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Two cases of primary pulmonary hypertension are presented, and the results of right heart catheterization are given. Infusion of acetylcholine caused large decreases in pulmonary arterial pressure in one subject, both at rest and during exercise. In the second subject, infusion of acetylcholine resulted in a lesser but still significant decrease in pulmonary arterial pressure. The criteria that must be met before conclusions are drawn as to the existence of vasodilation or vasoconstriction in the pulmonary vascular bed are discussed.

The variations in pulmonary artery mean pressure, pulmonary artery pulse pressure, right ventricular end-diastolic and left atrial mean pressures, and the mean diastolic left atrial-left ventricular gradients at rest, and during exercise and recovery have been analyzed. Several distinct patterns of change in these pressures have emerged. The reason for these patterns is not clearly understood. Several possibilities are proposed to explain the observed changes.

Eight patients with systemic arteriovenous fistulas have been studied with special emphasis on systemic arterial and multiple right heart indicator-dilution curves with indocyanine green. Seven patients were studied preoperatively; 4 subjects were restudied after surgical intervention. One patient was catheterized only after surgical correction of the fistula. Five subjects were investigated before and during acute occlusion of the fistula. Cardiac output was determined by indocyanine green in all patients; the Fick principle was also employed in 4 patients to determine cardiac output. The cardiac index was elevated before surgery; occlusion of the fistula resulted in a decreased cardiac index. Surgical correction of the fistula also led to a fall in cardiac index. The indocyanine indicator-dilution curves were utilized to demonstrate and localize the left to right extracardiac shunts. After surgical correction, physiologic evidence of the shunt was no longer evident.

The technique of P-wave synchrony utilizing bipolar atrial and ventricular catheters has been employed to determine the variations in cardiac excitability in different phases of the cardiac cycle. In this study, See Image in the PDF File a bipolar intraatrial catheter is used to detect a P-wave which is then transmitted via a Medtronic paired pulse pacemaker to a bipolar ventricular catheter. The stimuli can therefore be applied to the ventricles at various intervals after the P-wave and at various intervals within the cardiac cycle. When the stimulus is applied to the ventricle, shortly after the P-wave, a Wolff- Parkinson-White syndrome results. When the stimulus is applied to the ventricle, within the absolute refractory period, the stimulus is not effective. When the stimulus is applied to the ventricle, during the latter portions of the T-wave, a ventricular rhythm develops with retrograde P-wave conduction. Variations in the strength of the stimulus, as well as in its timing, were utilized in this study to demonstrate that there are considerable variations in cardiac excitability in different portions of the cardiac cycle. Thus, there is an increase in cardiac excitability in the latter portion of diastole, as opposed to early diastole, since the minimum stimulus strength that results in the onset of ventricular pacing is smaller later in diastole and conversely is larger earlier in diastole.

Intracardiac infusion of acetylcholine into the right atrium or right ventricle during steady-state exercise in 20 patients with rheumatic heart disease resulted in only minimal alterations in the pressure in the pulmonary artery. The vasodilator effect of acetylcholine on the pulmonary artery under these conditions is minimal and of little or no clinical significance.

The effect of both inspiratory and expiratory respiratory tract obstruction upon the ventilatory response to 3 and 5 per cent CO2 has been studied in 14 normal subjects. Three grades of obstruction were employed. In nine subjects the effects of two levels of obstruction were noted. Maximum breathing capacities were determined under both control and experimental (respiratory tract obstruction) conditions. The results indicate that mild degrees of obstruction have relatively little effect upon the response to inhaled CO2. A decrease in alveolar ventilation and arterial blood pH and an increase in arterial carbon dioxide tension result from interposition of more severe grades of obstruction. The etiology of the depressed ventilatory response to inhaled CO3 seen in patients with obstructive pulmonary emphysema and hypercarbia is discussed in relation to these experimental observations.

The experience of this laboratory in transseptal left atrial catheterization is described together with details of the technical approach employed. Three hundred ninety successful left atrial punctures have been performed, 65 by the earlier Ross technic, and more recently 325 studies by the percutaneous Brockenbrough approach. Utilizing the latter technic, the left atrium can be entered in 99 per cent of the patients; the left ventricle can be catheterized from the left atrium in 94 per cent of the studies in which attempts are made to manipulate the catheter through the mitral valve. The complications encountered in this and other laboratories are discussed together with means of minimizing and preventing these untoward reactions. The position of transseptal left atrial puncture among the various left heart catheterization procedures is discussed.

