Richard L. Kahler

Effects of beta-adrenergic blockade on the cardiac response to maximal and submaximal exercise in man.

Many of the changes in cardiac performance that take place during exercise resemble those that result from stimulation of the sympathetic nervous pathways to the heart. It has therefore been thought likely that an increase in sympathetic nervous activity occurs during exercise and is important in the mediation of the associated cardiac response. To test this hypothesis a variety of experimental approaches have been employed. Several investigators have studied the manner in which surgical denervation of the heart in the dog affects its performance during exercise (1-7), and others have examined the effects of a variety of antiadrenergic drugs on the response to exercise in man (8-12). The results have been conflicting, with some groups ascribing little, if any, importance to the sympathetic system in the over-all performance of the heart (1, 2, 4, 6, 7, 9-11), whereas others believe that the sympathetic nerves do play a major role (3, 5, 8). The interpretation of these earlier studies is complicated. In several of the experiments utilizing surgical denervation, section of the sympathetic nerves was not confined to those innervating the heart (1-3, 5). In others, the parasympathetic innervation of the heart was also interrupted (4-7), and some experiments were performed under general anesthesia (3). Furthermore, it is quite unknown to what extent conclusions based on studies in the dog can be applied to exercising man. In previous investigations on human subjects in which guanethidine or syrosingopine was administered, the sympathetic blockade involved not only the heart but the venous and arterial beds as well (8, 12). The recent development of spe-

THE EFFECTS OF ACUTE HYPOXIA ON THE SYSTEMIC VENOUS AND ARTERIAL SYSTEMS AND ON MYOCARDIAL CONTRACTILE FORCE

The circulatory changes that occur during acutely induced hypoxia have been of interest for many years (1-6). It now seems clear that many of the observed responses to this stimulus result from a complex interaction of its direct effects on the heart and the vascular bed and of its indirect effects mediated through nervous, or humoral mechanisms, or both. The present investigation was designed to study the circulatory effects of hypoxia in an experimental preparation in which the responses of the systemic venous bed, the heart, and the systemic arterial bed could be separated. Particular attention was directed to determining the effects of hypoxia on the total systemic venous bed. The potential importance of any changes in venous tone are apparent when it is considered that this segment of the circulation contains the major portion of the systemic blood volume (7). Small changes in the diameter of the veins might be expected to produce large changes in the volume of the venous bed and in the magnitude of the venous return to the heart; any such changes could, in turn, modify the cardiac output and, therefore, the arterial pressure (8-11 ). In the present investigation the activity of the chemoreceptors, the adrenal glands, and the spleen was also studied, since these organs have been implicated in the circulatory responses to hypoxia (1218).

Circulatory Effects of Acute Expansion of Blood Volume:: Studies During Maximal Exercise and at Rest

The maximum cardiac output that can be achieved during exercise might be limited either by extracardiac factors influencing ventricular filling, or by the heart itself. In order to investigate this problem, the effect on the cardiac response to maximum exertion of an acute expansion of blood volume was studied in six men with essentially normal cardiovascular systems. Augmentation of blood volume produced by infusion of 1000 to 1200 ml of the subjects own blood resulted in a small increase in central venous pressure at rest (avg = + 1.9 mm Hg) and a substantial increase in cardiac output (avg = + 1.47 liters/min). During exercise, however, the expansion of blood volume caused a large increase in central venous pressure (avg = + 7.4 mm Hg), but no significant increase in cardiac output or maximum O2 uptake. This finding suggests that the maximum cardiac output is not restricted by extracardiac factors and that the upper limit must therefore be determined by the heart itself.

