Br J: first published as 10.1136/hrt.33.2.173 on 1 March 1971. Downloaded from British Heart Journal, I971, 33, I73-I84.

Pathophysiology of coronary circulation'

Richard S. Ross2 From The Johns Hopkins University, School of Medicine, *Baltimore, Maryland, U.S.A.

I consider it a great honour to have been asked like to quote briefly from the introduction to to give the Sir Thomas Lewis Lecture, and I the first Herter Lecture as follows: have chosen for my subject the pathophysi- ,,ology of the coronary circulation - a topic 'Laboratory methods as applied to the which was of great interest to Sir Thomas. study of clinical medicine have come to stay; reason this is instruments and methods of precision are Another for selecting topic that gradually relieving medicine of its past so much of the good, recent work in this field stigma; they are lifting it to the plane of its * has been done in Britain and many of the sister sciences, its true and proper status. investigators who have made significant con- We have been too content in the past with tfributions are members of this distinguished opinion. In the future we shall rest our case society. This may possibly be a disadvantage upon fact.' (Lewis, I9I5.) m that I will have difficulty saying anything W which is not well known to a large segment of I would like to turn to the subject of my the audience. A third reason for this selection lecture by examining the history of clinical is that ischaemic heart disease is of interest to investigation of ischaemic heart disease. The me and has been the subject of much of the modem era begins with Sir Thomas who in -research with which I have been associated his Billings Lecture in Chicago in I93I sum- during the past nine years. Indeed, the Pro- marized the descriptive observations which Tessorship which I hold at The Johns had gone before and pointed the way for http://heart.bmj.com/ ,,Hopkins University School of Medicine is future studies (Lewis, I932). The first major supported by the Clayton Fund established investigative study on this subject came from _by the late Mr. William L. Clayton and his his department, the Department of Clinical wife to further research in arteriosclerosis, Research at the University College Hospital. especially of the coronary . I refer to the work of Wayne and Laplace Sir Thomas Lewis has been known to me published in Clinical Science in I933. This -through his work throughout my professional represents an important milestone along the life and I have had contact with many of his road to the understanding of the patho- on September 29, 2021 by guest. Protected copyright. ^upils. During the course of preparing this physiology of pectoris. This is a lecture I learned that Sir Thomas had come to classic of clinical investigation, and I point to Baltimore in October of 1914 and delivered it as an example of what can be accomplished .1he Herter Lectures at The Johns Hopkins by simple well-designed experiments and Hospital and I was delighted by what I found thoughtful interpretation. This was budget- -irw his introductory remarks (Lewis, I915). less research. Pulse and pressure were His words of 55 years ago bear repeating in measured during 400 attacks of chest pain -that they outline the philosophy upon which induced by exercise. Observations of great clinical investigation has moved forward. interest abound in this paper. Of special These remarks indicate to me that Sir interest is the observation of the effect of Thomas would have approved of much of the atropine on exercise tolerance and the onset active investigation of coronary disease of pain as depicted in Fig. i. and , which is currently The investigators measured blood pressure in progress. With your permission I would systolic and diastolic, pulse rate, and the onset The Sir Thomas Lewis Lecture ofthe British Cardiac and cessation of pain. The number of efforts Society I969. Delivered before the annual meeting of ascents over a step are recorded as the ,Qf the British Cardiac Society held at the Royal College height of the vertical bar. The panel at the ofPhysicians, London, 14 November I969. left displays the results of the control experi- m&Susan and William Clayton Professor of Cardio- iscular Disease. The work was supported in part by ment and the comparable observations after USPHS Grants and Contracts, and by Heart Asso- atropine are seen in the right-hand panel. It is ciation of Maryland. readily apparent that the control pulse rate is Br Heart J: first published as 10.1136/hrt.33.2.173 on 1 March 1971. Downloaded from x74 Richard S. Ross higher and the post exercise tachycardia of longer duration after atropine. The patient was able to do only approximately halfas much work after atropine and the pain persisted for a longer time. It is of interest that the blood pressure after atropine was lower than in the control state. These experiments provide a clear demonstration of the importance of pulse rate in the precipitation of angina. This effect has been demonstrated many times since I933 but never with more clarity. The design was simple, the results clear, and hence interpretation was easy. Wayne concluded from the atropine experi- ments that, 'The diminution in the number of 0 efforts (trips up the steps) and the increase in Minutes the duration of the pain under atropine . .. F I G. I The effect of atropine-induced can be attributed . . . to the more rapid action tachycardia on exercise tolerance. Observations of the heart, which increases its energy after atropine are shown in the right-hand expenditure without a concomitant increase panel and compared to control observation on in coronary flow...... ' These atropine experi- the left. The number in the clear vertical ments can be considered to be anticipatory of bar is the number of ascents over a step and the studies with pacing-induced tachycardia the length of the horizontal hatched bar which have occupied many of us in the past represents the duration ofpain. Reproduced few years. from Wayne and Laplace (1933) by permission It is also of note that in this same paper of Clinical Science. Wayne and Laplace reported observations on the effect of mechanical stimulation of the carotid sinus on angina pectoris. Thus, current decade and list coronary arteriography another area of interest in the seventh decade as one of the important developments, but of the century was pioneered in Sir Thomas may well consider it to be important because http://heart.bmj.com/ Lewis' laboratory in the fourth decade. it brought many patients with ischaemic heart disease into the haemodynamic labora- tory for study. Before I960, few patients with Haemodynamics of myocardial ischae- coronary heart disease were subjected to haemodynamic evaluation, as such a study In the late I950's the technique of right heart would have been purely investigational and catheterization was applied to the study of without any potential for therapeutic benefit. ii- in angina by Muller and R0rvik (I958) The active investigation of the past five on September 29, 2021 by guest. Protected copyright. Norway and by Johnson, Fairley, and Carter years has contributed to the current concept (i959) in the United States. Both groups of the pathophysiology of myocardial ischae- emphasized the many similarities between mia depicted in Fig. 2 in the form made angina and dyspnoea as manifestations of popular by the systems analyst. The central congestive failure. Both groups recorded in- point of this diagram is the equality between creased and pulmonary oxygen supply and demand at the cellular capillary wedge pressures in association with level. On the left are the mechanical factors anginal pain. After these two significant that influence demand, heart rate, wall tension, papers, the slow pace of clinical investigation and myocardial contractility. On the right are of ischaemic heart disease continued until the the several factors that influence supply, all of latter half ofthe current decade. Between I965 which are related to blood flow. At the bottom and the present time, many significant papers are listed the manifestations of ischaemia have been published on this subject; this which are the consequences of an imbalance current world-wide epidemic of publication between supply and demand. being attributed to the introduction of three This diagram could be rendered more new techniques. The first is the development comprehensive and hence more complicated of coronary arteriography, the second is re- by the addition of all the feedback relation- vascularization surgery, and the third is the ships which can be postulated. For example, development of techniques whereby the vasoactive substances may reduce coronary heart rate can be artificially controlled. vascular resistance and hence tend to correct Medical historians may well look back on this the situation that produced the ischaemia. On Br Heart J: first published as 10.1136/hrt.33.2.173 on 1 March 1971. Downloaded from Pathophysiology of coronary circulation 175

