Coronary Hemodynamic Effects of Increasing Ventricular Rate in the Unanesthetized Dog

Transcription

1 Coronary Hemodynamic Effects of Increasing Ventricular Rate in the Unanesthetized Dog By Bertram Pitt, M.D., and Donald E. Gregg, Ph.D., M.D. ABSTRACT In five unanesthetized dogs with surgical heart block, increasing ventricular rate from to beats/min demonstrated an optimum ventricular rate of 0 to 85, above which aortic pressure and cardiac output fell. In contrast, coronary blood flow continued to rise to a ventricular rate of 50 to 00 beats/min. Stroke systolic coronary flow was well maintained over the entire range of ventricular rates studied, while stroke diastolic coronary flow fell with an increase of ventricular rate. A reactive hyperemic response following release of a - to 0-second coronary artery occlusion at a ventricular rate of 50 to 00 suggests that the fall in aortic pressure and cardiac output which occurred at these rates may not be due to an insufficiency of total coronary blood flow. Beta-receptor activity did not appear to play a significant role in the hemodynamic adjustment to increases in ventricular rate within the optimum range for cardiac output and aortic pressure from 5-77 to 5-56 beats/min. ADDITIONAL KEY WORDS heart block cardiac output beta-receptor blockade reactive hyperemia coronary blood flow Hemodynamic studies both in the anesthetized dog and man have shown that aortic pressure and cardiac output fall above an optimum ventricular rate (-). There is also suggestive evidence that adrenergic receptor activity is of importance in the response of the systemic circulation to increases in ventricular rate (). Studies on the effects of increasing ventricular rate on coronary blood flow in the anesthetized dog have, however, given conflicting results (5-0). Because of this variability and because of possible differences between conscious and anesthetized animals, we have used implanted electro-magnetic flow transducers to study this problem in the unanesthetized dog. From the Department of Cardiorespiratory Diseases, Walter Reed Army Institute of Research, Washington, District of Columbia 00. A preliminary report of this work was presented at the spring meeting of the American Federation for Clinical Research, Atlantic City, New Jersey, May 966. Dr. Pitt's present address is The Johns Hopkins Hospital, Baltimore, Maryland 05. Accepted for publication April 0, 968. Methods In five dogs weighing 6 to kg and anesthetized with pentobarbitol, 5 mg/kg, surgical heart block was produced through a right lateral thoracotomy by a modification of the technique of Starzl and Gaertner () or by electrocoagulation of the A-V node. Two platinum wires were sutured to the apex of the right ventricle and the heart was paced with a variable-rate pacemaker. Two to four weeks after creation of surgical heart block, a left lateral thoracotomy was performed under anesthesia with pentobarbital, 5 mg/kg, and electromagnetic flow transducers were implanted around the central aorta and the circumflex branch of the left coronary artery, together with implantation of a central aortic catheter, as previously described (). Zero coronary blood flow was obtained by occlusion of a polyethylene snare distal to the flow transducer. Coronary blood flow and cardiac output were determined by planimetric integration of the phasic flow tracings. Late diastolic coronary resistance was calculated as the ratio of end-diastolic aortic pressure (mm Hg) to enddiastolic coronary flow (ml/min). Two of the five animals did not have an aortic flow trans- R-6 external pacemaker, range 50 to 00 beats/ min. Electrodyne Co., Norwood, Massachusetts. OrcnUlion Rtiurcb, Vol. XXII, Jttnt

