Pulsed inotropic therapy in chronic heart failure

Source: Adamopoulos S, Piepoli M, Qiang F et al: Effects of pulsed Beta-stimulant therapy on Beta-adrenoceptors and chronotropic responsiveness in chronic heart failure. Lancet 1995; 345: 344-349

Summary: Canadian Medical Association Journal 1996; 154: 208

Reduced ability to increase heart rate in response to exercise in patients with chronic heart failure is related to down-regulation of Beta-adrenergic receptors, which may be a result of persistent sympathetic hyperactivation leading to tolerance of Beta-stimulation. Some researchers have suggested that pulsatile rather than continuous stimulation might improve cardiac performance and minimize down-regulation in patients for whom physical conditioning is not feasible. However, trials of long-term Beta-stimulant therapy have had little success, mainly because of drug tolerance and increased frequency of ventricular arrhythmia. Researchers in England and Italy hypothesizing that the periods of drug infusion used in human studies were too long, used pulsed inotrope therapy to mimic the stimulus produced by short periods of exercise.

Ten patients with chronic heart failure were matched by age and severity of disease to 10 controls. After 2 to 4 weeks of evaluation, patients in the treatment group received 30-minute intravenous dobutamine infusions 4 days per week for 3 weeks. The dose was titrated to maintain the patient's heart rate at 70% to 80% of the baseline maximum during exercise. On the first and last two infusion days the dose was increased to achieve peak heart rate. The treatment group was assessed before and after the 3 weeks of infusion and 6 weeks later; the control patients were assessed before and after 6 weeks of normal physical activity.

After 3 weeks of therapy patients in the treatment group showed increases of 25% in exercise tolerance (p < 0.001) and 10% in peak oxygen uptake (p < 0.05), significant reductions in basal heart rate and heart rate during submaximal dobutamine infusion, and an increase in the difference between basal and peak heart rate. The resting plasma noradrenaline concentration was reduced in the treatment group, but there was no change in noradrenaline clearance. Findings related to heart-rate variability also indicated an attenuation of sympathetic drive. A significant increase (p < 0.05) in lymphocyte Beta-adrenoceptor density after therapy suggested up-regulation of receptors. A significant increase (p < 0.05) in cardiac output during submaximal stimulation, which was mainly due to increased stroke volume, was accompanied by decreased peripheral resistance. Patients in the treatment group rated their symptoms as substantially improved. Six weeks after the intervention period, exercise tolerance and chronotropic responsiveness in these patients were decreased but were still significantly higher than at baseline. The control subjects showed no changes in exercise tolerance or autonomic function.

The researchers concluded that brief, intermittent infusions of dobutamine can improve symptoms in patients with chronic heart failure while avoiding Beta-receptor down-regulation, and that the absence of ventricular arrhythmia may have been due to a restoration of autonomic balance. Pulsed inotropic therapy may prove especially useful in the management of chronic heart failure in patients ineligible for physical training.

| CMAJ January 15, 1996 (vol 154, no 2) |