Reflex Control of the Systemic Venous Bed

In a series of investigations on the control of venous tone, it was shown in anesthetized, open-chest dogs on cardiopulmonary bypass that venoconstriction occurs during the infusions of norepinephrine and epinephrine, while trimethaphan results in venodilatation. Lowering the pressure acting on the carotid baroreceptors and on the receptors within the left atrium and left ventricle results in reflex venoconstriction, while stimulation of these receptors relaxes the veins. Hypoxia produces venoconstriction as a result of stimulation of the carotid chemoreceptors, but the veno constriction which results from hypercapnia evidently is primarily central in origin. Reflex venoconstriction to carotid occlusion and central vagal stimulation can be blocked by the administration of guanethidine and reserpine. In intact, unanesthetized human subjects, to whom these drugs were administered orally in doses which are commonly utilized in clinical practice, reflex venoconstriction of the forearm veins was blocked. These investigations emphasize that the systemic venous bed reacts vigorously to neural and humoral stimuli, and that these reactions profoundly alter the cardiac output. In this manner, by exerting control of the rate at which the blood is delivered into the systemic arterial bed, the venous side of the circulation plays an important role in the control of the arterial pressure as well.

Familial congenital heart disease: Familial occurrence of atrial septal defect with A-V Conduction abnormalities; supravalvular aortic and pulmonic stenosis; and ventricular septal defect

Abstract This report documents the familial occurrence of three different types of congenital heart disease observed in seven families studied at the National Heart Institute. Three families with multiple instances of atrial septal defect are described. Associated atrioventricular conduction abnormalities were noted in two of them, and in view of the rarity of septum secundum or sinus venosus atrial septal defects with such conduction abnormalities it is suggested that this combination of findings should raise the possibility of the presence of familial atrial septal defect. In the third family the atrial septal defect was associated with mild peripheral pulmonary artery stenoses, a combination of malformations which has not previously been described in familial form. Familial supravalvular aortic and pulmonic stenosis was studied in three families, comprising a total of sixteen patients with one or both of these anomalies. In no instance was the malformation accompanied by mental retardation or a peculiar facial appearance, and there were wide variations both in the anatomic abnormalities and their severity in patients within each family. The broad clinical and hemodynamic spectrum of ventricular septal defect was observed in a family in whom four members had this defect. It is likely that hereditary transmission is responsible for the association observed in these seven families with congenital heart disease, and the mode of inheritance in each family appears most compatible with an autosomal dominant, nonsex-linked transmission, with variable expression.

THE EFFECTS OF AUTONOMIC NERVOUS SYSTEM INHIBITION ON THE CIRCULATORY RESPONSE TO MUSCULAR EXERCISE

One of the primary functions performed by the cardiovascular system is the delivery of oxygen and metabolic substrates to the peripheral tissues during varying levels of their activity. Accordingly , the manner in which the circulation is altered during muscular activity and the consideration that the cardiovascular response is mediated through the interaction of a number of mechanisms , prominent among which is the activity of the autonomic nervous system, are of interest. The present investigation was undertaken in an attempt to clarify the role of this mechanism in normal human subjects by determining the manner in which inhibition of the parasympathetic and the sympathetic divisions, or both, affected the circulatory response to exercise. Two pharma-cologic agents were employed to produce functional inhibition of the autonomic nervous system; atro-pine was used to inhibit the parasympathetic division , and guanethidine, an effective adrenergic blocking agent (1), was used to interfere with the activity of the sympathetic division. METHODS The investigations were carried out on six healthy male subjects whose ages ranged from 18 to 20 years. All studies were performed in the supine position, and measurements of heart rate, cardiac output, arterial blood pressure, and oxygen consumption were made at rest and during exercise in the four investigations performed on each subject. The first (control study) was performed without prior drug administration. Forty-five minutes after its completion, 2 mg of atropine sulfate was administered intravenously, and 5 minutes later the resting measurements were repeated, followed immediately by exercise. After these two studies oral guanethidine administration was begun at a daily dosage of 10 mg, which was progressively increased by 5 mg increments every other day for a period of 21 to 26 days. The maximum daily dosage reached ranged from 50 to 85 mg for each subject. The subjects were questioned about the side effects of guanethidine, and supine and standing blood pressures were recorded twice daily. The third study was performed at the end of the period of guan-ethidine administration while subjects were receiving the maximal doses. Forty-five minutes after completion of the third study, 2 mg of atropine sulfate was again administered intravenously, and five minutes later the fourth study was begun. Each subject had been thoroughly familiarized with the laboratory, the equipment, and the experimental procedure prior to the study, and all observations were carried out with the subj ects in the postabsorptive state. The control resting measurements …