2 75 PITT, GREGG H.R. L A. P. c. a F. S. F ad»..., B!D f.fv f """"I IV,ic i ( s t 9 I i i /... 9 ' 9, ' i/k. ;" " 5 D J V II I H.R. A. P. " / " " J a a F. LD.C R. S.F. aa i- t * '< K LI & It FIGURE Hemodynamic effects of increasing ventricular rate in an unanesthetized dog. H.R. = heart rate (beats/min). A.P. = phasic aortic pressure; numbers indicate mean pressure (mm Hg), but mean pressure line should be ignored. C.B.F. = phasic left circumflex coronary blood flow; numbers fust above early diastolic coronary flow curve indicate mean flow (ml/min). L.D.C.R. = late diastolic coronary resistance; numbers fust above late diastolic or systolic coronary flow curve represent aortic blood pressure (mm Hg) divided by coronary flow (ml/min) fust before ventricular isometric contraction. S.F. = stroke coronary flow; numbers fust above zero coronary flow line (dashed) under systolic coronary flow curve indicate stroke systolic flow (ml); numbers under diastolic coronary flow,curve indicate stroke diastolic flow (ml). CO. = cardiac output (ml/min). Paper speed 75 mm/sec. Vertical time lines 0. sec. TABLE Hemodynamic Effects of Increasing Ventricular Rate in the Unanesthetized Dog Dog Ventricular rate (beats/min) Coronary blood flow (ml/min) Stroke fybtolic flow (ml) Stroke dlaatollc flow (ml) Mean aortic prwmre (mm Hg) Lite diaitolic coronary resiltance (unlu) ihv. Cardiac output (ml/min) Circtthuion Rssetrcb, Vol. XXII, Jin* 968

3 HEMODYNAMIC EFFECTS OF INCREASING RATE 755 Table, dog ), the pacemaker rate was increased in small increments and 0 to 0 minutes for hemodynamic adjustment was allowed between each increase. The signifi ISO 00 Heart Rail/Beott/Mln FIGURE Hemodynamic effects of increasing ventricular rate in the unanesthetized dog. Graphic representation of the experiment shown in Figure. ducer. All animals were studied in the resting state to weeks after operation. Results In a representative experiment (Fig. and CUctUion R t s i srcb, Vol. XXII, }um 968

4 PITT, GREGG 756 HR baots/fnn. SO CBF ml/min. 6 LDCR units 5O FIGURE Reactive hyperemic response following release of coronary artery occlusion for second. Abbreviations as in Figure. Paper speed 75 mm/sec. Vertical time lines 0. sec. cant hemodynamic events can be appreciated by focusing on ventricular rates 50, 50, and 50. As the ventricular rate was increased from 50 to 50, there was an increase in mean aortic pressure from 65 to 85 mm Hg and an increase in coronary blood flow from 8 to 57 ml/min. Stroke systolic coronary flow increased from 0.07 to 0.09 ml, while stroke diastolic coronary flow fell from 0.6 to 0.9 ml. Late diastolic coronary resistance fell from.5 to. units. Cardiac output rose from 50 to 5500 ml/min. As the ventricular rate was increased from 50 to 50 beats/ min, there was a fall in mean aortic pressure to 80 mm Hg and in cardiac output to 50 ml/min. In contrast, the coronary blood flow continued to rise and reached a value of 6 ml/min, while late diastolic coronary resistance fell to 0.8 units. Stroke systolic coronary flow fell to 0.06 ml and stroke diastolic flow to 0.0 ml. These results are shown graphically in Figure. This pattern of response in which the coronary blood flow continued to increase up to a ventricular rate of 50 to 00 beats/min, despite a fall in mean aortic pressure and cardiac output from their optimum values at a ventricular rate of 0 to 85, was seen in all five unanesthetized animals (Table ). At the end of the study period, at a ventricular rate of 50 to 00, a myocardial reactive hyperemic response was present in each of the animals following release of the coronary artery occlusion obtained for zero mechanical flow (Fig. ). The duration of coronary artery occlusion varied from to 0 seconds, and therefore the absolute values of TABLE Hemodynamic Effects of Increasing Ventricular Rate within the Optimum Range for Aortic Pressure and Cardiac Output Dog Late diastolic Coronary Ventricular coronary Cardiac blood Aortic rate flow pressure resistance output (units) (ml/min) (beats/min) (ml/min) (mm Hg) Before Propranolol After Propranolol The values at the high ventricular rates were recorded 0 to 0 minutes after the increase in rate. Circulation Research, Vol. XXII, June 968

