden et al. J.Clin.Invest.

115:2025-2032; 2005)

Complicated approval

Moxifloxacin

Ziprasidone

Approved with QT cautions in labeling

numerous

Re-labeling

Thioridazine

Droperidol

Developmental cost

Withdrawal cost:

~ 800 million USD

~ 500 - ? million USD

RARE: with terfenadine 1/50000

Akar et al. Circulation. 2002;105:1247- 253.

Repolarization inhomogeneity based dog

arrhythmia model

substrate

Varro and Backó Pflugers Arch - Eur J Physiol (2010) 460:31–40

Repolarization inhomogeneity based simplified arrhythmia model

Atrial fibrillation

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. It

can occur at any age but becomes extremely common in the elderly, with a

prevalence approaching 20% in patients 85 years of age. AF is characterized

by disorganized, high-rate (300-500/min) atrial electrical activity and it is

associated with shorter action potential duration (APD) and effective

refractory period and a loss of rate-dependent APD adaptation that involve

concomitant alterations in ion current activity. In some cases AF episodes

can be asymptomatic but they are often associated with symptoms like

palpitations, dizziness, fatigue, angina, dyspnea and hemodynamic

impairment (reduced cardiac output, decreased exercise tolerance due to the

loss of atrial contribution to ventricular filling and rapid, irregular ventricular

contractions. These problems lead to tachycardia-induced cardiomyopathy

and other serious complications. Although AF itself is not a life threatening

arrhythmia it can increase the risk of thromboembolic events (five-fold

increase in the risk of stroke), the mortality of congestive heart failure (CHF,

two-fold increase in mortality, AF occurs in 10-30% of patients with CHF), and

is also a frequent complication of cardiac surgery occurring in up to 40% of

patients leading to prolonged hospitalization.

Atrial fibrillation - AF

WL (Wavelength) = ERP x conduction velocity

Principal mechanisms that can produce AF. Reentry involves a vulnerable substrate, which requires a trigger for

reentry initiation. Ischemia, inflammation, and dilation make atria more vulnerable to AF. AF that results from any

mechanism causes tachycardia-induced remodeling. Even if AF is initially maintained by ectopic activity or single-

circuit reentry in a given patient, ATR-induced spatially heterogeneous refractoriness abbreviation creates

conditions favorable to multiple-circuit reentry, which may then become the AF-maintaining mechanism. Thus,

multiple circuit reentry may be a final common pathway AF mechanism in many patients.

• The muscular sleeves of the pulmonary veins contains in large

amount (40 %) myoycytes able for spontaneous diastolic

depolarization (ectopic foci).

• The originating atrial systoles are the triggers of AFs. This can be

suppressed by ablation.

• There were often observed spontaneous DADs or chatecholamine

induced EADs.

• This PV-automaticity may be a therapeutically relevant

observation

The role of pulmonary veins

ERP 146 ms 95 ms Wijffels et al. Circulation 1995, 92: 1954-1968

Atrial fibrillation remodelling

AF is a progredient disease (paroxysmal → persistent → permanent)

(all changes, which are involved to initiate and maintain the AF)

Sarcolemmal ion channels

Signal transduction and „working” proteins

Gap-junctions, ECM

Neurohormonal systems,

Autonomic nervous system (RAAS)

etc.

Tachycardia

(ATR) Congestive heart failure

Circulus vitiosus, which promote the initiation,

renewal, stabilization and maintaing of the AF

The legendary hydra of Hercules Lloyd and Langberg (J Cardiov Electrophysiol, 2006; 17: 236)

1. Electrical remodelling

2. Contractile remodelling

3. Structural remodelling

AF - electrical remodelling

!!!

Contractile remodelling

Sun et al. Circulation 1998, 98: 719-727

The loss of contractile force of the myocardium, mainly due to ICaL reduction (as a

protective mechanism against Ca2+ overload) and consequently by the damage of the

Ca2+-homeostasis. Hipocontractility will increase the wall stretch, and thereby, causes

atrial dilation (LAV ). Electrical and contractile remodelling go hand in hand !!!

Representative recordings of cell-shortenings (right) and calcium transients (left) obtained from a

Ctl, a P7, and a P42 cells

Structural remodelling (ASR)

• increase in cell size

• perinuclear accumulation of glycogen

• central loss of sarcomeres (myolysis)

• alterations in connexin expression (gap-junctions)

• changes in mitochondrial shape

• fragmentation of sarcoplasmic reticulum

• homogeneous distribution of nuclear chromatin

• changes in quantity and localization of structural cellular proteins

• fibrosis !!!

A paradigm shift in treatment af atrial fibrillation: from electrical to

structural therapy ? (Heidbüchel, Eur Heart J, 2003; 24:2077-2078)

The importance of upstream/non channel treatment of AF !!!

