Therapy and Prevention Congestive Heart Failure

Studies in patients with congestive heart failure (CHF) have demonstrated an abnormal /3-adrenergic reflex vasodilation during orthostatic tilt. Baroreflex modulation of vascular resistance in patients with CHF was investigated during therapy with a vasoselective calcium antagonist, felodipinre. Eight patients on conventional therapy for severe CHF were studied after a 3 week course of additional felodipine or placebo treatment under randomized, double-blind, and crossover conditions. Forearm subcutaneous vascular resistance (FSVR) was estimated with use of the local '3Xe washout. Aortic pulsatile stretch, expressed as the systolic distension in percent of diastolic diameter, was calculated from echocardiographic measurements of aortic root diameters. At 3 weeks, felodipine reduced the arterial pressure, systemic vascular resistance, and FSVR, preserved cardiac filling pressures and heart rate, and increased cardiac output, stroke volume, and aortic pulsatile stretch. Upright tilt (45 degrees) was used to study baroreflex-mediated cardiovascular responses. The unloading of cardiopulmonary baroreceptors during upright tilt was substantial and about equal during both treatment courses, but the pulse pressure was maintained during the placebo and decreased during the felodipine period. During tilt, the patients on placebo failed to increase heart rate and their FSVR, systemic vascular resistance, and arterial mean pressure were decreased, whereas during tilt after felodipine, heart rate and systemic vascular resistance increased to maintain arterial mean pressure and FSVR also tended to increase. Both the stroke volume and aortic pulsatile stretch increased during tilt in patients on placebo but they decreased in those on felodipine. The tilt caused increments in circulating norepinephrine and epinephrine levels during both treatment regimens. Regulation of FSVR during the sympathetic stimulation of orthostatic stress was further elucidated. Proximal neural blockade caused an increase in FSVR during tilt in patients on placebo and a decrease in FSVR during tilt in those on felodipine. Local f8adrenoceptor blockade caused similar increments in FSVR during tilt in patients on both treatments. Combined proximal and local blockade still increased FSVR during tilt in those on placebo, but caused no change in FSVR during tilt in those on felodipine. This study demonstrates that felodipine normalizes baroreflex control of vascular resistance in patients with CHF. It seems unlikely that this is caused by a nonspecific effect of a vasodilator or an effect on the mechanical stimulus to baroreceptors; it is probably due instead to sensitization of cardiopulmonary and arterial baroreceptors by this calcium antagonist. Circulation 75, No. 6, 1204-1213, 1987. VAGAL AND GLOSSOPHARYNGEAL afferents from cardiopulmonary and arterial baroreceptors exert a restraint on the medullary vasopressor center that tonically regulates the sympathetic efferent outflow to the heart and peripheral circulation." 2 Loading of the From the Cardiology Department, Gentofte Hospital, University of Copenhagen. Address for correspondence: Eli Kassis, M.D., Cardiology Laboratory, Rigshospitalet, Blegdamsvej 9, DK 2100 0 Copenhagen, Denmark. Received Aug. 5, 1986; revision accepted Jan. 22, 1987. baroreceptors during augmentation of cardiac filling would increase their afferent restraint and reflexly reduce sympathetic efferent activity.3 Unloading of the baroreceptors during orthostatic tilt would activate the baroreflexes and elicit a regulated increment in heart rate and vascular resistance to maintain the arterial pressure.'1The human forearm has been used to study baroreflex-mediated vasoconstriction during upright tilt'4',5 and the regional distribution of this vasoconstriction in subcutaneous and skeletal muscle vascular beds.6 Evidence from these studies has suggested that CIRCULATION 1204 by gest on A ril 4, 2017 http://ciajournals.org/ D ow nladed from THERAPY AND PREVENTION-CONGESTIVE HEART FAILURE the arterial baroreflex is augmented in the upright posture,1 4 that the cardiopulmonary baroreflex plays an important part in regulation of the vasomotor tone in forearm vascular beds," 5'6 and that subcutaneous vascular resistance is selectively modulated by the cardiopulmonary baroreflex. Patients with congestive heart failure (CHF) have been demonstrated to have reduced cardiac responsiveness to sympathetic efferent activity7 8 and attenuated cardiovagal efferent control9 and autonomic control of the heart may thus be absent.'0 In contrast to individuals receiving cardiac transplants,'0 patients with CHF have been observed to have neurohumoral excitation'L13 and increased cardiac pressures and dimensions relating to ultrastructural changes in the myocardium. 4 Degenerative changes in human arterial'5 and animal cardiopulmonary'6 baroreceptor afferent endings have been noted in studies of heart failure. The animal studies have also reported reduced afferent activity from cardiopulmonary receptors 6 17 and impaired efferent control of arterial and cardiopulmonary baroreflexes."