Can outflow obstruction be induced within the normal left ventricle?

Can Outflow Obstruction

Be Induced

Within

the Normal Left Ventricle?* ANDREW G. MORROW, M.D., JOHN S. VASKO, M.D., R. PETER HENNEY, M.D. and ROBERT K. BRAWLEY, M.D. Bethesda,

I

Maryland

now generally recognized that in patients with idiopathic hypertrophic subaortic St& nosis, outflow obstruction results from contraction of the hypertrophied muscular walls of the left ventricle, and that the severity of obstruction is intensified when the systolic volume of the hypertrophied ventricle, and consequently the dimensions of the outflow tract, are reduced. The principal factors which cause a diminution in ventricular volume are decreased venous return and augmentation of myocardial contractile force. The effects of interventions which alter these two hemodynamic variables have been well documented, both in patients with hypertrophic subaortic stenosis and in animals with symmetric ventricular hypertrophy.1-3 This elucidation of the mechanisms that cause outflow obstruction within the hypertrophied ventricle has given rise to the important question as to whether or not outflow obstruction can be induced in the normal left ventricle. In a number of reported studies in normal dogs, large systolic pressure gradients have been demonstrated between the left ventricle and aorta during various interventions, and the gradients have generally been considered the result of outflow obstruction. Gauer4 recorded such gradients in dogs subjected to’hemorrhagic shock and found that the gradients increased in magnitude after the administration of epinephrine. Krasnow et a1.5 demonstrated peak systolic pressure gradients of 15 to 145 mm. Hg between the left ventricle and aorta in 4 normal anesthetized dogs. Isoproterenol was administered to 2 of these animals, and in both of them the pressure gradient increased and the calculated area of the stenotic orifice decreased. Cross and SalisburyG measured left ventricular and systemic arterial pressure in 21 dogs in which systemic venous return was controlled by

an extracorporeal pump. In 10 animals, a systolic pressure gradient was recorded when flow was reduced to approximately 50 ml./kg./ min. ; in the remaining dogs perfused at reduced flow rates, a gradient became apparent after the administration of isoproterenol or other inotropic drugs. Martin et al.’ and Braunwald et al.’ also recorded pressure gradients between the left ventricle and aorta in normal dogs in which systemic pressure had been reduced to shock levels. All of these experiments indicdte that obstruction to outflow may occur within the normal left ventricle under the conditions of hemorrhagic shock, and that the severity of obstruction is increased when the contractile force of the ventricle is augmented by pharmacologic agents with positive inotropic effects. Acceptance of these concepts would necessitate re-evaluation of much of the voluminous information concerning experimental hemorrhagic shock, particularly those data relating to the function of the heart. For example, if left ventricular systolic pressure were significantly greater than peripheral arterial pressure during a period of shock, then the relations of ventricular pressure work to coronary flow would be quite different from those which would obtain if the ventricular and aortic systolic pressures were equal. Furthermore, in evaluating the role of pressor drugs in the treatment of shock, it would be necessary to consider the possibility that outflow obstruction might be produced or augmented if the agent also increased the force of myocardial contraction. The present experiments constitute a reexamination of the hypothesis that outflow obstruction may occur in the normal left ventricle under conditions of reduced volume and increased contractile force. Particular attention

T IS

* From the Clinic of Surgery, National Heart Institute, Bethesda, Md. 20014. 540

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Outflow was directed to methods utilized for measuring left ventricular pressure under these circumstances. METHODS

