Effect of combined sympathetic and parasympathetic blockade on heart rate and cardiac function in man

Abstract

0 VER many years, isolation of the heart in animals has been used for investigation of intrinsic cardiac function, excluding the nervous and humoral stimuli which can modify this function so profoundly. In this study, our aim has been to examine abnormal cardiac function in man under conditions similar to those attained by surgical isolation of the heart in animals. By blocking the natural sympathetic and vagal stimuli to the heart with propranolol and atropine given together, we were able to produce a state closely resembling cardiac isolation in the intact animal, without surgery and without major paralysis of the systemic circulation. In the doses needed, neither drug had detectable direct effect on cardiac muscle, and we felt that this approach, if it could be applied safely in man, would satisfy our initial aim. Studies were therefore made during cardiac catheterization to assess the tolerance of cardiac patients to these drugs. From these evolved our present practice of giving doses of propranolol 0.2 mg./kg. body weight and atropine 0.04 mg./kg. as a single injection intravenously over two minutes. These doses totally block any chronotropic response of the heart to vagal or sympathetic stimuli for 20 minutes both in the dog and in man. Inotropic responses in the dog, as indicated by a strain gauge arch on the right ventricle, are at least 90 per cent blocked in the first 10 minutes. In man, no evidence of an inotropic response to isoproterenol can be obtained for 20 minutes. On this evidence, the assumption of total or near-total isolation in the 5 to 10 minutes after injection appears justified. The hemodynamic effects of isolation were then measured in a total of 71 patients, using left heart catheterization to obtain an assessment of left ventricular function in 56. In the latter patients, serial measurements of left heart pressures and output were made (1) in a control state, (2) after isolation, and (3) during isolation while an increased load was imposed on the ventricle by raising the arterial pressure with an intravenous infusion of angiotensin at an appropriate constant rate. These 56 patients comprised 12 with normal hearts, and 44 with known myocardial disease of varied severity, either primary, ischemic or secondary to aortic valve stenosis. In the normal subjects, isolation caused an increase in heart rate, no change in cardiac output and a rise in arterial pressure. With myocardial disease, these changes were smaller, and with severe disease sometimes reversed; there was often no change or a slowing in heart rate and usually a fall in cardiac output. By examining the effect of each blocking drug separately, we found that in certain patients with severe disease the heart showed little or no rate increase with atropine and less slowing than in normal subjects with propranolol. By measuring the heart rate changes during vagal and sympathetic stimuli of graded intensity, a marked reduction in sensitivity of the heart was found in these patients, relative to normal subjects. Usually, but not always, the reduced sensitivity to vagal and sympathetic stimuli was accompanied by a relatively slow heart rate after isolation. This depression of chronotropic response to nervous stimuli with myocardial disease appears not to have been recognized before and may have many implications important to clinical practice. Our studies of the inotropic response have not yet been adequate to show whether or not this too is depressed. The hemodynamic measurements after isolation.