Aortic LV ~~~~~~~~~~~Coronary LVe Ventricular Vascular Pesr Volume IResistance

%. |ISCHAEMIA

in | AbnormalityECG AbnormalityMetabolic DysfunctionLV VasoactiveSubstances FIG. 2 Systems diagram of the patho- experiences on exertion. In Fig. 3 the left -physiology of myocardial ischaemia. Repro- ventricular end-diastolic pressure is seen to duced by permission of Excerpta Medica rise before the onset of chest pain. The Foundation. pressure rise is associated with the appearance of a large 'a' wave. The chest pain dis- the other hand, deterioration of left ventricu- appeared after the administration of nitro- lar function results in an increase in ventricu- glycerin and the left ventricular pressure lar volume and wall tension, which leads to returned to normal. These direct observations 'increased oxygen demand and further of left ventricular pressure confirmed the in- http://heart.bmj.com/ ischaemia. Alterations in left ventricular direct observations of Muiller and R0rvik function and wall tension may also have (I958), and Johnson et al. (I959) who deleterious consequences on myocardial blood recorded increases in pressures in the pulmon- flow distribution. A lecture could be devoted to many aspects FIG. 3 Left ventricular diastolic pressure of this diagram but I have elected to confine before, during, and after a spontaneous attack ,Emy attention to only three aspects with which of angina pectoris. Note the appearance of a the group of investigators in my laboratory large 'a' wave in the record of 3.04 pm. on September 29, 2021 by guest. Protected copyright. - have been concerned. First, we will discuss Anginal pain appeared one minute later at Dr. G. C. Friesinger's work on the relation 3.05 pm and responded promptly to nitro- 'between ischaemia and left ventricular dys- glycerin. function followed by the work of Dr. B. Pitt and Dr. C. R. Conti with myocardial blood Left Ventricular Diastolic flow in association with angina and the mmHg A 1 Pressure possible role of vasoactive substances in its 40-J cwntrol, and then, the studies of Drs. Pitt, 3 5. N. J. Fortuin, and L. Becker on the myocar- 30 -'dial microcirculation as studied with micro- 25 f\L22/V spheres. 20- First, in accordance with this plan let us discuss the consequences of ischaemia on left 15 515 re'ntricular function. In I962, during the 10- 5.~ course of arteriographic study we made PL5 Jl 1ii7 /1 3.05_pm 5 observations of left ventricular pressure I/d Jiuring an anginal attack (Ross et al., I962). -2 ' define anginal pain as substernal pain or Pain 2.40pm 3.04pm Nitroqlycerin 3.18pm 'iscomfort of major severity, which is de- LAD occlusion scribed as a squeezing constriction or pressure col lateral 0.4 mg. which is identical to the sensation the patient RCA to LAD Br Heart J: first published as 10.1136/hrt.33.2.173 on 1 March 1971. Downloaded from 176 Richard S. Ross ary circulation during angina. The direct patients. No relation was apparent between the observations clearly indicated that the pri- magnitude of the blood pressure rise and the mary alteration in physiology was in the left rise in left ventricular end-diastolic pressure. and not in the . We have carefully examined the possibility Fortunately for the patients and unfortunately that these haemodynamic alterations might be for the investigator, angina pectoris occurs attributed at least in part to the administration relatively rarely during coronary arterio- of contrast material and feel certain that this is graphy. not the case. As further evidence for this, we Dr. Friesinger has collected observations on have examined the haemodynamic changes 20 patients who have developed spontaneous that follow injections of contrast material attacks of angina pectoris during cardiac cath- which are not associated with anginal attacks. eterization, and in Fig. 4 the results of these In only 2 of 23 such patients did the left studies are summarized (G. C. Friesinger, ventricular end-diastolic pressure exceed 20 unpublished observations). The left ventri- mm. Hg. cular end-diastolic pressure is consistently The two possible explanations for the raised in association with anginal pain. The observation of increased left ventricular end- heart rate did not change significantly, there diastolic pressure in association with angina being an increase of more than I0 beats a pectoris are presented diagrammatically in minute in only 3 patients. The systolic blood Fig. 5. This figure is based upon the pressure pressure was raised in some but not in all volume loop of the left ventricle shown at the left of the figure. In this presentation, left FIG. 4 Haemodynamic consequences of ventricular pressure is plotted on the ordinate spontaneous angina pectoris. LV systolic, peak and volume on the abscissa. At the lower left- left ventricular systolic pressure (top panel). hand corner ofthe loop, the opens LVED, left ventricular end-diastolic pressure and the diastolic filling of the ventricle begins (lower panel). Observations before the onset of and continues along the portion of the loop angina are plotted on the abscissa and those which parallels the volume axis (V). At the obtained during the anginal attach are plotted right-hand corner, the left ventricle pressure on the ordinate. rises and the mitral valve closes. At the upper "SPONTANEOUS" ANGINA right, the opens and ejection