AND RESULTS

Unselected mongrel dogs were studied. They were anesthetized with intravenous chloralose (60 mg./kg.) and ventilated with 100% oxygen supplied through a cuffed endotracheal tube by a positive pressure respirator. Body temperature, measured with a thermistor in the esophagus, was maintained at 35 to 37O C. by a heating pad on which the animal lay. Heparin (2 mg./kg.) was given intravenously. The catheters utilized to measure aortic and left ventricular pressure had closed distal ends and three pairs of laterally opposed side holes within 1.5 cm. of their tips.* The catheters were attached to Statham P23 Db pressure transducers positioned at the level of the left atrium and adjusted to be equisensitive. Recordings were made on a multichannel photographic recorder. The hearts of all dogs were in each, the aortic valve, examined at necropsy; Left mitral valve and left ventricle were normal. ventricular and central aortic pressure were recorded during various experimental conditions in three groups of animals. GROUP I Open Chest, Inotropic Drugs, Hemorrhagic Shock: The effects of hemorrhagic shock and inotropic drugs were In studied in 16 dogs in which the chest was open. was made, in 3 a left 11, a right thoracotomy thoracotomy, and in 2 a bilateral thoracotomy. NIH catheters, size 8F and 75 cm. in length, were The ascending aorta was catheterized from utilized. the carotid artery, and a second catheter was passed from a right or left lobar pulmonary vein into the left ventricle. In all experiments the pericardium was Left ventricular and central aortic pressures intact. were recorded during and following single intravenous injections of one or more pharmacologic agents. After the heart rate and pressures had returned to control levels, observations were made as blood was rapidly withdrawn from the femoral artery until the systolic aortic pressure stabilized at 40-50 mm. Hg. One or more single irrjections of isoproterenol, calcium chloride or metaraminol were then If the administration of a given drug resulted given. in a sustained increase in arterial pressure, the pressure was returned to 40-50 mm. Hg by the withdrawal of additional blood. Results: No systolic pressure gradient between the left ventricle and ascending aorta was observed in any of the 16 dogs under control conditions. All animals were given isoproterenol, and in 6, transient systolic gradients of 10 to 60

* NIH type thin-wall angiocardiography catheters, #354-Z, U. S. Catheter and Instrument Company, Glens Falls, N. Y. VOLUME 16, OCTOBER 1965

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mm. Hg were recorded after doses of from 4 to 50 &lg. In one of these 6 animals, a gradient of 60 mm. Hg followed the administration of 300 mg. of calcium chloride, while no gradients were observed in 8 additional dogs given 200 to 500 Nine dogs were given 1 to mg. of this agent. 20 mg. of metaraminol, and in none was a gradient recorded. None of the 16 dogs evidenced a ventriculoaortic gradient with the production of hemorrhagic shock alone, but systolic gradients of 20 to 85 mm. Hg were provoked in 9 of them when inotropic drugs, in the dosage ranges outlined above, were given during the period of hypovolemia. As noted previously, more than one agent, and different doses of a given agent, were often administered to individual animals. Isoproterenol produced a gradient in 5 of 12 dogs, calcium chloride in 5 of 11, and metaraminol in 4of9. GROUP II The Closed Chest, Inotropic Drugs, Hemorrhagic Shock: effects of shock and inotropic drugs were studied in 12 dogs with closed chests. Two 8F NIH catheters 75 cm. in length were employed. The left ventricle was catheterized in retrograde fashion from the femoral artery, and the centraI aorta from the carotid artery. Observations of left ventricular and central aortic pressure were made, as in the group I experiments, as inotropic drugs were given before and after the induction of hemorrhagic shock.

No systolic gradient was present in Results: All 12 dogs any dog under control conditions. were given isoproterenol, 2 calcium chloride, and 1 metaraminol; no gradient appeared in any animal. After the induction of hemorrhagic shock, no ventriculo-aortic gradient was Isoevident until a drug was administered. proterenol produced a gradient in 4 of 12 dogs, metaraminol in 2 of 10, while no gradients were provoked by calcium chloride or norepiThe nephrine in the 4 dogs given these agents. magnitudes of the gradients recorded in these closed-chest dogs were generally small, only one exceeding 15 mm. Hg. GROUP III Open Chest, Controlled Venous Return, Isoproterenol In 8 dogs, a bilateral thoracotomy was Administration: made and three 9F NIH catheters 15 cm. in length were placed (Fig. 1). One catheter was passed into the ascending aorta via the left subclavian artery, and a second was inserted from a left or right lobar pulmonary vein, across the mitraI valve, and into the left ventricle (transatrial catheter). A purse string suture was placed around the dimple in the apex of the left

