Safety Pharmacology Society Webinar:
Cardiac Physiology and Chronobiology
Maxim Soloviev, MD, PhD, DSP Incyte Corporation, Wilmington, DE
Overview
Basics of heart conductive system ECG 101 Diurnal variability in different species
Cardiac conduction system
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
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 Rate Regularity
•Sinus Node •Normal •Regular •Atrium •Fast •Irregular •AV node •Slow •Ventricle
•Consistency Sinus arrhythmia Common finding, more prominent in dogs
Sinus bradyarrhythmia Common finding, more prominent in dogs, especially during night hours (vagal prevalence)
Sinus arrhythmia with ventricular escape complex Less common finding, still can be observed in healthy animals
AV block
First degree AV block – prolongation of PR interval Second degree AV block – 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 Common finding in healthy animals, more frequent in dogs 3rd degree AV block 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 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 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 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 Other examples: (Human data) • 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
300 Difference up to 32 msec (12.7%)
270
240
QT (msec) 210
180
150
60-70 70-80 80-90 90-100 100-110 110-120 120-130 130-140 140-150 150-160 160-170 170-180 180-190 Heart Rate (bpm)
NHP Light NHP Dark Dog Light Dog Dark Suggested Literature
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 drug- naive 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 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!
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