Download Cardiac Physiology and Chronobiology

Safety Pharmacology Society Webinar:
Cardiac Physiology
and Chronobiology
Maxim Soloviev, MD, PhD, DSP
Incyte Corporation, Wilmington, DE
Overview
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Basics of heart conductive system
ECG 101
Diurnal variability in different species
Cardiac conduction system
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Impulse initiated by the Sinus
Node.
It travels to the atriums and to the
Atrioventricular (AV) Node located
between the chambers
The AV Node slows the impulse
down and passes it through to the
AV Bundle (or Bundle of His)
Bundle of His divides itself into two
tracts through the ventricles and the
Purkinje Fibers, which stimulate
muscle of the ventricles
ECG and Cardiac Activity
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Electrocardiogram (ECG) is a
representation of the heart's electrical
activity
The P wave, represents atrial
depolarization
The QRS complex represents ventricular
depolarization
The ST segment represents the
repolarization of the ventricles
The QT interval represents ventricular
depolarization and repolarization
AV Node
Normal ECG
Normal duration and amplitude of ECG waves,
complexes, and segments is variable in different
species
E.g. QT/RR ratio in normal conditions
human > monkey > dog
How to Think about Heart Rhythm
Electrical Impulse
Formation
Site of Origin
•Sinus Node
•Atrium
•AV node
•Ventricle
•Consistency
Rate
•Normal
•Fast
•Slow
Regularity
•Regular
•Irregular
Sinus arrhythmia
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Common finding, more prominent in dogs
Sinus bradyarrhythmia
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Common finding, more prominent in dogs,
especially during night hours (vagal prevalence)
Sinus arrhythmia with
ventricular escape complex
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Less common finding, still can be observed
in healthy animals
AV block
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First degree AV block – prolongation of PR interval
Second degree AV block
–
–
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Type 1 (aka Mobitz 1 or Wenckebach): Progressive prolongation
of PR interval with dropped beats
Type 2 (aka Mobitz 2 or Hay): PR interval remains unchanged
prior to the P wave which suddenly fails to conduct to the
ventricles.
Third degree AV block, also known as complete heart
block, condition when impulse generated in the sinus
node does not propagate to the ventricles
2nd Degree AV Block, Type 2
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Common finding in healthy animals, more frequent in
dogs
3rd degree AV block
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Impulse generated in the sinus node, conducts
to atria but does not propagate to the ventricles
If impulse for ventricles generated at AV node
or His Bundle before bifurcation, QRS complex
can be of normal shape
Single PVC
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Ventricular cell may initiate an impulse and
cause a premature ventricular contraction
(PVC)
A single occurrence is seen quite often an does
not cause any serious problems
Multiple polytopic PVC
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Abnormal finding, may suggest myocardial damage
and/or issues with repolarization
Frequent PVC dramatically increase probability of
polymorphic ventricular tachycardia aka Torsades de
Pointes (TpD)
Torsades de Pointes
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Torsades de pointes (TdP) – is a polymorphic ventricular
tachycardia that can cause sudden death
Although uncommon, TPD is one of the most severe cardiac
side effects
Chronopharmacology
Chronokinetics
of Indomethacin
(Human data)
Other examples:
• Amitriptylin
• Diasepam
• Digoxin
• Propranolol
• Verapamil
• Nidedipin
• Theophyllin
…
Clench et al., 1981
Chronopharmacology
Same amount of drug given at a
different time of the days may
result in different exposure
(Cmax, Tmax, AUC…)
- Chronopharmacokynetics
Same amount of drug given at a
different time of the days may
result in different
pharmacodynamic response
- Chronopharmacodynamics
v. Mayersbach, 1976
Diurnal Variability in HR
Difference
between
nocturnal
and diurnal
species
Minipigs
Sato et al, 1995;
Soloviev at al, 2006;
Stubban et al 2008
Diurnal Variability in BP
Minipigs
Sato et al, 1995;
Soloviev at al, 2006;
Stubban et al 2008
Diurnal Variability in Temperature
Rat, activity
Rat, temperature
Minipigs
Stubban et al 2008;
Soloviev at al, 2003;
Soloviev at al, 2006
Diurnal Variation of QT interval
Difference up to
32 msec (12.7%)
300
240
210
180
12
013
0
13
014
0
14
015
0
15
016
0
16
017
0
17
018
0
18
019
0
10
011
0
11
012
0
80
-9
0
90
-1
00
70
-8
0
150
60
-7
0
QT (msec)
270
Heart Rate (bpm )
NHP Light
NHP Dark
Dog Light
Dog Dark
Suggested Literature
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Authier, S et al., A cardiovascular monitoring system in conscious cynomolgus monkeys for regulatory
safety pharmacology. Part 1: Non-pharmacological validation. J Pharmacol Toxicol Methods, 2007.
56: p. 115-121.
Brown AM Drugs, hERG and sudden death. (2004) Cell Calcium 35(6):543-547.
Detweiler, D.K. (1988). The mammalian electrocardiogram, in Comprehensive Electrocardiography:
Theory and Practice in Health and Disease (MacFarlane, PW and Lawrie, T.D.V., eds.). Pergamon,
New York.
Dubin D. Rapid Interpretation of EKG's. 2000.
Hamlin RL. How many ECG leads are required for in vivo studies in safety pharmacology? (2008) J
Pharmacol Toxicol Methods. 57(3):161-8.
Gauvin DV et al (2006) Spontaneous cardiac arrhythmias recorded in three experimentally- and drugnaive laboratory species (canine, primate, swine) during standard pre-study screening. J Pharmacol
Toxicol Methods. 59(2):57-61.
Gauvin, DV et al (2006). Electrocardiogram, hemodynamics, and core body temperatures of the
normal freely moving cynomolgus monkey by remote radiotelemetry. J. Pharmacol. Toxicol.Methods
53(2):140–151.
Suggested Literature
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Leishman, D et al., Best practice in key nonclinical cardiovascular assessments in drug development:
current recommendations from the SPS. J Pharmacol Toxicol Methods, 2012 May-Jun;65(3):93-101.
Lemmer B. Relevance for chronopharmacology in practical medicine. Semin Perinatol. 2000
Aug;24(4):280-90.
Lemmer B. Chronobiology, drug-delivery, and chronotherapeutics. Adv Drug Deliv Rev. 2007 Aug
31;59(9-10):825-7.
Markert, M., et al., Validation of the normal, freely moving Göttingen minipig for pharmacological
safety testing. J Pharmacol Toxicol Methods, 2009. 60: p. 79-87.
Mayersbach H. (1976). Time – a key in experimental and practical medicine. Arch. Toxicol. 36 185–
216.
Sato, K. et al, Circadian and short-term variabilities in blood pressure and heart rate measured by
telemetry in rabbits and rats. J Auton Nerv Syst, 1995. 54(3): p. 235-46.
Soloviev MV et al. (2006) Different species require different QT corrections. Cardiovascular
Toxicology, 6(2): 145-157.
Soloviev MV et al. (2006). Variations in hemodynamic parameters and ECG in healthy conscious
freely moving telemetrized beagle dogs. Cardiovasc. Toxicol. 6(1):51–62.
Tilley LP et al. Canine and Feline Cardiac Arrythmias Self Assesment. 1999.
Thank you!
Questions?