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FIG. 1. Schematic representation of the methods utilized to measure aortic and left ventricular pressures and to provide controlled venous return in the group III experiments. After control observations had been made, the cavae were ligated and venous blood was returned to the right atrium through the azygos vein at various flow rates. The transatrial catheter was inserted into the left ventricle through either a left or right pulmonary vein, and the transmural one through the ventricular wall at Unless otherwise designated, the pressure rethe apex. corded from the transatrial catheter is labeled LV-1, and that from the transmural catheter as LV-2 in succeeding figures. ventricle, the bites of the suture passing into the myocardium through the intact pericardium. The third catheter was passed into the left ventricle via a stab wound in the area of the heart and pericardium encompassed by the suture (transmural catheter); the catheter was advanced into the ventricle until a mark 3 cm. from its tip lay flush with the pericardium, ensuring that all of the side openings lay within the Pressures were recorded conventricular cavity. tinuously from the three catheters throughout each study. Plastic cannulas were then inserted into the superior and inferior venae cavae from the jugular vein They were and both femoral veins, respectively. connected to a reservoir into which venous blood could be drained, and returned through a calibrated occlusive finger pump to the cannulated azygos vein. The perfusion system was primed with dextran in four experiments and with a 1: 1 mixture of dextran and homologous blood in the others; both perfusates were adjusted to a pH of 7.35 to 7.45 by the addition of THAM.

Henney

and Brawley

FIG. 2. Records of central aortic pressure (.40) and left ventricular pressures recorded from a transatrial catheter (LV-1) and a transmural catheter (LV-2) in a normal dog after the administration of 4 pg./kg. of isoproterenol. A systolic pressure gradient of 115 mm. Hg was indicated by the transatrial catheter, but the pressure from the transmural catheter equaled aortic pressure. In the last three complexes, only the two ventricular pressure pulses are shown; they have similar configurations in diastole. When these preparations had been completed, 4 pg./kg. of isoproterenol was given as a rapid intravenous injection. After 5 to 10 minutes, and when the heart rate and aortic pressure had returned to control levels, the venae cavae were ligated, the cannulas opened, and perfusion instituted. The effects of the same dose of intravenous isoproterenol were then recorded at high, medium and low perfusion rates in every dog; the rates averaged In 4 animals 94, 56 and 28 cc./kg./min., respectively. the initial rate was high, and medium and low flows were subsequently studied. In the other 4 animals, this order was reversed, and the study was begun at With the initiation of perfusion, the low flow rate. after each change in the flow rate and after each injection of isoproterenol, a 5 to 10 minute stabilization The duration of abnormally low period was allowed. flow was relatively brief in each animal, and the arterial blood pH, measured during each observation

period, remained above 7.35 at all times. Results: As noted above, left ventricular For pressure was recorded from two catheters. purposes of brevity, the term “transatrial gradient” is utilized to indicate a difference between the aortic and the ventricular systolic pressures recorded from the transatrial catheter passed from the pulmonary vein. Similarly, “transmural gradient” designates any systolic pressure difference between the aorta and the pressure recorded from the transmural catheter passed THE AMERICAN

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FIG. 3. (Continuous recordings of central aortic pressure and left ventricular pressure made after the administration of 4 pg./kg. of isoproterenol (arrow) during controlled venous return of 30 cc./ kg./min. The transatrial catheter (LV-1) indicated the devrelopment of a large pressure gradient, while the systolic pressure from the transmural catheter (LV-2 ) remained equal to aortic pressure.

FIG. 4. Central aortic and left ventricular pressures recorded after isoproterenol administration during controlled venous return of 45 cc./kg./min. Again, a large gradient was indicated by the transatrial catheter (LV-1) and none by the transmural one (LV-2). The absence of a true gradient is more clearly shown in the last four complexes when the factitious LV-1 pressure was not recorded.

