Assessment of pharmacological effects of inotropic drugs on left ventricular pressure and...
1
shortened the QT-interval (200±5 vs. 181±7 ms), shifting the QT- RR relationships to the steeper restitution region of (bottom- leftward shift), as well as decreasing QT-RR variability (VQT-RR: 39±6 vs. 11±1 ms). Similar changes were observed following the administration of Levocromaklin (e.g., QT: 217±8 vs. 160 ± 4 ms; VQT-RR: 218±30 vs. 15±2 ms). On the other hand, dofetilide prolonged QT (226±8 vs. 260 ± 8 ms), increased variability in the QT-RR plane (VQT-RR: 169 ± 16 vs. 275 ± 43 ms), and shifted the QT- RR relationship upwards, suggesting an increased torsadogenic risk. Taken together, these data suggest that drug-induced QT-shortening, and not torsadogenic QT-lengthening, mimics the beat-to-beat restitution profile of an acute coronary event in animals prone to ischemic sudden death. Therefore, the detection of QT-shortening may be necessary for the complete evaluation of arrhythmic liability. doi:10.1016/j.vascn.2010.11.154 Poster Number: 151 Board Number: 90 Influence of nyctemeral cycle on cardiovascular parameters in dogs, primates and minipigs Virginie Jacquot, Thomas Schwitzer, Anne-Marie Betat, Guillaume Froget Centre International de Toxicologie (CIT), Evreux cedex, France Dogs, primates and minipigs are non-rodent species usually used for cardiovascular safety pharmacology studies. In order to perform accurate interpretation of modifications of cardiovascular parameters, it is important to understand the influence of the nyctemeral cycle, feeding and gavage on cardiovascular parameters. Arterial pressure and heart rate were recorded for at least 24 hours in conscious telemetered dogs, primates and minipigs. Prior to the measurement, the animals were habituated to experimental conditions, similar to those of standard cardiovascular safety pharmacology studies. The recording period included a 12/12 light/dark cycle. Food was delivered once during the daylight period. A mock administration procedure (gavage) was also performed to evaluate the influence and duration of the dosing procedure on the cardiovascular parameters of each species. Oral gavage produced a significant tachycardia (+30% in minipigs and primates, +50% in dogs) and increased arterial pressure in each species (~20%). Time needed for cardiovascular parameters to recover their pre-treatment level after gavage was shorter in dogs (15–20 minutes) than minipigs (30–40 minutes) or monkeys (~30 minutes). In minipigs, feeding induced an increase in heart rate for several hours, while the impact was much more limited in the other species. Nyctemeral cycle, gavage and feeding consider- ably influence blood pressure and ECG in experimental animals, therefore this should be taken into consideration for the design and for the interpretation of cardiovascular studies. doi:10.1016/j.vascn.2010.11.155 Poster Number: 152 Board Number: 91 Assessment of pharmacological effects of inotropic drugs on left ventricular pressure and contractility in Cynomolgus monkeys Kevin Norton, Giuseppina Iacono, Mark Vezina Charles River Laboratories, Quebec, Canada The ICH S7A and S7B guideline require that effects of test substances on the cardiovascular system be assessed with respect to blood pressure, heart rate and electrocardiogram intervals with particular emphasis placed on assessment of potential delays in cardiac depolarization, most frequently associated with Torsades de Pointes. Meanwhile other potential indicators of cardiac toxicity such as cardiac contractility have been largely overlooked, despite evidence suggestive of a higher incidence of contractility modifica- tion noted during the conduct of phase 1 clinical studies, compared to prolongation of QT intervals (Moors et al., 2007). The objectives of this study were to 1) develop a model for chronic evaluation of LVP and contractility in monkeys, 2) illustrate changes in LV contractility without concurrent proportional changes in heart rate and/or systemic blood pressure, 3) determine if LVP catheter placement resulted in PVC or arrhythmias and 4) determine if the QA interval can be used as a indicator of altered LV contractility. Results indicated that the method was suitable for chronic assessment of contractility, with little artifact noted. Administration of Atenolol and Pimobendam resulted in a decrease and increase in maximum left ventricular contractility (+dP/dt mmHg/secs) which in the case of Pimobendam was not proportional with associated heart rate changes. doi:10.1016/j.vascn.2010.11.156 Poster Number: 153 Board Number: 92 Prevalence and challenges of ventricular arrhythmia associated with intra-ventricular telemetry instrumentation David