begins, and at the upper left, ejection is http://heart.bmj.com/ LV Systolic mmHg terminated and the aortic valve closes. 22or To illustrate the two explanations for the increased end-diastolic pressure in ischaemic 200[ heart disease, the bottom of this loop or the g /1

ISO 'n * ../ FIG. 5 Pressure volume loop of the left DURING ventricle. Theoretical considerations of -.4 160 'I ANGINA alterations which may be associated with on September 29, 2021 by guest. Protected copyright. 1 S, spontaneous angina. 1401 SPONTANEOUS ANGINA 120 DECREASED COMPLIANCE DO 120 140 160 180 200 220 mmHg CONTROL BEFORE ANGINA loor LVED IX mmHg 50r

40[ 70 'a: p 30[ * AL DURING 0 INCREASED ANGINA 20 VOLUME ,

10 10 20 ___I 30 70 10 20 30 40 50 mmHg V BEFORE ANGINA 30 50 90 Br Heart J: first published as 10.1136/hrt.33.2.173 on 1 March 1971. Downloaded from Pathophysiology of coronary circulation I177

diastolic filling phase has been enlarged and PRIOR to PACING modified in the two panels at the right. At the top, the effect of decreased compliance of the ventricle with no change in volume is shown. The left ventricular end-diastolic pressure is increased because the pressure volume curve rises more steeply with decreased compliance, and hence a higher pressure is reached with the same filling volume. In the lower diagram the compliance has remained unchanged but the rise in end-diastolic pressure has been brought about by an increase in volume. Therefore, the pressure change that has been observed could have resulted from either an S increase in volume or a decrease in compliance, but the evidence to be presented suggests that FIG. 6 Left ventricular pressure before the decreased compliance is a more likely explana- beginning ofpacing. tion. The introduction by Sowton et al. (I967) of Control 30 Sec. 60 Sec. the technique of atrial pacing for the study of 1AAi LA.1A angina pectoris represented a major step for- 0 4 ward in this investigation and helped provide i an answer to the question posed by the HR= 11 - observation on spontaneous angina. This story would have given Thomas Lewis pleasure as it illustrates so beautifully the close interaction between the clinic and the Y -5 Secon s 31 laboratory. Physiologists have for many years U > used repetitive electrical stimulation to con- trol heart rate of experimental animals, but

- only recently has the technique been brought http://heart.bmj.com/ to the clinic for use in the management of -1 Al1$ heart block. Now the clinical technique is taken back into the laboratory and used as a * powerful tool for clinical investigation of angina pectoris. Pacing provides a safe reproducible method UP I A,whereby the oxygen demands of the myo- No Pain No Pain No Pain #1128 can be increased while the patient is (Pain 2min.) on September 29, 2021 by guest. Protected copyright. > at rest on the cardiac catheterization table. The changes in peripheral circulation which FIG. 7 The onset of pacing (left panel). The * accompany exercise are not present. Catheters middle and right-hand panels show recordings can remain in the left ventricle, coronary obtained at 30 and 6o seconds after the onset arteries, and coronary sinus during pacing, ofpacing. Left ventricular diastolic pressure and hence measurement can be made which has risen but one patient remains symptomatic. would not be possible during exercise. > The records of a typical pacing study per- has risen and that this rise preceded the onset formed by Dr. Friesinger are shown in of pain. In Fig. 8, the pacemaker has been Fig. 6, 7, and 8. In Fig. 6, the resting heart turned off and the left ventricular end- rate is 72 and the left ventricular pressure is diastolic pressure, which is difficult to easily measured at the termination of the 'a' measure during pacing, is clearly raised in the wave. A pacing catheter in the right or beats which immediately follow the end of -*coronary sinus is used to increase the heart the pacing. The pressure can be seen to rise rate by IO beats a minute increments until during the first two beats at the slower spon- anginal pain or ST segment changes appear. taneous rate. In Fig. 7 the paced heart rate is IO beats a In Fig. 9, the experience with 3I patients minute and it is not possible to clearly identify subjected to pacing stress testing has been N the point at which the end-diastolic pressure summarized (Friesinger, Conti, and Pitt, should be measured. It can be seen, however, I967). In the bottom panels it can be noted that the early and lowest diastolic pressure that in the absence of angina there was no Br Heart J: first published as 10.1136/hrt.33.2.173 on 1 March 1971. Downloaded from 178 Richard S. Ross