5 HEMODYNAMIC EFFECTS OF INCREASING RATE 757 Btfor* Propranotol! ur x f JO o G /TO' JO - / - ^ i »«..,» - - «ccrri» 8 0 IS l«0 6 ZB 0 Mlnoin FIGURE Hemodynamic effects of increasing centrtcuzar rate in an unanesthetized dog before propranohl (dog, Table ). The pacemaker rate was increased rapidly from the control paced rate and continuous recordings taken. ii the reactive hyperemia response were not comparable in the five animals. Increasing the ventricular rate from 50- to 5-56 in a single step, within the optimum range for aortic pressure and cardiac output, resulted in an instantaneous increase in aortic pressure, coronary blood flow, and cardiac output, as shown graphically for a representative experiment in Figure. Within 5 seconds, these hemodynamic measurements fell from their peak to a new level above control values, while the ventricular rate was held constant. This new level was maintained for the 0- to 0-minute study period and then the ventricular rate was returned to the control level. The aortic pressure, coronary blood flow, and cardiac output immediately fell below control and then rose toward control values within 0 to 0 seconds. The animals were then given propranolol, mg/ CircuUlim Rtsttrcb, Vol. XXII, Jtm* 968

6 758 PITT, GREGG Afttr PropfonokH 0 00 BO / 60 -,. ~ - IDiO.0 h a E u JO : ''V-,jr ----» i v JLJ _ JO FIGURE 5 Hemodynamic effects of increasing ventricular rate in the unanesthetized dog after propranolol, mg/kg iv, (dog, Table ). kg iv, a dose sufficient to block the coronary vasodilator effect of isoproterenol, 0.5 /xg/kg iv. After propranolol, increasing ventricular rate to similar levels resulted in a hemodynamic response almost identical to that prior to beta-adrenergic receptor blockade (Table ). Figure 5 graphically illustrates the effect after propranolol in the same animal shown in Figure. Discussion The effect of increasing ventricular rate in the unanesthetized dog can be divided into three phases. The first phase from 50- to beats/min is characterized by a rapid increase in mean aortic pressure, coronary blood flow, and cardiac output. During the second phase, from to 0-85 beats/ min," there is a more gradual increase in CirctUtion Riittrcb, Vol. XXII, Junt 968

7 HEMODYNAMIC EFFECTS OF INCREASING RATE 759 coronary blood flow while mean aortic pressure and cardiac output either remain constant or also gradually increase. The third phase, above ventricular rate 0-85, is characterized by a fall in cardiac output and mean aortic pressure; in contrast, the coronary blood flow continues to increase up to ventricular rates of 50 to 00. The fall in cardiac output at high ventricular rates has been shown to be largely due to decreased ventricular filling as a result of the shortened diastolic filling time (). Since coronary blood flow occurs mainly in diastole (), it has been thought that coronary blood flow would also fall at high ventricular rates and that this could contribute to myocardial failure with a resultant fall in cardiac output (5). The results of the present investigation in conjunction with previous studies in the anesthetized dog (6-8) suggest that coronary blood flow is maintained at high ventricular rates. The explanation for the rise in coronary blood flow despite a fall in cardiac output and aortic pressure during the third phase can be found in studies demonstrating a direct relationship between ventricular rate and myocardial oxygen consumption (7, ). The increase in myocardial oxygen consumption at high ventricular rates has been explained in part by the increase in tension-time' index due to a relative increase in systolic ejection time/min (). The finding of a myocardial reactive hyperemic response following release of short periods of coronary artery occlusion at ventricular rates above the optimum for aortic pressure and cardiac output, makes it unlikely that the fall in cardiac output and aortic pressure at these rates is due to a relative insufficiency of total coronary blood flow. Since the presence of a reactive hyperemic response indicates a reserve coronary flow capacity, hypoxia would be expected to result in the necessary coronary vasodilation to supply the myocardial flow demands. The possibility remains, however, that at rapid ventricular rates there may be an alteration in the intramyocardial distribution of coronary flow. The shortened diastolic time may be inadequate to allow perfusion of the subendocardial region. With coronary artery narrowing, however, there is suggestive evidence that coronary flow may be relatively insufficient at high ventricular rates. Berglund and associates showed that while coronary blood flow increased with ventricular rate in anesthetized dogs with normal coronary arteries, it reached a plateau at a ventricular rate of 50 in dogs with coronary artery narrowing (7). Under these circumstances, the increased myocardial oxygen demands of increasing ventricular rate may not be adequately met and myocardial failure may occur. Recent studies in patients with angina pectoris would also suggest that coronary blood flow may be relatively inadequate to supply myocardial demands at high heart rates.. In patients with normal coronary arteries, an increase in heart rate by atrial pacing results in a decrease in left ventricular end-diastolic pressure without the appearance ob ischemic ST-T wave changes in the electrocardiogram. In patients with severe coronary artery disease, an increase in heart rate to 0 to 60 beats/min results in angina pectoris accompanied by an increase in left ventricular end-diastolic pressure and significant ischemic ST-T wave changes (). The' results- of the present investigation suggest that stroke systolic coronary flow is relatively well maintained over the entire range of ventricular rates studied - Although stroke diastolic coronary flow progressively decreases with increasing ventricular rate, coronary blood flow per minute increases. The flow patterns found in this study at a ventricular rate of 50 to 00 are different from those found when similar ventricular rates are achieved during exercise or excitement. Under those circumstances there is a marked increase in stroke systolic flow, sometimes as much as 500% above control (5, 6). Prior to this study, we had considered the possibility that the increase in stroke systolic flow during exercise or excitement at 00 to 00 beats/min was due to the effect of ventricular rate alone, with the redistribution of coronary blood flow within the cardiac cycle due entirely to mechanical factors. It CircnUtioH Rtsttrcb, Vol. XXII, ]u% 968