The structural remodelling is the main cause for the progredient behaviour of the AF

(paroxysmal → persistent → permanent). In long lasting AF the following „low flow

ischaemia” –type structural changes occur:

Electrical and contractile remodelling may occur in minutes, hours and days – reversible after conversion

Structural remodelling develops within 3-4 months, and is hardly or even nonreversible

Allessie et al. Cardiovasc Res, 2002, 54: 230-246

The positive feedback correlation between the three types of atrial remodellings

The four main repolarizing K+ currents under the action potential shape

IKs and repolarization reserve in human and dog ventricular preparations

a+b <c

Jost et al, J Physiol, 591, 4189–4206, 2013.

IK1 and repolarization reserve in human and dog ventricular preparations

200 ms 5

0 m

V

0 mV

EAD

CL = 3000 ms

*

50

mV

100 ms

0 mV

50 nM dofetilide (DOF)

10 µM BaCl2

10 µM BaCl2+50 nM DOF

DOG

0 mV

Control

HUMAN

0

10

20

30

40

50

60

70

80

BaCl2

(a)

Human (n=6)

AP

D90

ch

an

ge

(%)

DOF

(b)

BaCl2+DOF

0

10

20

30

40Dog (n=5)

AP

D90

ch

an

ge

(%)

(a)+(b)

*

**

N.S.

BaCl2

(a)

DOF

(b)

BaCl2+DOF

(a)+(b)

* *

# p<0.05

A B

APD90=58.8±5.0 % (n=6)

APD90=44.1±4.3 % (n=6)

APD90=24.8±2.0 % (n=5)

APD90=16.0±2.1 % (n=5)

(c)

(c)

a+b <c

Jost et al, J Physiol, 591, 4189–4206, 2013.

• In the mammalian (human, dog and rabbit) ventricular muscle when

only one type of potassium channels is inhibited, excessive APD

lengthening is not likely to occur. This is probably due to the

capability of the various potassium channels to substitute and/or

supplement each other. Human and dog ventricular myocytes seem

to repolarize with a strong safety margin (“repolarization reserve”).

• When this normal repolarization reserve is attenuated (due to drugs,

increased sympathetic activity, remodelling or genetic disorders),

the otherwise minimal or moderate potassium current inhibition can

result in excessive and potentially proarrhythmic prolongation of

the ventricular action potential duration.

• Multiple K+ channel block can result excessive repolarization

lengthening by eliminating the repolarization reserve and therefore it

can associate with increased proarrhythmic risk.

Specific conclusion considering the role of repolarization reserve

• In pathological settings, when repolarization reserve is

impaired, the relatively mild block of additional K+ current

can cause marked APD/QT interval prolongation.

• Congenital ion channel defects, ion channel remodeling

due to myocardial infarction, heart failure, diabetes

mellitus, etc. - can lead to impaired repolarization reserve

SUMMARY

• Administration of IKr-blockers (cardiac and non-cardiac drugs) in the setting of

decreased repolarization reserve can increase Torsade de Pointes (TdP)

incidence

• QT interval measurements: not reliable in arrhythmic risk prediction –

repolarization reserve impairment: no measurable prolongation of ventricular

repolarization in significant number of cases

• We should re-evaluate our safety pharmacology concept related to possible QT

lengthening effect of drugs to apply tests in preparations where the

repolarization reserve is impaired instead of using preparations where this

reserve is normal

General conclusion !!!

Without the thorough investigation and

understanding the physiological, biophysical and

pathophysiological phenomenons, ie. without basic

science there is no chance for sucesful applied

(R&D) science for example drug development

Thanks for your attention !!

spont.

extra beat

ATP

3Na+

2K+

Na+ pump

Ca2+

SR

RyR

Na+

INa

Na

HX

H+

Na+

NHE

Myofilaments

Ca2+

Ca2+

Ca2+

Na

CaX

Na

CaX

3Na+ Ca2+

NaCaX

Forward Reverse

3Na+

SL Ca2+

pump

ATP

Mitochondria

Ca2+

PKA

b-AR

AC

ATP

cAMP

PLB

SERCA

P

ATP

T-T

ub

ule

Ca2+

ICa

PDE

AMP

ARRHYTHMIA IN HEART FAILURE

K+ Ik1

K+ IKs

K+ Ito

K+ IKr

RE

PO

LA

RIZ

AT

ION

RE

SE

RV

E

Cl- ICl

Na+ If

DAD

extra beat

DAD

Upregulated NCX

Increased sympathetic tone

EAD

trigger

substrate

Jost et al, British Journal of Pharmacology, 2013

INHIBITION OF NCX ABOLISHES EAD AND DAD

trigger

E. Cerbai et al. J Mol Cell Cardiol 33, 441–448 (2001)

If REMODELLING

trigger