*Pacer Off FIG. 8 Pacing is terminated after the ,L appearance ofpain. .1i r FIG. 9 Experience with 31 patients sub- o t jected to pacing stress testing. Observations on mmHg patients who developed angina in response to 40- pacing are shown in the two right-hand panels and observations on those who did not develop angina are shown at the left. Left ventricular 30- (LV) systolic pressure is shown in the top III panels and left ventricular diastolic pressure 'ElI (LVED) in the lower panels. In all four panels 20- L\ )- observations during pacing are plotted on the ordinate against control observations on the abcissa. Patients with arteriographically normal I0- are represented by (X) and I Sec- patients with ischaemic heart disease (IHD) by imwm Hi I,I,III1 solid dots (a). PainEl #1128 NO A NGINA A NGINA mmHg LV Systolic mmHg LV Systolic 180 180r 0 r / / / x / 0 w 160[ 160[ 0 / x / 140 140 DURING DURING 0 / / x t PACING PACING * , / http://heart.bmj.com/ 120 120 * / x / / 0 0 NORMAL x I 00O 00 / / IHD 0 100[ / /

a a 80 100 120 140 160 180 mmHg 10 100 120 140 160 180 mmHg

CONTROL CONTROL on September 29, 2021 by guest. Protected copyright.

mmHg LVED mmHg LVED / / 50r / 50r / 0 40j / 401 / 0 / 30 0 / 30 0 / DURING DURING 0 * 0/ / PACING / PACING 20h / 201 / / I0 / . 0 0 0 so 01 0 x x IOF x / x t x /

0 10 20 30 40 50 mmHg 10 20 30 40 50 mmHg CONTROL CONTROL Br Heart J: first published as 10.1136/hrt.33.2.173 on 1 March 1971. Downloaded from Pathophysiology of coronary circulation 179

rise in left ventricular end-diastolic pressure. of Kingston, Ontario, and others who clearly There was an increase in pressure in I3 of I7 showed that stroke volume decreases as the patients who developed angina and 2 of the 4 heart rate is accelerated while the cardiac out- patients who did not exhibit a rise had chest put remains constant (Parker et al., I969). pain which was considered to be atypical Thus, the left ventricular end-diastolic pres- angina pectoris. There was no consistent sure is increased during pacing-induced relation between the rise in systolic blood angina and ventricular volume is decreased, pressure and the increase in left ventricular and, therefore, the compliance of the ventricle end-diastolic pressure. The failure of other must be decreased. After pacing, the stroke investigators to confirm this relation between volume returns to normal, the decreased haemodynamic changes and anginal pain may compliance persists, and, therefore, the in- be attributed to difference in the definition of crease in end-diastolic pressure is augmented. angina and hence variation in the duration of At this point in the development of the the pacing stress. Another explanation may be argument it is reasonable to ask whether found in the difficulty encountered in pacing-induced angina is the same as that measuring the left ventricular end-diastolic which occurs spontaneously. As a partial pressure during pacing at rapid rates. When answer to this question we can show the this difficulty has been encountered we have record of one of three patients who developed measured the end-diastolic pressure on the angina pectoris both with pacing and spon- beat following the termination of pacing. taneously. In Fig. ii are displayed the heart A concept of the haemodynamic conse- rate, systolic blood pressure, and left ven- - quences of myocardial ischaemia occurring in tricular end-diastolic pressure measurements a variety of circumstances is summarized in obtained during two spontaneous attacks of Fig. io. The three factors which relate to the angina pectoris and during two attacks pro- haemodynamics of the left ventricle are duced by pacing. First, let us consider the shown across the top of the table. End- two spontaneous attacks and note that diastolic pressure has been measured; volume systolic blood pressure was I40 mm. Hg in cannot be measured directly but it can be one, and I20 mm. Hg in the other. Heart rate predicted from other observations, and com- was the same and left ventricular end- pliance, as discussed in conjunction with Fig. diastolic pressure was raised in both. During