8 760 PITT, GREGG now appears that the increase in stroke systolic flow seen under these circumstances is due to active vasodilation. Recent studies in our laboratory suggest that this redistribution of coronary blood flow during the cardiac cycle is due, at least in part, to beta-adrenergic receptor stimulation (6, 7). In the unanesthetized dog, increasing the ventricular rate in a single step within the optimum range for aortic pressure and cardiac output resulted in an instantaneous increase in aortic pressure, coronary blood flow, and cardiac output, and a fall in late diastolic coronary vascular resistance. Within 5 seconds, these measurements fell from their peak values and reached a new level above control which was maintained for the duration of the 0- to 0-minute study period. After beta-adrenergic receptor blockade with propranolol administered intravenously, increases in ventricular rate to similar levels resulted in an almost identical hemodynamic response. The results of the present investigation do not, therefore, indicate an important role for beta-adrenergic receptors in the control of the coronary or systemic circulation during changes in ventricular rates within the optimum range for aortic pressure and cardiac output. The coronary circulation thus appears to be under metabolic rather than neurogenic regulation under these circumstances. The mechanisms for correcting the initial overshoot in aortic pressure, coronary blood flow, and cardiac output, after rapid increase in ventricular rate, have not been elucidated. These findings indicate the importance of studies in conscious animals to evaluate sympathetic activity, for many of the differences between the hemodynamic adaptations in conscious and anesthetized dogs are due to the greater influence of the sympathetic nervous system during anesthesia. Thus, recent studies in the conscious dog and man have shown that beta-adrenergic receptor activity is minimal in the resting state (8, 9) and that in the supine, conscious dog propranolol fails to alter appreciably coronary blood flow, coronary vascular resistance, cardiac output, and heart rate (8). By contrast, in the anesthetized dog, resting beta-adrenergic receptor activity has been significant, as evidenced by a 0% fall in coronary vascular resistance and a fall in cardiac output after propranolol (0). Furthermore, it is even possible that an increase in ventricular rate above the optimum for cardiac output and aortic pressure in the open-chest, anesthetized dog might lead to congestive heart failure. It has been shown that the failing myocardium is dependent upon stimulation of beta-adrenergic receptors (). References. MILLER, D. E., GLEASON, W. L., WHALEN, R. E., MORRIS, J. J., AND MCINTOSH, H. D.: Effect of ventricular rate on the cardiac output in the dog with chronic heart block. Circulation Res. 0: 658, 96.. SOWTON, E.: Hemodynamic studies in patients with artificial pacemakers. Brit. Heart J. 6: 77, 96.. NAKANO, J.: Effects of atrial and ventricular tachycardia on the cardiovascular dynamics. Am. J. Physiol. 06: 57, 96.. NAXANO, J,: Effects of atrial and ventricular tachycardia on the cardiovascular dynamics in reserpinized dogs. Am. J. Cardiol. : 89, CORDAY, E., GOLD, H., DEVEHA, L. B., WIL- LIAMS, J. H., AND FIELDS, J.: Effect of the cardiac arrhythmias on the coronary circulation. Ann. Internal Mad. 50: 55, LAURENT, D., BOLENE-WIIXIAMS, C., WILLIAMS, F. L., AND KATZ, L. N.: Effect of heart rate on coronary flow and cardiac oxygen consumption. Am. J. Physiol. 85: 55, BERCLUND, E., BORST, H. G., DUFF, F., AND SCHREINER, G. L.: Effect of heart rate on cardiac work, myocardial oxygen consumption and coronary blood flow in the dog. Acta Physiol. Scand. : 85, MAXWELL, G. M., CASTILLO, C. A., WHITE, D. H., JR., CBUMPTON, C. W., AND ROWE, G. G.: Induced tachycardia: Its effect upon the coronary hemodynamics, myocardial metabolism, and cardiac efficiency of the intact dog. J. Clin. Invest. 7:, WEGRIA, R., FRANK, C. W., WANG, H.-H., AND LAMMEHANT, J.: Effect of atrial and ventricular tachycardia on cardiac output, coronary blood flow and mean arterial blood pressure. Circulation Res. 6: 6, ANHEP, G. V., AND SEGALL, H. N.: The regulation of the coronary circulation. Heart : 9, 96. Circulation Rjuurcb, Vol. XXII, Jtau 968