The role of bronchospirometry in evaluation of differential left to right congenital shunting from the two lungs is illustrated in an eighteen year old white girl who was found, at cardiac catheterization, to have an interatrial septal defect and anomalous pulmonary venous drainage from the right lung only. During bronchospirometry, administration of pure nitrogen to the right lung (the lung with anomalous pulmonary venous drainage) did not result in a fall in arterial oxygen saturation after ten minutes. However, administration of pure nitrogen to the left lung resulted in a rapid fall in oxygen saturation after a three-minute period. These observations suggest that blood draining the right lung in this patient does not directly reach the periphery at any time, but may only reach the systemic arterial blood after circulation through the left lung. This technic may also be of value in demonstrating differential left to right shunting from the two lungs in patients with interatrial septal defect.

The hemodynamic sequelae of sequential atrioventricular pacing were compared to those of atrial and ventricular pacing and analyzed. The results clearly demonstrate that aberrant ventricular depolarization per se is of relatively minor hemodynamic import but that sequential atrial and ventricular activity is essential for optimal ventricular function even in the normal subject.

The differential effects of alterations in the diastolic filling period of the left ventricle and in cardiac flow upon the mean diastolic left atrial-left ventricular gradient have been investigated in 8 subjects with atrial fibrillation studied at diastolic filling intervals of similar magnitude. The results demonstrate the sensitivity of the magnitude of the gradient to even small alterations in blood flow.

The results of atrial and ventricular pacing upon cardiovascular dynamics in 20 subjects with normal cardiovascular systems have been analyzed. The average cardiac index during atrial pacing was 3.17 L./min., M. 2 compared to 2.66 during ventricular pacing. Similar conclusions were possible by analysis of the data at varying heart rates of 60 to 89,90 to 109 and 110 to 140. It is concluded that the atrial contribution to ventricular function is significant even in normal subjects.

The injection of indicator into the pulmonary artery and left atrium, with systemic arterial sampling, resulted in similar levels of output. The flow levels after injection into the left atrium were not higher, but, on the contrary, were some-what lower than those after injection into the pulmonary artery. These data validate the assumption that measurements of left ventricular output may be made via injection of indicator into the right heart.

The hemodynamic effects of right atrial and ventricular bipolar catheter pacing were investigated in fifty-four subjects in sinus rhythm. Right and left heart pressures were measured, and cardiac outputs determined by the indicator dilution method, at both control sinus rates and during atrial and ventricular tachycardias at varying rates above the control sinus rate, induced by atrial and ventricular catheter electrodes. The results of this study clearly demonstrate that, in intact man, ventricular pacing, at ventricular rates similar to those induced by atrial pacing, result in decrements in cardiac output and in systemic arterial pressures, together with atrioventricular regurgitation. The application of these data to synchronous or idioventricular pacing in patients in complete heart block seems evident.

Pulmonary vascular disease, mitral valve block, left heart failure, or any combination of these factors may cause pulmonary hypertension. Right heart catheterization alone, in rheumatic heart disease, cannot differentiate among these possibilities. Right and left heart catheterization is of great aid, however, in resolution of the problem. Five cases are discussed to illustrate the value of combined heart catheterization.

Right and left ventricular pressure curves were recorded simultaneously with the electrocardiogram in the dog. Control observations were made during sinus tachycardia with normal intraventricular conduction, and repeated after production of right and left bundle-branch block and after production of complete heart block with idioventricular rhythm. The mode relationship between onset of isometric contraction in the two ventricles was 0.00 seconds during sinus tachycardia. During right bundle-branch block, left ventricular contraction started 0.01 second prior to the right; during left bundle-branch block, right ventricular contraction started 0.02 second prior to the left. During left ventricular idioventricular rhythm, left ventricular isometric contraction started 0.01 second prior to the right; during right ventricular idioventricular rhythm, right ventricular contraction started 0.01 second prior to the left. These changes in relative onset of ventricular contraction are far less than those expected on theoretical grounds. Submitted on March 26, 1959

Acetylcholine was infused into the right atrium or right ventricle in the course of seventy-nine cardiac catheterizations in sixty-seven patients with rheumatic heart disease with mitral stenosis and/or aortic valve disease. Measurements of pulmonary and systemic arterial pressures and cardiac output were carried out before and during acetylcholine infusion. The data demonstrate a slight pulmonary vasodilator effect of acetylcholine; the magnitude of these changes suggests that acetylcholine offers little promise in the treatment of pulmonary hypertension in patients with mitral stenosis.