5, is the reciprocal of stiffness. The higher the the first period of paced tachycardia, the heart http://heart.bmj.com/ pressure rise per unit of volume, the less the rate was increased to 170 beats a minute with- compliance. It has been pointed out that the out the onset of pain and with a decrease in increase in left ventricular end-diastolic left ventricular end-diastolic pressure. Subse- t pressure could result either from an increased filling volume or a decreased compliance. FIG. I i Haemodynamic observations in The observations made with the pacing single patients during five attacks of angina. _ technique enable us to differentiate between A, angina; TNG, nitroglycerin; LVED, left these two possibilities. More specifically, we ventricular end-diastolic pressure. on September 29, 2021 by guest. Protected copyright. know that ventricular volume is decreased during pacing, as indicated by Sowton et al.'s "SPONTANEOUS " PACING ingenious radiographic studies (I967). Addi- 170- 150- Heart Rote tional evidence for a decreased volume during 130 FA Beas/ pacing is provided by the work of John Parker min. 110- 90 FIG. 10 Possible explanationsfor the 70 haemodynamic consequences of myocardial 1501 LV Systolic ischaemia. 140] LEFT VENTRICULAR 130 Diastolic mmHg 1201 ANGINA End Diastolic Compliance Ito ~ Pressure Volume AV/AP

_-b- ~ O ~~t~ LVED AH SPONTANEOUS

20-A nmHg 0 \me\me PACING t4 4

O I , .Fi. ii,, # POST PACING f O 4, 0 5 10 15 20 40 45 85 90 95 100 110 115 120 125 MINUTES 01095 Br Heart J: first published as 10.1136/hrt.33.2.173 on 1 March 1971. Downloaded from igo Richard S. Ross quently, lesser degrees of pacemaker-induced Pacin tachycardia were associated with both anginal ISObeats7min pain and a rise in left ventricular end-diastolic * 70 l * 0: pressure. The heart rates required to produce 8 angina with pacing are lower than those U- _60 z Eg associated with the spontaneous attacks, an 0 _ 50 observation reflecting the lesser ventricular E volume and hence wall tension during pacing. The conclusion from these studies is that increased left ventricular end-diastolic pres- 20- sure is a consistent accompaniment of anginal pain. _ 15 - O 1[AOr |~~ Ao. Ao l c. fAo. r- E 10 Myocardial blood flow during ischaemia I I I would like now to turn from haemodynamics 0_ 5 I I c. to blood flow and report some recent observa- . . ' tions made by Dr. Conti and Dr. Pitt on myo- 0 a 5 10 15 20 25 30 cardial blood flow during pacing. These Minutes studies were stimulated by the observations made by Dr. Pitt in association with Dr. FIG. I2 Myocardial bloodflow changes in Donald Gregg in dogs with surgically in- association with pacing-induced tachycardia. duced heart block and implanted electro- Ao, ; CS, coronary sinus; MBF, magnetic flowmeters (Pitt and Gregg, I968). myocardial bloodflow. It was shown that as heart rate was increased by pacing, the cardiac output rose initially, Arterial and coronary sinus oxygen content but soon reached a plateau, and failed to in- have also been measured. This patient did not crease more with further increases in rate. In develop ischaemia as manifest by chest pain contrast, it is seen that coronary blood flow or electrocardiographic change during the continues to rise as the heart rate is increased period of tachycardia and the expected rise in by the pacemaker. This progressive rise in myocardial blood flow occurred. It was coronary flow which is linked to heart rate anticipated that a patient who developed http://heart.bmj.com/ reflects the increase in myocardial oxygen ischaemia would have a rise in myocardial consumption which is associated with tachy- blood flow of less magnitude. cardia. These observations suggested that a The data from 28 patient studies similar to similar technique might be applied in clinical that shown in Fig. I2 are summarized in Fig. investigation to show the inability of patients I3 (Conti et al., I970). Fourteen of the 28 with ischaemic heart disease to increase patients developed ischaemia during pacing myocardial blood flow in proportion to the as manifest by chest pain or electrocardio- increased myocardial oxygen consumption graphic change. Prepacing values are plotted on September 29, 2021 by guest. Protected copyright. required by the tachycardia. on the horizontal axis and values obtained We used the xenon method to study the during pacing are plotted vertically. The response of myocardial blood flow to pacing- solid symbols represent patients who exhibited induced tachycardia in patients (Ross et al., an ischaemic response, and the open symbols I964; Conti et al., 1970). A saline solution of those who did not. The results were not those radioactive xenon is injected through the that were anticipated because a larger increase arteriographic catheter into the coronary in myocardial blood flow was recorded in the artery, and after injection the disappearance patients with an ischaemic response. The of radioactivity from the heart is monitored by average increase in the nonischaemic group a scintillation counter positioned over the was I2 ml./min. per ioo g. while that in the praecordium. The rate of disappearance of ischaemic group was 25 ml./min. per ioo g. radioactivity is proportional to the blood flow The difference between the two groups was to the region into which the gas has diffused. statistically significant at the S per cent level. The larger the flow, the steeper the dis- This response was the opposite of that which appearance curve. was anticipated and a number of explanations The results of a single experiment are for this set of observations can be offered. shown in Fig. I2 to illustrate the experimental One possible explanation is that the area of procedure. Myocardial blood flow has been ischaemic myocardium is relatively small measured by xenon disappearance before, compared to the entire mass of myocardium during, and after pacing-induced tachycardia. in which flow is measured by the xenon wash- Br Heart J: first published as 10.1136/hrt.33.2.173 on 1 March 1971. Downloaded from Pathophysiology of coronary circulation i8I

