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Clinical significance of drug induced
QT-prolongation and related syndromes an update
The importantance of cardiac repolarization
reserve in safety pharmacology
András Varró Department of Pharmacology
and PharmacotherapyUniversity of Szeged,
Hungary Albert Szent-Györgyi Medical Center 2007
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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. 1152025-2032 2005)
RARE with terfenadine 1/50000
Due to Torsades de pointes

• Withdrawn drugsTerfenadineAstemizoleGrepafloxac
  inCisapride
• None approval or suspended developmentseveral
• Complicated approvalMoxifloxacinZiprasidone
• Approved with QT cautions in labelingnumerous
• Re-labelingThioridazineDroperidol

If you remember, I did mention possible
side-effects.
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Drugs That Prolong the Q-T Interval and/or Induce
Torsades de Pointes www.Torsades.org Raymond L.
Woosley, MD, Ph.D. Arizona CERT (Center for
Education and Research on Therapeutics) Informatio
n from the FDA-approved drug labeling and the
medical literature.
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Closed and last revised 03/01/2006
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Current clinical view of drug induced torsade
pointes arrhythmia

• Primary drug effect (IKr IHERG blockade)
• Secondary risk factors (effect amplifiers)

• High doses or rapid administration
• Metabolic inhibition
• Impaired elimination
• Bradycardia
• Hypokalemia hypomagnesemia
• Heart disease (CHF, LVF, diabetes)
• Female gender 70
• Concomittant ion-channel modifier
• Undetected ion channel polymorphisms or mutation(
  LQT)

E. Kevin Heist et al. Heart Rhythm 20052S1S8
Moxifloxacin (fluroquinolone) as positive control
6 10 ms QT prolongation
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QT lengthening
Important antiarrhythmic mechanism
Sign of dangereous side effect of various drugs
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Regional differences
Gaborit et al. J Physiol 582.2 (2007) pp 675693
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regular heart beat
regular heart beat
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Experimental demonstration of the repolarization
reserve
The effect of IKs block on the APD in dog right
ventricular muscle and Purkinje fiber
PURKINJE FIBER
VENTRICULAR MUSCLE
CONTROL
100 nM L-735,821
0 mV
0 mV
50 mV
200 ms
CONTROL
10 µM CHROMANOL 293B
0 mV
0 mV
50 mV
200 ms
Varro et al. J Physiol. 200052367-81.
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Experimental demonstration of the repolarization
reserve
The effect of IKs block in pharmacologically
lengthened APD in dog right ventricular muscle
CONTROL
E-4031 VERATRINE
100 nM L-735,821
100 nM L-735,821
0 mV
1 µM E-4031 1 µg/ml VERATRINE
420
50 mV
400
380
360
100 ms
?
340
20
320
APD (ms)
18
300
16
14
280
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APD CHANGE ()
260
10
8
240

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n7
220
4
140
0
20
40
60
80
100
120
2
TIME (min)
0
Varro et al. J Physiol. 200052367-81.
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Conclusion in 2000
Varro et al. J Physiol. 200052367-81.
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Role of IKs in the repolarization reserve in the
human ventricle
Jost et al., Circulation. 2005 1121393-1400.
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Multiple K channel block and repolarization
reserve
Dofetilide Chromanol 293B
0 mV
0 mV
Chromanol 293B
50 mV
IKs
50 mV
CL 5000 ms
200 ms
Dofetilide BaCl2
BaCl2
Bilicki et al. Br J Pharmacol 2002 137 361-368
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Repolarization Reserve
18
200 ms
CHANNEL PROTEIN
CURRENT
Nav1.5Navb1
INa
ICa
Cav1.2Cava2d1
Ik1
Kir 2.1 (Kir2.x)
NCX
INCX
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The role of repolarization reserve in patients
Sotalol test
Kääb et al. 2003 Eur Heart Journal
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The role of repolarization reserve in patients
Ibutilide test
Ibutilide test
Number of Subjects
Change in QTc (msec)
Kilborn et al. Circulation 2000. 102 II-673
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Decreased repolarization reserve due to
ventricular electrophysiological remodelling

• Pharmacogenetics (LQT syndrome, ion-channel
  polymorphysm etc.)
• Gender
• Ischaemia
• Renal failure
• Diabetes
• Drugs
• Heart failure

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DIAMOND-CHF Trial and repolarization reserve
0.5
0.4
0.3
Cumulative mortality
0.2
0.1
0.0
0
1
2
3
Years
QTc Interval as Guide to Select Those Patients
With Congestive Heart Failure Brendorp et al.
Circulation 2001 1031422-1427
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Repolarization reserve and gender
Rodriguez et al. JAMA 2001, Vol 2851322-1326
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Cisapride rescues misprocessed mutant (LQT3)
sodium channel trafficing
Liu et al. Circulation. 20051123239-3246.
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How to predict torsades de pointes arrhythmia ?
HERG assay ? Action potential duration in dog Pf
? QTc ? QT dispersion ? APD triangularization
(SCREENIT system Hondeghem) ? QT/APD short term
variability ?
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Variability of Repolarization
What does it mean?
temporal beat-to-beat
spatial Purkinje fiber, M-cell,
Subendocardial, Subepicardial,Basal, Apex
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How to measure?
QT or APD
Varriability index
Poincaré plot
Berger et al., Circulation, 1997
Short-term beat-to-beat varriability
Brennan et al. IEEE, 2001 481342-47
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Different effects of sotalol and amiodarone two
drugs lengthening QT on the short term
repolarization variability
Thomsen et al, Circulation. 2004 1102453-2459.
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Combined IKr plus IKs block in the ventricular
myocyte beat-to-beat variability of
repolarization
Volders et al. Circulation. 20031072753-2760
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Effects of IKr-blocker dofetilide and IKs-blocker
HMR-1556 on QT-interval variability in conscious
dogs
TdP
Dog 1
Dog 2
Dog 3
Dog 4
Dog 5
TdP
Lengyel et al. Br J of Pharmacol 2007 advance
online publication
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Changes in cardiac repolarization in patients
with heart failure
Changes in cardiac repolarization in patients
treated with antipsychotic drugs
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Drug indrustry
Development of life saving drugs (antiarrhythmics,
cardiotonics, AIDS drugs etc.)
Endpoint mortality
Development of quality of life improving
drugs (pl. antihistamins, CNS and GI drugs etc.)
Endpoint not mortality
I guess we should have tried it on the rats
first.
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General conclusion

1. We should first reach a concensus what degree or
   any kind of mortality can be tolerated.
2. Before treatment we should assess the
   susceptability of the patients regarding possible
   QT lengthening (repolarization reserve)
3. In the future during drug development, to design
   and control safety pharmacology studies deeper
   cardiac electro-physiological background and
   further basic research is required.

Are you coming hunting, or are you gonna sit
around here all day inventing?
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Specific conclusion considering the role of
repolarization reserve

1. Cardiac muscle has strong safety margin of
   repolarization (REPOLARIZATION RESERVE).
   Decrease of this repolarization reserve does not
   necessarily lead to marked change of
   repola-rization but makes hearts susceptible to
   arrhythmias.
2. Multiple K channel block can result excessive
   repolarization lengthening by eliminating the
   repolarization reserve and therefore it can
   associate with increased proarrhythmic risk.

REPOLARIZATION RESERVE
Are you sure about this, Dave? It seems odd that
a pointy head and long beak is what makes them
fly.
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