Electrical ventricular asynchronism may occur in man in bundle branch block, complete heart block with an idiovcntricular rhythm, ventricular premature beats and the Wolff-Parkinson-White syndrome. This paper is a study of the problem of whether mechanical ventricular asynchronism is a necessary consequence of electrical ventricular asynchronism such as occurs in the above situations. The data were obtained in intact man during the course of simultaneous right and left heart catheterization. The results indicate that mechanical ventricular asynchronism is infrequently seen in ventricular premature beats produced during the course of simultaneous combined heart cathetcrization. Mechanical asynchronism in onset of ventricular isometric contraction was absent in 72 of 100 ventricular premature beats with widened aberrant QRS complexes.

"True" pulmonary blood volume has been determined by three indicator-dilution methods in 96 subjects. In two methods a right or left ventricular mixing chamber is interposed between the injection and sampling sites while in the third such a mixing chamber is absent. The results strongly suggest that a ventricular mixing chamber is essential for valid determination of true pulmonary blood volume.

Comparison of the effects of atrial, ventricular, and sequential atrioventricular pacing in a group of patients with rheumatic heart disease and in a group with pulmonary emphysema has demonstrated that the absence of synchronized atrioventricular activity rather than aberrant ventricular depolarization is primarily responsible for the hemodynamic difference between atrial and ventricular pacing.

Physiologic data obtained during right and combined right and left heart catheterization are presented in a variety of subjects with mitral valve disease. These studies have led to a broader understanding of the pathophysiology of this disease. The clinical value of combined heart catheterization is illustrated.

SUMMARY Several methods of indicator cardiac output determination have been utilized. Despite differences in true pulmonary blood volumes by these methods, all three approaches result in similar cardiac output data. The reasons for this are discussed.

Dissociation of electrical and mechanical asynchronism in the right and left ventricle of the dog has been studied by simultaneous registration of the precordial electrocardiogram and right and left ventricular pressure curves. Observations were made during sinus rhythm and during digitalis-induced ventricular premature beats with widened aberrant QRS complexes. Measurements were made of the time of onset of isometric contraction in the ventricles, relative to each other, and to the onset of the QRS complex. The results indicate that mechanical asynchronism in onset of isometric contraction is not a necessary consequence of the asynchronous electrical depolarization of ventricular premature systoles. Submitted on November 10, 1958

The contributions of atrial systole to ventricular filling are emphasized by analyses of pressure curve data in (1) patients with complete heart block studied by right and left heart catheterization, (2) patients with sinus rhythm and atrial fibrillation and (3) sinus rhythm and ventricular premature beats. The level of systolic and diastolic right and left heart pressures varies with the temporal relation between the P and QRS complexes in patients with complete heart block. Peak pressures are recorded when there is a normal temporal relation between the P and QRS complexes. The rate of rise of the systemic arterial pressure curve is also at a maximum when the normal P-QRS relation is maintained. Comparison of left ventricular and systemic arterial pressures during sinus rhythm and ventricular premature beats demonstrates higher systolic peak pressures during sinus rhythm with normal atrioventricular conduction; of equal importance is the observation that left ventricular end-diastolic pressures are higher during sinus rhythm than during a series of ventricular premature beats. One subject was studied during both atrial fibrillation and normal sinus rhythm in the course of left heart catheterization. Left ventricular. systolic and end-diastolic pressures were higher during normal sinus rhythm than during atrial fibrillation. The development of mitral regurgitation during ectopic ventricular beats is also illustrated. These data demonstrate the physiologic importance of maintaining the normal temporal sequence of atrioventricular activity.

The acute effects of oral ethacrynic acid administration upon red cell mass and plasma volume are reported in 30 patients. A significant decrease in plasma volume has been observed and is in all probability secondary to the profound diuretic effect of the drug, unlike the transient effect of phlebotomy which is largely gone by one hour. The effect of ethacrynic acid in lowering the plasma volume persists for at least 2 to 3 hours. The therapeutic implications for the patient with pulmonary edema are readily evident.