Myocardial Blood Flow angina pectoris led to a series of experiments 150 - lw in which the kallikrein system was studied in patients during pacing-induced myocardial ischaemia. This was a collaborative effort with the blood samples being collected during A /, pacing studies, identical to those previously ,'A described, performed at The Johns Hopkins 100 *0S& ,* Hospital by Drs. Pitt and Conti and the * 0t , kallikrein assays being performed by Drs. Colman and Mason at the Massachusetts General Hospital (Pitt et al., I969). ,,'0 O ' 0 The operation of the kallikrein system of -* plasma is outlined in Fig. 14. Bradykinin is 50 the pain-producing substance which is also a 0 -. vasodilator and it is the end-product of a reaction which is initiated by Factor XII or 50 K.O150 the Hageman Factor. As a result of activation, Control (ml./min. / 100g.) the concentration of kallikreinogen in the FIG. I3 Myocardial bloodflow response to serum falls. It is kallekreinogen which is pacing-induced tachycardia in 28 patients. measured and, therefore, a decrease in the Solid symbols identify patients with an concentration of this substance is indicative ischaemic response to pacing as manifested by of activation of the system. chest pain or electrocardiographic change. The results of kallikreinogen assays on Open symbols identify patients who had samples of blood collected from the coronary neither manifestation of ischaemia. sinus and aorta of 17 patients before, during, and after right atrial pacing are shown in Fig. I5. The values obtained at rest are plotted on out. The flow in the normal, nonischaemic the horizontal axis and those obtained during area is increased because it has to do more pacing are shown on the vertical axis. It must 'work to compensate for the dysfunction of the be remembered that a decrease in kalli- ischaemic area and hence its oxygen con- kreinogen indicates that the system has been sumption and flow are increased (Rees and activated. Patients who developed ischaemia http://heart.bmj.com/ Redding, I969). An alternative or perhaps an as manifested by anginal pain or electro- additional explanation would be the liberation cardiographic change are indicated by solid of a substance from the ischaemic tissue figures. It is noteworthy that no patient which produced dilatation in the surrounding showed activation of the system in the absence areas. The same substance might produce pain and hyperaemia. This might well be the of manifestations of ischaemia. All values in 'P' substance with which Thomas Lewis was

concerned (I932). More recent work with FIG. I4 Schema of human plasma on September 29, 2021 by guest. Protected copyright. vasoactive substances in ischaemia has led to kallikrein enzyme system (after Sherry). the suggestion by Berne that adenosine may (From Pitt et al., 1969.) be liberated from ischaemic tissue and serve SCHEMA OF HUMAN PLASMA as a powerful vasodilator (Rubio and Berne, I969). Another powerful vasoactive substance KALLIKREIN ENZYME SYSTEM is bradykinin which has been shown to be a coronary vasodilator and, under other circum- KALLIKREINOGEN (PREKALLIKREIN) -,,stances, to produce pain (Maxwell, Elliott, (Enzyme Precursor) and Kneebone, I962; Armstrong et al., 1954). These two facts suggested that bradykinin might play a role in the haemodynamic FACTOR XII response to myocardial ischaemia and, indeed, KINI NOGEN (Hagemon Factor) KALLIIKREIN INHIBITOR wight be the substance responsible for the (Plasma Substrate) I ischaemic pain, the search for which was initiated by Thomas Lewis. < KALLIKREIN > "I%,. ~~(Protoolytic Enzymeol Vasoactive substances - the kallikrein and Esterase) system 8~~~~~ ~(rtoyi Enym These considerations of the possible role of BRADYKININ INACTIVE1bCOMPLEX the kallikrein system and bradykinin in (Vasoactive Peptide) Br Heart J: first published as 10.1136/hrt.33.2.173 on 1 March 1971. Downloaded from i82 Richard S. Ross

Kallikreinog2en A words, but I would like to suggest trans- 150- A myocardial blood flow distribution in the microcirculation as another To IS Non-ischatmic 0 /,w' possibility. lschaemic A direct attention to this area I 0 your important now to some animal ,,,8< 0 would like present experi- ments was ao in which the microcirculation ffi 100- A ,o' studied by radioactive microspheres. There is E as yet no method whereby similar observa- £ tions can be made in man, but it seems likely 21: that the distribution of blood across the myo- < cardium is important in man both in health 50 and in the presence of coronary atherosclero- sis. Therefore, it is appropriate to include a AA A A discussion of the observations of Drs. Pitt, A Fortuin, and Becker, which may possibly lead 0 A * * the way for future investigation (Fortuin et al., 0. 50 Rest. ,uM TAME Hy d./ml. plasma/hour I969; Becker, Fortuin, and Pitt, 197I). The radioactive microsphere method for FIG. 15 Activation of thd kallikrein enzyme the study of the myocardial circulation is out- system in response to pacinAg-induced tachy- lined in Fig. i6. Radioactive microspheres cardia. I5 ,um in diameter are labelled with radioactive material, and a suspension of the radioactive the nonischaemic group remained in the microspheres is injected through a catheter normnal range. Eleven ]patients developed into the left atrium of the experimental ischaemia with pacing, anLd in 7 of these the animal. The microspheres are distributed kallikrein system was activrated as indicated by throughout the body in accordance with the a fall in the kallikreinogen concentration. In 4 distribution of the blood flow and by virtue of patients with ischaemic mianifestations which their size become wedged in precapillary were identical to those iin the other 7, no vessels throughout the body. The number of activation occurred. Thes4e 4 patients without spheres is small relative to the number of