Under into the ventricle through its apex. control conditions no transatrial or transmural gradient was evident in any dog. When isoproterenol (4 mg./kg.) was given prior to perfusion, transatrial gradients of 85 to 115 mm. Hg developed in 4 animals but no transmural dog had both gradients (Fig. 2); 1 additional transatrial and transmural gradients of 48 mm. Hg. With controlled venous return at a high, medium or low rate, transatrial gradients of 6 to 15 mm. Hg were recorded in 3 dogs, in none of which was a transmural gradient also present. When isoproterenol was administered during controlled venous return, transatrial gradients were recorded at high flow in 3 dogs, at medium flow in 4 dogs, and at low flow in 6 . In only 1 animal was a transmural gradient recorded it was 10 mm. Hg. Typical simultaneously; tracings of the aortic and both left ventricular pressures, recorded as isoproterenol was given,

FIG. 5.

Pressures recorded from transatrial (LV-1) and transmural (LV-2) left ventricular catheters during controlled venous return and after isoproterenol administration. The systolic pressures were essentially equal until point A, at which time the transatrial catheter was advanced slightly toward the ventricular apex. \Yith this maneuver, the recorded pressure from the transatrial catheter suddenly increased, and an anacrotic notch became evident on its ascending limb. The catheter was then withdrawn slightly (point B), and the two ventricular pressures again became equal.

are reproduced in Figure 3, and the difference in the systolic pressures recorded from the transatria1 and transmural catheters in another animal are illustrated in Figure 4. The results of the studies in all 8 dogs may be summarized asfollows: In two dogs, no transatrial

or transmural gradient was noted under any circumstances; in the remaining 6 dogs: transatria1 gradients were recorded on 21 occasions during controlled venous return or isoproterenol administration, or both; only twice, however, and in the same animal, did a transmural gradient accompany the transatrial gradient ; a transmural gradient was never recorded in the absence of a transatrial one. DISCUSSION In 21 of the 36 normal dogs utilized pressure gradients between studies,

in these the left

Morrow,

Vasko,

Henney

FIG. 6. Central aortic pressure and left ventricular pressures recorded from a transatrial catheter (LV-1 ), and from a catheter with its side openings lying z&thin the left ventricular wall (LV-2). The systolic pressures were equal; both indicated a large gradient; and the diastolic configurations were similar. Observations were made during controlled venous return, and after isoproterenol administration. ventricle

and

aorta

were

recorded,

during

the

interventions noted, when left ventricular pressure was measured from a catheter introduced These observafrom the aorta or the left atrium. tions thus confirm the results of the similar experiments performed by others, which are summarized in the introduction. However, in the experiments in which turo left ventricular catheters were placed (group III), the pressure recorded from the transatrial catheter frequently indicated a large systolic gradient, while the ventricular systolic pressure recorded simultaneously from the apical (transmural) catheter It seems clear, equaled aortic systolic pressure. therefore, that the pressure recorded from the transatrial catheter was often higher than the pressure in the left ventricular cavity, and that the gradients observed were not the result of obstruction within the ventricular outflow tract. The systolic pressure gradients recorded in these experiments were the result of artifacts in the left ventricular pressure tracings, but the precise mechanisms responsible for the artifacts Very small changes in the remain uncertain. position of the tip of the transatrial catheter caused striking alterations in the pressure recorded from it. This phenomenon is illustrated by the two records of left ventricular pressure reproduced in Figure 5. During controlled flow

and Brawley

FIG. 7. Central aortic and left ventricular pressures recorded after isoproterenol administration and during controlled venous return of 55 cc./kg./min. The transatria1 catheter (LV-1) indicates a large gradient, and the transmural catheter (LV-2), none. When a ventricular premature contraction was induced, the aortic pulse pressure increased normally in the beat following the extrasystole, and the gradient indicated by the transatrial catheter remained unchanged. These hemodynamic responses are incompatible with the presence of true muscular outflow obstruction.