Dissociation of electrical and mechanical asynchronism in the canine right and left ventricles has been studied by simultaneous registration of right and left ventricular pressure and strain gauge arch curves and the electrocardiogram. Observations were made during sinus rhythm and during acetylstrophanthidin-induced ventricular premature beats with widened aberrant QRS complexes. The data demonstrate only limited mechanical asynchronism during the asynchronous electrical depolarization of ventricular premature systoles. Submitted on October 19, 1961

Two patients are described in whom the mitral diastolic gradients noted during left heart catheterization were not satisfactorily explained by the anatomic findings observed at cardiac surgery. In one subject aortic and tricuspid stenosis was found at surgery without significant stenosis of the mitral valve. In the second patient a large mitral diastolic gradient persisted after the mitral valve was opened to a size of 4.5 sq. cm. In both instances marked hypertrophy of the anterior papillary muscle in the left ventricular cavity is considered one of the causes of these anomalous mitral diastolic gradients.

SUMMARY Measurements of the mean systolic left ventricular-brachial artery gradient and cardiac output at rest and during exercise in four subjects with aortic stenosis were made in the course of combined right and left heart catheterization. Only minimal elevations were noted in the aortic systolic gradient during exercise despite significant flow increases in three of the four patients.

A total of 532 groups of indicator-dilution determinations of cardiac index were performed in four groups of patients, many with mitral regurgitation. The indicator, indocyanine green, was injected into the right atrium and sampled from both the pulmonary and systemic arterial trees. The potential problem imposed by early recirculation of indicator particles was present in the latter but not the former dilution curves. The absence of physiologically significant differences between the two sampling sites demonstrates that even severe mitral regurgitation does not vitiate indicator-dilution determination of cardiac output after right heart injection and systemic arterial sampling if the downstroke of the primary dilution curve permits a straight line semilogarithmic extrapolation.

SUMMARY The results of right heart catheterization and transseptal left heart catheterization in 32 normal subjects have been outlined. These data will serve as a baseline for comparison with left heart data in patients with various types of heart disease. The normal levels of left atrial and left ventricular pressure and the normal levels of cardiac index as well as the normal true pulmonary blood volume hâve been given as part of this study.

Cardiac output studies were performed in 6 patients with complete heart block during four kinds of ventricular rhythm. These include ventricular or His-bundle pacing at the control rate, right ventricular outflow tract catheter electrode pacing, and both synchronous and atrial synchronous pacing by means of a Cordis Synchrocor unit. The latter two rhythms are defined as those with P wave, ventricular stimulus and QRS complex sequences, and atrial stimulus, P wave, ventricular stimulus and QRS complex sequences, respectively. Thirty-four paired observations were made during equal atrial and ventricular pacing rates in these patients. The importance of atrial systole for maintenance of cardiac output is clearly demonstrated by these data.

Oral acute and prolonged salicylate administration to ten male patients with obstructive pulmonary emphysema and hypercarbia failed to improve the impaired ventilatory response to inhaled carbon dioxide so characteristic of this group of subjects. Ventilatory depression consequent to inhalation of high oxygen gas mixtures was not inhibited, in these patients, by salicylate therapy.

The results of P wave synchronization in man employing a bipolar atrial and a bipolar ventricular catheter have been presented. As the P-ventricular stimulus interval is increased, a ventricular rhythm with retrograde P waves and a re-entry mechanism was found. The characteristics of the rhythm are discussed together with the possible significance thereof.

Evidence is presented, both from a review of the literature and from original observations in this laboratory during cardiac catheterization in man, to demonstrate that the cardiac output in the majority of patients with complete heart block can be increased with increments in ventricular rate. These data, especially when considered in conjunction with the demonstrated importance of synchronous as opposed to asynchronous atrioventricular contraction, strongly suggest that synchronous P-wave pacemakers, such as the one developed by our group, are physiologically and clinically superior to idioventricular pacemakers of either the fixed or variable rate types.

The diagnosis of right-to-left and left-to-right cardiac shunts in patients with complicated atrial septal defects is illustrated by indicator dilution curves following injections of indocyanine green. The lesions illustrated are Ebstein's anomaly of the tricuspid valve, total anomalous pulmonary venous drainage, tricuspid atresia and left anomalous pulmonaryvein.