activation had pain ancd, therefore, it is precapillary vessels in the vascular bed, and http://heart.bmj.com/ difficult to attribute the Ipain to bradykinin. there are no haemodynamic consequences of Myocardial blood flow wais measured in only sphere injection. The most sensitive indicator 3 of the patients with kallikrein activation and of the capacity of the vascular bed to dilate is raised values were obtairied in all of these. the magnitude of the reactive hyperaemic There was no significant difference between response and it can be shown that this the concentrations of kallULkreinogen in aorta and coronary sinus, so:it is impossible to FIG. i6 Diagrammatic representation of

localize the activation in on September 29, 2021 by guest. Protected copyright. not always present in ischaemiaheia kallikrein*kallikrein microsphere methodfor determnination of activation never occurred lInin 1LS HESCUL>C. I 11LC regional myocardial bloodflow. significance of these findirngs is unknown but the role of this system in the response to ischaemia deserves furtheir investigation.

Myocardial microcirculation I would like to turn now to the third phase of the lecture and discuss the possible role of the microcirculation and tramnsmyocardial dis- tribution of blood flow in tthe pathophysiology of ischaemic heart disea;se. Thomas Lewis said, and I quote, 'It appeaars almost necessary Desc. Circ. to assume that the strict relation between pain and the energy expended is broken by some factor of interference and the factor in mind is an inconstant state of tUhe coronary vessels' (Lewis, 1932). Thomas Lewis was undoubtedly thinking of coronary spasm whein he wrote these Br Heart J: first published as 10.1136/hrt.33.2.173 on 1 March 1971. Downloaded from Pathophysiology of coronary circulation 183

response is not blunted by repeated injections to the area of the anterior descending (circ/ of microspheres. desc = o98). There is, however, a significant At the conclusion of the experiment the difference between endocardial and epicardial animal is killed and samples of myocar- blood flow in the circumflex region of the left dium are removed, weighed, and the radio- ventricle with a significantly greater blood activity determined. This radioactivity is flow to the (circ endo/epi= expressed as counts per unit weight of myo- I*I7). ' cardium and this value for one region of the The results ofexperiments designed to show myocardium compared to a similar value for the effects of ischaemia on microsphere dis- another region. The ratio of counts per tribution and hence blood flow are presented gramme from one region to a comparable in Fig. i8. An injection of microspheres was value from another region reflects the ratio of made before and 5 minutes after acute blood flow of the two regions. In the example occlusion of the circumflex coronary artery by in Fig. i6, the ratio of blood flow in the area a snare. Analysis revealed that there was a perfused by the anterior descending coronary decrease in the circumflex descends ratio from artery to that in the area perfused by the I.00 tO 022 reflecting the ischaemia in the circumflex would be i. It is also possible to area of circumflex perfusion. Of more slice the myocardium parallel to the epicardial surface and measure flow in the endocardial and epicardial portions separately. In the DESC. example in Fig. i6, the ratio of flow in the endocardium to that in the epicardium would be 4:3. An essential feature of the method is the fact that spheres can be labelled with different isotopes and the isotopes measured separately. Thus, it is possible to obtain IS ,um micro- spheres labelled with three different isotopes. CIRC DESC ENDO CIRC ENDO ,.An injection of spheres labelled with isotope DESC EPI EPI No. i is made, and then an intervention can be CONTROL 1.00 0.99 1.13

. carried out after which an injection of spheres http://heart.bmj.com/ labelled with isotope No. 2 will be made. If OCCLUSION 0.19* 1.00 0.85* necessary, a third injection with isotope No. 3 OCCLUSION 0.22 1.03 0.88 can also be made. After death, differential counting for the three isotopes is carried out *p<0.05 to obtain three different sets of flow measure- FIG. I8 Effect of ischaemia on myocardial ments in relation to the experimental inter- bloodflow distribution in 7 anaesthetized dogs Fvention. as measured by microspheres. (From B. Pitt, The result of a typical experiment showing L. Becker, and N. J. Fortuin, to be published.) .the distribution of microspheres, and hence on September 29, 2021 by guest. Protected copyright. blood flow, are shown in Fig. I7. It is apparent FIG. I9 Effect of nitroglycerin on the that the flow to the area perfused by the myocardial blood flow distribution in ischaemia circumflex coronary artery is equal to the flow in zi anaesthetized dogs.

FIG. I7 Myocardial bloodflow distribution DESC zn 28 anaesthetized dogs measured by micro- ,spheres.

