CARDIOVASCULAR-RESPONSES TO GRADED TREADMILL EXERCISE DURING THE DEVELOPMENT OF DOXORUBICIN INDUCED HEART-FAILURE IN RABBITS

Study objective - The aim was to examine the haemodynamic and humoral responses to graded treadmill exercise, serially during the development of congestive heart failure. Design - Doxorubicin (1 mg.kg-1) was given to rabbits twice weekly intravenously over 8 weeks to induce a low output congestive cardiomyopathy. Treadmill exercise at 8 and 16 m.min-1 was performed at weeks 0,2,4,6,7, and 8. During each exercise study, continuous recordings were made of cardiac output, mean arterial pressure, and heart rate, and central venous blood was sampled at rest and during the last 10 s of exercise for plasma noradrenaline and plasma renin activity. Experimental material - Six cross-bred English rabbits, mean weight 2.6 kg, received doxorubicin treatment; three control rabbits received vehicle injection. Measurements and main results - Over the first 2 weeks, resting haemodynamic variables and responses to exercise were normal in all rabbits. Thereafter, doxorubicin treated rabbits had progressive falls in resting cardiac index and mean arterial pressure, and rises in resting heart rate and systemic vascular resistance. The normal increases in cardiac index and mean arterial pressure with exercise were progressively attenuated, despite an increase in resting and exercising heart rate. The resting levels of plasma noradrenaline and plasma renin rose after the fourth week of doxorubicin treatment. Throughout the experiment, exercise consistently raised plasma noradrenaline and renin, but the exercising levels of both hormones increased as heart failure progressed. Four of the six doxorubicin treated rabbits became exhausted in the final run and there was an intense rise in systemic vascular resistance. Conclusions - In this rabbit model of chronic heart failure, sympathetic vasoconstrictor drive is greater than normal at rest, and is greatly exaggerated during exercise. It is suggested that this abnormal response to exercise results from a combination of failure of arterial pressure to reach the elevated set point of the arterial baroreflex, increased afferent input from exercising muscles due to their underperfusion, and increase in central command due to muscle fatigue.