L. Holdsworth a , Kyle P. O'Donohue a , Matthew Abernathy a , Francis W.K. Smith Jr. b , Jill A. Dalton a , Theodore J. Baird a a MPI Research, Mattawan, MI, United States b VetMed Associates, Greendale, WI, United States Minimally invasive implantable telemetry devices are routinely used in pre-clinical cardiovascular safety evaluation of readily accessible experimental endpoints. However, investigators are some- times interested in assessing myocardial performance in addition to such cardiovascular endpoints, which requires a pressure catheter/ transducer to be secured into the left ventricle to determine dP/dt max or other indicators intrinsic to cardiac work. Increased ventricular arrhythmia has historically been observed, at least anecdotally, in both beagle dogs and cynomolgus monkeys following this surgical procedure. The current investigation was initiated to quantitatively assess the incidence of ventricular arrhythmia, particularly those characterized as abnormal in either frequency or type. While these have naturally been accepted as potential artifacts of such instrumentation, possible challenges may include: 1) definitive determination of the origin of arrhythmia observations on study as surgery-related, iatrogenic, or drug-induced, and 2) resultant potential for inaccurate conclusions in the context of heightened industry and regulatory concern regarding temporal alterations in repolarization and pro-arrhythmia. ECG data were reviewed from ~100 subjects pre-and post-implantation, including ≥20 hours/subject of continuous pre-study telemetry data. A high frequency of arrhythmias was noted in a significant number of animals post surgery, particularly in cynomolgus monkeys. Details of the experimental methodology and implications of these findings will be discussed. doi:10.1016/j.vascn.2010.11.157 Abstracts e46
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Transcript of Assessment of pharmacological effects of inotropic drugs on left ventricular pressure and...
shortened the QT-interval (200±5 vs. 181±7 ms), shifting the QT-RR relationships to the steeper restitution region of (bottom-leftward shift), as well as decreasing QT-RR variability (VQT-RR:39±6 vs. 11±1 ms). Similar changes were observed following theadministration of Levocromaklin (e.g., QT: 217±8 vs. 160±4 ms;VQT-RR: 218±30 vs. 15±2 ms). On the other hand, dofetilideprolonged QT (226±8 vs. 260±8 ms), increased variability in theQT-RR plane (VQT-RR: 169±16 vs. 275±43 ms), and shifted the QT-RR relationship upwards, suggesting an increased torsadogenic risk.Taken together, these data suggest that drug-induced QT-shortening,and not torsadogenic QT-lengthening, mimics the beat-to-beatrestitution profile of an acute coronary event in animals prone toischemic sudden death. Therefore, the detection of QT-shorteningmay be necessary for the complete evaluation of arrhythmic liability.
doi:10.1016/j.vascn.2010.11.154
Poster Number: 151Board Number: 90
Influence of nyctemeral cycle on cardiovascular parameters indogs, primates and minipigsVirginie Jacquot, Thomas Schwitzer, Anne-Marie Betat,Guillaume Froget
Centre International de Toxicologie (CIT), Evreux cedex, France
Dogs, primates and minipigs are non-rodent species usually usedfor cardiovascular safety pharmacology studies. In order to performaccurate interpretation of modifications of cardiovascular parameters,it is important to understand the influence of the nyctemeral cycle,feeding and gavage on cardiovascular parameters. Arterial pressureand heart rate were recorded for at least 24 hours in conscioustelemetered dogs, primates and minipigs. Prior to the measurement,the animals were habituated to experimental conditions, similarto those of standard cardiovascular safety pharmacology studies. Therecording period included a 12/12 light/dark cycle. Food wasdelivered once during the daylight period. A mock administrationprocedure (gavage) was also performed to evaluate the influence andduration of the dosing procedure on the cardiovascular parameters ofeach species. Oral gavage produced a significant tachycardia (+30%in minipigs and primates, +50% in dogs) and increased arterialpressure in each species (~20%). Time needed for cardiovascularparameters to recover their pre-treatment level after gavage wasshorter in dogs (15–20 minutes) than minipigs (30–40 minutes) ormonkeys (~30 minutes). In minipigs, feeding induced an increase inheart rate for several hours, while the impact was much more limitedin the other species. Nyctemeral cycle, gavage and feeding consider-ably influence blood pressure and ECG in experimental animals,therefore this should be taken into consideration for the design andfor the interpretation of cardiovascular studies.