CIRC DESC ENDO CIRC ENDO DESC EPI EPI CONTROL 0.98 1.06 1.21 OCCLUSION 0.19* 1.05 0.84* OCCLUSION and CI RC DESC ENDO CIRC ENDO 0.22 1. 1 6* 1.01* DESC EPI EPI NITROGLYCERIN NORMAL 0.98 1.04 1.17 *p<0.05 Br Heart J: first published as 10.1136/hrt.33.2.173 on 1 March 1971. Downloaded from x84 Richard S. Ross interest, however, is the decrease in the endo/ Conti, C. R., Pitt, B., Gundel, W. D., Friesinger, G. C., and Ross, R. S. (I970). Myocardial blood flow in epi ratio in the ischaemic area indicating that pacing-induced angina. Circulation, 42, 8x5. the ischaemia is most severe in the endocardial Fortuin, N. J., Kaihara, S., Becker, L., and Pitt, B. portions of the myocardium. This finding that (I969). Regional myocardial blood flow in the dog ischaemia is most severe in the endocardium is studied with radioactive microspheres. Cardio- vascular Research. In the press. consistent with the clinical observation which Friesinger, G. C., Conti, C. R., and Pitt, B. (I967). indicates that the subendocardial regions are Observations on left ventricular pressure during most vulnerable to ischaemia during exercise angina pectoris (abstract). Circulation, 36, Suppl. and in myocardial infarction. II, I15. The studies have also added Johnson, J. B., Fairley, A., and Carter, C. (I959). microsphere Effects of sublingual nitroglycerin on pulmonary useful information concerning the mechanism arterial pressure in patients with left ventricular of action of nitroglycerin. The experiment failure. Annals of Internal Medicine, 50, 34. depicted in Fig. I9 is similar to that in Fig. i8 Lewis, T. (I9I5). Lectures on the Heart, p. 36. Paul B. but an injection of has been Hoeber, New York. microspheres - (I932). Pain in muscular . Archives of made after an occlusion which was preceded Internal Medicine, 49, 7I3. by the administration of nitroglycerin. Nitro- Maxwell, G. M., Elliott, R. B., and Kneebone, G. M. glycerin did not result in an increase in the (I962). Effects of bradykinin on systemic and circ/desc ratio and hence, there was no in- coronary vascular bed of the intact dog. Circulation Research, 10, 359. crease in total flow into the area of ischaemia Muller, O., and Rorvik, K. (1958). Haemodynamic distal to the occlusion. There was, however, consequences of coronary heart disease; with an increase in the endo/epi ratio in the observations during anginal pain and on the effect ischaemic area which indicates that the of nitroglycerine. British Heart3Journal, 20, 302. Parker, J. O., Ledwich, J. R., West, R. O., and Case, blood flow to the endocardium had been R. B. (I969). Reversible cardiac failure during improved. angina pectoris. Hemodynamic effects of atrial Much has been learned about the patho- pacing in . Circulation, 39, physiology of ischaemic heart disease since 745. Pitt, B., and Gregg, D. E. (I968). Coronary hemo- the time of Sir Thomas Lewis, and the rate at dynamic effects of increasing ventricular rate in the which new information is being acquired is unanesthetized dog. Circulation Research, 22, 753. increasing. Emphasis has shifted from haemo- - , Mason, J., Conti, C. R., and Colman, R. W. dynamics to considerations of vasoactive (I969). Observations of the plasma kallikrein system during myocardial ischemia. Transactions substances and myocardial blood flow distri- of the Association of American Physicians, 82, 98. http://heart.bmj.com/ bution. Many questions first posed by Sir Rees, J. R., and Redding, V. J. (I969). Increase in Thomas Lewis still remained unanswered myocardial collateral capacity following drug- and foremost among these is the question induced coronary vasodilatation. American Heart the cause of ischaemic Journal, 78, 224. concerning pain. Ross, R. S., Schwartz, N., Gaertner, R. A., and Friesinger, G. C. (I962). Electrocardiographic and The author thanks Drs. G. C. Friesinger, B. Pitt, hemodynamic observations during selective coron- C. R. Conti, N. J. Fortuin, L. Becker, and W. D. ary cineangiocardiography. Journal of Clinical Gundel for permission to include portions oftheir Investigation, 41, I395. work in this lecture. -, Ueda, K., Lichtlen, P. R., and Rees, J. R. (I964). on September 29, 2021 by guest. Protected copyright. Measurement of myocardial blood flow in animals and man by selective injection of radioactive inert gas into the coronary arteries. Circulation Research, 15, 28. References Rubio, R., and Berne, R. M. (I969). Release of Armstrong, D., Keele, C. A., Jepson, J. B., and adenosine by the normal myocardium in dogs and Stewart, J. W. (I954). Development of pain- its relationship to the regulation of coronary producing substance in human plasma. Nature resistance. Circulation Research, 25, 407. (London), I74, 79I. Sowton, G. E., Balcon, R., Cross, D., and Frick, M. H. Becker, L., Fortuin, N. J., and Pitt, B. (I97i). Effect of (I967). Measurement of the angina threshold using ischemia and anti-anginal drugs on the distribution atrial pacing. Cardiovascular Research, I, 301. of radioactive microspheres in the canine left ven- Wayne, E. J., and Laplace, L. B. (1933). Observations tricle. Circulation. In the press. on angina of effort. Clinical Science, I, I03.