1. Cardiovascular Safety Assessment Before and During Exercise Stress in Normal and Heart Failure Dog Models
Presenting Author: Craig Hassler
Additional Authors: Matthew Coffee, Michael Hawk, Michael Stonerook, Matthew Ellinger, Thomas Vinci, Alecia Peppers, Zhenxu Ma, Vedat Yildiz, Brandon Wood, Robert Lordo, Brian Roche, Stanley Kopp, and Robert Hamlin*.
Affiliation: Battelle and The Ohio State University*, Columbus, Ohio, USA.
Introduction
Pre-clinical cardiac safety is typically conducted in healthy sedentary mature young research animals. However, drugs are never administered only to healthy people and/or sedentary people. The cardiac-related complications of orthostatic hypotension and exercise intolerance are adverse effects noted during clinical trials. Diseases and drugs can often impair cardiovascular reserve. Consequently, animal models more relevant to the treatment population may predict such potential liabilities of a candidate compound. Exercise is a well-documented useful stressor of the cardiovascular and pulmonary systems. Several heart failure models are well-documented. Exercise stress alone or in combination with a heart failure model may be useful to amplify adverse or even beneficial effects of a compound. This study was designed to determine if exercise stress in normal dogs and dogs in heart failure can unmask hemodynamic changes that cannot be observed in sedentary animals.
Heart Rate in Normal Dogs
Heart Rate in Heart Failure Dogs
Rest
Exercise
Recovery NS
Rest
Exercise
Recovery
C+E Decrease
C and C+E Decrease NS
dP/dtmax in Heart Failure Dogs
dP/dtmax in Normal Dogs
Methods
Carvedilol (C) is a ß1-2 and α1 adrenergic receptor antagonist and free radical scavenger. Enalapril (E) is an ACE inhibitor, anti-adrenergic, decreases thirst, diuretic, smart vasodilator, and prevents cardiac and vascular remodeling. These are commonly used drugs which exhibit modest cardiovascular effects. Mongrel dogs (N=4) were instrumented with telemetry units for systemic and left ventricular pressures, heart rate, as well as load-dependent and load-independent measures of contractility. They were conditioned to accept treadmill exercise. They were given P.O. carvedilol, enalapril, or both at dose levels of 1.0 mg/kg and placebo utilizing a Latin Square design. Ninety minutes after dose administration, at the time of approximate Tmax, animals were treadmill exercised for 12 minutes using progressive increases of treadmill speed and incline. The maximum speed and incline were 6 mph and 10º, respectively. Cardiovascular data were collected continuously before, during, and after exercise. Following completion of exercise stress paradigm for normal dogs, heart failure was induced in the same animals by pacing at progressively increasing rates (160 to 200 BPM) until a stable level of cardiac failure was demonstrated via echocardiography. The dosing and exercise paradigm was then repeated. The pacemakers were turned off 15 minutes before baseline or exercise data collection.
Rest
Exercise
Recovery
C+E Decrease
C+E Decrease E Increase
E Increase
Rest
Exercise
Recovery NS
C and C+E Decrease
Mean Arterial Pressure in Normal Dogs
Mean Arterial Pressure in Heart Failure Dogs
Rest
Exercise
Recovery
C+E Decrease
Rest
Exercise
Recovery NS
Results
Heart rate in the normal dogs was not different for any dose before, during, or after exercise. However, heart rate for the heart failure dogs was significantly decreased for C+E at rest and significantly decreased for C and C+E during exercise. The dP/dtmax in normal dogs was significantly decreased for C+E at rest and during exercise and was significantly increased for E during exercise and recovery. However, dP/dtmax in heart failure dogs was significantly decreased for C and C+E only during exercise. Mean arterial pressure in normal dogs was significantly decreased for C+E before, during and after exercise. Mean arterial pressure in heart failure dogs was not significantly decreased at any time. Pulse pressure in normal dogs was significantly increased for E during exercise (diastolic pressure decrease). However, pulse pressure in heart failure dogs was significantly decreased for C and C+E during exercise. Systolic pressure in normal dogs for C+E was significantly decreased before, during, and after exercise. Systolic pressure in heart failure dogs was not significantly different before, during, or after exercise. Diastolic pressure in normal dogs was significantly decreased before, during, and after exercise for C+E. However, diastolic pressure in heart failure dogs was not significantly different before, during, or after exercise. Two animals administered combination of carvedilol and enalapril could not complete exercise paradigm: one normal animal during exercise prior to heart failure and one animal during exercise after heart failure. Delayed post-exercise test article-related heart rate recovery was observed only in normal dogs.
Pulse Pressure in Heart Failure Dogs
Pulse Pressure in Normal Dogs
Rest
Exercise
Recovery NS
E Increase
Rest
Exercise
Recovery NS
C and C+E Decrease
Systolic Blood Pressure in Normal Dogs
Systolic Blood Pressure in Heart Failure Dogs
Rest
Exercise
Recovery
C+E Decrease
Rest
Exercise
Recovery NS
Conclusion
This study demonstrated that subtle cardiovascular effects of two commonly used drugs, enalapril and carvedilol, individually and in combination were altered by exercise in normal and heart failure dogs. These parameters presented significantly different results when normal animals and heart failure animals were compared. The data suggest that exercise and heart failure models or a combination thereof can unmask significant cardiovascular alterations or lack thereof that were not observable in the sedentary normal animal model. Subtle effects do matter. Such models should be considered.
Diastolic Blood Pressure in Normal Dogs
Diastolic Blood Pressure in Heart Failure Dogs
Rest
Exercise
Recovery
C+E Decrease
E and C+E Decrease
Rest
Exercise
Recovery NS