Surgical production of bilateral bundle branch block resulted in complete heart block in fourteen dogs. In eight dogs, left bundle branch block resulted from the initial bundle branch section. In six animals, right bundle branch block was produced at first. In either circumstance, section of the opposite bundle branch resulted in complete heart block. Limited correlation between the electrical and mechanical events of the cardiac cycle under these circumstances was demonstrated. The data indicate that complete right and complete left bundle branch block were produced by surgical section of the respective bundle branches.

Right and left ventricular pressure curves and electrocardiogram were recorded in the dog during sinus rhythm and during mechanically induced right and left ventricular premature systoles. The normal range during sinus rhythm for the relationship between onset of right and left ventricular contraction was determined. At one extreme, right ventricular contraction commenced 0.02 second before the left; at the other extreme, left ventricular contraction started 0.03 second before the right. In most instances, the onsets of ventricular contraction were either temporally identical or one ventricle contracted 0.01 second prior to the other.

In 10 patients, 24 episodes of supraventricular tachycardia were treated by rapid electrical stimulation of the right atrium. One episode of sinus tachycardia, eight episodes of atrial tachycardia, two episodes of atrial flutter, and 13 episodes of A-V junctional tachycardia occurred. In each case the diagnosis of the arrhythmia was documented by obtaining unipolar and bipolar intra-atrial electrograms. In three cases of supraventricular tachycardia the ventricular rate was slowed as a result of an increased atrial rate. The increased atrial rate caused an increase of the functional refractory period of the A-V junction, and thus, fewer atrial impulses were transmitted to the ventricles. In seven cases, 21 episodes of supraventricular tachycardia were terminated by rapid atrial stimulation. In six of these cases the tachycardia was converted to normal sinus rhythm either during or shortly after atrial stimulation. In one case, 12 episodes of A-V junctional tachycardia were converted to rhythms varying between normal sinus rhythm and a slow A-V junctional rhythm. In this case, after termination of the last episode of A-V junctional tachycardia, the rhythm was stabilized by atrial pacing.

A case of herniation of the left atrial appendage through a partial defect in the left side of the pericardial sac is presented. The diagnosis was suspected on the basis of the chest roentgenogram and was proved by right and left heart cineangiography. The differential diagnosis is discussed.

Rotating and nonrotating venous tourniquets were applied to the extremities at pressure levels of 5 to 10 mm. Hg below the diastolic blood pressure in twenty-five and twenty-three studies, respectively. This procedure resulted in only modest decreases in plasma volume and red cell mass, totaling less than 5 per cent of the total blood volume. Similar results were obtained in subjects studied during congestive heart failure (but not acute pulmonary edema) and in patients with compensated cardiac disease. The physiologic mechanism responsible for the clinical improvement noted with application of venous tourniquets in acute left ventricular failure is, therefore, uncertain. Several alternative mechanisms remain to be evaluated.

A follow-up case report of primary pulmonary hypertension is described. In 1959, intracardiac infusion of acetylcholine resulted in a considerable decrease in pulmonary arterial pressure both at rest and during exercise. In 1962, acetylcholine failed to elicit a decrement in pulmonary arterial pressure, demonstrating a loss of vasodilator reactivity of the pulmonary vascular bed over this period of time.

The varied approaches to the utilization of indicator-dilution curves in the diagnosis of congenital cardiac lesions involving the ventricles and great vessels have been outlined. Representative curves have been presented.

SUMMARY The effect of increasing heart rate above control sinus rate was investigated in 136 patients with pulmonary emphysema or rheumatic or congenital heart disease. Bipolar right atrial electrode catheter pacing was utilized to increase the atrial rate. At all atrial pacing rates, significant cardiac output increments are noted compared to the outputs during the control sinus rates. The cardiac indices are generally similar at the various atrial pacing rates.

Systemic arterial and right heart pressure curves are reviewed in 3 patients with complete heart block. In all three the ventricles were driven by ventricular pacemakers so that the normal sequence of atrioventricular contraction was absent. Some of the hemodynamic consequences of such idioventricular pacemaking are reviewed, and the important role played by atrial systole in ventricular filling is emphasized.