and after isoproterenol administration, the systolic pressures recorded from the two ventricular catheters were initially similar; however, when the transatrial catheter was advanced an additional 1 or 2 mm. toward the ventricular apex, the systolic pressure suddenly increased by more than 50 mm. Hg; and an anacrotic notch, typical of hypertrophic obstruction, became evident. Such observations suggested that when the ventricular volume was reduced, the catheter tip was sequestered within a muscular loculus isolated from the ventricular cavity and created by apposition of adjacent structures, a possibility considered by Gauer and Henry.* The systolic pressure within such an isolated pocket might be expected to approximate intramyocardial rather than intracavitary pressure. This mechanism is given credence by the tracings illustrated in Figure 6. In this dog, the transatrial catheter was positioned in the usual way, but the apical catheter, instead of being passed into the ventricular cavity, was placed with all of its side openings lying within the wall of the left ventricle. As illustrated, the systolic pressures recorded from the transatrial and intramyocardial catheters were identical, and both were greatly in excess of aortic systolic pressure. The tips of the left ventricular catheters, passed either from the aorta or left atrium, were frequently found at THE

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at any site.

necropsy to be positioned in the recess between the posterolateral wall of the left ventricle and the anterior papillary muscle, and it appeared that approximation of these structures may have created a loculus. The tips of the transmural catheters, on the other hand, lay anterior to the papillary muscle and in the free cavity of the ventricle. In recently reported studies, Martin and associate2 recorded pressure gradients of 150-300 mm. Hg in the left ventricles of normal dogs subjected to hemorrhagic shock. Cineangiocardiographic studies indicated to them that as the volume of the ventricle was reduced, the apical portion of the left ventricular cavity became isolated from the remainder of the chamber, and that the pressure gradient occurred between this apical chamber and the body of the ventricle. On the basis of the present experiments this explanation appears incorrect, however, since the lowest ventricular pressure was always recorded from the catheter inserted into the apex of the ventricle. As noted previously, in 1 dog, pressure gradients were indicated by both the transatrial and transmural catheters when isoproterenol was given under control conditions and at a high perfusion rate at the beginning of the experiment. Later, however, at medium and low perfusion rates, a gradient was recorded only from the transatrial catheter after isoproterenol administration. At necropsy, the VOLUME

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transmural catheter was in the usual site, and it must be postulated that it had initially been improperly positioned. Finally, it is well recognized that lateral acceleration, imparted to a cardiac catheter by the movement of the heart, can also give rise to artifactual systolic pressure peaks, and this mechanism may also have been of importance, particularly under the circumstances of augmented contractile force and reduced ventricular dimensions. Further evidence that left ventricular outflow obstruction did not occur during these experiments is presented in Figure 7. In this dog, while a large systolic pressure gradient was indicated by the transatrial catheter, a ventricular premature contraction was induced. In the following cycle, the aortic pulse pressure increased, and the pressure recorded from the transatrial catheter returned to its previous level. This hemodynamic response is, of course, not characteristic of muscular subaortic outflow stenosis. When such obstruction is present, the arterial pulse pressure is decreased or unchanged in the postextrasystolic beat, while the left ventricular pressure and the pressure gradient usually increase strikingly.‘,? The absence of obstruction was proved in a more direct manner in the experiment illustrated in Figure 8. Initially, a catheter was passed from the apex of the heart into the ascending aorta. After the administration of isoproterenol, and when a large