Effect of Alterations of Coronary Blood Flow on the Oxygen Consumption of the Nonworking Heart

The effect of varying CBF and myocardial O2 delivery on MVO2 was studied in 23 experiments. In 14 of the experiments an isolated dog heart was perfused, while in the others the heart of a dog, whose systemic circulation was maintained on cardiopulmonary bypass, was studied. The ventricles were kept empty, developed no pressure and performed no external work, while their temperature was held constant. CBF and myocardial O2 delivery were controlled by pumping blood into the coronary arteries, total coronary venous return was collected from the right side of the heart and MVO2, was calculated during a steady state by the Fick principle. Myocardial anoxia was avoided by maintaining the coronary venous O2 content above 4 vol % and myocardial O2 extraction below 78%. A comparison of MVO2 at two levels of CBF (and O2 delivery) was made in 42 instances, and in 32 of them 11 MV increased substantially as CBF was elevated, or vice versa. The ten exceptions all occurred when O2 delivery greatly exceeded MVO2 with O2 extraction ratios below 35%. The fundamental mechanisms responsible for these findings are not clear, but a number of possible explanations are discussed.

Studies on Digitalis VI. Reduction of the Oxygen Debt after Exercise with Digoxin in Cardiac Patients without Heart Failure

Three patients with acquired valvular heart disease and cardiac enlargement who were able to perform normal everyday activity without difficulty in the absence of digitalis therapy were exercised while receiving a placebo and again while receiving digoxin. Digoxin administration did not produce a significant change in body weight or in the subjective condition of the individuals. Varying degrees of exercise were performed on a treadmill in a Metabolic Chamber and oxygen consumption was measured cotinuously before, during, and after the period of exercise, utilizing a continuous gas flow paramagnetic oxygen analyzer. The oxygen debt that developed during digoxin administration was compared to that observed during placebo administration.In all patients the oxygen debt was smaller during the period of digoxin administration, although the external work performed was identical. In the first patient, following a 7-minute walk, the oxygen debt was 53 per cent more and following a 10-minute walk it averaged 40 per cent more while not receiving digoxin than when receiving this drug. In the second subject the oxygen debt following a 7-minute walk was 34 per cent more and following 10-minute walk it averaged 74 per cent more when he was not receiving digoxin than when receiving this drug. In the third subject the oxygen debts were 46 per cent and 41 per cent greater following 10- and 15-minute walks respectively, when she was not receiving digoxin.The accumulation of a smaller oxygen debt following exercise while these subjects were receiving digoxin indicates that the functional status of their circulatory system was improved by the drug. It would appear that digitalis administration is beneficial to at least some patients who have cardiac disease and enlarged hearts and some decrease in cardiac reserve without signs or symptoms of heart failure.

Primary Myxoma of the Right Ventricle* Clinical, Hemodynamic and Angiographic Findings Before and Following Operative Treatment

Abstract A patient is described in whom a myxoma originated within the cavity of the right ventricle. The tumor, which caused severe right ventricular outflow obstruction, was successfully excised. The results of pre- and postoperative clinical, hemodynamic and angiographic assessments, and the operative methods are presented. From the findings in this patient, and those in nine others described in the literature, certain conclusions are presented concerning the natural history and clinical manifestations of this unusual cardiac malformation, and the role and results of operative treatment are discussed.

Influence of Syrosingopine on the Cardiovascular Response to Acute Hypoxemia and Exercise

Large parenteral doses of a rauwolfia alkaloid, syrosiiigopine, administered to normal volunteers, although inducing a consistent reduction in pulse rate, did not interfere with the increase in cardiac output resulting from acute hypoxemia and exercise. The physiological and pharmacological implications of these observations are discussed.