` Reduced baroreceptor afferent restraint has recently been suggested to modify a f3-adrenergic reflex mechanism operating during upright tilt in both subcutaneous'9 and skeletal muscle20 vascular beds in patients with severe CHF. Few data are available regarding the effects of vasodilator therapy on autonomic control mechanisms in CHF,2' although such therapy has been increasingly used in the management of patients. Currently available calcium antagonists have vasodilator and negative inotropic properties.22 Felodipine, a new calcium antagonist with a pronounced vascular selectivity,23 has been shown to exert sustained hemodynamic efficacy in patients with CHF.24 The present study was undertaken to test the hypothesis that effects of felodipine therapy on baroreceptor mechanisms in CHF are an important reason for the clinical efficacy of such a therapy. Cardiovascular responses to upright tilt in patients with severe CHF were assessed during a 3 week course of adjunctive felodipine treatment under placebo-controlled conditions. Methods Patient selection and study design. Eight patients from 47 to 65 (mean 54.5) years old were selected because they had severe CHF (New York Heart Association functional class III) while on treatment with digoxin and diuretics. They all had severe left ventricular myocardial dyssynergy, as disclosed by angiographic studies performed 1 to 2 months before our study. Their left ventricular end-diastolic and end-systolic volumes were abnormally augmented and ejection fraction ranged from 14% to 29%. Baseline assessment was carried out 2 weeks before randomization and digoxin and diuretic regimens were optimally set. Medications were continued unchanged and patients entered the study 2 weeks later if they were clinically stable and had normal blood counts, electrolytes, and therapeutic serum levels of digoxin. They were randomly assigned in a double-blind fashion to treatment with felodipine, 10 mg twice daily, or with matching placebo tablets. After 3 weeks of therapy, the patients were hemodynamically investigated, and the next day they crossed over to the second 3 week period of therapy under double-blind conditions. The hemodynamic investigations were repeated at the end of the second treatment period. The study protocol was approved by the official ethical committee in Copenhagen. Informed consent was obtained from each patient. Procedures. The hemodynamic investigations were carried out twice in each patient at the end of a 3 week treatment period with either felodipine or placebo. The compliance of patients was checked by determination of plasma levels of trial drug. Careful clinical assessments of patients were carried out the day before the hemodynamic studies and ensured that they had normal blood counts and electrolytes. The hemodynamic measurements were started 2 hr after administration of the trial drug and baseline therapy. Central hemodynamic measurements. All catheter procedures were performed under fluoroscopic control. A balloontipped triple-lumen thermodilution catheter (Gould SP 1435) was placed in the pulmonary artery for pressure measurements and determination of cardiac output (dilution curves of five consecutive measurements were recorded). All pressures were recorded with Statham P23Db transducers. Supine hemodynamics were measured after patients had rested 1 hr on a tilt table. Thereafter, the patients were passively and slowly (within 1 min) tilted to a 45 degree angle with the feet supported by a base platform, and hemodynamic measurements were repeated within 5 to 10 min after initiation of tilt. All pressures were measured with reference to the midaxillary level while patients were supine and with reference to the right atrial level individually set for each patient during tilt. Arterial blood pressure was measured by cuff and mercury column sphygmomanometer. Concordance between the left ventricular end-diastolic and pulmonary capillary wedge pressures and between the aortic and arm blood pressures had previously been established in these patients while in the supine and tilted positions. Systemic vascular resistance (dynes-sec-cm5) was calculated as 80 x (mean arterial pressure minus right atrial pressure) / (cardiac output). Vascular hemodynamic measurements. Echocardiographic measurements of aortic root dimensions were obtained with a phased-array scanner (Aloca SSD-800). AnM mode scan of the aortic root was recorded while patients rested supine and 5 to 10 min after initiation of 45 degree upright tilt, as described above. Aortic diameters were measured as the distance (mm) between the leading edges of the anterior and posterior aortic wall, at diastole (R wave on the electrocardiogram), and at systole (peak anterior motion of anterior wall).25 Aortic pulsatile stretch was calculated as the systolic distension in percent of diastolic diameter of the aortic root. Forearm subcutaneous blood flow was measured by the local '33Xe-washout technique.26 Measurements were begun 1 hr after patients had been resting supine on a tilt table at a room temperature constantly kept at 220 C. Via a thin cannula, 0.1 ml (1 mCi) of 133Xe (Radiochemical Centre, Amersham, U.K.) dissolved in saline and mixed with 0.1 ml of saline was injected subcutaneously into the skin covering the left brachioradial muscle. An equal deposit of '33Xe solution was mixed with 0.1 ml (10 ng) of propranolol solution in saline (0.1 mg/liter) and injected at a corresponding site on the right forearm. Measurements were started 30 min after the subcutaneous injections to avoid influences of the injection trauma on the washout rate of Vol. 75, No. 6, June 1987 1205 by gest on A ril 4, 2017 http://ciajournals.org/ D ow nladed from