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Transcript of Norbert Jost, PhD - web.med.u-szeged.huweb.med.u-szeged.hu/phcol/notes/elphys_2018/Angol/...General...
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