doi:10.1016/j.vascn.2010.11.155
Poster Number: 152Board Number: 91
Assessment of pharmacological effects of inotropic drugs on leftventricular pressure and contractility in Cynomolgus monkeysKevin Norton, Giuseppina Iacono, Mark Vezina
Charles River Laboratories, Quebec, Canada
The ICH S7A and S7B guideline require that effects of testsubstances on the cardiovascular system be assessed with respect toblood pressure, heart rate and electrocardiogram intervals withparticular emphasis placed on assessment of potential delays incardiac depolarization, most frequently associated with Torsades dePointes. Meanwhile other potential indicators of cardiac toxicitysuch as cardiac contractility have been largely overlooked, despiteevidence suggestive of a higher incidence of contractility modifica-tion noted during the conduct of phase 1 clinical studies, comparedto prolongation of QT intervals (Moors et al., 2007). The objectives ofthis study were to 1) develop a model for chronic evaluation of LVPand contractility in monkeys, 2) illustrate changes in LV contractilitywithout concurrent proportional changes in heart rate and/orsystemic blood pressure, 3) determine if LVP catheter placementresulted in PVC or arrhythmias and 4) determine if the QA intervalcan be used as a indicator of altered LV contractility. Resultsindicated that the method was suitable for chronic assessment ofcontractility, with little artifact noted. Administration of Atenololand Pimobendam resulted in a decrease and increase in maximumleft ventricular contractility (+dP/dt mmHg/secs) which in the caseof Pimobendam was not proportional with associated heart ratechanges.
doi:10.1016/j.vascn.2010.11.156
Poster Number: 153Board Number: 92
Prevalence and challenges of ventricular arrhythmia associatedwith intra-ventricular telemetry instrumentationDavid L. Holdswortha, Kyle P. O'Donohuea, Matthew Abernathya,Francis W.K. Smith Jr.b, Jill A. Daltona, Theodore J. Bairda
aMPI Research, Mattawan, MI, United StatesbVetMed Associates, Greendale, WI, United States
Minimally invasive implantable telemetry devices are routinelyused in pre-clinical cardiovascular safety evaluation of readilyaccessible experimental endpoints. However, investigators are some-times interested in assessing myocardial performance in addition tosuch cardiovascular endpoints, which requires a pressure catheter/transducer to be secured into the left ventricle to determine dP/dtmax
or other indicators intrinsic to cardiac work. Increased ventriculararrhythmia has historically been observed, at least anecdotally, in bothbeagledogs and cynomolgusmonkeys following this surgical procedure.The current investigation was initiated to quantitatively assess theincidence of ventricular arrhythmia, particularly those characterizedas abnormal in either frequency or type. While these have naturallybeen accepted as potential artifacts of such instrumentation, possiblechallenges may include: 1) definitive determination of the origin ofarrhythmia observations on study as surgery-related, iatrogenic, ordrug-induced, and 2) resultant potential for inaccurate conclusions inthe context of heightened industry and regulatory concern regardingtemporal alterations in repolarization and pro-arrhythmia. ECGdata were reviewed from ~100 subjects pre-and post-implantation,including ≥20 hours/subject of continuous pre-study telemetry data.A high frequency of arrhythmias was noted in a significant numberof animals post surgery, particularly in cynomolgus monkeys. Detailsof the experimental methodology and implications of these findingswill be discussed.
doi:10.1016/j.vascn.2010.11.157
Abstractse46