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gradient was indicated by the transatrial catheter, the apical catheter was withdrawn across the aortic valve, through the entire length of the left ventricular outflow tract, and finally out of No intraventricular pressure gradithe heart. ent could be demonstrated at any site. It would appear that in experiments of this type the specific type of cardiac catheter utilized to measure left ventricular pressure is less important than the way it is introduced, and the way it is positioned in the ventricle. The catheters employed in the present experiment., were specificaIly selected because it was considered that the multiple side holes would serve to eliminate recording artifacts. This, of course, was not the case when they were inserted from the The catheters employed aorta or left atrium. by Krasnow et aL5 and by Cross and Salisburye are not described in detail but were apparently of conventional type. Gauer, in his studies,4,8 employed a catheter-tip manometer as did Martin et al.‘ss In their abstract, the latter authors state that they could demonstrate intraventricular gradients during shock with the Gauer catheter-manometer, but not when a Cournand catheter was used. In additional experiments in this laboratory, left ventricular pressure artifacts such as those illustrated have also been recorded when end-hole Cournand catheters, Ross transseptal catheters and Gensini catheters were introduced from the atrium or aorta. The methods employed in the experiments described were generally designed to duplicate those utilized by previous investigators; and when retrograde aortic or transatrial catheters were used to measure left ventricular pressure, gradients between the left ventricle and aorta, comparable to those illustrated by others, were obtained. It was further demonstrated, however, that the pressure gradients measured in It is conthis manner were the result of artifact. cluded, therefore, that there is presently no valid hemodynamic evidence that outflow obstruction can be experimentally induced within the norOne may specumal left ventricle of the dog. late as to whether factitious ventricular pressures may also be recorded during certain physiologic and pharmacologic interventions in man, but the answer to this question must await further investigation. SUMMARY Previously reported experimental indicated that outflow obstruction

studies have can be pro-

Henney

and Brawley

duced within the normal left ventricle of the dog under conditions of reduced cardiac output or augmented myocardial contractile force, or both. This hypothesis was re-examined in the experiments described. In 36 normal dogs, isoproterenol and other inotropic drugs were administered before and during hemorrhagic shock or a period of controlled decreased venous return. In 21 dogs, systolic pressure gradients between the left ventricle and central aorta were recorded when left ventricular pressure was measured from a catheter introduced from the aorta or left atrium. The elevated left ventricular pressures responsible for the gradients were shown to be artifacts, however, when the pressure was simultaneously measured from a catheter in the apex of the ventricle. It is concluded that there is presently no valid hemodynamic evidence that outflow obstruction can be induced within the normal ventricle of the dog, and consideration is given to possible mechanisms responsible for the factitious pressure pulses recorded in these and other investigations. REFERENCES 1. BRAUNWALD, E., LAMBREW, C. T., ROCKOFF, S. D., Ross, J., JR. and MORROW, A. G. Idiopathic hypertrophic subaortic stenosis. I. A description of the disease based upon an analysis of 64 patients. Circulation, 30 (Suppl. IV): 3, 1964. 2. PIERCE, G. E., MORROW, A. G. and BRAUNWALD,E. Idiopathic hypertrophic subaortic stenosis. III. Intraoperative studies of the mechanism of obstruction and its hemodynamic consequences. Circulation, 30 (Suppl. IV): 152, 1964. 3. MCLAUGHLIN, J. S., MORROW, A. G. and BUCKLEY, M. J. The experimental production of hypertrophic subaortic stenosis. J. Thoracic @ Cardiouas. Surg., 48: 695,1964. 4. GAUER, 0. H. Evidence in circulatory shock of an isometric phase of ventricular contraction following ejection. Fed. Proc., 9: 47, 1950. 5. KRASNOW, N., ROLETT, E., HOOD, W. B., JR., YURCHAR, P. M. and GORLIN, R. Reversible obstruction of the ventricular outflow tract. Am. J. Cardiol., 11: 1.1963. 6. CROSS, C. E. and SALISBURY,P. F. Functional subaortic stenosis produced in animals. Am. J. Cardial., 12: 394, 1963. 7. MARTIN, A. M., HACKEL, D. B. and SIEKER, H. 0. Intraventricular pressure changes in dogs during hemorrhagic shock. Fed. Proc., 22: 252, 1963. 8. GAUER, 0. H. and HENRY, J. P. Negative (-G2) acceleration in relation to arterial oxygen saturation, subendocardial hemorrhage and venous pressure in the forehead. Aerospace Med., 35: 533, 1964. 9. MARTIN, A. M., JR., HACKEL, D. B., SPACH, M. S., CAPP, M. P. and MIKAT, E. Cineangiocardiography in hemorrhagic shock. Am. Heart J., 69 : 283, 1965. THE AMERICANJOURNAL OF CARDIOLOGY