Effects of pulsed beta-stimulant therapy on beta-adrenoceptors and chronotropic responsiveness in chronic heart failure

Abstract

In animals, intermittent sympathomimetic stimulation with dobutamine produces benefits analogous to those of physical conditioning. Longer intermittent or continuous beta-stimulant therapies have not, however, been successful in managing patients with chronic heart failure. We have investigated the role of beta-receptor stimulants in patients with severe chronic heart failure by changing the method of administration to intermittent, very short-duration pulsed intrope therapy (PIT). We studied 10 patients (mean age 64 [SE 2] years) with stable moderate to severe chronic heart failure (ejection fraction 23 [3]%) who received PIT, and 10 control patients matched for age and severity. We infused sufficient dobutamine to raise heart rate to 70-80% maximum for 30 min per day, 4 days per week for 3 weeks. PIT increased exercise tolerance (from 10.4 [1.2] min at baseline to 13.0 [1.5] min at 3 weeks; p < 0.001, 95% CI for difference 1.6 to 3.9) and lowered peripheral vascular resistance (19.8 [3.1] to 17.7 [2.4] mm Hg.min.L-1; p < 0.05, -4.1 to -0.1). PIT produced significant increases in lymphocyte beta-receptor density (502 [110] to 1200 [219] per cell, p < 0.02, 258 to 1138) and chronotropic responsiveness to exercise (change in heart rest to peak exercise 51.0 [3.2] to 57.5 [3.9] beats per min; p < 0.01, 2.9-10.1). Plasma noradrenaline concentrations (2.39 [0.28] to 1.65 [0.19] nmol/L, p < 0.05) were reduced. The patients' symptoms were also improved. By contrast, no change in autonomic function or exercise capacity was seen in the control group. Short-duration PIT induces pharmacological conditioning with improved symptoms, autonomic balance, exercise tolerance, beta-receptor up-regulation, and enhanced chronotropic responsiveness in chronic heart failure.