9 HEMODYNAMIC EFFECTS OF INCREASING RATE 76. STARZL, T. E., AND GAERTNER, R. H.: Chronic heart block in dogs. A method for producing experimental heart failure. Circulation : 59, GREGG, D. E., KHOURL E. M., AND RAYFORD, C. R.: Systemic and coronary energetics in the resting unanesthetized dog. Circulation Res. 6: 0, BADEEB, H. S., AND FEBAL, K. A.: Effect of atrial and ventricular tachycardia on cardiac oxygen consumption. Circulation Res. 7: 0, FHTESINGEH, G. C, CONTI, C. R., AND PITT, B.: Observations on left ventricular pressure during angina pectoris. Circulation 6 (suppl. II): -5, KHOUBL E. M., GREGG, D. E., AND RAYFORD, C. R.: Effect of exercise on cardiac output, left coronary flow and myocardial metabolism in the unanesthetized dog. Circulation Res. 7: 7, PITT, B., ELLIOT, E. C, KHOURL E. M., AND GREGG, D. E.: Coronary hemodynamic effects of exercise at fixed ventricular rates in the unanesthetized dog. Circulation (suppl. Ill): -88, PITT, B., ELLIOT, E. C, KHOURL E. M., AND GRECC, D. E.: Effect of adrenergic blockade on the coronary hemodynamic response to excitement at fixed ventricular rates in the unanesthetized dog. Physiologist 9: 67, PITT, B., GREENE, H. L., SUCISHTTA, Y., AND Ross, R. S.: Effect of beta adrenergic receptor blockade on coronary hemodynamics in the supine unanesthetized dog. Federation Proc. 7: 6, ROBINSON, B. F., EPSTEIN, S. E., BEISER, G. D., AND BBAUNWALD, E.: Control of heart rate by the autonomic nervous system. Circulation Res. 9: 00, PARRATT, J. R.: Blockade of sympathetic beta receptors in the myocardial circulation. Brit. J. Pharmacol. Chemo. : 60, GAFFNEY, T. E., AND BRAUNWAXD, E.: The importance of the adrenergic nervous system in the support of the circulatory function in patients with congestive heart failure. Am. J. Med. : 0, 96. Circulation Rtstmcb, Vol. XXII, Jmu 968

10 Coronary Hemodynamic Effects of Increasing Ventricular Rate in the Unanesthetized Dog BERTRAM PITT and DONALD E. GREGG Circ Res. 968;:75-76 doi: 0.6/0.RES Circulation Research is published by the American Heart Association, 77 Greenville Avenue, Dallas, TX 75 Copyright 968 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: 5-57 The online version of this article, along with updated information and services, is located on the World Wide Web at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Circulation Research is online at: