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SERIAL ASSESSMENT OF DISORDERS OF LEFT VENTRICQAR FUNCTION

USING RADIONUCLIDE VENTRICQOGRAPHY

ANTHONY P. FREEMAN

A THESIS SUBMITTED FOR THE DEGREE OF

DOCTOR OF MEDICINE

OF

THE UNIVERSITY OF NEW SOUTH WALES

APRIL 1985 UNniERSITY OF N.S.W. 29SEPI986

BIOMEDICAL LIBRARY STATEMENT OF ORIGINAUTY OF STUDY

"I hereby declare that this thesis is my own work and that, to the best of my knowledge and belief, it contains no material previously published or written by another person nor material which to a substantial extent has been accepted for the award of any other degree or diploma of a university or other institute of higher learning, except where due acknowledgement is made in the text of the thesis".

ANTHONY PHILIP FREEMAN

FRACP INDEX

Acknowledgements

Published Work Arising from Study

Summary

Chapter 1 PROLOGUE 1

Chapter 2 HISTORICAL PERSPECTIVES & CURRENT CONTROVERSIES 5 Radionuclide Ventriculography

Myocardial Revascularisation

Ventricular Aneurysmectomy

Iron Chelation Therapy in Thalassaemia Major

VALIDATION OF METHODOLOGY 27

Chapter 3 EQUIPMENT 28 Camera Characteristics

Computer System

Exercise Bicycle

Chapter 4 GAMMA CAMERA DATA ACQUISITION 38

Design of Cardiac Phantom

Choice of Frame Duration

Chapter 5 RED CELL LABELLING 48

Red Blood Cell Labelling with Tc99m Comparison In Vitro versus In Vivo Technique Chapter 6 LEFT VENTRICULAR EJECTION FRACTION 56

Comparison with Contrast Angiography

Reproducibility

Inter-observer Error

Intra-observer Error

Comparison between two Analysis Programmes

Normal Values in Children and Adults

Chapter 7 EXERCISE LEFT VENTRICULAR FUNCTION 82

Comparison of Supine Bicycle with Erect Treadmill Exercise

Chapter 8 VENTRICULAR VOLUMES 94

Cardiac Phantom Study

Human Studies

Chapter 9 REGIONAL WALL MOTION ASSESSMENT 123 Comparison Of Radionuclide Angiography with Contrast

Angiography and Two-Dimensional Echocardiography

Chapter 10 SUMMARY OF METHODOLOGY 145

CLINICAL APPLICATIONS 148

Chapter 11 MYOCARDIAL REVASCULARISA TION 149

Long Term Results of Bypass Grafting in Patients with

Severely Depressed Left Ventricular Performance Chapter 12 MYOCARDIAL VIABILITY 173

Effect of Revascularisation on Resting Left Ventricular

Wall Motion Abnormalities

Prediction of Improvement in Left Ventricular Wall Motion

Chapter 13 LEFT VENTRICULAR ANEURYSMECTOMY 199

Effects on Left Ventricular Function

Preoperative Determinants of Clinical Outcome

Chapter 14 IRON OVERLOAD AND THE HEART 220

Identification of Subclinical Abnormalities of Ventricular Function

Effects of Iron Chelation Therapy on Left Ventricular Function

Chapter 15 EPILOGUE 253

REFERENCES 257 ACKNOWLEDGEMENTS

Associate Professor I. Provan C. Murray, Director of the Department of

Nuclear Medicine at the Prince of Wales Hospital, was my supervisor during this

project. At all times he provided the utmost in support, encouragement and

direction, with continued enthusiasm throughout the four years spent in

performing these studies and preparing this manuscript. My interest in this

subject was initiated by Professor Ralph Blacket, who always showed interest in

the project as the Director of the Department of Medicine.

This whole study would not have been possible without the co-operation of

the members of the Division of Cardiovascular Medicine at the Prince Henry and

Prince of Wales Hospitals who permitted me to study their patients and provided

unfailing co-operation. I am indebted to many of them for their interest and

helpful discussion and in particular to Dr. Robert Giles who was of enormous

assistance for his ongoing interest and guidance, not only in relation to cardiological aspects but also his readiness to share his experience in nuclear cardiology. In addition I would like to thank Dr. Warren Walsh who similarly provided continuing guidance and support.

I would also like to acknowledge the co-operation of all the Nuclear

Medicine technicians in the Department, particularly in relation to patient care

and most especially to Mrs. Jenny Dixon, Chief Technologist, and Miss Penny

Steele, Senior Technologist in the Computer Section. A member of the

Department of Medical Physics, Mrs Brenda Walker, was always available to provide advice about relevant aspects of the physical principles behind many of the techniques used. This period of research would not have been possible without provision of a postgraduate research scholarship from The National Heart Foundation of

Australia. This work was greatly facilitated by a computer system donated by the Raymond E. Purves Foundation.

Finally, without the encouragement, support and patience of my wife,

Kerry, I would not have completed this thesis. PUBLISHED WORK ARISING FROM THESE STUDIES

Freeman, A.P ., Giles, R. W., Mcilveen, B., Murray, I.P .C.: Radionuclide

ejection fraction:. comparison of response to treadmill and bicycle

exercise. Eur. J. Nucl. Med. 7:393-396;1982.

Freeman, Z.S., Freeman, A.P.: Coronary bypass surgery:A re-appraisal.

Aust. N.Z. J. Med. 309-320; 1982.

Freeman, A.P., Walsh, W.F., Giles, R. W., Choy, D., Murray, I.P.C.:

Early left ventricular dysfunction in thalassaemia major:potential efficacy

of intensive chelation therapy. Ann. Intern. Med. 99. 450-454;1983.

Freeman, A.P., Walsh, W.F., Giles, R.W., Choy, D., Murray, I.P.C.:

Early and long term results of myocardial revascularisation in patients with

severely depressed left ventricular performance. Am J Cardia! 54. 749-

754; 1984.

Freeman, A.P., Giles, .R.W., Walsh, W.F., Wilcken, D.t:.L., Fisher, R.,

Murray, I.P.C;: Regional left ventricular wall motion assessment:

Comparison of 2-dimensional echocardiography and radionuclide angiography with contrast angiography in healed myocardial infarction.

Am J Cardiel In Press July, 1985.

Morgan, A.P., Freeman, A.P., Mclean,R.G., Jarvie B.H., Giles R. W.: Late

cardiac,thyroid and pulmonary sequelae of mantle radiotherapy for

Hodgkin's disease. Inter J Radial Oneal Bioi Phys. In Press.

ABSTRACTS

Freeman A.P., Choy D. Wright J.S., Murray I.P., Walsh W.F.:

Does coronary bypass surgery or aneurysmectomy improve cardiac

performance in patients with severe left ventricular dysfunction. Aust.

N.Z. J. Med. 11:491;1981.

Freeman A.P., Choy D., Murray I.P., Berdoukas V., Walsh W.F.:

Unsuspected cardiac dysfunction in patients with thalassaemia. Aust. N.Z.

J. Med. 11: 491; 1981.

Murray, I.P .C., Giles, R., Mcilveen, S.M., Freeman, A., Molk, G.M.,

Freeman, J.M.: The radionuclide ejection fraction response to stress: A

comparison of three methods. Aust. N.Z. J. Med., 11:438; 1981. Choy, D., Hosch!, R., Freeman, A., Murray, I.P .C., Berdoukas, Y., Walsh,

W., Molk, G., Dixon, J.: Left ventricular function and kidney /bone ratio in

patients with congenital transfusion dependent anaemias and chronic iron

overload. Aust. N.Z. J. Med. 11, 581; 1981.

Freeman, A.P., Walsh, W.F., Hickey, A., MacArthur, C., Choy, D., Murray,

I.P.C., Wilcken, D.E.L.: Comparative assessment of regional wall motion I by two dimensional echocardiography, radionuclide angiography and

contrast ventriculography. Aust. N.Z. J. Med. 12:309; 1982.

Freeman, A.P., Walsh, W. F., Giles, R.W., Choy, D., Murray, I.P.C.:

Thallium imaging predicts improvement in resting left ventricular wall motion abnormalities following revascularisation. Aust. N.Z. J. Med.

13:416;1983.

Freeman, A.P ., Walsh, W. F., Giles, R. W., Murray, IPC.:Left ventricular aneurysm resection: determinants of clinical outcome. Aust. N.Z. J. Med.

14:5 92;1984

Bowman, L.K., Freeman, A.P ., Horton, D.A.,Newman, D.C., Wright, J.S.,

Walsh, W.F.: The volume overloaded heart : long tern, effects of valve replacement in the patient with depressed ventricular performance. Aust.N.Z. Med. 14: 592;1984 Freeman, A.P ., Giles, R. W., Berdoukas V., Walsh W., Murray IPC.: High dose chelation therapy reverses left ventricular dysfunction due to transfusional iron overload in patients with thalassemia major. JACC.5,2:

445;1985.

Walker, B.M., Freeman, A.P., Steele P., Giles R. W., Murray, I.P.C.

Comparison of three non-geometric methods of radionuclide estimation of left ventricular volumes Aust. N.Z. J. Med. In Press. ABSTI::;;ACT

In this th~·r:;ir.;., gated equilibrium radionucl ide angiography was

evaluated and applied to assess the effects of therapy. In ttr.IO discrete patient groups.

A correlation of 0.93 was obtained for measurement of left ventricular ejection fraction (LVEF) when compared with contrast

Measurement of LVEF was reproducible {+/-· 1 .3X

I :;:;;[I) " with low interobserver +/- 1.0% ISD), and val"iability <+ 1- 1 .. o:%; r ::::o > • Nol"mal ranges of LVEF at rest· and duPing semi-supine bicycle exerc1se wel"e established in children and adult volunteers. A valid measurement of ventricular volume was obtained when compared to contrast angiography r·=(l .. 91) using two methods. Agreement levels, sensitivity and specificity between radionucl ide angiography and con t l~ast angiography were calculated for assessment of Pegional wall motion in a group of patients with priol" myocardial infarction.

SURGERY AND DEPRESSED VENTRICULAR PERFORMANCEn ------

In patients with LVEF less than 40%. l"evasularisation did not

incpease Pesting LVEF but improved exercise LVEF. particularly in patients in whom exercise LVEF fell significanty pre-operatively.

Im; rovement of segmental LV function could be predicted ii:t•:•:ul~.::\ t eJ. y us.ing pr·e-oper·at ive Thallium =·•= int igl"'.::tphy.

Aneurysmectomy. performed for symptoms of heart failure. resulted

:1. in long term improvement in 50% of patients. Pre-operative endsystol ic volume and the size of the LV aneurysm were most

important predictors of clinical outcome.

CHELATION THERAPY AND THE IRON OVERLOADED HEART.

Twenty three ch~ldren with Thalassaemia MaJor and transfusion dependent anaemia were studied prospectively for 4 years to examine the effects of intensive sub-cutaneous infusions of desferrioxamine on LV function. Abnormalities of LV function were present in 18 <78%) prior to therapy. Despite the obligatory increase in iron load due to transfusion, with chelation. was a fall in serum ferritin levels each year. Annual serial assessment of LV function showed a progressive rise in rest1ng

LVEF and exercise LVEF. Of the 18 patients at the start of the study with abnormal LV performance. 5 continued to have abnormal

LV function. 2 died and 11 showed improvement. The 5 patients with normal LV function at the start of the study remained normal.

2 SUMMARY

The technique of gated equilibrium radionuclide angiography offered the potential to assess many parameters of left ventricular function serially, at rest and during exercise. In this study, the accuracy of the gated equlibrium technique was evaluated and applied in two discrete patient groups with abnormal LV function, exemplifying the use of the technique to assess the effects of therapy serially.

METHODOLOGY

Various parameters of LV function were evaluated using a cardiac phantom and in human subjects. A correlation of 0.93 was obtained using gated equilibrium angiography for measurement of left ventricular ejection fraction

(L VEF) when compared with contrast angiography. Measurement of L VEF was reproducible C:r1.3% 1SO) with low inter-observer (:1.0% 1SO) and intra-observer variability (:rl.O% 1SO). Normal ranges of LVEF at rest and during semi-supine bicycle exercise were established in children and adult volunteers. A valid measurement of ventricular volumes was obtained without (r=0.88) and with individualised (r=0.91) correction for photon attenuation when compared to contrast angiography. In patients with prior myocardial infarction, qualitative assessment of regional wall motion was evaluated and compared to bi-plane contrast angiography and 2-dimensional echocardiography. Agreement levels between radionuclide angiography and contrast angiography were 1-:gh and ranged from 91% in the antero-basal to 68% in the diaphragmatic segments. Sensitivity and specificity for the detection of abnormal segmental wall motion were calculated. SURGERY AND DEPRESSED VENTRICL.LAR PERFORMANCE

Following evaluation of the technique, gated equlibrium angiography was used

in various patient groups with coronary artery disease and depressed LV function,

to examine LV performance before and after cardiac surgery. In patients with

LVEF < 40%, revascularisation did not increase resting L VEF but improved

exercise LVEF, particularly in a sub-group of patients in whom exercise LVEF

fell significantly pre-operatively. Following surgery, these patients had an

improved long term prognosis. Improvement of resting segmental function

ocurred also in a sub-group of patients following revascularisation, and could be

predicted accurately using pre-operative Thallium scintigraphy.

Aneurysmectomy, however, performed for symptoms of heart failure in patients

without angina, resulted in long term clinical improvement in only 50% of

patients. Although in these patients resting LVEF did not improve significantly,

there was a significant reduction in segmental wall motion abnormalities. Pre­

operative end-systolic volume and the size of the LV aneurysm were the most important long term predictors of clinical outcome.

CHELATION THERAPY AND THE IRON OVERLOADED HEART

Twenty-three children with Thalassaemia Major and transfusion dependent anaemia were studied prospectively for 4 years to examine the effects of intensive subcutaneous infusions of desferrioxamine on LV function.

Aunormalities of LV function were present in 18 (78%) prior to therapy, particularly those that had received a heavy iron load from transfusion. Despite an obligatory increase in iron load due to transfusion, with chelation, there was a fall in serum ferritin levels each year, reflecting the adequacy of the chelation regime. Annual serial assessment of LV function using radionuclide angiography showed a progressive rise in resting LVEF and exercise LVEF. Of the 18 patients at the start of the study with abnormal LV performance, 5 continued to have abnormal LV function, 2 died and 11 showed improvement. The 5 patients with normal LV function at the start of the study remained normal throughout the study. - 1 -

CHAPTER 1

PROLOGUE

The technique of gated equilibrium angiography to measure left ventricular function is now established and plays a fundamental role in most cardiological centres for the non-invasive assessment of ventricular function. When the studies reported in this thesis began, the procedure had been applied to a variety of cardiac disorders but the emphasis in most clinical and research applications had been to examine the value of exercise equilibrium angiography in the evaluation of patients with chest pain. Some authors had examined the effect of various therapeutic measures designed to improve ventricular function but these studies had been largely restricted to evaluating changes in resting left ventricular ejection fraction in the assessment of the immediate response to therapy. It seemed probable that this technique had potential to assess cardiac status long term by serial measurements and that the estimation of parameters of ventricular function in addition to left ventricular ejection fraction might provide further crucial information.

Various difficulties with the procedure were apparent at this time and although the mee$'lurement of ejection fraction at rest had been well validated 'A :th contrast angiography, further work was necessary to assess the usefulness of the technique to measure ventricular volumes, assess regional wall motion and to evaluate exercise performance. In addition, at the start of this work, - 2-

computer programmes for processing of data in cardiac analysis differed from

centre to centre and numerous modifications of analysis methodology had been

advocated. These packages varied in the methods by which cardiac studies were

acquired, in the amount of observer intervention, in the techniques for edge

detection and background subtraction and in the types of image display. Little

work was available about the reproducibility, inter and intra-observer variability

of the technique, not only for the most commonly measured parameter, left

ventricular ejection fraction, but for assessment of regional wall motion,

ventricular volumes and exercise functional response. Various methods had been

proposed to label red cells with technetium 99m, a technical step critical for the

performance of the gated equilibrium technique. Careful evaluation of these

methods was necessary to provide information about the most efficient way to

label red cells to provide the best possible image quality.

It was the aim of this thesis to evaluate the gated equilibrium blood pool

technique for assessing various parameters of left ventricular function and compare it with other non-invasive and invasive techniques in both clinical and phantom studies. The technique was then applied to assess the effects of two quite different forms of therapy, using serial measurements of left ventricular function with the equilibrium radionuclide technique in patients with known cardiac disease. Two quite discrete, original patient groups were studied. They differed in that one required surgical intervention whereas the other exemplified long term medical therapeutic regimes. In neither had it been possible previously to assess the effect of therapy on left ventricular function due to the disadvantages of other methods of examining left ventricular function. It was hoped that these data would illustrate the use of the technique to provide - 3-

insights into prognosis. Thus it might be possible to utilise it as a means of

selecting patients for surgical or medical therapy and monitoring the effect of

such interventions.

The search for a favourable effect of revascularisation surgery on ventricular

function has interested many investigators. Most studies, including radionuclide studies, had focused on patients with normal or near normal left ventricular function. Although there were some early invasive haemodynamic data in patients with impaired left ventricular function, little information was available about the effects of revascularisation on the severely impaired left ventricle in patients with stable angina. In particular, it was uncertain' whether there were any pre-operative non-invasive methods of predicting those individuals most likely to derive a favourable effect on left ventricular function following revascularisation and thus possibly improve prognosis. Additionally, little information was available about the the efficacy of aneurysmectomy, also performed in patients with severely depressed left ventricular performance with symptoms of heart failure. It was unclear whether aneurysmectomy did improve left ventricular function and, if so, which, if any, were pre-operative predictors of long term clinical improvement following this operation.

The second group of patients chosen for study were children with transfusion dependent thalassaemia major. Children with this disorder had usually died in their latn teens and early twenties as a result of iron overload of the heart ""ith subsequent refractory cardiac failure or ar.rhythmias. In the first place it appeared important to ascertain wh~ther the impairment of ventricular function could be detected at an early stage, prior to clinical evidence of cardiac -4- disability. The atraumatic nature of the gated radionuclide technique made it ideal for such an investigation. More particularly, however, it also made it feasible to study serially, over several years, the response to current therapeutic approaches. Modern management of this disorder now involves not only optimal transfusion regimes but also chelation therapy from the time of diagnosis. However no information is available about the efficacy of this painful, expensive, tedious and time-consuming form of treatment on cardiac status and prognosis. Accordingly, it was considered important to ascertain whether the toxic effects of iron on the heart were reversible. -5-

CHAPTER 2

HISTORICAL PERSPECTIVES & CURRENT CONTROVERSIES

Interventions designed to improve left ventricular function have interested physicians for centuries. William Withering in his treatise on the use of fox­ glove extract to treat congestive cardiac failure was one of the first of the modern physicians to illustrate that cardiac function could be altered favourably.

Since that time, a wide variety of pharmacological and surgical interventions have been applied in an array of cardiac disorders with the aim of altering loading conditions and intrinsic contractility of the left ventricle to improve cardiac output. For a considerable period, bedside clinical judgement, and later electrocardiographic and radiologic techniques, were the only tools with which clinicians were able to assess these interventions. In the early 1950's, cardiac catheterisation revolutionised cardiology. This procedure provided accurate haemodynamic and angiographic information about systolic and diastolic function of the left ventricle, hitherto unknown in living man. This invasive technique provided data for the definitive standards against which any non-invasive procedure could be judged. Many non-invasive techniques used to assess left ventricular function have been examined and validated. Phonocardiography, apex cardiography, and systolic time intervals have been used to assess physiological and pharmacological interventions. These, however, are essentially methods of displaying the findings of clinical examination and - 6- largely document that which a skilful observer could appreciate from a good physical examination. Echocardiography and radionuclide techniques are newer non-invasive techniques that have the advantage of not causing haemodynamic changes, such as occur, with iodinated contrast agents. Using echocardiography and radionuclide techniques, serial studies can be performed at intervals that could not be performed without a considerable radiation burden of repeated cineangiography at cardiac catheterisation. In particular, the radionuclide methods provide measurements of left ventricular ejection fraction and ventricular volumes without assumptions about chamber geometry inherent in cineangiographic and echocardiographic techniques. In addition, the radionuclide technique, unlike two-dimensional echocardiography, can be performed easqy during exercise, is technically feasible in almost all patients and is largely independent of the skill of the technician performing the studies.

RADIONUCLIDE VENTRICULOGRAPHY

TECHNIQUES:

The use of radioactive tracers to study the cardiovascular system was first reported by Blumgart and Weiss in 1927. They used injected radon gas and a modified cloud chamber as a detector to measure circulation times in man.

Twenty years later, Prinzmetal et al (1948 and 1949) described the characteristics of the first pass radiocardiogram in normal subjects anrl in patients with congenital heart disease, using !131 sodium-iodide and a Geiger­

Muller counter. Donato et al (1962) applied quantitative analyses to the radiocardiogram obtained with a shielded collimation scintillation - 7-

probe and evaluated this method in a broad spectrum of patients with cardiac

and pulmonary disease. Following a direct injection of technetium 99m

pertechnetate into a dog's left ventricle, Mullins et al (1968) used a triggering signal to obtain an isolated image of the heart in one phase of the cardiac cycle.

The nuclear data were video taped from an Anger camera's oscilloscope screen while the audio channel recorded the R-wave signal. On replay of the video tape, the film recorded was gated using the R-wave of the electrocardiogram and an end-diastolic image of the left ventricle was recorded. This end-diastolic volume calculated from the outline of the chamber, correlated against the volume of the left ventricle measured by contrast angiography. 5 trauss et al (

I"971) described the gated equilibrium technique for the first time in man and fundamentally distinguished this technique from the first transit bolus method.

In this description imaging was performed without the aid of a computer, after equilibration of an intravascular tracer, technetium 99m labelled albumin.

Images of the central circulation were acquired during several hundred cardiac cycles at end-diastole and end-systole, as determined from the electrocardiogram. Recording required 20 minutes per image and results were of relatively poor quality. Images were recorded initially in the right anterior oblique projection only. In this projection there is a maximum supra-imposition of the right ventricular silhouette on that of the left and there is a large gap between the collimator and the left ventricle, reducing the resolution of left ventricular borders. Analysis of the images were completed by drawing the borders of trr left ventricle from a life-size projection and applying the area length formulation of Sandler and Dodge (1968) to calculate the volume of the chamber at end-diastole and end-systole. In addition to quantification of left ventricular ejection fraction and volumes, Zaret et al (1971) was able to apply - 8- the technique to define regional wall motion abnormalities by percentage changes in hemi-axes.

With the application of computer technology to this technique, the entire cardiac .cycle was examined. Instead of forming images at end-diastole and end­ systole, each phase of the cardiac cycle was recorded into the computer memory at pre-determined time intervals. The gating concept of synchronising data over many heart cycles to form composite images using the R-wave of the electrocardiogram to signal the start of each cardiac cycle basically was unchanged. This signal was used to start and stop the scintillation camera recording, in order to assemble identically phased brief recording ·periods, either continuously throughout successive cardiac cycles, or for discrete periods such as end-diastole and end-systole. Since insufficient counts are available during a single cardiac cycle, multiple cycles must be recorded, the number depending on the heart rate, amount of radioactivity administered, the detector characteristics, and desired number of counts per selected time period.

Typically, from 10,000 to 20,000 counts in each 0.04 second gated period can be accumulated in approximately five minutes and are sufficient for most purposes.

All counts accumulated for identically phased time periods throughout multiple cycles are integrated and may be examined in the form of discrete images on photographic film or obtained as a separate recording in a digital memory for later display. Variation exists between laboratories as to the duration and number of samples obtained throughout a given cardiac cycle.

Labelling red cells with technetium 99m provided a means of recording data with a higher target to background ratio than was obtained with the earlier - 9 -

blood pool labelling used initially by Donato (1971), i.e. technetium 99m bound to

albumin. Labelling of red cells with technetium 99m has been shown to provide a

greater labelling efficiency than technetium 99m bound to albumin (Thrall et al

1978). Although red cell labelling can be performed either in vivo or in vitro

(Smith et al 1979) , the first step includes pre-tinning of the red cells with

stannous ion. It is still uncertain whether the in vivo or in vitro method of

labelled cells is more efficacious (Hegge et al1978).

The collimator-object relationship was optimised by selecting high resolution collimators for rest studies and positioning the heart as close to the collimator as possible. Riga et al (1974) was the first to recognise the value of alternative projections necessary to visualise residual contractile segments in patients with coronary artery disease and left ventricular aneurysms by adding the left anterior oblique view. Modifications in positioning the camera head or the patient have led to the ability to examine most of the left ventricle.

Nowadays, data are usually recorded in the anterior view to image the right • atrium, tricuspid valve plane, right ventricle, pulmonary artery outflow tract and the antero-lateral and apical portions of the left ventricle; the left anterior oblique view is optimal for the examination of the septum and provides the best separation of the right and left ventricles; the posterior oblique view and left lateral were used to examine the long-axis of the left ventricle and allows examination of the inferior wall without over lying right ventricular activity. It is generally acc~pted that the combination of these views provides accurate assessment of impaired regional wall motion, but documentation of this accuracy is lacking. Alongside these advances, are improvements in camera resolution and count rate capacity. - 10-

The pioneers of the gated equilibrium technique calculated left ventricular ejection fraction and regional wall motion changes without the aid of a computer. Nowadays, sophisticated computer programmes are available for the measurement of many systolic and diastolic parameters of ventricular function.

Of these parameters, only the measurement of left ventricular ejection fraction has been adequately evaluated and accepted in most cardiological institutions.

There is still controversy about the accuracy of quantitating regional left ventricular function, ventricular volumes and various aspects related to filling and emptying rates of the left ventricle.

Calculation of left ventricular ejection fraction is performed only after a region of interest is defined over the left ventricle from which a time-activity curve is constructed. Selection of this region of interest is performed differently by various investigators. Borer and co-workers (1977 a) selected a region of interest over the end-diastolic frame and used this region unchanged over the entire cardiac cycle. Burow et al (1977) selected a region of interest over the end-diastolic frame and used a computer to make this region contract, as the left ventricle contracted. Sorenson et al (1979) used Burow's approach but processed the data through a resolution recovery algorithm to assist the computer in defining the edges of the contracting left ventricle. Marshall et al

(1981) used a manually determined region of interest for each frame of the cardiac cycle. The correct methods for assigning this region of interest to calculate left ventricular function is therefore controversial. Sorenson et al

(1979) compared the accuracy of left ventricular ejection fraction calculation using three methods of region of interest selection with angiography and showed that although all correlated well with angiography and were reproducible, the use -11- of a fixed region of interest under-estimated ejection fraction, whereas a variable region of interest accurately quantitated ejection fraction.

Subsequently, Sorenson et al (1981) showed that an apparently abnormal response of the ejection fraction with exercise may be obtained in normal subjects, solely due to region of interest selection method. This false-positive response could be resolved by analysis using a variable region of interest method. This conflict between methods of analysis is most noticeable for subjects with normal or high­ normal resting ejection fractions.

Slutsky et al (1980 a) assigned five different background images to determine the most appropriate method of background subjection for calculation of ejection fraction. They concluded that the combination of a variable region of interest with an automatic computer assigned background region of interest outside the left border of the ventricle at end-systole provided the best correlation with contrast angiography in association with modest inter- and intra-observer and serial variability. This therefore, now appears to be the accepted choice of the site of background designation for most cardiac analysis programmes, usually located a few pixels widths outside the systolic frame near the apex or lateral wall of the left ventricle.

These technical advances were accompanied by major advances in application. Radionuclide ventriculography can detect changes in regional and/or global ventr;~ular function from a baseline recording while the patient is at rest. With the gated equilibrium blood pool technique, measures can be made following multiple interventions without additional tracer injection. Exercise testing is the most common intervention used for diagnosis and - 12- assessment of cardiac diseases. Exercise studies using the equilibrium technique may be performed during supine, or semi-erect cycling, which has the advantage of a stable chest position against the camera for imaging, but the disadvantage of a clumsy and unaccustomed form of exercise. Walking on a treadmill is easier for the subject but is more difficult to maintain stability for imaging despite achieving a greater aerobic capacity during treadmill exercise. Ventricular volumes are altered by posture, (Wilson 1962) and it appears that the ultimate ejection fraction response to maximal exercise in normals and in patients with coronary artery disease may be altered significantly by posture (Poliner et al

1980). It is uncertain whether imaging immediately following treadmill exercise will provide the same information as imaging during bicycle exercise.

Other stresses such as isometric hand-grip (Peter and Jones 1980), intravenous catecholamine stimulation, and atrial pacing do not require patient co-operation to the same degree but have been applied for specific reasons rather than for routine clinical application (Slutsky et al 1981). Using gated blood pool imaging, Wainright et al (1979) demonstrated that the left ventricular ejection fraction falls during cold pressor testing and suggested its use for diagnostic evaluation of patients with suspected coronary artery disease. The cold pressor test involves the sympathetic response associated with a reflex increase in blood pressure. In certain patients it provokes increases in coronary vascular resistance and focal coronary artery spasm. It is less accurate than exercise and because of greater discomfort to the patient is difficult to repeat.

The gated equilibrium technique is utilised now in many pharmacological studies, either alone, or, in combination with measurement of central -13-

haemodynamics. Some reagents that have been used thus far include the

vasodilator nitroglycerine (Ritchie et al 1979), inotropic agents such as Digitalis

(Morrison et al1980) and Amrinone (Wynne et al1980), afterload reducing agents

such as Prazosin (Goldman et al 1980), and beta blockers such as Propranolol

(Marshall et al1981).

CLINICAL APPLICATION

Understanding the left ventricular response to exercise has led to the use of the gated equilibrium technique in the functional assessment of abnormal exercise reserve in a wide spectrum of patients. Evaluation of the ambulatory patient with chest pain represents the broadest application of cardiac radionuclide studies to date. Many studies from data derived from both first pass and equilibrium studies have attempted to define the accuracy of radionuclide ventriculographic techniques in diagnosing coronary artery disease.

This has been extensively reviewed by Slutsky (1981), and Berger and Zaret

(1981). The key initial data about changes in ejection fraction in patients with coronary artery disease were published by Borer et al in 1977 b. Using supine bicycle exercise, this group reported that in 11 patients with coronary artery disease and normal wall motion at rest, left ventricular ejection fraction fell in ten patients and remained unchanged in one at peak bicycle exercise. In all patients there was evidence of new regional left ventricular dysfunction during exercise. · In contrart, all normal subjects increased their left ventricular ejection fraction with exercise and had no regional dysfunction. Subsequently, using the same technique, Borer et al in 1979, in a larger population of 63 patients with coronary artery disease and 64 normals, demonstrated 94% of -14- patients with coronary artery disease developed regional wall motion abnormalities during stress. In controls, left ventricular ejection fraction rose with exercise while in 89% of those with coronary artery disease, left ventricular ejection fraction fell or failed to rise. Similarly Jengo et al (1979), using the first pass technique, showed that 8 control subjects had an increase in left ventricular ejection fraction and normal regional wall motion with exercise, and all patients with coronary artery disease had a failure to rise or a fall in left ventricular ejection fraction with exercise, associated with abnormal wall motion with exercise. Many centres now use the equilibrium technique for diagnosis of coronary artery disease, and Berger and Zaret (1981) stated "on the basis of results on 427 patients described in the literature from 1978 to 1980, the sensitivity of exercise radionuclide angiocardiography for the detection of coronary artery disease was 87% with the specificity of 92%." Subsequently,

Rosanzky et al (1983) more recently failed to confirm the high specificity of the left ventricular ejection fraction response for the diagnosis of coronary artery disease. Possible explanations for these controversial results include the variable effects of therapy, the incidence of coronary artery disease in the populations studied, and the categorisation of patients by contrast angiography on the basis of morphological coronary artery lesions which may not correspond to segments with exercise induced ischaemi1:1,. Variability of stress protocols, exercise position and intensity of exercise leads to a variability in the response to exercise studies (Foster et al 1983). Brady et al (1980 a) using the equilibrium technique, demonstrated the necessity to achieve maximal exercise to obtain a high sensitivity for the diagnosis of coronary artery disease. In addition, Berger et al (1979) demonstrated that using the exercise left ventricular ejection fraction response as a test for detection of coronary artery disease was most sensitive in patients in whom stress was terminated with - 15- electrocardiographic evidence of ischaemia as opposed to fatigue.

It is unknown whether maximum exercise is required to provide the greatest information about functional impairment in patients with other cardiac disorders. A failure of left ventricular ejection fraction to rise with exercise can also be due to primary muscle disease rather than to myocardial ischaemia, as shown by Forfar et al (1982) in patients with hypothyroidism, by Wainright et al (1979) in patients with cardiomyopathy, and by Borer et al (1978) in patients with aortic regurgitation. However, the enthusiasm that greeted the introduction of the gated equilibrium technique has been tempered by studies that have questioned the promise of some of these initial studies. For example, it is now felt that the wide variety of loading conditions in patients with asymptomatic aortic regurgitation may explain the failure of ejection fraction to rise with exercise in those patients rather than being due to an abnormality of intrinsic myocardial contraction as was suggested by Borer et al(1978).

On the basis of these studies and work by Slutsky et al (1979 a) and

Marshall et al (1978), it was possible to calculate the confidence levels of observed changes in ejection fraction. It is now accepted generally that significant changes in ejection fraction must exceed 5% left ventricular ejection fraction units and that the normal left ventricular response to exercise has been defined as an increase of 5% left ventricular ejection fraction units in both right and left ventricular ejec'";on fractions without the development of new regional wall motion abnormalities. However, as methodology varies among laboratories, it is important for each laboratory to validate its technique in a control group.

If the resting left ventricular ejection fraction is greater than -16-

75% it is accepted that a normal response can be defined as no fall in ejection fraction with exercise (Berger & Zaret, 1981). In normal subjects over 60 years old, Port et al (1980), has shown that the left ventricular ejection fraction may not increase normally with exercise and may in fact decrease in some subjects.

Alongside the controversy that exists about many technical aspects of the method, and despite widespread application, there is little information on the use of the technique to follow changes in left ventricular function in the long-term, and on its potential value to predict, prior to a change or modification in therapy, which individual patient benefits. In fact, stratification of patients on the basis of rest and exercise left ventricular performance may result in more appropriate therapeutic decisions. - 17-

MYOCARDIAL REV ASCULARISA TION SURGERY

The first saphenous vein aorta-coronary bypass operation was performed in the Methodist Hospital, Houston, Texas in 1964 (Garrett et al 1973). By 1970 considerable experience had been gained in a number of centres of the feasibility of performing the operation on large numbers of patients with a low operative mortality and high incidence of relief of pain. Soon after the introduction of coronary artery bypass grafting, interest arose as to the influence of revascularisation on impaired ventricular performance. In 1970, Morris et al first reported on the use of coronary artery bypass grafting in the treatment of cardiac failure in 161 patients, 82 of whom showed clinical improvement.

Mundth et al (1971) in 40 patients, reported a good clinical outcome in 80% of 31 survivors, contrasting with the high mortality (37%) in the 40 patients studied by

Spencer et al(1971). The presence of angina pectoris in association with cardiac failure correlated with clinical improvement in this latter study. Cardiac catheterisation in ten patients postoperatively demonstrated no improvement in elevated left ventricular filling pressures. Kouchoukos et al (1971) reported their experience in nine patients with congestive cardiac failure. The operative mortality was 33%, four additional patients dying within four months. Neither of the survivors showed improvement of the level of activity or symptoms. Most of the studies which examiPP.d indices of total or global left ventricular function in groups of patients with impaired ventricular performance have not shown a rise in resting left ventricular ejection fraction or a reduction in left ventricular volumes. In 1974, Hammermeister et al, in the sub-group of 15 patients with an -18-

ejection fraction of less than 50%, found no improvement in resting ejection

fraction or ventricular volumes, despite improved functional capacity. Several

other authors, Young et al (1971), Itscoitz et al (1973) and Arbogast et al (1973)

also failed to show improvement in resting global ejection fraction.

Mare encouraging than the studies of the effect of coronary graft surgery

on global indices of resting left ventricular function have been investigations on

the effect of revascularisation on regional left ventricular function. Bourassa et al (1972) examined 37 segmental wall motion abnormalities two years to one year after surgery in 87 patients. Nineteen out of 37 (51%) of ventricular wall motion defects revascularised by patent grafts were improved following surgery.

This suggested that a state of chronic ischaemia existed affecting the contraction of these segments. Chaterjee et al (1973), in a sub-group of 11 patients with previous infarction, showed significant improvement in asynergy in possibly ischaemic non-infarcted segments following revascularisatian, associated with a rise in global ejection fraction. Wolf et al (1978), also in a sub­ group of seven patients with a documented previous infarction at a mean of 13 months after operation, using bi-plane cineangiography showed improvement of percentage shortening and mean velocity of circumferential shortening in previously asynergic segments now supplied by patent grafts. In these studies assessment of left ventricular function was performed generally at cardiac catheterisatian, using contrast angiography at rest in one cineangiographic view only. There are a few radionuclide studies which have specifically examined the affects of revascularisation in patients with reduced global ventricular performance. Hellman et al (1980) using the first pass technique, studied 19 patients with pre-operative resting ejection fractions of <40% at two weeks - 19- following revascularisation and demonstrated improvement in both resting (16 patients) and exercising ejection fraction (18 patients). This work is yet to be confirmed by other authors. Hung et al (1980), also using radionuclide techniques, on the other hand, showed that left ventricular ejection fraction in patients with pre-operative resting left ventricular ejection fractions of <35% was unchanged unless left main coronary artery disease was present. Rosanzky et al (1981) using radionuclide techniques, demonstrated post-operative improvement in 54% of 72 asynergic segments and felt that the segments which demonstrated improvement in function could be predicted by pre-operative thallium scintigraphy. The mean preoperative LVEF for the group was 53%.

Although improvements in left ventricular exercise performance after aorta-coronary bypass, in patients with normal or near-normal resting left ventricular function, have been noted by others who have used haemodynamic measurements (Barry et al 1976), roentgenography (Bussmann et al 1979,

Chesebro et al 1982), and radionuclide cineangiography (Kent et al 1978,

Freeman et al 1981 a, Lim et al 1982, and Kronenberg et all983), there is again little information about post-operative changes in exercise left ventricular performance in patients with pre-operatively reduced global resting left ventricular function. - 20-

VENTRICULAR ANEUR YSMECTOMY

A number of studies have examined the natural history of patients with ventricular aneurysm subsequent to myocardial infarction. Schlichter et al (1954) reviewed the clinical course of 102 patients with autopsy- proven left ventricular aneurysm and observed a five year mortality of greater than 80%, and a high incidence of thrombo-emboli. Abrams et al (1963) also observed a high five year mortality rate of 30% in 65 patients with ventricular aneurysm at autopsy.

Both these autopsy studies were retrospective and selected on the basis of the presence of an aneurysm at autopsy. The exact time of aneurysm formation was uncertain, estimating the age of aneurysm without the benefit of angiographic data. Mourdjinis et al (1968) conducted a prospective study of patients with radiographic evidence of ventricular aneurysm after myocardial infarction. They observed a five year mortality rate of 50% in patients with large aneurysms and a five year mortality rate of <10% in patients with small aneurysms. In a large series of 601 patients at ten year follow-up. Proudfit et al (1978) showed that patients with an aneurysm with definite paradoxical bulging during systole had a five year mortality rate of approximately 50%. There is conflicting evidence from all these studies whether death occurs as a result of recurrent infarction or from cardiac failure.

Several workers focused attention on the increased burden placed on the heart by an increase in diastolic radius of the left ventricle. Both end-diastolic - 21- pressure and volume increase in proportion to the relative size of the aneurysm.

Although this increase in end-diastolic volume should enable residual contractile segments to maximise the stroke volume there is an associated increased in wall stress and thereby, a greater impedance to ejection which may further decrease systolic shortening. In addition, enhanced wall stress may increase myocardial oxygen requirements and provoke ischaemic dysfunction in residual, non­ aneurysmal segments perfused by diseased coronary arteries. These observations and the poor natural long-term course of patients with aneurysms provided the impetus for a search to find a surgical approach to treat left ventricular aneurysms. Twenty-four years ago, Likoff and Bailey (1955) reported the first successful left ventricuiar aneurysmectomy in a human being. This was followed by by a description of aneurysmectomy using cardiopulmonary bypass (Cooley et a11958). The accessability to the aneurysm provided by cardiopulmonary bypass and the initial encouraging clinical results, made left ventricular aneurysmectomy an accepted therapeutic option.

Most investigators observed distinct clinical improvement of symptoms in the majority of patients, with severe congestive cardiac failure, who had undergone aneurysmectomy. Objective improvement of clinical symptoms by exercise testing was shown by Cullhed et al (1975). Best results are thought to occur in patients with a combination of good residual contractile segment function, a discrete apical aneurysm and isolated left anterior ascending disease.

Several groups (Kitamura et al (1 972, 1976), Hazan et al 1973, Cullhed et al

1975, Schonbeck et al1975, Aranda et a11977, Le Femme et al1977, Swan et al

1978, Rivera et al 1979, Sesto et al 1979, Otterstad et al 1981) have evaluated haemodynamic variables before and after aneurysmectomy. Some authors have - 22- reported an improvement in haemodynamics, some showing no change and others a deterioration. These data may reflect small sample size, retrospectivity, different operative procedures and re-evaluation performed at various periods following surgery. Kitamura (1972) reported an increase in stroke volume at lower end-diastolic pressures in six of nine patients after aneurysmectomy; this change was not statistically significant. Shonbeck et al (1975) studied 13 patients undergoing aneurysmectomy and coronary artery graft surgery and observed an increase in the mean value for stroke volume at the same end­ diastolic pressure. Cullhed et al (1975) reviewed 14 patients post-operatively in whom seven had adequate haemodynamic measurements pre- and post­ operatively. Although four showed improvement, three had a rise in filling pressures and a fall in stoke volume. Sesto et al (1979) found no change in left ventricular end-diastolic pressure or left ventricular ejection fraction in six patients, six to ten months after aneurysmectomy. Otterstad et al (1981) observed decreases in left ventricular end-diastolic pressure in the majority of his patients, but no mention was made of changes in stroke volume. Only

Froehlich et al (1980) measured ejection fraction by isotope ventriculography in

15 patients before and after surgery. Despite dramatic improvements in functional class, no change was demonstrated in mean ejection fraction.

However, one-third of their patients had normal pre-operative end-diastolic pressure and at operation were found to have a small aneurysm.

Some of the symptomatic relief ai:tributed to aneurysmectomy may be the result of successful coronary artery bypass grafting. There is less information about the effects of aneurysmectomy in patients whose predominant symptom was dyspnoea. This is reflected in defining what is a left ventricular aneurysm, - 23-

quantitating the effects of the residual functioning myocardium and the

contribution of the akinetic motion of the affected segment on cardiac

performance. As a consequence the decision to resect a segment of the left ventricle is often not made until surgery and largely depends on the epicardial appearance of the myocardium, often described by the surgeons as appearing somewhat different to what was suggested at contrast angiography. For this reason, a more rational approach to the question of which patient should have excision of left ventricular segments or revascularisation is required. - 24-

IRON CHELATION THERAPY AND THALASSAEMIA MAJOR

Thalassaemia major was first recognised by Cooley in 1925, a Detroit

paediatrician, when he described the syndrome occuring in children of Italian

descent.It is characterised by profound anaemia, hepatosplenomegaly and bone

deformities. Untreated patients often died by the age of two or three, due to

profound anaemia. Prior to 1960, therefore, treatment consisted of intermittent

transfusions primarily aimed at palliation. These transfusions were as infrequent

as possible, ostensibly to prevent iron build-up. However, Whipple and Bradford

(1932), in their histological description of tissues from children who had not been transfused, demonstrated a degree of iron over load comparable with that of adult haemochromatosis, suggesting marked augmentation of gastrointestinal absorption of iron. Ellis and co-workers (1954) measured the iron recovered at post-mortem analysis and showed this exceeded that given by transfusion.

Earlandson et al (1962), demonstrated that excessive iron absorption was a consequence of anaemia and that iron absorption was corrected towards normal by transfusion. After Wolman (1964) reported that patients who underwent regular transfusion felt better and showed a marked improvement in growth and a decrease in thallassaemic stigmata, the concept of an optimal transfusion regime generally has been accepted. However, regularly transfused patients died in the second and third decade from camp lications of iron over load of the heart, due to either bi-ventricular congestive cardiac failure or to sudden cardiac death, presumably from malignant cardiac arrhythmias. Patients appeared to be - 25-

at most risk after receiving 40 grams of iron from transfusion, although Buja and

Roberts (1971) found extensive iron deposits after 100 units (approximately 20

grams). They found that once iron deposits occurred in the heart, extensive

deposits could also be found in other organs such as the liver, spleen, pancreas,

lymph nodes and various endocrine organs. Buja and Roberts (1971) showed that

iron deposits were greatest in the subepicardium, intermediate in the

subendocardium, and least in the middle third of the ventricular myocardium.

The presence of iron within the cell causes hypertrophy so that ventricular walls

become thickened. However, even in the later stages of the disease process

there is evidence of only patchy death of individual muscle fibres and, as a result, little evidence of fibrosis.

As cell death is not involved until the terminal phase, it is possible that normal function may be retained or recovered if iron could be removed. At the

Great Ormond Street Hospital for Sick Children in 1962, Sephton-Smith showed that iron could be chelated in thalassaemic children following intramuscular injection of desferrioxamine. Desferrioxamine is a complexed hydroxy !amine produced by Streptomyces pilosus (Bickel et al 1960, Wohler et al 1963). A colourless long-chain compound is secreted into the medium where it binds specifically with ferric iron, to make a rust coloured stable octahedral chelate.

If the actinomyces are grown in an iron depleted environment desferrioxamine can be produced and if given parenterally chelate iron before appearing in the urine. Desferrioxamine appears to bind iron from the labile iron pool inside the cell. Propper et al (1976), showed that a given dose of desferrioxamine removed more iron when given as a slow intravenous infusion than as an intramuscular injection. This is because the intracellular chelatable iron pool is small and - 26-

prolonged exposure to relatively low doses of desferrioxamine allows time for a

steady flow of iron into, and removal from the labile pool. Propp~r et al (1977)

found that subcutaneous infusions from small portable syringe pumps proved very

successful, free from the many hazards of intravenous infusion and manageable

by patients at home. Now chronic subcutaneous infusion of desferrioxamine is

the preferred effective treatment of transfusional iron load.

The Great Ormond Street controlled trial of intramuscular desferrioxamine provided the first clinical evidence that drug treatment made some impact on transfusional iron over load. Liver fibrosis was altered in the treated group and survival appeared to be improved with a six times more likelihood of chelated children reaching the age of 20 years (Modell, Personal Communication, 1979).

However, there is little information available about the effects of desferrioxamine on cardiac function. Kaye et a! (1978) comparing unche!ated and chelated patients over 14 years of age showed less severe cardiac arrhythmias in the chelated group. It has been shown by Leon et a! (1979) using radionuclide angiography, that abnormalities of exercise left ventricular performance may occur despite normal resting ventricular function, and is associated with heavy iron loads due to recurrent transfusions.

It is unknown at what stage of the disease these abnormalities of exercise ventricular function occur and whether, if identified early, progressive chelation regimes may improve or maintain left ventricular performance and alter the otherwise dismal prognosis. - 27-

VALIDATION OF METHODOLOGY - 28-

CHAPTER 3

EQUIPMENT

The equipment used for all the studies is described in this chapter.

I CAMERA

All radionuclide studies were performed using a small field of view single crystal Ohio Nuclear 420 Gamma camera. Resting studies were acquired using a medium sensitivity parallel hole collimator and rest-exercise studies using a high sensitivity 30° slant hole collimator. The pulse height analyser was set up daily at the Tc-99m photo peak energy of 140 keV using a 20% window. The quality control checks of field uniformity using a flood source and resolution using a bar phantom were made daily. Bar system resolution was 3.2 mm.

Performance Characteristics

The specifications provided by the manufacturer for the gamma camera were suitable for performance of gated equilibrium angiography. However, these performance characteristics were measured to confirm the validity of the quoted specifications for this camera. - 29-

Camera Sensitivity

The sensitivity was determined for both collimators in units of

counts/minute /37 KBQ. A sample of Tc-99m of known activity was dispersed in

a petri dish. The dish was placed approximately 10 em from the face of the

collimator and counts per minute were recorded. The sensitivity of the medium

sensitivity collimator was 436 counts/minute/37 KBQ and for the slant hole

collimator 542 counts/minute/37 KBQ. The higher sensitivity of the slant hole

collimator allowed better counting statistics for limited acquisition times eg. exercise studies.

Maximum Count Rate

Tc-99m samples of known activity ranging from 10 MBq to 1 GBq were prepared. The count rate was recorded for each sample, placed approximately 1 metre from the centre of the camera's field of view. The measured maximum count rate for the camera was 73 K counts/second, far in excess of the number of counts acquired/second during a routine equilibrium radionuclide study, i.e. 20 to 30 K counts/second.

Camera Dead Time

The dead time of the gamma camera W!'IS measured. Two Tc-99m samples

(A and B) of approximately equal activity were prepared. Count rates in sample

A alone, followed by source A and B, followed by B alone, were measured at a distance of greater than 1 metre from the collimator. To compensate for the - 30- decay of Tc-99m the procedure was then repeated in reverse order. Paralysing dead time was calculated according to the following formula:

T = 2RAB/(RA + RB) 2 ln (RA + RB)/RAB

Where RA, RB, RAB, are measured count rates for samples A, B, A and B, and

BK, is the background activity. Paralysing background for the camera was calculated at 5.5 llseconds. This dead time will not cause significant loss of counts at count rates obtained in typical equilibrium studies.

Camera Resolution

The spatial resolution of the camera and the computer system with the medium sensitivity and slant hole collimators was measured. A line source consisting of a capillary (1 mm) tube filled with Tc-99m pertechnetate, was placed in air at lOcm from the collimator face. A static image was acquired on the computer and the count profile obtained across the line source. The full width half maximum resolution (FWHM) is defined as the distance in mm between the points on the profile equal to half the maximum count value. This was measured in pixels on the computer and a known calibration factor of mm/pixel was used for the conversion. The FWHM in air of the medium sensitivity collimator was 12mm and for the slant hole collimator 15mm.

Camera Position and Patient Orientation

For the resting studies, the patient is placed on a trolley under the camera

(Fig 1). Resting images for all studies in which regional wall motion was assessed were performed using the medium sensitivity parallel hole collimator in - 31- the following projections; 40-45° left anterior oblique, which enabled the best separation of both right and left ventricles, anterior, 30° right anterior oblique, left lateral and/or left posterior oblique views. The anterior, left anterior oblique, and right anterior oblique views were performed with the patient supine.

The lateral and/or left posterior oblique views were performed with the patient in the right decubitus position which enabled the collimator to be placed against the chest wall and allowed a more vertical orientation of the left ventricle.

Exercise studies were performed with the patient semi-supine on a specially designed exercise bed in the left anterior oblique view. The 30° slant hole collimator was used to obtain images of the heart in the LAO projection. The collimator could be placed closer to the chest wall and did not cause as much interference to the exercising patient. - 32-

Figure 1. Typical resting radionuclide study being performed

in the left lateral view. - 33-

II COMPUTER SYSTEM

The camera was interfaced to a Digital Equipment Corporation (DEC), PDP

11/40 Computer (Gamma - 11) with 48 K words of memory and in later clinical

studies to a Medtronics Medical Data Systems A 2 Computer with 128 K words of

computer memory. Both systems were checked for dead time losses in a similar

fashion to the camera and no further data loss was observed.

Data Acquisition

There are two forms of data acquisition available, matrix mode and list

mode.

Matrix Mode: The gamma camera image recorded in the computer is a

digital image. It is stored in the memory as a matrix that is composed of

discrete areas or cells (pixels) that have distinct boundaries. Each frame is stored as a matrix. Each cell of this matrix holds a count of the radioactivity

for a small area of the organ being studied.

list Mode: List mode stores a list of the counts in the memory in the order

that they occur (unlike matrix mode which stores an image). Each element of the image is one computer word which consists of an X co-ordinate and a Y co­ ordinate, a time mark and a physiological trigger rnark. List mode data must then be reformatted into matrix to be analysed.

In general, all clinical studies on the computer were acquired using matrix - 34-

mode. Multiple gated acquisition is an extension of matrix mode acquisition

which incorporates the R wave trigger (see Chapter 4). Due to a limitation of

computer memory, early studies were acquired with a matrix size of 32 x 32

pixels, but with subsequent improvement in hardware, studies were acquired with

a matrix size of 64 x 64 pixels. An R wave trigger from the patients

electrocardiogram (V5) provided the physiological signal for initiation of data

acquisition at the start of each cardiac cycle. The studies of patients with

atrial fibrillation or with numerous ventricular ectopic beats were acquired using list mode. The study was reformatted in matrix mode and the R wave histogram examined. For analysis, cycles of a certain R-R length were used and shorter cycle beats or ectopic beats excluded.

The four views obtained were anterior and /or right anterior oblique, to image the right atrium, tricuspid valve plane, pulmonary outflow tract, and anterolateral and apical portions of the left ventricle; left anterior oblique for examination of the septum and posterolateral segments; left lateral and/or left posterior oblique for examination of the inferior wall. These views were displayed in a flicker free cine format with nine to twelve images/sequence at a rate of 80 cardiac cycles/minute.

Cardiac Analysis Programmes

Gated cardiac studies using the Digital .Equipment Corporation (DEC)

Computer used programmes which were developed at the Nuclear Medicine

Department at Royal Prince Alfred Hospital and were made available to all DEC users throughout Australia (Hutton et al 1982). The programme designed to -35-

minimise operator intervention and to minimise inter- and intra-observer

variability is described in detail in the (DEC) users manual. Briefly, the

programme uses an edge detection algorithm based on concavity mapping for

determining the left ventricular edges throughout the cardiac cycle. Initially the

cardiac images are spatially smoothed twice using a standard weighted nine point

smooth and thresholded to 25% of the maximum count. The operator is required

to select end diastolic and end systolic images and draw outlines of end-diastolic

and end-systolic regions from the left anterior oblique view and to monitor the

programmes performance in tracking ventricular motion. The programme

generates left ventricular regions for the frames between the end-diastolic and end-systolic images based on the concavity niapping for the appropriate frame and the previously defined regions at end-diastole and end-systole.

After the left ventricular region of interest is determined, a background region of interest is defined automatically. This consists of a region of one pixel width, one pixel away from the ventricular edge of the end systolic image drawn as an arc at the apex of the ventricle, 45° up the septum and 90° up the lateral wall. The left ventricular ejection fraction is calculated from the background corrected left ventricular time activity curve according to the following formula:

L. V.E.F. = End-Diastolic counts - End-Systolic counts/End-Diastolic counts

The MDS cardiac analysis programme has a semi-automated edge detection programme which uses moving regions of interest with the left ventricular edge defined by a second derivative technique. Background is automatically defined - 36- as a region five pixels wide, five pixels out from the left ventricular edge, laterally on the end-systolic image. The top and bottom of the end-systolic region of interest serves as top and bottom of the background region and the average counts/pixel of the lower two-thirds of the region is used for the background correction.

III EXERCISE BICYCLE

Exercise studies were performed on a specially designed stress bed with a bicycle ergometer cantilevered at the foot of the bed as illustrated in Figure 2.

The bed was contoured with shoulder and hip restraints and hand grips to minimise patient movement during exercise. The load to the patient

(watts/second) was electronically adjusted and digitally displayed alongside· an elapsed time counter (Fig.2). - 37-

Figure 2 Typical exercise .. study being performed with the subject

in the semi- supine position on the exercise bed. - 38-

CHAPTER 4

GAMMA CAMERA OAT A ACQUISITION

The measurement of left ventricular ejection fraction using the technique

of gated equilibrium radionuclide angiography relates the activity contained

within left ventricle to a function of time. Since physiological information about

ventricular function is contained in this relationship, correct sampling of these data is essential. Prior to the application of computer technology to radionuclide angiography end systolic and end diastolic images were acquired until enough counts were available to create images of the ventricle. By interfacing a computer to the camera, the entire cardiac cycle can be examined, and instead of having images at end diastole and end systole, each phase of the cardiac cycle can be recorded. The R wave on the electrocardiogram which has a relatively constant electro-mechanical relationship to myocardial contraction is used to signal the start of the cardiac cycle. The cardiac cycle can be divided into a number of short time intervals, or frames and for each frame , gamma camera data are acquired in an orderly manner over a number of cardiac cycles. The exact number and length of the frames acquired for each cardiac cycle is uncertain. The technique becomes impractical for exercise studies if too many frames are used due to the time required to acquire the data. Alternatively reducing the number of frames degrades the ultimate time activity curve, resulting in a loss of resolution and image quality. - 39-

A balance between the number of frames/cycle and the duration of the

total period of acquisition must be achieved. This study was undertaken to

determine the optimum number of frames/cycle required to generate an

accurate time activity curve and enable calculation of left ventricular ejection

fraction with the time constraints required for a graded exercise protocol. A cardiac phantom was constructed to simulate the left ventricle permitting repetitive studies in identical conditions, with the ability for the operator to

alter the cycle length, frame duration and chamber volume. -40-

Methods

Cardiac Phantom

The cardiac phantom was designed to simulate the beating left ventricle in

man. Therefore, the shape of the chamber at normal volumes was elliptical and

became spherical as the volume was increased to a maximum of 500ml, a size

consistent with marked left ventricular dilatation. The rate of contraction of the

balloon could be altered to mimic rest and exercise. A special cam was made to

simulate differences in filling and emptying rates which occur during systole and

diastole respectively in man.

This cardiac phantom is shown in Figs 3 & 4. A rubber balloon represented the

left ventricle. This balloon was placed in a water bath in an aery lie container

200 x 180 x 300 em. i.e. roughly the size of the chest. The pump consisted of a piston within an aery lie cylinder sealed tightly with rubber "0" rings. This balloon and pump were connected by a thin walled rubber hose 2.5 em in diameter, fitted with a stopcock tap for filling and evacuating air and water from the system. The piston was attached axially to a cam which was specifically designed to provide a fixed stroke volume of 62 ml and simulate the differences in filling and emptying rates seen at diastole and systole respectively. This cam was driven by an electric motor. The cam could be driven from 30 to 180 cycles/minute. A photo-electric cell, activated by cam rotation, provided an electrical signal to co-incide with ma>.:imal chamber dilatation ("end-diastole"), simulating the R wave trigger. Within the bath, the balloon chamber could be placed at various distances from the camera to simulate tissue attenuation in different chest cavity sizes. Tc-99m could also be - 41 -

Figure 3 The cardiac phantom (anterior) view. The balloon (B) is shown in a water bath (WB) in front of the gamma camera (Ca) • Water is pumped in and out of the balloon via a hose (H). Tr.- rate of contraction of the balloon can be electronically adjusted and an ECG signal provided to coincide with maximal balloon dilatation and initiate acquisition .. - 42-

Figure 4 The cardiac phantom (posterior view). The pump (P) consisted of a piston within an aery lie cy Under sealed tightly with rubber "0" rings. The piston was axiaUy attached to a cam which provided a fixed stroke volume of 62 ml.

The cam was driven by an electric motor (M). -43-

added to the bath to simulate surrounding extra-cardiac activity always present

during a gated equilibrium blood pool study in man.

Study Protocol

Tc-99m was added to the phantom balloon and titrated to provide

sufficient activity for a count rate of 20 K/second, similar to the count rates

obtained during a standard cardiac study. Acquisition was performed in list mode

at three chamber volumes, arbitrarily chosen to represent three different end­

diastolic volumes, 168 ml, 138 ml, and 111 ml. As the stroke volume was fixed

at 62 ml by the design of the cam, an ejection fraction for each balloon volume

could be accurately calculated:

E.F. (phantom balloon) = stroke volume of balloon I maximal volume of balloon.

The studies were acquired at 70 and 150 cycles/minute to simulate an acquisition in man at rest and during exercise. After acquisition, the studies were reformatted at 8 different frame durations corresponding to a range of frames/cycle from 4 to 32. Using standard methods of data analysis described previously, ejection fraction was calculated for each of the 48 studies. -44--

Results

It can be seen from Table 1, that at 24, 28 and 32 frames/cycle at rates of

70 and !50/minute, the calculation of ejection fraction did not vary greatly from that of the actual ejection fraction. The optimal number of frames/cycle for accurate measurement of ejection fraction over a range of cycle rates and volumes was 24 using the usual counting statistics obtained with the camera and collimator. At a cycle rate of 70/minute, this corresponded to a frame duration of 35 msec/frame and at a cycle rate of !50/minute to 16 msec/frame. As the number of frames/cycle were reduced below 24, there was a fall in t.he measured value of ejection fraction (Fig. 5). -45-

Table 1. Effect of frame duration on LVEF at 70 & 150 phantom cycles/min

Rate Frame duration No of frames/cycle Actual Ejection Fraction

(Cycles/min) (sec) (37%) (45%) (56%)

70/min 0.21 4 24 28 38

0.11 8 26 36 46

.0.07 12 31 39 52

0.053 16 31 41 52

0.043 20 33 42 52

0.035 24 34 44 54

0.030 28 35 45 55

0.026 32 35 45 55

150/min 0.10 4 20 22 40

0.05 8 28 36 50

0.033 12 30 41 58

0.025 16 31 43 58

0.02 20 32 43 56

0.016 24 35 44 61

0.014 28 35 44 65

0.012 32 35 45 62 The effect of frame duration on ejection fraction

EF=56% .~ .....X EFzss% -x-x-x u. w EF=45% ' x' >4.... ~ •---x-w-EF= 37% x'x )( •--x-._-,e-x- ~ ~ ·~ Cycle length • 70/min Cycle length • 150/ min

I I I I I I I I I I 32 24 16 8 0 32 24 16 8 0 Number of frames Number of frames

The effect of altering frame duration on ejection fraction at three Figure 5 known balloon volumes at 70 and 150 cycles/min. -47-

Discussion

The determination of the optimum frame rate to calculate ejection

fraction accurately at varying cycle rates and varying balloon volumes had

important practical implications in the performance of cardiac studies. With the

need to examine the effects of interventions such as exercise, measurement of

ejection fraction over short acquisition periods was required. It was therefore, important to establish the minimum number of frames and the length of the acquisition period which would provide an adequate level of accuracy and reproducibility.

These data provided a logical basis for selection of appropriate frame rates for the recording of left ventricular time activity curves in man. Frame rates as low as 14 frames/cycle (Brady et al 1979 (a) & (b)) have been used in clinical studies for the calculation of ejection fraction during rest and exercise, but according to these data this could lead to under-estimation of ejection fraction.

Bacharach et al (1979) suggested that frame durations up to 50 msec/frame were adequate for resting studies and that a length of 40 msec was acceptable for exercise. Results of this phantom study indicated ejection fraction would be underestimated if these frame durations were adopted. In patients with normal left ventricular performance, using these recommendations an abnormal ejection fraction response to exercise may artificially be demonstrated. Accorr:lingly, in the clinical studies, a frame duration of 40msec was used, that being reduced as the cardiac rate increased with exercise. -48-

CHAPTERS

RED CELL LABELLING

Technetium 99m (Tc-99m) was the radionuc!ide used for all clinical and phantom radioangiocardiography. Tc-99m has been used for a wide variety of studies in Nuclear Medicine owing to its short half-life (six hours) and photon energy of 140 KeV, ideally suited for standard gamma camera imaging. It is readily ·available from a sterile 99m Mo-99m Tc generator system in very high specific concentrations (> 100 mCi/ml). Fundamental to imaging of the cardiac blood pool is the use of a radiopharmaceutical that achieves a reproducible steady high blood pool concentration. Radiopharmaceuticals that have been used for this purpose include Tc-99m human serum albumin (HSA), "in vivo" labelled

Tc-99m red blood cells and "in vitro" labelled Tc-99m red blood cells. Despite reported labelling efficiencies of 90 to 99%, Tc-99m HSA is not available in this country, possibly because of previously recognised allergic reactions and the unpredictable leakage from the vascular space.

To determine the efficiency of red blood cell labelling with Tc-99m, and to determine which was the superior method, a comparison was made of the red cell labelling efficiencies of both "in vitro" and "in vivo" techniques. -49-

Methods

Study Protocol

Thirty-nine consecutive patients without known red cell antibodies or

taking drugs known to precipitate the formation of red cell antibodies were studied. The red cells of 20 patients were labelled using the "in vitro"technique and 19 patients the "in vivo" technique. Patients' red cells were labelled alternatively in order of admission to the study. All patients continued to receive their usual cardioactive medications and these were not stopped prior to study·

Description of the "In Vitro" Tc-99m Red Blood Cell Label

An "in vitro" method of labelling the blood pool using a freeze dried mixture of stannous chloride and calcium gluconate was developed in this laboratory. The kit was produced by the Australian Atomic Energy Commission with each vial containing 20 mg of calcium gluconate and 10 mg of stannous chloride. After the addition of 2 ml of sterile water to the vial, one ml of stannous chloride was mixed and incubated with the patient's blood for five minutes. The blood was then centrifuged and 2 ml of packed red cells were

2 mixed with a dose of 99m Tc pertechnetate (500 MBq/m ) and re-incubat'"'d and centrifuged. The supernatant was then removed and the labelled red cells were re-injected into the patient. -50-

Description of the "In Vivo" Tc-99m Red Blood Cell Label

The "in vivo" method originally described by Pavel et al (1977) was

modified by Callahan et al (1982). Their method which has been colloquially

referred to as "in vivtro" was used in this study. With this technique, the patient

was injected intravenously with 0.01 mg/kg of stannous pyrophosphate. Twenty

minutes later, 3 ml of blood was drawn from the patient and mixed in a shielded

syringe containing 500 MBq/m 2 of Tc-99m pertechnetate. This was mixed gently

and incubated for 10 minutes and re-injected into the patient.

Measurement of Labelling Efficiency

At 20 minutes after injection of tracer, 3 ml of blood was withdrawn from all patients. Aliquots of the supernatant plasma and red cell fractions were counted in a gamma red cell counter. The percentage of activity carried in the red cells and in the plasma was calculated according to the method described by

Kato et al (1979).

% P = c/ml P (1 - % Hct / 100) x 100

c/ml Wb

then %RBC = 100 - % P

Where P =plasma, Wb = whole blood, RBC =red blood cells, Hct = haematocrit. -51-

Results

The red blood cell labelling efficiencies in patients labelled alternatively by both techniques measured at 20 minutes following the injection of tracer are shown in Table 2.

As can be seen from Table 2 only one patient using the "in vitro" technique had a labelling efficiency of <90%, in contrast to six patients with labelling efficencies of < 90% labelled using the "in vivo" technique. The mean percentage red blood cell activity of red cells labelled using the "in vitro" technique was 94.4 !. 3% which was significantly greater than for red cells labelled using the modified "in vivo" technique, 90.7 !. 4% (P <0.005 ).

Calculation of left ventricular ejection fraction using the semi-automated programme described previously was possible in all patients. -52-

Table 2. RBC Labelling efficiency with TC 99m using the "in vitro" and "In VIV0 11 methods in 39 consecutiVe patients

Pt In "vitro" In "vivo" (% RBC label) (% RBC label)

1 94.7 2 89.0 3 93.6 4 93.5 5 93.6 6 82.6 7 96.1 8 86.2 9 96.3 10 95.5 11 91.3 12 95.9 13 96.1 14 95.9 15 95.8 16 90.7 17 95.7 18 95.1 19 87.6 20 93.7 21 93.2 22 91.1 23 94.2 24 83.5 25 96.4 26 90.3 27 91.7 28 93.6 29 91.2 30 88.7 31 96.3 32 93.0 33 95.1 34 88.5 35 92.9 36 88.5 37 98.3 38 94.0 39 97.9

Mean±=SD 94.4 * 2.6 90.7 * 3.9 (P<0.005) -53-

Discussion

Although it may be possible to calculate left ventricular ejection fraction with

a less efficient label, the best ratio of cardiac to background activity was

considered important for analysis of regional wall motion essential to many of the proposed studies. This study showed that the "in vitro" method of red blood cell labelling was significantly more efficient than the modified "in vivo" method described by Callahan et al (1982), although all studies were adequate for calculation of ejection fraction. The observed advantage of the "in vitro" method of red blood cell labelling was off-set by a somewhat more complicated preparative procedure which required about 20 minutes of manipulation and great care to maintain sterility to produce the labelled product. On the other hand, the modified "in vivo" method of Callahan et al (1982) also required two venepunctures and two separate periods of incubation, the first to ensure saturation of the red blood cells with stannous ion and the second period to obtain binding of pertechnetate to the red blood cells. The total preparation time from initial patient contact to the start of cardiac imaging was about the same for both methods.

The original "in vivo" method of red cell labelling decribed by Pavel et al

(1977) is simpler to perform than these two techniques. However although Pavel et al (1977) reported higher blood pool concentrations of >95% at one hour after injection, other workers, Stokely et al (1976), Hegge et al (1978), Zimmer et al

(1979) , Kato et al (1979) have shown that this original "in vivo" method of labelling red blood cells provided variable intravascular activity (76-98%). -54-

Hegge et al (1978), using this method found only 76% of activity was retained in the blood pool at 30 minutes at which time most radionuclide studies are still being performed. Callahan et al (1982), suggested, that in the original "in vivo" technique there was competition for the pertechnetate between red blood cells and the extracellular fluid space, thyroid, gastric mucosa and salivary glands.

For these reasons, the method described by Pavel et al (1977) was not examined.

Both the methods used in this study however, provided adequate time for labelling to take place by isolating the Tc-99m and pretinned red blood cells from competing body compartments.

Relatively little is known about the mechanism of binding of technetium to red blood cells. Stannous ion is required for efficient red cell labelling in both animals and humans, whether the cells are labelled "in vivo" or "in vitro" or by a hybrid method. Callahan et al (1982), showed that labelling kinetics are critically dependent on temperature, stannous ion concentration and haematocrit. The binding of the tracer is to the beta chain of haemoglobin but the mechanism of transport across the membrane, as well as the means by which stannous ion mediates binding are obscure. Hamilton and Alderson (1977) have shown that, maximum "in vivo" labelling of red cells occurred when technetium was injected 5 to 30 minutes after stannous ion although adequate images could still be performed two hours after injection.

Interference v•:th radionuclide distribution can also be related to commonly used drugs. Hegge et al (1978) reported that when a heparinised catheter was used as the injection port for "in vivo" red blood cell labelling, the result showed consistently poor quality studies with diminished cardiac chamber activity and -55 - increased renal uptake and excretion. Zimmer et al (1981), investigated the effect of heparin and four other widely used cardiac drugs on "in vivo" radiolabelling of red blood cells using an "in vitro" model. Two of these, methyldopa and hydrallazine, significantly decreased the labelling efficiency, possibly through oxidation of the stannous ion when it is added to whole blood containing either drug. However, clinically relevant concentrations of lignocaine, quinidine and heparin did not alter red blood cell labelling in their system.

Red blood cell antibody formation may be the primary factor causing inefficient radiolabelling of red cells "in vivo". Commonly used cardioactive drugs may be partly responsible for such red blood cell antibody formation (Leitl et al (1980)). Patients with known red cell antibodies and patients taking drugs such as alpha methyldopa, hydralazine and quinidine were therefore excluded from this study. In all subsequent clinical studies, medications were noted and red cell antibody producing therapy was ceased if clinically practical. However, a more recent paper by Lee et al (1983) suggested that the antihypertensive agent prazosin and the inotrope digitalis may affect red blood cell labelling.

These latter drugs were not routinely ceased. In this present study only eight patients had a red blood cell labelling efficiency of <90%. Two of these patients were receiving digitalis therapy and none prazosin.

In conclusion, both methods of labelling red blood cells with Tc-99m provided a high enough level of efficiency to calculate left ventricular ejection fraction.

However, the "in vitro" method provided a significantly more efficient label than the modified "in vivo" method and wasthe most reliable and consistent method to label red cells with Tc-99m for the proposed clinical studies. -56-

CHAPTER 6

LEFT VENTRICULAR EJECTION FRACTION

SECTION A.

Accuracy of Left Ventricular Ejection Fraction (LVEF) by Gated Equilibrium

Angiography

Various techniques have been described for performing gated equilibrium angiography, requiring some observer interaction. It was important to establish whether the methods described in Chapter 3 for measuring LVEF were accurate.

Accordingly three studies were undertaken to validate radionuclide methods of measuring LVEF.

1) Comparison of LVEF measured using gated equilibrium angiography with

contrast angiography using the DEC programme.

2) Examination of the reproducibility, inter-observer and intra-obse·rver

error for measuring LVEF using the DEC programme.

3) Comparison of LVEF measured using the DEC Gamma-11 programme

and the MDS A 2 programme. -57-

STUDY 1

Comparison of L VEF measured using Gated Equilibrium Angiography with

Contrast Angiography.

Methods

Twenty-six patients underwent gated equilibrium angiography within 3 days of contrast ventriculography • There were 21 males and 5 females, aged SL~11 years. These patients had stable angina and underwent cardiac catheterisation prior to elective coronary artery surgery. They were selected for this study so as to represent a range of left ventricular performance commonly found in patients with coronary disease. The left ventricular ejection fraction (LVEF) measured from the radionuclide angiogram was compared with LVEF measured from single plane contrast angiography. This was performed in the right ·anterior oblique projection during injection under pressure of 30 -35 ml of urograffin contrast material at a rate of 10 to 12 ml/sec. Only sinus beats, two cycles removed from the last premature beat were selected for quantitative analysis of L VEF, using the area-length formulae of Sandler and Dodge (1968) as described by Kasser and

Kennedy (1969).

Linear regression analysis was used to calculate correlation coefficients comparing LVEF as measured by the radionuclide technique with that of contrast angiography. -58-

Results

In Fig. 6, the LVEF values measured using contrast angiography were compared with those obtained using radionuclide angiography in the 26 patients. There was a highly significant correlation of r = 0.93, y = 0.92x - 2.68 (p

Comparison of radionuclide LVEF with contrast LVEF

>­ .J: ea. -~ ·a,~ 60 c: C'CLL Q)w ~ :::;. 40 (.) c:~ n=26 0 20 r =0·93 ·-"'C ca a: y = 0·92X-2·7 0~-r~-,--.-.-.-~~~~ 0 40 60 80 100 LVEF% Contrast angiography

Figure 6 Comparison of left ventricular ejection fraction (L VEF) by gated equilibrium radionuclide angiography and contrast angiography in 26 subjects. - 60-

Discussion

The correlation coefficient of 0.93 between contrast angiography and radionuclide angiography for LVEF over a wide range of left ventricular function compares favourably with other similar studies (Folland et al 1977, Burow et al

1977, Brady et al 1979 b, and Pfisterer et al 1979 a). The correlation coefficients of these studies comparing L VEF measured by radionuclide techniques and contrast angiography ranged from 0.84 to 0.93.

The relatively low correlation of 0.84 with contrast angiography observed by

Folland et al (1977) may have been due to the use of a fixed region of interest to measure counts within the left ventricle • A fixed region of interest is a region around the left ventricle identified manually by the operator at a single point in the cardiac cycle from the end diastolic frame. A manually derived fixed region of interest at end-diastole may result in an under-estimation of the calculated

LVEF. This is because the left atrium and, on occasion, right ventricle may move into the region as the ventricle contracts, so that at end-systole as the left atrium is maximally filled it may contribute counts to end-systolic volume, thereby causing over-estimation of end-systolic volume and under-estimation of

LVEF. Sorensen et al (1979) observed that the slope of a regression line of LVEF measured using a varic:'-!le region of intrest when compared with contrast angiography was greater than with a fixed region of interest. They also found the greatest underestimation of L VEF occurred when the L VEF was high as there is greater variation in ventricular size between diastole and systole. - 61-

Folland et al (1977) also used a manually designated technique of background

assignment. Using this method a small change in the distance of the background

area from the ventricular cavity may result in relatively large changes in

calculated background activity and hence of LVEF. Later studies by Burow et al

(1977), Brady et al (1979 b), Pfisterer et al (1979 a), all employed semi-automatic

edge detection programmes and automatic background subtraction programmes

which reduced inter-observer and intra-observer variability and is very

reproducible.

In the technique used in this study a region is drawn manually around the left

ventricle and the automatic programme then defines activity in the left

ventricle separately from each frame of the cardiac cycle using a variable region

of interest. As end-systolic counts were obtained only from the end-systolic

area, the contribution from the left atrium and the right ventricle were

minimised.

Although LVEF by contrast angiography was used for comparison there are

many well recognised limitations of results obtained by this technique.

Calculation of L VEF by contrast angiography uses geometric assumptions that

become increasingly invalid in patients with marked regional left ventricular

dysfunction. Many of the patients examined in my study, had extensive regional

wall motion abnormalities subsequent to previous infarction. Okada et al (1980

a), and Chaitman et al (1975) have shown that manually drawn outlines from the

contrast angiogram at end-systole and end-diastole have a wide inter-observer

and intra-observer variance. However despite these limitations contrast

angiography has been used as the reference standard for most comparative studies of the non-invasive imaging methods because it still has the highest spatial resolution of all imaging techniques. - 62-

STUDY 2

To determine the Reproducibility, Inter-observer and Intra-observer error of measuring LVEF using the DEC cardiac analysis programme ••

Methods

To examine the reproducibility of the gated equilibrium method, 20 patients,

18 males and two females, aged 48 2:. 12 years were studied using the described radionuclide techniques on· two occasions separated by one hour. All 40 studies were analysed independently using the DEC programme by two trained operators without knowledge of the patients' clinical or investigational data. Fifteen studies were chosen at random and the analysis repeated by a third trained operator without knowledge of the results obtained previously. The results were analysed to examine reproducibility, inter-observer variability and intra-observer variability.

Results

The individual LVEF values at the initial and repeat studies are shown in

Fig. 7 & Table 3. In the first study, the mean LVEF for the 20 patients was 52 !

7% and in the second study, Dne hour following injection of radiotracer, it was 51

+ 7%. The correlation of the first study with the second study was 0.96, y =

0.97x + 1.0, with a mean difference between studies of 1.6:1. 7. - 63-

The inter-observer error for two trained operators, Observer A and Observer

B, for al140 studies is shown in Fig. 8. The LVEF measured by Observer A was 51

2: 7% and for Observer B was 51 + 7%. The correlation of Observer A with Observer B was r = 0.94, y = .0.87x + 6 with a mean difference between observations of 1. 7 + 1.0%.

The intra-observer error for 15 studies selected at random for repeat analysis by an experienced operator was calculated. The L VEF measured at the initial analysis was 55±9% and on the second analysis, 55*9%. The correlation of the initial with the subsequent analysis was 0.99, y = 0.97x + 1.3, with a mean difference between observations of 1.1 ± 1.0%. - 64-

Reproducibility of LVEF measurement

100

> "C 80 ::I .....en -ca ·-..... 60 ·--c: ~ 40 u.. w n=20 >....1 20 r =0·96 y = 0·94x+3·0

0 0 20 40 60 80 100 LVEF 96 Second study

Figure 7 Reproducibility of LVr::F ·measured on two occasions separated by a one

hour interval in 20 subjects. - 65-

Table 3. Reproducibility of LVEF measured on two occasions separated by a one hour interval in 20 subjects,

Pts Age LVEF LVEF

( Yrs) (initial) (after 1 hr)

MC 35 51 51

PF 57 61 56

WP 43 44 43 HL 58 52 52

RW 20 54 55

VM 20 59 57

JD 42 49 49

ES 48 60 60

AM 67 48 50 vw 42 46 47 AB 53 50 48

EC 53 54 50

IL 61 46 46 PM 48 54 58 EQ 54 41 40

WA 45 48 49 AW 54 37 36

JM 57 66 65

RP 51 51 50 MF 53 61 64

Mean±so 48:1:12 51.6:1:7.3 51.3:1:7.4 -66-

lnterobserver variability

100

u. w ~ 60 I tll ~ ~ 40 ~ C1) n=40 (I) ~ 20 r = 0·94 y= 0·87x +6

0;--.-.~.-~~--~~~~-- 0 20 40 60 80 100 Observer A- LVEF%

Figure 8 Interobserver variability study. Comparison of L VEF measured by two

observers in 40 studies. - 67-

Discussion

For a difference in repeat LVEF measurement to be significant at the 95%

confidence level for a given individual, the change must be greater than twice

the standard deviation of the mean difference between observations. The results

of this study show that at 95% confidence levels, repeat LVEF determinations at

very short intervals of time should vary by more than 3% at rest to indicate a significant change. Patients were imaged twice during a one hour period using the same Technetium red cell label (as outlined in chapter 3) to avoid differences in LVEF that could have been caused by changes in physiological status (such as fluid balance, sympathetic tone etc.) if the studies had been separated by long time intervals on two different occasions. Upton et al (1980) examined the reproducibility of radionuclide measurements of L VEF two days apart, repeating the red blood cell label in ten normal subjects. The variability in LVEF between studies was 4 .:, 3.8% at rest and 3.2.:, 2.5% during exercise. Therefore, at 95% confidence limits in their study, repeat LVEF should not vary by more than 8% at rest and 5% during exercise, in normal subjects. A similar difference in calculation of LVEF of 4.4.:, 3.6% was reported by Marshall et a! (1978) using the first pass technique in 20 cardiac patients, who had resting radionuclide studies separated by an average of 4.3 days.

The results of my investigation, and those reported above, compare more than favourably with those studies of reproducibility of measurements made with contrast angiography. McAnulty et al (1974) showed variability between LVEF measurements of 4 + 10% in 14 patients who had contrast ventriculograms - 68- performed on successive days. Cohn et al (1974) reported a similar variability when the studies were repeated at 90 minutes. The invasive nature of cardiac catheterisation usually causes increased sympathetic tone, and effects of the contrast agent on the ventricle in repeated studies may explain a lower reproducibility of LVEF with contrast angiography than with radionuclide angiography.

Using radionuclide angiography, inter-observer variability for measurement of L VEF was .!. 1.0% (1 SO) and intra-observer variability was -;~: 1.0% (SO) which were lower than that which has been reported with contrast angiography. Okada et al (1980) and Chaitman et al (1982), using contrast angiography, have shown that manually drawn estimates of ejection fraction have an inter-observer variance of.!. 5.8% (.!_ 1 SO) and.!. 4% (.!_ 1 SO) respectively.

In conclusion, LVEF determined by equilibrium radionuclide angiography provided reproducible results with low inter- and intra-observer error. Serial measurement of L VEF could be made and relatively small changes in LVEF would indicate a significant change in left ventricular performance. - 69-

STUDY 3

Comparison of Left Ventricular Ejection Fraction (LVEF) Analysed Using the

DEC Gamma-11 and the MDS A 2 cardiac analysis· programmes.

Methods

To compare L VEF determined by both computer programmes, the gamma camera was interfaced with both computers so data could be obtained simultaneously. The same acquisition parameters, using a matrix size of 64 x 64 and 24 frames/cardiac cycle were chosen for both systems.

Thirty-four patients were chosen at random to undergo resting and peak exercise gated equilibrium angiography. L VEF for each patient at rest and peak exercise was calculated using simultaneously obtained data for the DEC Gamma

11 system and by MDS A 2 system (previously described in Chapter 3). The results obtained from both systems were compared. - 70-

Results

Results comparing LVEF measured by the DEC and MDS programmes are shown in Fig. 9. The resting LVEF for the 34 patients was 42 + 17% and 44::!:-20% using the DEC Gamma-11 and the MDS A 2 programme respectively. The mean absolute difference in LVEF between programmes was 4.3 .:_ 3.6%. The correlation coefficient between analyses was 0.97, ie. y(DEC)= 0.81x(MDS) + 6.2.

Results comparing peak exercise L VEF measured by DEC and MDS programmes are shown in Fig. 10. The peak exercise LVEF for the 34 patients was 57 .:_ 14% and 57±16% using the DEC Gamma 11 and MDS A 2 programme respectively. The mean absolute difference in peak exercise L VEF between programmes was 3.9 .:_ 3.1 %. The correlation coefficient between analyses was

0.94, ie. y(DEC) = 0.85x(MDS) + 8. - 71-

. Comparison of DEC and MDS LVEF {Rest) 80 X

60 ~ u. w ~ 40 I (.) w c 20 n=34 r =0·97 y =0·81X+6·2 0;---r--.--.--.--~--~--~~ 0 20 40 60 80 MDS-LVEF %

Figure 9 Resting LVEF acquired and analysed using the DEC gamma 11 and MDS

A 2 cardiac analysis programmes in 34 subjects. - 72-

Comparison of DEC and MDS LVEF (Peak exercise)

~ u. w > ...J 40 I (.) w n= 34 c 20 r = 0·94 y =0·85x+8

07--r--.--.-,,-~~-----~~-- 0 20 40 60·80 MDS-LVEF%

Figure 10 Peak exercise L VEF acquired and analysed using the DEC gamma 11 and MDS A 2 cardiac analysis programmes in 34 subjects. - 73-

Discussion

The results of this study suggest that the DEC Gamma-11 cardiac analysis programme developed in Sydney and used in most of the clinical studies is comparable to the analysis programme of the MDS A 2 system providing a measure of L VEF of a similar order of magnitude.

A comparison between the DEC and MDS cardiac analysis programmes has been performed also by Shuter et al (1982), although their studies were not simultaneously acquired but translated from one computer system to the other.

They showed a similar correlation of 0.96 for resting studies and a correlation of

0.94 for exercise studies. An analysis of that study indicated that the few major discrepancies in the calculation of LVEF occurred due to differences by which the edge detection programmes located the atrio-ventricular boundary on the end-systolic frame. The location of the background region also gave significantly different counts producing, however, only small consistent changes in the calculated LVEF. -74-

LEFT VENTRICULAR EJECTION FRACTION.

SECTION B.

Normal Left Ventricular Performance at rest and during exercise

in Children and Adult Volunteers

It was important to establish the range for resting L VEF obtained by radionuclide angiography and to define the ventricular response to exercise in normal subjects. Little data are available concerning the rest and exercise left ventriclular performance in young adults and children. These data could then be used to determine the presence of abnormal ventricular performance and to examine the effects of therapy. - 75-

Methods

Patient Population

Children

Ten children or adolescents, six males and four females, aged 14.:!:. 3 years

(range 11 to 21 years) were studied as normal control subjects. They were

normal siblings of children affected by thalassaemia major and had no historical

or clinical evidence of cardiac disease.

Adults

Ten normal healthy adult volunteers, nine male and one female, aged 40 .:!:.

11 years (range 27 to 64 years) were studied. No subject had a history of cardiac

disease and all had a normal physical examination and electrocardiogram.

Study Protocol

All subjects were studied at rest and during semi-supine bicycle exercise.

All the younger subjects underwent a trial period of exercise with the bicycle to

familiarise themselves with the technique. Exercise was increased in 25 watt

increments in four-minute stages until limited by fadgue. Exercise was maximal

in all patients and not ceased in any individual as a result of electrocardiographic changes, fall in blood pressure or development of an arrhythmia. The first - 76- minute of each stage was allowed for stabilisation of heart rate and blood pressure, and radionuclide data were acquired for the subsequent three minutes of each stage as described in Chapter 3 ••

Heart rate and blood pressure were measured and double product of heart rate and blood pressure was calculated at each level of exercise. LVEF was measured at rest and at each stage of exercise in all 20 subjects. -77-

Results

L VEF at rest, L VEF for each stage of exercise and double product achieved with exercise are shown for children in Fig. 11 and for a~ults in Fig.12.

The resting LVEF for both groups of volunteers was not significantly different,

66 + 8% for the children versus 61 + 7% in the adults (P = NS). Therefore according to these data(:~.- 250), the minimum normal L VEF for children was 50% and for adults was 47%. Resting LVEF was greater than 50% in 19 of the 20 subjects studied; one subject had an LVEF of 49%. With exercise, the adults achieved a higher peak exercise double product, 310.:!:. 86 x 10 2 versus 227.:!:. 46 x

102 (P <0.05), but exercise load achieved was not significantly greater, 97.5.:!:. 30 watts for the children and 105 + 47 watts for the adults • Peak exercise L VEF was 76 2:. 11% for the children and 73 2:. 8% for the adult group (P = NS). L VEF rose progressively during exercise in 18 of the 20 subjects, rising at least 5%

L VEF units above the resting value. Of the remainder one had a resting L VEF of

73% and 76% at peak exercise and the other 59% at rest and 62% at peak exercise. No patient had a regional wall motion at rest or developed any regional abnormalities with exercise. -78-

Exercise responses in normal subjects (Age 11-21 yrs)

LL w ....> 40

20

0=10 n=10 0 I I I I I I I I 0 50 100 150 0 50 100 150 Work load- watts Work load- watts

Figure 11. Left ventricular ejection fraction (LVEF) and Double product (DP)

2 (Systolic BP • HR • 10 ) in 10 normal subjects, aged 11 to 21 years at rest and

during exercise • - 79-

Exercise responses in normal subjects (Age 23-60yrs) 100 a: J: 0,380 80 J: E Eaoo ~ 60 C\11 LL. •o w ';22Q.... ~ (J ..J>40 :::s "C 2140 20 c. ::cen n .. 10 :::s n=10 0 0 I I I I I c I I I I I 0 50 100 150 200 0 50 100 150 200 Work load - watts Work load - watts

Figure 12. Left ventricular ejection fraction (LVEF) and Double product (DP)

2 (Systolic BP • HR • 10 ) in 10 normal subjects, aged 23 to 60 years, at rest and during semi-supine bicycle exercise. - 80-

Discussion

This study has shown that a resting LVEF in a normal subject is usually 50% or greater. Nineteen of the 20 normal subjects in this study had an L VEF of >

50%; one subject having an L VEF of 49%.

Precise definition of the normal ventricular response to exercise is necessary to allow interpretation of the results of these procedures in individual patients. From studies in subjects without evidence of cardiopulmonary disease, the normal ventricular response to exercise has generally been defined as an absolute increment of at least 5% L VEF units without development of regional wall motion abnormalities, (Rerych et al 1978, Berger et al 1979 , Caldwell et al

1980, Pfisterer et al 1979 b,c). Such a response occurred in 18 of 20 subjects studied. Berger and Zaret (1981), have emphasised that in some individuals with an increase in sympathetic tone , L VEF is markedly elevated at rest and may not show any change with exercise. One of the remaining two subjects had a resting

LVEF of 73% and only 76% at peak exercise. It was unlikely that this subject had an abnormality of left ventricular function. However, one subject despite

2 achieving a high level of exercise (double product, 370x10 ) did not augment

L VEF adequately, rising to an L VEF of 62% at peak exercise from a resting value of 59%. This subject was a fit, healthy, 24 year old rnqle and the failure to rise

5% in this subject cannot be explained.

Little was known about the response of the left ventricle to stress in young adults and children, although recently Parrish et al (1982 a) and DeSouza et al

(1984) have examined the normal response to exercise using radionuclide - 81- angiography in children and observed a rise of at least 5% LVEF units. Age has been shown to affect the normal left ventricular response to exercise. Port et al

(1980) has shown that the L VEF may not increase with exercise in normal subjects over 60 years old and may decrease in some patients. Only 1 patient was aged greater than 60 years in this study and had a normal LVEF rise with exercise.

In conclusion, it has been shown that in normal subjects, a resting LVEF of

<50% is likely to be abnormal. Similarly, it has been established, if haemodynamic stress is adequate, LVEF will rise in both normal children and adults by at least 5% LVEF units above the resting value. - 82-

CHAPTER 7

EXERCISE LEFT VENTRICULAR FUNCTION

Quantitative radionuclide angiography at rest and during bicycle exercise has been shown to be a sensitive technique for the detection of patients with ischaemic heart disease, (Borer et al 1977 b, Pfisterer et al 1979, Jengo et al

1979, Berger et al 1979). However, in patients with atypical symptoms and in those who do not develop objective signs of myocardial ischaemia during bicycle exercise, this technique is less sensitive (Berger et al 1979). This may be due in part to difficulty with unaccustomed exercise on a bicycle , particularly in the supine position, and failure to reach adequate aerobic capacity or peak predicted heart rate. During treadmill exercise, the method most commonly used for exercise electrocardiography, subjects usually achieve a higher oxygen uptake than with bicycle exercise and are more likely to reach aerobic capacity or their peak predicted heart rate (Bruce et al1971, Niederberger et al1974).

The purpose of this study was to determine if gated equilibrium angiography performed immediately following treadmill exercise enables detection of ischaemic left ventricular dysfunction. Treadmill exercise was compared with c.onventional bicycle exercise using gated equilibrium blood pool techniques. In addition, it was possible to determine if the greater execise stress achieved on the treadmill resulted in additional information concerning left ventricular dysfunction in patients with myocardial ischaemia. - 83-

Methods

Patient Population

Studies were performed on 14 patients with angiographically proven coronary artery disease and 9 patients with atypical chest pain, angiographically normal ventricular function and coronary anatomy. The age of the patients with coronary artery disease was 53 .!. 7 years, (range 39-67 years), and of normal subjects was 38 .!_16 years, (range 20-57 years).

All 14 patients with coronary artery disease had angina pectoris on exertion despite adequate medical therapy and were candidates for myocardial revascularisation; 6 patients were functional class II, and 8 patients functional class III, according to the Canadian Heart Association classification, (Campeau

1976). Of the 14 patients, 13 were receiving beta blockade, with a mean dose of 95 mg Propranolol/day (range 40-320 mg/day). Twelve patients had a documented myocardial infarction, ranging from 2 months to 8 years previously.

Myocardial infarction was diagnosed on the basis of a typical history of chest pain, diagnostic electrocardiographic changes and evolutionary CKMB isoenzyme changes. All 14 patients had significant coronary artery disease, ie. luminal narrowing greater than 70%, including 2 with single vessel disease, 6 with double vessel disease, and 6 with triple vessel disease. Coronary angiography and ventriculography were performed within 14 days of the radionuclide studies. - 84-

A comparison was made of exercise responses obtained in patients with atypical chest pain who had entirely normal coronary anatomy without evidence of arterial narrowing. None of these patients had clinical or electrocardiographic evidence to suggest coronary artery spasm. Four of the nine patients were receiving Propranolol with a mean dose of 150 mg (range 120- , 240 mg) at the time of cardiac catheterisation. In these patients Propranolol therapy was stopped at least three days prior to the radionuclide studies.

All subjects involved in the study were in sinus rhythm without clinical evidence of heart failure or valvular heart disease.

Study Protocol

Exercise was performed using two methods; the first on a treadmill, using three minute stages according to the Bruce protocol, and secondly using a supine bicycle ergometer with a graded protocol as described previously in Chapter 3.

Radionuclide angiography was performed in all 23 patients underwent at rest and 2-4 minutes post maximum symptom limited treadmill exercise and at rest and during peak bicycle exer.cise in 18 patients using the gated equilibrium method decribed in Chapter 3. A rest period of at least 1-hour was allowed between the exercise studies. Prior to the second exercise study, heart rate and blood pressure were assessed and exercise only performed if these values were equal to the first pre-exercise baseline values. To ensure adequate recovery, left ventricular ejection fraction (L VEF) was measured before the repeat exercise study. - 85-

L VEF was measured at rest, during peak bicycle exercise and 2-4 minutes following peak treadmill exercise, using the DEC cardiac analysis programme described in Chapter 3. Heart rate and blood pressure were measured at each level of exercise and the double product (heart rate X systolic blood presure, mmHg) was calculated at each le~el of exercise. The double product has been correlated with myocardial oxygen consumption and enabled a comparison to be made between the two methods of exercise, Kitamura et al (1972), Nelson et al

(1974). All patients were monitored throughout exercise using the lead system described previously in Chapter 3. Exercise was maximal in all patients and was not stopped in any individual as a result of electrocardiographic changes, fall in blood pressure or a development of an arrhythmia. A positive electrocardiographic test was indicated by greater than 1mm of flat or downsloping ST segment depression at 80 msec after the J point. - 86-

Results

Patients With Coronary Artery Disease

Results of the group of patients with coronary artery disease are shown in

Fig. 12 and Table 4.

Angina was the limiting factor in 10 of the 14 patients, fatigue in 2, dyspnoea in 1 and claudication in 1. Exercise electrocardiography was positive in 13 of the

14 patients, whilst one patient who was limited by fatigue had no ST segment changes. The mean peak exercise double products were 213 + 65 X 102 and

2 during bicycle exercise 195 + 45 X 10 •

The mean L VEF at rest was 49 + 10% and 2-4 minutes following peak treadmill exercise 47 + 8%. With bicycle stress, the LVEF response fell from a resting value of 49 + 8% to a value of 42 + 12% at peak exercise, this fall being significant (P <0.05). The mean peak exercise LVEF by both methods was lower than the peak exercise values achieved by the normal group of subjects (P

Table 4. Mean left ventricular ejection fraction (EF), heart rate (HR) and double product (DP x 10-2) response to exercise in normal subjects and patients with coronary artery disease (CAD)

Treadmill equilibrium Bicycle equilibrium Rest EX PEX Rest EX

· Normal subjects EF~o 54~ 64•7 52•5 61*7

HR±so 75:8 161-:L-30 97:13 87*13 129-:L-31

DP:tso 93:18 280-:L-83 149*35 110-:L-21 204:58

CAD patients EF:tso 49:!:10 47:1:8 49*8 42:!:12

HR:tso 64•ll 135•30 84•15 7l•ll 117•23

DP:rso 85•21 213~5 136>140 94•12 195~5 - 88-

Treadmill and bicycle exercise in patients with coronary artery disease Treadmill Bicycle 80 n•14 n=11

LVEF 60 % 40

R PPEX R PEX

130 HR min 110 70 ~ ox I PEX

230 DPX10-2 150 ) 70 PEX I I I I I R PPEX R PEX

Figure 12.Stress response in patients with coronary artery disease • Left ventricular ejection fraction (LVEF), heart rate (HR) and double product (DP) at rest (R), peak bicycle exercise (PEX) and 2 to 4 minutes post treadmill exercise

(PPEX). - 89-

Results

Patients With Normal Coronary Arteries

Results of the normal group of patients are shown in Fig. 13 and Table 4.

Fatigue was the limiting factor in 7 of the 9 subjects at maximal exercise,

whereas 1 was ceased at the limits of the Bruce protocol and 1 was limited by

angina. This patient also developed 5 mm horizontal ST segment depression

while another developed rate dependent left bundle branch block. The double

products achieved were 280 .::_ 83 X 10-2 with treadmill exercise and 215 .::_ 61 X

10-2 with bicycle exercise being significantly smaller (P <0.05).

The mean LVEF at rest by the equilibrium method was 56±6% increasing to 64

~ 7%, 2-4 minutes following peak treadmill exercise, and 61 *7% during peak bicycle exercise. The increase in LVEF by both methods was significant (p<0.01) but peak exercise LVEF by bycycle stress was not significantly different from that obtained following peak treadmill exercise. - 90-

Treadmill and bicycle exercise in normal subjects

80 Treadmill Bicycle n=9 n=7 LVEF60 ~ % 40 e. e- 6-~.g. '?' p<0·01 p<0·01 R PPEX R PEX

170

HR 130 min 90 oX I PEX 310~ 230 2 DP•16 150j

701 PEX oY l l ! I I R PPEX R PEX

Figure 13. Stress response in normal subjects. Left ventricular ejection fraction (LVEF), heart rate (HR) and Double product (DP) at rest , peak bycycle exercise (PEX) and 2 to 4 months post treadmill exercise (PPEX). - 91-

Discussion

Due to problems of motion during treadmill exercise, accurate radionuclide evaluation of ventricular function is not feasible. This data demonstrates that quantitative radionuclide angiography following either maximal treadmill exercise or during peak bicycle exercise can discriminate between patients with coronary artery disease and normal subjects. Treadmill exercise yields more clinical information and allows a higher level of cardiovascular stress than does bicycle exercise (Bruce 1971, Niederberger et al1974). For this reason treadmill exercise is more commonly used in exercise laboratories, Ellestad et al (1979) and is often preferred by the patient. Treadmill exercise radionuclide angiography may be useful in the patient who is unwilling or unable to exercise on the supine bicycle.

The level of cardiovascular stress, as assessed by the maximum rate pressure product, was greater on the treadmill than on the bicycle. Patients with coronary artery disease showed either failure to increase ejection fraction normally or demonstrated a slight decrease in ejection fraction following treadmill exercise. In contrast, these same patients, when imaged at peak supine bicycle exercise, demonstrated a significant decrease in ejection fraction (P

<0.01). In comparing the results of these two techniques, it should be noted that imaging was performed immediately following maximal treadmill exercise, when the rate pressure product had fallen, indicating that, although there was some haemodynamic recovery from exercise stress by the time of imaging, ischaemic left ventricular dysfunction persists for some time following treadmill studies. - 92-

In only 1 of the 28 studies performed in patients with ischaemic heart disease was a normal exercise response obtained. This may be an example of the "over shoot" phenomenon noted by Caldwell et al (1980) and Pfisterer et al (1979 c).

They described the transient improvement in ventricular function in patients with coronary artery disease during the early recovery period. This recovery phenomenon is more commonly observed in those patients studied following supine bicycle exercise in whom legs are lowered early in the recovery period.

This leads to a reduction in venous r~turn and lower ventricular preload. In our patients, treadmill exercise was performed upright and imaging was performed supine, which may have prevented the marked immediate post-exercise reduction in preload. Battler et al (1980) also found the magnitude of the ejection fraction change from rest and that following treadmill exercise could identify coronary artery disease patients. They concluded that this differentiation from normal subjects was more marked at the period eight to ten minutes post treadmill exercise. In our patients, heart rate and blood pressure would have returned almost to normal by this time.

Although imaging of the subjects with normal coronary arteries following both forms of exercise showed a clear differentiation from patients with coronary artery disease, one patient showed a fall in ejection fraction following treadmill exercise. It could be argued that these subjects serving as normal controls may not respond to exercise in a homogenous manner. These subjects presented with chest pain syndromes resembling angina pectoris nece~sitating coronary angiography for evaluation. Berger et al (1979) examined a group of patients with chest pain and normal coronary angiograms and demonstrated that a - 93- significant proportion of this group had abnormal left ventricular responses to exercise.

Adequate intervals of at least one hour were allowed between each exercise study to allow full recovery with each patient returning to baseline haemodynamic values prior to either treadmill or bicycle exercise. The evaluation of ventricular function before the second exercise study demonstrated stable baseline function and thus it is unlikely that the performance of serial exercise studies on the same day significantly affected these results.

In conclusion, it has been shown that radionuclide angiography performed following treadmill exercise results in an abnormal ventricular response and allows discrimination of normal subjects from patients with ischaemic heart disease. The magnitude of the abnormal response was greater however, with bicycle exercise, suggesting that bicycle exercise is a more sensitive technique in detecting ischaemic changes in left ventricular function. - 94-

CHAPTER 8

VENTRICULAR VOLUMES

Invasive left ventricular angiography and pressure recordings have led to the

quantification of sensitive parameters of left ventricular performance such as

ejection fraction, wall stress, pressure volume relationships, and changes in left

ventricular compliance. Central to the calculation of these parameters is an

accurate measure of left ventricular volumes. End-diastolic volume can reflect

the filling or preloading conditions of the left ventricle. Left ventricular end­

systolic volume, when related to left ventricular end-systolic pressure, is an

important indicator of intrinsic myocardial contractility independent of the

loading conditions of the left ventricle (Mehmel et all981, Slutsky et all980 c).

Changes in end-diastolic and end-systolic volumes may explain alterations in

ejection fraction following pharmacological intervention or after exercise stress.

The original methods of measurement of ventricular volumes using

angiocardiography required direct manual measurements based on a tracing of

the ventricular outline from the ventriculogram, geometric assumptions and subsequent mathematical calculations. Generally these calculations were made according to the methods described by Sandler and Dodge (1967), assuming the left ventricle is shaped in the form of a prolate ellipse. Using a standard geometric model, m!=lasurements of left ventricular volume may be affected by significant wall motion abnormalities commonly seen in patients with coronary artery disease. Decisions must be made concerning the outline of papillary - 95- muscles derived from the analysis of the left ventricular silhouette. In addition, angiocardiography is invasive, making serial studies difficult and may itself produce haemodynamic changes that will affect left ventricular performance.

Both echocardiography and early radionuclide techniques that were used to measure left ventricular volumes relied on similar geometric assumptions often utilising a single linear dimension to obtain a volume measurement.

Measurements using M-mode echocardiography have relied heavily on assumptions that relate the long and short axis, and are particularly susceptible to error. With the gated equilibrium technique separation of the right ventricle and left ventricle using radionuclide angiography is only possible in the left anterior oblique view and thus measurement of the long axis of the left ventricle in this view is particularly difficult.

Slutsky et al (1979 c) introduced a non-geometric method of calculating left ventricular volume using the radionuclide gated equilibrium technique. They used the counts from the left ventricular region of interest to calculate left ventricular volumes and showed that left ventricular volume could be calculated independently of geometry ie. assumptions used in cineangiography.

Slutsky et al (1979 c) normalised activity within the left ventricular region of interest to the concentration of activity in a known volume of peripheral blood measured in a auto-gamma counter. The technique of measuring this peripheral blood sample was modi lied by Dehmer et al (1980) and also by Slutsky et al (1980 b)by measuring the activity in a standardised container in front of the collimator · acquiring the counts on the computer using identical settings to the patient's study. This method enabled calculation of left ventricular volume in - 96- arbitrary radionuclide units.

However this count based method of calculating left ventricular volumes also has several assumptions. There is substantial photon attenuation caused by extra­ cardiac and chest wall structures. Both Slutsky et al (1979 c) and Dehmer et al

(1980) relied on a uniform correction for this attenuation by previously deriving a regression equation using these arbitrary radionuclide volume units and contrast angiographic volumes. Using this regression equation, absolute volume measurements could be made by substitution of the radionuclide units into this equation and calculation of an absolute left ventricular volume in mls. Links et al (1982), described a method in which an individual estimate of tissue attenuation was calculated for each patient by calculating the depth to the centre of the left ventricle, and proposed that it was more accurate for general use than the simpler methods of both Slutsky et al (1980 b) and Dehmer et al

(1980). Links et al (1982), found there was great variation in attenuation between individuals while the use of a regression equation necessitated its re­ establishment whenever the acquisition or analysis programmes were changed.

Further the count based method ignores self attenuation. Slutsky et al (1980 b), noted a loss of the linear relationship between volumes and observed counts at higher values. They suggested this was due to increased photon attenuation within the left ventricle. Self attenuation did not present a problem with small or normal sized hearts. Parrish et al (1982 b), did not note any effect of self attenuation in the children he studied. Links et al (1982) showed that in patients with very small ventricles (<50 ml) or very large (>500 ml) attenuation would be significantly different from the patient with a normal size left ventricle - 97- although the amount of self-attenuation was not calculated in their study.

Selection of a left ventricular region of interest is crucial to the accurate calculation of left ventricular volumes. Links et al (1982) demonstrated that the use of a semi-automated programme to define left ventricular activity and background led to a consistent underestimation of volumes not found using manually drawn regions of interest. However manually drawn regions were associated with considerable (12%) intra-observer variability in volume measurement and they admitted this problem was a limitation of their method.

Dehmer et al (1980) stressed the importance of reproducible background determinations which were unlikely to be achieved using manual observer dependentana~seL

In this study the radionuclide count based method of calculation of left ventricular volumes was evaluated, using firstly, a cardiac phantom and secondly, confirming the accuracy of methods reported previously in human subjects.

I. A cardiac phantom was used :

(a) to examine the effects of photon attenuation on the relationship between observed counts and volume within a chamber similar to a left ventricle.

(b) to examine the accuracy of a semi-automatic programme used for deriving a background region, at various chamber volumes and depths within an attenuating water bath. - 98- n. In human subjects studies were performed:

(a) to compare the accuracy of three previously described methods of measuring left ventricular volumes in human subjects.

(b) to examine the accuracy of two methods of counting the peripheral blood sample for normalisation of the observed counts within the left ventricular region of interest.

(c) to examine the inter-observer error in deriving end-systolic and end­ diastolic counts within the left ventricle using a semi-automatic programme.

(d) to examine the reproducibility of measuring the depth from the chest wall to the centre of the left ventricle • - 99-

1. CARDIAC PHANTOM STUDY

The cardiac phantom described in Chapter 3 was used in this study to examine the effects of photon attenuation on the relationship between observed counts and balloon volume. The balloon volume was adjusted to include volumes usually found in the normal and pathological human heart. As radioactivity could easily be added to the surrounding water bath to simulate blood background, the adequacy of an automatically derived method of background subtraction was also assessed.

Methods

The balloon of the cardiac phantom was placed in an aery lie bath which was designed to mimic the left ventricle within the thorax. The balloon was filled to a volume of 500 ml and an aliquot of Tc-99m (168 MBq) was added.

Approximately 12 litres of water was added to the tank to submerge the balloon completely. Water was used as it has a half value layer for Tc-99m similar to that of soft tissue. A half value layer is defined as the thickness of material which attenuates one half of the incident photons. The half value layer of both water and soft tissue for Tc-99m is 4.5 em. The study was performed with the balloon at two depths of water, ie. 7 and 14 em, to examine the effects of attenuation by water on activity within the balloon. These distances were chosen as they represent the • unge of depth to the centre of the left ventricle commonly found in man, derived from examination of a number of routine computerised tomographic images performed in this hospital on adults. To examine the linearity of the estimation of left ventricular volumes and effects - 100- of self attenuation counts were obtained at decrements of 25 ml until the balloon was emptied.

The balloon was imaged for periods of two minutes and the edge defined using the MDS cardiac analysis semi-automatic programme as previously described in Chapter 3. Counts were obtained for each volume of the balloon.

To compare the counts obtained from each of the acquisition periods, the decay of the isotope Tc-99m was corrected by the following formula:

No = Nc exp(0.693T /T t) where No = corrected counts, Nc = measured counts, T = time from the start of the study T t = half life of Tc-99m.

The accuracy of an automatically designated area simulating left ventricular background outside the lateral wall of the balloon was assessed by adding a further aliquot of Tc-99m (120 MBq) to the water bath and the study repeated at the same two distances. Background was automatically defined as a region five pixels wide, five pixels lateral from the balloon edge. The top and bottom of the region of interest of the balloon served as top and bottom of the background region and the average counts/pixel of the lower two-thirds of the region was then used for background correction. - 101-

Results

The relationship between observed counts and volume of water within the balloon is shown in Fig. 14 and Table 5. It can be seen that for volumes up to 500 ml at both depths of 7 and 14 em, this relationship is linear without evidence of the reduction of counts at larger volumes which would suggest attenuation of photons within the chamber itself, ie. self-attenuation. However, attenuation by water outside the balloon within the tank resulted in a marked reduction of observed counts in the balloon placed at 14 em of water between it and the detector, compared with the closer distance of 7 em. The ratio between the observed counts at both depths remained very similar throughout, the range of values varying from 2.49 to 2.77. With the difference of 7 em between these two studies, the predicted ratio using the linear attenuation for Tc-99m in water of

0.15 cm-1 is 2.87.

Activity was added to the bath and a background region drawn outside the balloon as designated by the routine semi-automatic programme . The counts in this background region were corrected to the balloon size and were then subtracted from the total observed counts resulting in values virtually identical to that obtained without background added to the surrounding water bath (Fig.

14). - 102-

Table 5. Counts within the balloon and following subtraction of added activity at 7 & 14 ems of water.

Voh.Jme Depth NoBkg Bkg corrected Depth NoBkg Bkg corrected (mls) (em) (ctsx10-4/min) (ctsx10-4/min) (em) (ctsx10-4/min) (ctsx10-4/m in)

0 7 0 0 14 0 0

25 7 1 4.1 14 0.95 50 7 8.1 11.2 14 3.1 4.1

75 7 :).9.0 20.9 .14 6.9 7.2

100 7 26.9 27.5 14 9.7 10.0

125 7 34.2 35.2 14 12.7 13.4

150 7 41.2 41.6 14 15.1 15.8

175 7 48.2 48.8 14 18.1 19.0

zoo 7 55.9 56.9 14 21.3 22.4

225 7 64.0 65.0 14 25.2 26.1

250 7 73.9 25.8 14 27.9 29.4

275 7 14 30.6 32.8

300 7 85.8 87.8 14 33.2 36.9

325 7 92.6 94.2 14 35.9 37.7

350 7 100.8 101.5 14 38.8 4_0.9

375 7 106.4 107.4 14 41.2 43.3

400 7 114.7 115.8 14 43.6 44.7

425 7 121.5 126.1 14 46.6 48.0

450 7 128.8 130.2 14 50.0 52.4

475 7 135.0 136.8 14 53.7 56.9

500 7 139.2 140.7 14 55.8 58.5

Abbreviations: Bkg = background; cts = counts. -103-

Effect of attenuation within the water bath

140 x No bkg in bath • Bkg subtraction of 120 activity in bath

~•o 100 ~ )( 7cm depth .5 80 ...... __E ....,fl) c 60 :l 8 40

0~-.--.-.--.--.--.-.--~~~ 0 100 200 300 400 500 Volume- ml

Figure 14. The relationship between observed counts and balloon volumes from 0 ml to 500ml at two water bath depths, 7 and 14 em, without background activity

(bkg) added to the water bath and with background activity added and then subtracted using a standard background subtraction programme. - 104-

Discussion

The phantom work showed that when activity was added to the phantom

balloon the volume of that balloon was linearly related to observed counts at a

range of volumes up to 500 ml. It appeared unlikely therefore, that with the

sizes of the left ventricle commonly observed in man, self-attenuation within the

left ventricular cavity would be a problem.

The semi-automatic programme used for selecting the regions of interest

around the balloon and for the background region lateral to the balloon were reliable, although any consistent under or over-estimation of counts within these

regions were not examined in this study.

A predictable amount of photon attenuation occurred in the water bath at

varying depths, suggesting that attenuation will occur in humans, and this

attenuation could be predicted if the depth to the centre of the ventricle could

be measured, assuming the attenuation coefficient for water is in fact similar to

soft tissue.

The obvious limitations of this phantom study are that the chamber shape was

uniform without overlap of other structures; that the background within the

water bath was uniform and the balloon was stationary. Clearly this is not the

case in the human heart where the delineation of the left ventricular edge is

difficult due to other cardiac chambers. Furthermore, regional abnormalities of

left ventricular function can alter the shape of the left ventricle considerably

and background activity can be quite variable. -105-

2. HUMAN STUDIES

The aim of this study was to examine the three non-geometric radionuclid~

methods described in the medical literature for the measurement of ventricular

volumes to determine the most suitable for the proposed clinical studies (Slutsky

et al (1979 c), Dehmer et al (1980) and Links et al (1982)). The first two techniques do not utilise an individual attenuation correction and volume is

measured in arbitrary radionuclide units. To correct for attenuation and to

obtain an absolute volume, the radionuclide unit volume is substituted into a regression equation which must be derived previously by comparing radionuclide volumes with cineangiographic volumes. Both these techniques differ in the method by which the peripheral venous sample is counted, either in an auto­ gamma counter (Slutsky et al 1979 c) or on the face of the gamma camera, as subsequently described by Dehmer et al (1980). Links et al (1982), who described the third technique, counted the activity in the peripheral venous sample on the face of the gamma camera and provided a method for calculation of attenuation for each patient based on the depth of the left ventricle from the skin. The values obtained for volume were therefore, absolute and independent of a regression equation • - 106-

2. HUMAN STUDIES

The aim of this study was to examine the three non-geometric radionuclide methods. All patients were in sinus rhythm and none had mitral or aortic regurgitation. Contrast ventriculography was performed before coronary angiography when all patients were stable and free of angina. All ventriculograms in the study were performed using an 8 French Judkins pigtail catheter carefully positioned in the centre of the left ventricle in the right anterior oblique projection (RAO). Forty to 45 ml of Urograffin was injected under pressure at a rate of 10 ml/second. Correction for magnification was made using a a bar of predetermined length positioned at the estimated centre of the left ventricle at the same distance the left ventricle was from the x-ray tube. The left ventricular long axis was measured from the plane of the aortic valve to the left ventricular apex. Left ventricular volumes were calculated from the end-systolic (maximal inward movement of the left ventricle) and end­ diastolic frames (maximal outward motion) of an ectopic free beat using the single plane formula of Sandler and Dodge (1967):

where LV = the LV volume measured in the RAO projection, A = LV area, L = the length from the centre of the aortic valve to the LV apex, CF = correction factor for magnification. - 107-

The volume was then corrected using the modified single plane RAO regression equation of Wynne et al (1978):

LVv = 0.938 LVRAO- 5.7 cc

where L Vv = actual volume, L VRAO = the volume measured in the right anterior oblique projection.

Radionuclide studies were performed within 7 days of contrast angiography. No patient had a change of medication and all were clinically stable. The red cells were labelled using the in vitro method previously described. A left anterior oblique view (LAO) which provided the best separation of the right and left ventricles, was acquired on the computer for 3 minutes. At the middle of the acquisition period, a peripheral sample of blood was taken. End-systolic and end-diastolic counts were obtained from the time volume curve using the MDS cardiac analysis programme outlined previously in

Chapter 3. With Method 1 -Slutsky et al (1979 c) , activity in the peripheral blood was counted in an auto-gamma counter and in Method 2 - Dehmer et al

(1980), in a standard container 5 em from the face of the collimator in the centre of the field of view, acquiring the counts on the computer using identical settings to the patient's study. - 108-

End-diastolic (EDVr) and end systolic volume (ESVr) were measured in arbitrary radionuclide units ie:

EDVr = end-diastolic counts (blood counts/ ml x number of cardiac cycles x time/frame).

ESVr = end-systolic counts

(blood counts/ ml x number of cardiac cycles x time/frame)

Using Method 3 described by Links et al (1982), individual measurements of tissue attenuation were made after determination of the depth of the left ventricle within the body. This was achieved by placing a radioactive marker on the skin in the left anterior oblique view as shown in Figure 15 such that the source was equidistant from the left ventricular (LV) borders. The camera was then rotated to the anterior position and an image acquired on the computer.

The angle of the LAO view was noted and the foreshortened distance d' from the centre of the left ventricle to the skin mark as seen on the computer image was measured in pixels which is converted to centimeters. The true depth d of the centre of the LV in the LAO position was calculated as:

d = d'/Sin €) where C.: the angle of the LAO view. (Fig.15). -109-

Measure of depth to centre of LV

A B

Figure 15. Schematic representation of the method for measuring the depth (d)to the centre of the left ventricle (A). • A radioactive marker was placed on the skin as seen in the LAO view. The camera was then rotated to the anterior projection

(B) and an image acquired on the computer .The angle of the LAO view was noted and the distance (d') from the centre of the LV to the skin mark was measured. Then d = d'/sin9. -110-

The radionuclide volume obtained by Method 2 was corrected for tissue attenuation using the linear attenuation coefficient ll of Tc-99m in water of

0.15 cm-1 for the estimated depth of the left ventricle. The absolute volumes were then calculated by the following equation:

EDV = EDVr/e-!ld and

ESV = ESVr/e-lld where e-!ld = depth correction factor.

Interobserver variability

To examine interobserver variability counts measured at end-diastole and end­ systole were repeated by a second blinded independent observer. Each observer defined the edge of the left ventricle at end diastole by placing a box around the left ventricle excluding other cardiac and extra-cardiac structures. The programme subsequently defined the left ventricular edge throughout the cardiac cycle.

Distance d was measured by a second independent observer to examine the potential source of error of this measurement.

Data Analysis

The first two Methods (1 and 2) were compared to determine whether the result was affected by counting the peripheral blood in the well counter (Method

1) or on the camera (Method 2); the step required for normalisation of activity - 111- in peripheral blood. These uncorrected methods and the attenuation corrected method (Method 3) were then compared with a corresponding single plane cineangiographic left ventricular volume by least square linear regression analysis to obtain correlation coefficients, regression equations and standard errors of the estimates. These correlation coefficients were compared by

Fischer•s Z transformation. Group mean data were expressed as a mean~ SO.

Results

Fig. 16 shows a comparison of the two non-attenuation corrected methods for all volumes (Methods 1 and 2) which differ only by the method of counting the peripheral venous sample. It shows a high correlation of r = 0.98, y = 25x -

40. As the same end-diastolic (ED) and end-systolic (ES) counts were used this indicates that both methods were accurate for measuring counts in the peripheral blood and no obvious errors had occurred in this part of the study for any patient.

The range of angiographic volumes was 15 to 205 ml. The correlation between end systolic and end diastolic volumes obtained from Method 1 and contrast angiography was 0.83, SEE = 169 units and the regression equation was y = 4.86x + 100. Figure 17 shows a correlation of end-diastolic and end-systolic volumes using Method 2 measured in arbitrary radionuclide units with single plane cineangiography. Using Method 2, the carreL ~ion was 0.88, SEE = 6 units, Y =

D.2x + 4.9 (Fig. 17).

Fig. 18 shows the comparison of Method 3, ie. the attenuation correction method of Links et al (1982) with single plane cineangiography. There was a significant correlation of 0.91 and a regression equation of y = D. 7lx +20, SEE = - 112-

COMPARISON OF TWO NON-ATTENUATION CORRECTED METHODS

1400

1200

1000 ;::t "C 0 .r:: • ED Q,) 800 • ::!:- ... ES -X cLIJ z 600 LIJ ::!: ::::;:) = ....J • N 38 0 > 400 r = 0.98 z c::: 200

0 0 10 20 30 40 50 RN VOLUME INDEX (Method 2)

Figure 16. Comparison of 2 non attenuation corrected methods (Methods 1 & 2)

for determining a radionuclide volume in arbitrary units. - 113-

COMPARISON OF RN VOLUME INDEX WITH CONTRAST ANGIOGRAPHY

50 • ED •

& ES C\i -o 40 • • .s::::0 - • Q,) :E- • • ...... X 30 I.U • c z I.U ... N = 38 :E ... • :::1_. 20 r = 0.88 0 > z y = 0.20x + 4.9 c:: SEE = 6 10 ...... 0 0 50 100 150 200

CONTRAST ANGlO VOLUME (ml)

Figure 17. Comparison of all end diastolic and end end systolic volumes using

Method 2 (non -attenuation corrected) with contrast angiography. -114-

COMPARISON OF RN VOLUME WITH CONTRAST ANGIOGRAPHY

• ED 200 ... ES . • 150 E

LIJ :E ::::>_, 0 N = 38 > 100 z r = 0.91 c:: y = 0.71x +20 50 SEE = 17

0 0 50 100 150 200

CONTRAST ANGlO VOLUME (ml)

Figure 18. Comparison of actual radionuclide volume in mls (Method 3) with

contrast angiography. - 115-

20 ml. The results of both Method 2 in arbitrary radionuclide units and Method 3

in mls were plotted together against cineangiographic volumes with a line of

identity placed as shown in Fig. 19. The effect of attenuation can be seen for the

uncorrected values of Method 2 and the manner in which these effects are

reduced by the use of an individualised attenuation correction method (Method

3). Table 6 shows correlations of end systolic and end diastolic radionuclide

volumes for the three methods with cineangiographic volumes. The correlation

at end systole was better than at end diastole as is graphically shown in Fig. 19,

where there is greater scatter for the end diastolic volume values. Depth

correction did not cause a significant improvement in the individual correlation coefficients, and in fact,

for end systolic volume it decreased slightly. Using Fischer1s Z transformation

there were no signficant differences between these correlations for the volumes

measured by each of the three methods for end diastole and similarly for those

measured at end systole.

Interobsever Variability.

End diastolic and end systolic counts from the left ventricular region of interest.

Twelve of the 19 studies were randomly selected and the counts at ED and

ES were remeasured by a second independent observer without knowledge of the

initial result. Using the semi-automatic edge de:: 3ction programme, highly reproducible values for end diastolic and end systolic counts were obtained with

a correlation of 0.99 between the initial and second observer with no statistical differences demonstrated. - 116-

EFFECT OF ATTENUATION CORRECTION ON RN VOLUME

• ED Method 3 A ES

• ED 200 Method 2 o ES

150 • • =- -E IJJ • :E • • • => ...J 100 • 0 • > A • A z A • c::: A A 50 • • • db • •·- • 0 0 0 • • • 0 • • • • 0 0 • • 0 0 50 100 150 200

CONTRAST ANGlO VOLUME (ml)

Figure 19.Comparison of Methods 2 (uncorrected) and Methods 3 (corrected) with contrast angiography shown with the line of identity. Without attenuation correction, radionuclide volume units are much lower than actual volumes. - 117-

Table 6 Comparison of Radionuclide Volumes with Contrast Angiography.

rVALUE REGRESSION EQUATION SEE

END-SYSTOLIC VOLUME

METHOD 1 0.91 y =7.68x + 27 94

METHOD 2 0.93 y = 0.29x + 0.50 3

METHOD 3 0.88 y = 0.87x + 11 13

END DIASTOLIC VOLUME

METHOD 1 0.63 y = 4.5x + 133 212

METHOD 2 0.69 y = 0.17x + 8.4 7

METHOD 3 0.74 y = 0.57x + 40 20 - 118-

Estimation of depth (d) to the centre of the left ventricle.

The same observer also repeated the measurement of distance to the centre of the LV crucial to the calculation of absolute volume in Method 3. These depths ranged from 6.8 to 11.9 em. The second observer showed a maximum difference of 0.4 em (1 pixel) in this measurement of tissue depths. Allowing for the difference, the maximum error in the calculation of the previously derived left ventricular volume using Method 3 was only :1:5%. - 119-

Discussion

This study has confirmed the observation using the cardiac phantom that

there is a linear relationship between counts within the left ventricle and volume

of that chamber. The gated equilibrium technique can be used to calculate

ventricular volume using either uniform attenuation correction factors for all

patients derived from a linear regression analysis with cineangiography or an

individualised method for attenuation correction based on the measurement of chest wall thickness. In the subgroup of patients in this study undergoing cardiac catheterisation for investigation of chest pain, both the techniques appear to be suitable. A superior correlation with cineangiography occurred with the

measurement of end-systolic volume rather than end-diastolic volume.

Possible sources of error using the radionuclide technique were examined.

As shown by the cardiac phantom study, self-attenuation within the dilating ventricle was not significant for volumes as large as 500 ml, despite the previous report by Slutsky et al (1980 b) which suggested self-attenuation was significant at volumes > 400 ml. However, it is true in our human subjects that correlation with contrast angiography was poorer for end-diastole than for end-systole as found by Slutsky et al (1980 b). Starling et al (1984), found a poorer correlation of radionuclide angiography with cineangiography for end-diastolic volumes. It is possible that accurate delineation of larger left ven .. 1 icular volumes using cineangiography may be affected by increasingly poor edge delineation due to overlap of extra-cardiac structures and dilution of contrast. - 120-

The manner in which the peripheral sample of venous blood was counted was

cross-checked by counting on the camera head and it has been shown that this

error was minimal. It was felt that Method 2 of Dehmer et al (1980), which

involved counting the peripheral sample on the gamma camera head, was not

only easier, but more closely related to the patient situation. Clements et al

(1981), also preferred this technique.

Other potential sources of error include improper selection of background and left ventricular regions of interest. Both these regions were drawn using the routine semi-automatic programmes used for calculation of ejection fraction.

The choice of these programmes can be justified on a purely empirical basis, because good correlations were obtained with contrast angiography without systematic under- or over-estimation. My results, however, differ from

Rabinovitch et al (1984), who found that the use of second derivative edge detection programmes excluded some LV counts as they under-estimated LV v.olumes even with attenuation correction. No study has examined the effect of varying the threshold for calculation of left ventricular volumes using the automated second derivative edge detection programme. They agreed however, that a region of interest drawn manually, larger than the ventricular region would introduce considerable inter-observer variability as shown by Links et al

(1982). It is possible that manually derived regions of interest for the LV edge and background may improve the correlation with contrast angi11graphy, but this was not examined in my study.

The linear attenuation coefficient for water 11 of 0.15 cm-1 was used on the basis of water's similarity to blood and soft tissue. Although lung tissue, which is less dense than water, is in the path of photons from the left ventricle, bone, which is denser than water, is also in the path, tending to make the effective - 121-

attenuation coefficient closer to that of water. However, this value

theoretically applies to a narrow beam of photons passed through an infinitely

thin section of water, clearly not the circumstances in this study where there is a bulk source located some distance from the camera. In this situation some photons would be expected to undergo multiple scatters and be directed back towards the detector, lowering the value of !.1. by a small amount.

Although reproducibility data of vc;:llumes measured by cineangiography were not examined in this study, it is known that considerable inter-observer error occurs in the measurement of left ventricular volumes by this technique.

Ejection fraction which is derived from a measure of left ventricular volumes has been shown by O'Kada et al (1980 a), to have an inter-observer variability of

11.6% and by Chaitman et al (1975), 8%. In addition, their measurements were based on geometric assumptions about the shape of the left ventricle. In the group of patients studied on this occasion, all had coronary artery disease, many with regional left ventricular dysfunction, in whom geometric assumptions essential to these calculations may be less applicable. It is also well known that due to the invasive nature of the technique and the direct effect of contrast on the ventricle, left ventricular function may be different to that measured in a stable state. To minimise these possible errors, contrast angiography was performed prior to coronary angiography while the patients' were clinically stable. Only ectopic free beats of the ventriculogram were chosen for analysis.

There was not a large inter-observer error in the analysis of radionuclide volumes. Despite observer interaction at various stages of the measurement of volumes used in the radionuclide techniques, there was a close correlation for - 122-

counts obtained within the ventricular regions of interest at both end-systole and

end-diastole as was the measurement of the depth to the centre of the left

ventricle, crucial to the measurement of attenuation. Thus the source of error

from the radionuclide data in estimation of left ventricular volumes appeared to

be quite small.

In conclusion, the use of an individualised method for correction of attenuation does not appear to offer significant advantages over the use of a

uniform correction factor based on linear regression analysis. Mainly for

practical reasons related to methodology, the method described by Dehmer et al

(1980) appeared to be preferable for patients having serial studies as it was

unlikely that attenuation would be altered significantly from study to study.

Care however, was necessary to extrapolate the results of this study to patients with widely variable body habitus, patients in whom attenuation was likely to be non-uniform. It is in this situation that an individualised correction for attenuation using the method described by Links et al (1982) would be preferable. Certain difficulties arise using cineangiography as a standard for this study, and it is possible that certain inherent advantages of the radionuclide technique may make it a more reliable method of measurement of absolute volumes in the future. - 123-

CHAPTER 9.

REGIONAL WALL MOTION ASSESSMENT

Regional wall motion assessment: comparison of 2-dimensional echocardiography and radionuclide angiography with contrast angiography in healed myocardial infarction.

Accurate evaluation of regional left ventricular function is important for the assessment of patients with coronary heart disease. Radionuclide angiography (RNA) and two dimensional echocardiography (ZOE) are now two widely available techniques used to assess wall motion and to detect ventricular aneurysms. Although there are studies (Hecht et al 1981, Sorensen et al 1982,

Kisslo et al 1977, Brady et al 1980 b, Freeman et al 1981 c, Kelly et al 1981,

Berman et al 1975, Okada et al 1980 b, Federman et al1978, Heger et al 1979 , Schad, 1977) showing that each method correlates closely with cineangiography for the evaluation of regional wall motion, there is a paucity of data comparing the ability of these techniques to examine segmental motion of the left ventricle in the same group of patients (Heger et al1981, Sorensen et al1982). Technical advances have also made comparisons of imaging modalities from some earlier studies invalid since alternative projections to visualise the left ventricular wall optimally and additional methods of analysis of wall motion data are now available. Furthermore, most previous studies have involved many patients with normal left ventricular function. As normal left ventricular wall motion can be recognised more easily than abnormal motion, diagnostic accuracy may have been influenced in these studies. - 124-

In this study regional left ventricular wall movement was assessed in a patient population with a high likelihood of significant abnormalities of left ventricular performance, using in each patient radionuclide angiography and biplane contrast angiography. The results were compared to a similar assessment in the same patients using two-dimensional echocardiography. The aim of the study was to assess the accuracy of radionuclide angiography in identifying abnormalities shown at cardiac catheterisation and comparing these results with another widely used imaging technique. - 125-

Materials & Methods

Patient Population

The study group consisted of 52 consecutive patients undergoing elective cardiac catheterisation for the evaluation of angina who had sustained a previous myocardial infarction from 2 months to 12 years previously. There were 44 males and 8 females, age 58±9years of whom 39 had Q wave infarcts and 13 non-Q wave infarcts.

Study Protocol

All patients had RNA and 2DE studies performed within 48 hours of cardiac catheterisation and were clinically stable requiring no changes of therapy.

(a) Radionuclide Angiographic Technique

Gated equilibrium biood pool imaging was performed after in vitro labelling of the patient's red cells with 13.5 mCi/m2 or 500 MBq/m2 of technetium-99m pertech.1etate which gave a total body radiation dose of 340 mRads (Hegge et al

1978). Data were collected using an Ohio Nuclear 420 gamma camera interfaced with a Digital gamma 11 PDP 11/40 computer (Chapter 3). Using a high resolution collimator, computer data were acquired in frame mode at 24 frames/cardiac cycle in a 64 x 64 matrix with 350,000 counts acquired per frame in each study. Studies were performed at rest in a 30° right anterior oblique, - 1Z6-

anterior, modified left' anterior oblique and left lateral views. The four views

obtained Were displayed and interpreted in a flicker free cine format with 9-1Z

images/sequence at a rate of 80 cardiac cycles/minute.

(b) Echocardiographic Technique

All ZOE studies were performed by two experienced ultrasonographers.

Echocardiograms were obtained with a commmercially available phased array system (Toshiba [SSH10A]) using a Z.4 megahertz transducer with 3Z elements

and a sector scan of 84°. ZOE examinations were performed using parasternal and apical windows to view all left ventricular wall segments. Parasternal views were recorded in the long axis in the 3rd and 4th interspace, while apical views were obtained with the patient lying on the left side with the transducer placed near the maximal apical impulse. An apical four chamber view was obtained in a plane perpendicular to the interatrial and interventricular septa. The transducer was then rotated anti-clockwise, 90°, for the orthogonal apical two chamber view of the left ventricle and left atrium. Real time images were recorded on video tape. The recorded images wre replayed for analysis in real time, slow motion and stop action modes. -127-

(c) Contrast Angiography

Cardiac catheterisation was perfor~ed using the percutaneous femoral artery approach. Biplane ventriculography was performed in the 30° right anterior oblique and the 60° left anterior oblique views prior to coronary angiography.

Each ventriculogram was performed with an 8 French Judkins pigtail catheter shaped to lie centrally in the body of the left ventricle to minimise ectopic activity. Contrast medium, 0.55-0.65 ml/kg, was injected under pressure (1000. psi) at a rate of 10 ml/sec and the study filmed at 50 frames/sec. Following ventriculography all 52 patients underwent coronary angiography by the Judkin's technique. All ectopic beats and first post-ectopic beats were excluded for wall motion analysis. All contrast studies were analysed in real time from the cine display.

(d) Left Ventricular Regional Wall Motion Assessment

All RNA, ZOE and contrast angiographic studies were interpreted independently by two blinded, experienced observers without knowledge of the patient's clinical data. Wall motion could not be assessed in 5 echocardiographic studies d·:e to the inadequate endocardial definition and these patients were therefore excluded from all subsequent comparative analysis. Comparative analysis of LV segmental wall motion obtained by all three imaging techniques was possible in the remaining 47 patients. -1Z8-

LV images obtained from each of the three techniques were divided into seven segments for analysis: anterobasal, anterolateral, apical, diaphragmatic, posterobasal, septal and posterolateral as shown in Figures Z1, ZZ, and Z3. Each LV segment was graded as having either normal or abnormal motion. Segments with abnormal motion were further graded as hypokinetic, akinetic or dyskinetic according to the classification of Herman et al (1967). Differences in wall motion assessment between observers was recorded and then resolved by consensus.

The consensus assessment of wall motion of the contrast angiogram was was used as the standard for comparison with RNA and ZOE for the 7 LV segments

(Fig.Z3). The results of the segmental comparison were analysed by agreement levels for the presence of normal versus abnormal wall motion and grade of abnormal wall motion. To further determine the diagnostic accuracy of ZOE and

RNA in the evaluation of LV segmental wall motion the diagnostic sensitivity and specificity for ZOE and RNA for the detection of abnormal wall motion was calculated.

Differences between ZOE and RNA in percentage agreement, sensitivity and specificity were examined using the McNemar's test of significance. I

- 129-

Parasternal Ant long Axis Parasternal Short Axis A-L-L Mid level I Post

f"igure 21. '1egional wall motion assessed by two dimensional echocardiography in

4 views : parasternal long axis and short axis, apical 2 & 4 chamber views. Seven

LV wall segments were identified: AB = antero-basal, AL = antero-lateral, AP= apical, If\F = diaphragmatic, S = septum, PB = postero-basal, and PL= postero- lateral.' -130-

RAO

PL

AP

ANT

AP

Figure 22. Regional wall motion assessed by radionuclide angiography in 4 views :

LAO = left anterior oblique, RAO "'= right anterior oblique, ANT = anterior, LLr" T

= left lateral. Seven LV segments were identified, AB = antero-lateral, AP = apical, D = diaphragmatic, PB = posterobasal, S = septal, PL = posterolateral. - 131-

7 LV segments visualized by 3 imaging techniques.

Contrast angiography

8 L

PB AP 6.Ol RAO Radionuclide angiography

I s PL I r,~'i: \ .. _~ AP/01 ~ ANT LAO LLAT 20 Echocardiography /tDPL AP/01 Apical · Apical Parasternal 2 chamber 4 chamber short axis

Figure 23. Left ventricular wall segments visualised by contrast angiography, radionuclide angiography, (up'per two panels) and two dimen!'lional echocardiography (lower panel). Seven segments of the left ventricular wall were def_ined for analysis: AB = anterobasal, AL = anterolateral, AP = apical, S = septum, DI = diaphragmatic, PB = posterobasal. The -projections used for the silhouette techniques were: RAO = right anterior oblique, LAO = left anterior oblique, ANT = anterior and LLAT = left lateral views. - 13Z-

Results

Contrast Angiographic Findings

Cineangiography segmental wall motion abnormalities were present in 89% (4Z) of the patients. The mean LVEF for the group was 47±11 %. Of 3Z9 left ventricular segments analysed by contrast angiography, 57% (190) had normal wall motion; Z1% (69) were hypokinetic, 17% (55) akinetic and 5% (15) dyskinetic. Only Z anterobasal segments had abnormal motion and therefore only a limited comparative analysis for this segment was performed. Interobserver agreement for analysis of segmental wall motion for all 7 LV segments was 91;

5%. When significant coronary artery obstruction was defined as >70% luminal narrowing, 3Z patients (68%) had significant right coronary, 35 patients (74%) left anterior descending and 18 patients (38%) circumflex artery disease.

Comparison of ZOE with Contrast Angiography

When the LV images derived from ZOE and contrast angiography were compared, there was complete agreement for the detection of either normal or abnormal segmental wall motion in 91% anterobasal, 87% anterolateral, 94% apical, 64% diaphragmatic, 68% posterobasal, 7Z% septal and 77% posterolateral wall segments (Table 7). In the septum 9 (19%) segments interpreted as normal by - 133-

Table 7. Percentage agreement between contrast angiography

and radionuclide angiography or two dimensional

echocardiography for LV wall motion assessment.

% AGREEMENT LV

SEGMENT

2DE RNA

Anterobasal 91 91

Anterolateral 87 79 Apical 94 81*

Diaphragmatic 64 68 Posterobasal 68 74 Septal 72 77

Posterolateral 77 79

*p < 0.05 RNA vs 2DE -134- contrast angiography were considered abnormal by ZOE. Thirteen (Z8o/o) diaphragmatic, 9 (19%) posterobasal and 7 (14%) posterolateral segments were abnormal by contrast angiography but wre considered to have normal motion by ZOE.

When segmental wall motion was compared using the four grades of normal, hypokinesia, akinesia and dyskinesia, ZOE was at variance with contrast angiography in 10Z segments (43%). Interobserver agreement for assessment of wall motion grade by ZOE was 80±5% for all 7 LV wall segments. Fifty of these 10Z discrepant segments (50%) were due to failure to distinguish normal from hypokinetic segments or vice versa. Of the total number of wall motion grade discrepancies, 85 (83%) differed by only one grade (Table 8), anterobasal 3%, anterolateral 10%, apical13%, diaphragmatic 13%, posterobasa113%, septal18o/o and posterolateral1Zo/o. Discrepancies with contrast angiography of two or more grades of wall motion occurred in 17% of segments by ZOE. Eleven segments which were interpreted by contrast angiography to be akinetic were considered to have normal motion by ZOE. Nine of these 11 segments were diaphragmatic, posterobasal or posterolateral segments.

The sensitivity and specificity of ZOE for detecting wall motion abnormalities are shown in Table 9. ZOE was more sensitive for the detection of anterolateral

(83%), and apical wall motion abnormalities (95%) but least sensitive for diaphragmatic abnormalities (48%). The diagnostic specificity for all segments was higher, ranging from 94% for the anterolateral wall to 71 o/o for the interventricular septum. - 135-

Table 8. Assessment of the segmental wall motion grade

by contrast angiography and two-dimensional echocardiography.

Contrast Two-dimensional echocardiography

Angiography Normal Hypokinesia Akinesia Dyskinesia

Normal 161 25 4 0

Hypokinesia 27 32 9 1 Akinesia 11 15 26 3

Dyskinesia 1 3 3 8 -136-

Table 9 Diagnostic sensitivity and specifk:i:ty for the assessment of regional

wall motion abnormalities by radionuclide angiography and

two-dimensional echocardiography

SENSITIVITY (%) SPECIFICITY (%)

LV WALL SEGMENT

2DE RNA 2DE RNA

Anterobasal 91 93

Anterolateral 83 77 94 82

Apical 95 84 87 73

Diaphragmatic 48 4'8 82 91

Posterobasal 57 67 77 81

Septal 75 69 71 81

Posterolateral 50 50 88 91

Abbreviations: 2DE -Two dimensional echocardiography. RNA- Radionuclide angiography

- Insufficient data for calculation. -137-

Comparison of RNA with Contrast Angiography

Comparison of RNA and contrast angiographic LV images showed complete

agreement for the detection of either normal or abnormal segmental wall motion

in 91% anterobasal, 79% anterolateral, 81% apical, 68% diaphragmatic, 74%

posterobasal, 77% septal and 79% of posterolateral segments (Table 7). Similar

to ZOE, 13 (28%) diaphragmatic, 7 (15%) posterobasal and 7 (15%) posterolateral

segments considered abnormal by contrast angiography were considered normal

by RNA.

When the grade of segmental wall motion was compared, RNA was at variance

with contrast angiography in 117 segments of which 56 (48%) were due to failure

to distinguish normal from hypokinetic segments or vica versa. Interobserver

agreement for RNA analysis was 85±6% for all 7 LV wall segments. There was a

diffference of one grade of abnormal wall motion in 92 (78%) of segments (Table

10), anterobasal 4%, anterolateral 13%, apical 16%, diaphragmatic 11%, posterobasal 13%, septal 10% and posterolateral 11%. Discrepancies with contrast angiography of two or more grades of wall motion occurred in 20% of segments by RNA. Ten of 14 akinetic segments considered normal by RNA

involved the diaphragmatic, posterobasal or posterolateral segments.

The sensitivity and specificity of RNA to detect or exclude wall motion abnormalities is shown in Table 9. RNA was most sensitive for the detection of anterolateral (77%), apical wall motion abnormalities (84%) and least sensitive for the diaphragmatic segment (48%). The specificity for all segments ranged -138-

Table 10. Assessment of segmental wall motion grade by contrast angiography

and radionuclide angiography.

Radionuclide Angiography Contrast

Angiography Normal Hypokinesia Akinesia Dyskinesia

Normal motion 161 24 5 0

Hypokinesia 30 28 11 0

Akinesia 14 13 19 9

Dyskinesia 1 2 5 7 from 93% for the anterobasal segment to 73% for the apical segment.

Comparison of RNA with ZOE

The analysis of regional wall motion determined by RNA and ZOE were compared. Of the 7 LV segments examined for each patient, ZOE showed a closer agreement with contrast angiography only for the apical left ventricular segment compared to RNA (p<0.05). For the remaining six segments there was no significant difference in levels of agreement when contrast angiography was compared with ZOE or RNA. There was no significant differences between these techniques for diagnostic sensitivity and specificity of segmental wall motion abnormalities for each of the 7 segments including the apex. -140-

Discussion

The increased used of non-invasive imaging technology in recent years has made it importa·nt to conduct careful comparative studies of global and regional left ventricular function with the traditional invasive method to evaluate these new techniques. The present study of a patient population with a high prevalence of wall motion abnormalities, has shown close agreement between both RNA and ZOE and contrast angiography for the assessment of wall motion in the anterior and apical left ventricular segments; and there was a correspondingly high diagnostic sensitivity and specificity for the detection of abnormal wall motion in these segments when contrast angiography was used as a standard. In contrast, there was a lower agreement level between either RNA or

ZOE and contrast angiography for diaphragmatic, posterior and septal left ventricular segmental wall motion, with the non-invasive techniques showing diagnostic sensitivity for wall motion abnormalities as low as 48%

(diaphragmatic). Not only were ZOE and RNA relatively insensitive in detecting abnormal wall motion in the diaphragmatic and posterior regions of the left ventricle, but these techniques were also poor in assessing the grade of wall motion abnormality.

Despite its known limitations, (Chaitman et al 1975), contrast angiography has traditionally been used as the reference standard for comparative studies of non-invasive imaging · methods. It is possible that discrepancies between the invasive and non-invasive techniques may be due in part to incorrect assessment by contrast angiography rather than by ZOE or RNA. The invasive nature of a cardiac catheterisation plus the well documented effects of contrast media on - 141- myocardial function, together may have influenced independently segmental wall

motion - two factors which are not relevant to RNA and ZOE examinations.

However, in all patients meticulous attention was directed to relieving their anxiety and maintaining a stable clinical sta~e prior to and during the cardiac· catheterisation to optimise the performance of the contrast ventriculogram. No attempt was made to correlate wall motion abnormalities with the coronary anatomy in these patients as the contraction pattern of LV wall segments supplied by stenotic coronary arteries may not necessarily be abnormal at rest.

One area which may present difficulties with contrast angiography is the septum. This was evaluated in the LAO view and therefore may be overlapped by the anterior wall, especially if the latter shows abnormal wall motion. In this situation the motion of the septum frequently has to be judged as a shadow in the background of anterior wall motion and hence errors are likely to occur. This same difficulty with the assessment of septal motion might be expected to occur also with RNA since the silhouette image is similar to that of contrast angiography. Two dimensional echocardiography is a tomographic technique, which visualises the septum directly in the short axis parasternal and apical four chamber axis and is devoid of problems of overlap. It might be therefore expected to assess this segment best. However, this data suggests that this is not the case as both non-invasive techniques gave similar levels of agreement for the septum when compared with contrast angiography.

Both RNA and ZOE, as mentioned above, were relatively insensitive in detecting wall motion abnormalities of the diaphragmatic and posterobasal regions. These segments are best imaged by ZOE in the apical two chamber view - 142- but this is not uncommonly a difficult positon to achieve a high quality image compared to the apical four chamber view. Furthermore, endocardial targets are positioned parallel to the ultrasound beam leading to potential problems with lateral resolution and hence errors in the assessment of endocardial motion

(Weyman et al 1982). One of the well known limitations of echocardiography is the inconsistent image quality between patients related to differences in body configuration and to the presence of lung disease (Bansal et al1980). Five of the original 52 patients had to be rejected because it was considered that adequate ultrasonic studies could not be obtained in these patients. Although the remaining 47 patients were considered to have adequate studies, it is also possible that discrepancies in inferior and posterior wall analysis may be related to subtle difficulties in imaging the diaphragmatic and posterior walls by 2DE.

Radionuclide angiography has the advantage of providing a high quality non-invasive image in all patients regardless of body size and lung disease.

Nevertheless, similar difficulty was experienced in correctly assessing motion of the diaphragmatic and posterobasal regions. These particular segments are best visualised in the left lateral view since the right ventricle usually overlaps the inferior wall in the anterior view (Fig.23). With contrast angiography images obtained in the anterior, 30° RAO view are conventionally used to assess diaphragmatic and posterobasal wall motion and were used in this study to compare with the RNA assessment obtained in the left lateral view. It is therefore possible that each technique is visualising these LV segments differently. It is also likely that some foreshortening of the inferoposterior wall occurs in the left lateral position with RNA leading to potential failure to detect abnormal wall motion in this view. - 143-

Previous studies comparing RNA, 2DE and contrast angiography, to determine their usefulness in detecting segmental wall motion abnormalities have been seriously limited by the inclusion of a large number of subjects with normal regional wall motion, (Kisslo et al 1977, Brady et al 1980 b, Freeman et al1981 c, Kelly et al 1981, Berman et al 1975, Okada et al 1980 b, Federman et al 1978), or non-segmental myocardial dysfunction (Kisslo et al 1977, Kelly et al

1981, Berman et al 1975, Okada et al 1980 b, Federman et al 1978), failure to use apical views for 2DE studies (Kisslo et al 1977, Heger et al 1979) or the left lateral (or LPO views) for RNA (Hecht et al 1981, Sorensen et al1982, Brady et al1980 b, Freeman et al1981 c, Berman et al1975, Federman et al1978).

Hecht et al (1981) used both 2DE and RNA to examine segmental wall motion in 58 patients with previous myocardial infarction and compared the results to those obtained 'by contrast angiography. These investigators also recorded relatively low agreement levels between contrast angiography and either 2DE or RNA for the inferior wall (58% 2DE, 69% RNA) and the septum

(38% 2DE, 64% RNA). The highest agreement level in their study was obtained for the apical region (96% 2DE, 89% RNA). However, only 18 of their 58 patients underwent all three imaging studies and RNA was performed in the LAO and anterior views only. Failure to perform RNA in the left lateral or left posterior oblique views may partly account for the relatively poor agreement levels noted in the RNA study. -144-

Clinical Implications

This study has shown that currently available RNA and ZOE systems may

still have shortcomings in the accurate evaluation of diaphragmatic and posterior regions of the left ventricle. Although it was thought the septum would be

difficult to assess using RNA because of the tangential views obtained, our data

indicates that ZOE and RNA are comparable in their assessment of this segment.

Because of the subjective assessment of wall motion and the variable resolution

of RNA and ZOE, mild hypokinesia may be either missed or incorrectly diagnosed as being present. Image quality of ZOE and RNA is continually being improved, particula~ly with further developments in digital imaging processing and edge detection and this may increase the diagnostic sensitivity and specificity of RNA and ZOE for the detection of wall motion abnormalities.

Since there was a high level of agreement in the assessment of the anterior and apical segments, both the non-invasive techniques were reliable for the detection of the more common anteroapical wall motion abnormalities (eg. aneurysm), LV segments in which the presence of high grade wall motion abnormalities have important prognostic implications. - 145-

CHAPTER 10

METHODOLOGY -SUMMARY

Radionuclide Technique

On the basis of the previous section, in all proposed clinical studies, left ventricular function was measured using the gated equilibrium blood pool technique after in vitro labelling of the patient's own red cells with technetium-

2 2 99m pertechnetate (13.5 mCi/m or 500 MBq/m ). Data were collected using an

Ohio Nuclear 420 gamma camera interfaced to a Digital Gamma 11-40 computer. Resting studies were performed using a medium sensitivity parallel­ hole collimator and rest-exercise studies using a high sensitivity 30° slant-hole collimator. Resting images for all studies in which regional wall motion was assessed were performed in the following projections: 40-45 ° left anterior oblique, which enabled the best separation of both right and left ventricles, anterior, 30° right anterior oblique, left lateral and/or left posterior oblique views. Exercise studies were performed semi-supine on the exercise bed in the left anterior oblique view.

Computer data were acquired in frame mode using a frame duration of 40 msec for resting studies, (being reduced appropriately as the cardiac rate increased with exercise) in a 64 x 64 matrix. Left ventricular ejection fraction -146-

(LVEF) was calculated from background corrected time activity curves derived from a variable region of interest drawn over the left ventricle. Background was drawn using an automatic operator independent assigned program, lateral to the left ventricular apex on the end-systolic image. In our laboratory, for normal adults and children, the lower limit of left ventricular ejection fraction using this method was 50%.

Patients when studied during stress underwent semi-supine maximal bicycle exercise. Exercise was increased by 25 watt increments over four-minute stages. Exercise end points in our laboratory were fatigue, limiting symptoms, fall in blood pressure >10 mg Hg, ventricular arrhythmias or marked ST segment depression of > greater than 4 mm. Providing haemodynamic stress was adequate, a normal LVEF response to stress in both adults and children were defined by an increase of at least 5% L VEF units above the resting value.

Left ventricular volumes were measured according to the non-geometric method described by Dehmer et al (1980). Volume measurements were calculated at end-systole from a left anterior oblique projection that provided the best separation, using background corrected left ventricular counts normalised for activity /ml of peripheral venous blood. Corrections were made for the number of cardiac cycles, frame duration and radionuclide decay. After the end-systolic volume index· was measured, a uniform attenuation correction was made after substitution in the regression equation previously derived in a similar group of patients. After. end-systolic volume was measured, end-diastolic volume was calculated from the scintigraphically derived measurement of ejection fraction.

Left ventricular volumes were corrected for body surface area expressed as

2 ml/m • -147-

Regional wall motion was assessed by two independent blinded observers without knowledge of the patients clinical data. The left ventricle was divided into five segments for analysis rather than seven, as analysed in Chapter 9. It appeared that there was little advantage from assessing the antero-basal from the antero-lateral and postero-basal from the diaphragmatic segments separately. Regional wall motion was therefore, assessed in the following segments: antero-lateral, apical, postero-lateral, inferior and septal. Exercise wall motion was assessed in the segments seen in the left anterior oblique view only: septal, apico-inferior and postero-lateral. Disagreement between observers was resolved by concensus.

Ethical Considerations

Informed consent was obtained from all patients or parents of children involved in the studies. These studies were approved by The Prince Henry and The Prince of Wales Hospital Ethics Committee. For each gated equilibrium study 500 MBq/m 2 of technetium-99m pertechnetate was used, giving a total body radiation dose of approximately 340 m rads/patient. - 148-

CLINICAL APPLICATIONS -149-

CHAPTER 11

MYOCARDIAL REVASCULARISATION

Early and long term results of coronary artery bypass grafting in

patients with severely depressed LV performance

Progressive improvements in the anaesthetic and surgical management of patients with coronary artery disease and left ventricular dysfunction have resulted in a steady decline in peri-operative mortality and morbidity, now permitting these patients to have successful coronary artery bypass surgery with an acceptable risk (Rahimtoola et al 1981, Kennedy et al 1981). Most studies which have evaluated the effect of myocardial revascularisation on ventricular function and prognosis have been performed in patients with either normal or near normal resting ventricular function (Barry et al 1976, Kent et al 1978,

Bussman et al 1979 , Freeman et al 1981 a, Wolf et al 1977, Lim et al 1982).

Consequently little information is available about the effects of surgery in patients with severely depressed performance (Hellman et al 1980, Hung et al

1980).

Accordingly, a group of patients with marked depression of ventricular function and undergoing coronary bypass surgery for relief of angina was prospectively studied. Early post-operative ventricular function was examined with radionuclide angiography and the patients followed long term to assess clinical status and prognosis. The results were analysed to determine if there were any pre-operative variables which might have predicted the effects of surgery on ventricular performance and long term prognosis. - 150-

Material and Methods.

Patient Population

Eighteen consecutive patients with chronic stable angina, New York Heart

Association (NYHA) functional class (FC) II or IV, with an angiographic left

ventricular ejection fraction (L VEF) of less than 40% who were undergoing coronary artery bypass graft surgery were studied. Patients requiring additional aneurysm resection or valve surgery were excluded.

Clinical details of these 18 patients are given in Table 11. There were 15 males and three females, age 58 .:!:. 6 years, range 50-69 years. All patients had at least one prior myoc(lrdial infarction diagnosed by the triad of typical history, development of >0.04 sec Q waves on the electrocardiogram and elevated cardiac enzymes. Six patients suffered FC III and 12 patients FC IV angina. For the 18 patients the mean angiographic LVEF was 28 .:!:. 8%, and left ventricular end-diastolic pressure 23 .:!:. 8 mmHg. When significant coronary arterial obstruction was defined as >50% luminal narrowing, 12 patients had triple vessel coronary artery disease and six patients two vessel disease. Using the coronary artery scoring method of Brandt et al (1977), the mean score of the patient group was 9.6 .:!:. 2.4, range 4.8-12.5 (a maximum score of 15 points represents total occulusion of all three major vessels).

Thirteen patients required long acting nitrates as Isorbide Dinitrate (45 .:!:. 9 mg/day, range 30-120 mg/day); 17 patients were receiving beta blocker therapy -151-

Table 1l.Pre-operative clinical, haemodynamic and angiographic data in 18 patients

Pt Age Sex FC LVEDP LVEF Coronary Drug Therapy (yrs) (NYHA) (mmHg) (%) Score (mg/day)

cw 50 M III 16 33 8.8 Me 100, Isd 40, F 40

JD 62 M IV 18 39 12.0 P 160, Isd 30

JP 52 M IV 20 36 4.8 At 100, Isd 30

AM 53 M III 11 39 12.0 P 160, Isd 40

IL 68 M IV 20 31 9.4 P 40, Isd 30, F 40, 0 0.25

LP 54 M IV 34 30 11.8 At 100, Isd 30, F 40

MF 61 M III 23 31 10.5 Verapamil 240, Isd 120

BR 56 M IV 28 37 9.2 Me 50, 0 0.25

LS 54 M III 10 19 6.4 Me 100, F 40, 0 0.25

BH 52 M III 27 19 5.6 Timolol 10, Isd 40, F 40, 0 0.25

JL 52 M III 36 23 12.5 Al 300, Isd 30

ES 62 M IV 12 37 12.2 Me 200, Isd 40, F 40

MV 61 F IV 22 37 11.0 P 120, F 40

NF 60 F IV 25 27 9.0 Me 250, F 80, D 0.25

FB 57 M IV 25 22 10.0 Al 400, Isd 40

PS 69 M IV 36 20 8.6 Me 100, Isd 40, F 120

GM 61 F IV 28 15 7.2 Me 100, 0 0.25

KW 55 M IV 18 20 11.2 Isd 40, F 160, 0 0.25, Hyd 150

Abbreviations+ FC(NYHA) = Functional class (New York Heart Association); L VEDP = left ventricular end diastolic pressure; LVEF = left ventricular

ejection fraction; Me = Metoprolol; Isd = Isorbide Dinitrate; F = Frusemide;

P = Propranolol; At = Atenolol; 0 = Digoxin; Al = Alprenolol; Hyd = Hydrallazine. - 152-

and ten patients required Frusemide (64 ~ 21 mg/day, range 40-160 mg/day).

Study Protocol

Informed consent was obtained from all patients prior to the study. All

patients underwent rest and exercise radionuclide angiography one week prior to

surgery. Using previously described techniques LVEF, ventricular volume and

regional wall motion was assessed • Coronary artery surgery was performed

using standard surgical techniques with cold potassium cardioplegic arrest for

myocardial protection (Berger et al 1981). At surgery, 2.5 .:.': 0.5 grafts were

placed per patient.

The clinical course of the patients was closely followed after surgery and

their symptomatic status assessed at frequent intervals. Three months after surgery (99 ~ 11 days, range 90-130 days), all patients underwent repeat rest and exercise radionuclide angiography. The mean period of clinical follow-up was 27

.:.': 3 months (range 22-33 months). - 153-

Results

Early Clinical Assessment

All 18 patients survived surgery and were discharged from hospital. Nine

patients required parenteral inotropic therapy for at least 48 hours. Four of

these nine required additional support with intra-aortic balloon conterpulsation.

One of the 18 patients (IL) developed electrocardiographic evidence (new Q

waves) of a peri-operative myocardial infarction.

At three months after surgery all patients were free of angina. Thirteen

(72%) of the 18 patients were asymptomatic. Four patients had dyspnoea on moderate exertion (FC II) and one patient remained breathless on minimal activity (FC III). There was a marked reduction in drug therapy and no patient required either beta blocking drugs or nitrates.

The improved symptomatic status after three months was corroborated by objective measurement of exercise performance. Exercise capacity for the group improved from 40 :t:, 22 watts pre-operatively to 71 :t:, 30 watts post­ operatively (P <0.001). Peak exercise double product also improved from 176 :t

52 x 10 2 to 255 .:!:. 69 x 102 following surgery (P <0.001) (Fig. 24). AlliS patients were limited by angina in the pre-operative ex"'rcise study, but at three months,

12 were limited by leg fatigue and six by dyspnoea. - 154- 400 n=18 * p< 0·01 350

300

250 • 2 DP x 10- 200 mmHg.HR

150

100

Peak Ex Peak Ex Preop Postop

Figure 24. Double product at' peak exp.rcise (PEAK EX) measured before and

three months after surgery for all 18 patients. The mean double product

increased significantly for the patient group. -155-

Effect of Surgery on Global Ventricular Function

To assess the effect of myocardial revascularisation on ventricular

performance more accurately, patient IL, who had a definite peri-operative

myocardial infarction, was excluded from subsequent analysis of global and regional performance. In this patient, the resting ejection fraction fell from

40% pre-operatively to 23% following surgery. The effect of coronary artery

bypass graft surgery on left ventricular performance for the remaining 17

patients is shown In Table 12.

The resting L VEF for the patient group was 27 ~ 9% pre-operatively and 29

~ 12% post-operatively (P = NS) • There was no significant change in resting left

2 ventricular end-diastolic volume index (159 ~ 78 ml/m ) preoperatively versus

138 ±78mls/m 2 postoperatively, or end-systolic volume index (120 + 60 ml.m 2

2 versus 106 ~ 69 ml/m ) following surgery (Table 12).

Post-operative L VEF at peak exercise was significantly higher than the pre­

operative value, 27 ~ 14% versus 22 ~ 7% (P <0.05), although the LVEF fell for the patient group during exercise both before and after surgery (Fig. 25). There was no significant change in the left ventricular end-diastolic volume index at

2 2 peak exercise (195 ~ 75 ml/m versus 160 ~ 75 ml/m ) (Table 12). Fourteen

(78%) of the 17 patients showed a reduction in peak exercise end-systolic volume index following surgery, although there was no significant change for the entire

2 2 group (155 ~ 69 ml/m versus 125 + 71 ml/m ) following surgery. - 156 -

Table.l2. Radionuclide Angiographic data for the 17 patients

Ff£-

LVEF ESVI ED/I LVEF ESVI ED/I

2 2 2 2 (%) (ml/m ) (ml/m ) (%) (ml/m ) (ml/m )

ON R 40 85 141 42 70 121 Ex 30 ·140 202 43 65 114 JD R 37 37 59 41 32 51 Ex 20 88 110 33 48 72 JP R 35 69 107 35 57 87 Ex 25 93 124 43 68 119 PM R 32 98 144 43 27 48 Ex 32 113 167 44 42 75 LP R 17 150 181 19 165 204 Ex 17 164 197 11 209 235 ivF R 38 83 133 41 56 95 Ex 24 153 202 34 89 133 ER R 29 52 73 34 61 92 Ex 24 61 80 34 81 122 LS R 21 199 251 14 154 179 Ex 16 258 306 11 156 175 EH R 18 160 195 21 151 192 Ex 18 186 226 21 181 230 JL R 23 96 125 21 272 344 Ex 22 119 153 21 272 343 ES R 40 59 98 44 35 62 Ex 30 91 131 43 40 71 MJ R 35 56 86 44 21 37 Ex 34 75 114 47 33 62 w:;. R 22 155 199 17 146 176 Ex 15 183 216 10 184 204 F8 R 22 159 203 24 123 161 Ex 23 180 207 22 166 213 PS R 14 238 276 14 176 205 Ex 10 322 357 10 204 227 CJv1 R 17 171 205 14 147 171 Ex 13 237 274 11 150 169 I

tvean + SO R + + + + + + - 27 - 9 120 --60 159 64 29 - 12 106 - 69 139 - 78 Ex 22 + 7 + + - 155 --69 195 + 74 27 -+ 14 125 -+ 71 160 - 75

Abbreviations: LVEF = left ventricular ejection fraction; ESVI = end-systolic volUTe index; BDVI = end-diastolic volUTe index; R = rest; Ex = peak exercise. -157-

n=17 n=17 n=17 50 50

40 40 -~

30- % 20 I 10 ~~ 10 ~

0 0 0 Preop Po stop Preop Preop Po stop Postop Rest Rest Rest Peak Ex Rest Peal< Ex

Figure 25 The individual left ventricular ejection fractions for each patient measured at rest pre- and post- operatively (left panel), rest and peak exercise pre-operatively (centre panel) and rest and peak exercise post- operatively (right panel). PEAK EX= peak exercise, PREOP =pre-operatively, POSTOP =post-operatively. -158-

Analysis of the peak exercise L VEF data after surgery showed that there were patients in whom there was an increase in peak exercise L VEF ~ 10% LVEF units and those in whom there was no change or deterioration in peak exercise L VEF response.

The results were reviewed in two groups; patients who improved their peak exercise LVEF after surgery by ~ 10% L VEF units (Group A, eight patients) and those who did not (Group B, 9 patients) (Fig. 26). Left ventricular end-systolic volume increased with exercise both before and after surgery in Group A patients, but the magnitude of change in the end-systolic volume index was

2 2 significantly less in the post-operative study (13 2:. 7 ml/m versus 34 2:. 22 ml/m )

(P <0.05). In contrast, in Group B patients, the magnitude of the change of end­ systolic volume index with exercise was unchanged post-operatively (Fig. 27).

Left ventricular end-diastolic volume index increased with exercise pre-and post-operatively in both Group A and Group B patients; however, these changes did not reach statistical significance for either group (Fig. 27).

The pre-operative status of the two groups was examined to determine if there were any important differences. There were no significant differences in anginal symptoms, drug therapy or coronary angiographic score between Group A and

Group B. The pre-operative ventricular performance data for Group A and

Group Bare shown in Table 13. Patients who improved their peak exercise LVEF by at least 10% (Group A) had higher resting and peak exercise ejection fractions

(P <0.001). Group A had smaller end-systolic volumes both at rest (p < 0.001) -159-

----Group A (n=S) Group 8 (n=9) ,Jt , , , ... .. , ,', ,.,,.... ,....'' , , ,~~,, I~ .. ""':: ,' ,'-1, ·~"'--~~- , ,.,. , , ...... --• .. ,.~, ... ·--~~--~... _... --...-...... :;., , ,' , , , . "' .... , .. , . ',', .. ... , ,,' ,' -...... , , , ---..... ~. ',' ,' % '-~ ., ,'

o~-r-----.r-----~- Rest Peak Ex Peak Ex Preop Preop Postop

Figure 26 Left ventricular ejection fraction for Groups A and B measured at rest pre-operatively (PREOP) and ·at peak exercise bot: a pre-and post-operatively

(POST -OP). - 160 -

Table 13. Pre-op~rative rest and exercise perforrrance in ~oups A and B.

Gn.PA CR1P B P value

LVEF R 36 + 4 19 + 3 < 0.001

(%) Ex 27 + 5 17 + 4 < 0.001

-8 + 6 -2 -+ 3 < 0.05

ESVI R 67 -+ 20 167 -+ 38 < 0.001 2 (ml/m ) Ex 102 -+ 32 205 + 59 < 0.001 % 55 -+ 39 21 + 11 < 0.05

ED/I 105 + + R - 32 207 43 < 0.001 2 (ml/m ) + + Ex 141 - 45 243 62 < 0.005 % 36 -+ 25 16 -+ 10 =1\B

Abbreviations: LVEF = left ventricular ejection fraction; ESVI = end­ systolic volUTe index; EDVI = end-diastolic volUTe index; R = rest, Ex = peak exercise; = change. -161-

r1 Preop ~ Postop 70 * p

A ESVI 40 A EDVI

ml/m2 30 ml/m2 30 20 20 10 0 0 A 8 A 8

Figure 27 Changes in end-systolic volume index (ESVI) and end-diastolic volume

index (EDVI) with exercise for Groups A and B. Note magnitude of change of

end-systolic volume index for Group A is significantly less following surgery.

There was no difference in the exercise response of end-diastolic volume index for Groups A and B pre- and post-operatively. - 162-

and with exercise (P <0.001) and smaller end-diastolic volumes at rest (P <0.001)

and with exercise (P < 0.005) compared to Group B. Pre-operative LVEF in

Group A patients fell with exercise by at least 10% LVEF units in five of the

eight patients and was unchanged in three patients (36 .:!:. 4% to 27 .:!:_5%, P <0.05).

This contrasted with the nine patients in Group B in whom there was no

significant change in LVEF with exercise pre-operatively (19 + 3% versus 17 +

4%) (Fig. 27).

Effects of Surgery on Regional Ventricular Function

There were 25 (62%) of 40 segments in Group A patients showing abnormal

motion, of which 20 segments were hypokinetic and five akinetic. In contrast,

there were 41 (91 %) of 45 segments in Group B patients which had abnormal

motion, of which 23 segments were hypokinetic, 16 akinetic and two dyskinetic.

In the 17 patients analysed, 12 (18%) of the 66 abnormal segments (seven hypokinetic and five akinetic segments) showed improved motion following surgery. Eight (67%) of these 12 segments showing improved motion were in

Group A patients. Of the remaining 54 abnormal segments, regional wall motion was unchanged in 45. Nine segments showed deterioration of contraction: seven of these involved the septum and six (65%) of the nine were in Group B patients.

Pre-operatively, deterioration of wall motion during exercise occurred in 11 of 40 segments (28%) in Group A and two of 45 (4%) in Group B. Post­ operatively, ten of the 11 segments in Group A and both segments in Group B showed improvement in segmental wall motion with exercise. - 163-

Late Clinical Follow-Up

At late follow-up of the entire group of 18 patients (27 .!. 3 months) there

were 16 survivors. Two patients died (patient LP and patient KW) at 11 months

and 13 months following surgery after developing severe heart failure. Of the 16

survivors, eight patients (including patient I~, who suffered a peri-operative

infarction) developed clinical evidence of cardiac failure requiring diuretic therapy (Frusemide 120 .!. 146 mg, range 40-480 mg/day). Five of these eight

patients also developed recurrent angina requiring sublingual or oral nitrate

therapy.

The long term outcome for Groups A and B is compared in Fig. 28. Seven of

the eight patients in Group A remained in NYHA FC I or II with only one of these

patients requiring a diuretic. The eighth patient (patient MF) remained

symptomatically unchanged after surgery with FC III dyspnoea. Patients who

failed to increase their peak exercise LVEF at least 10% after surgery (Group B)

had a more malignant long term course than Group A. Six of the nine Group B

patients showed deterioration in NYHA functional class at long term follow-up

including the two patients who died. -164-

GROUP A likllUP B

NVHA 3 MO, POSTOP LONG TERM F/U NVHA 3 MO, POSTOP LONG TERM F/U FC FC

!> 2 5 0

II II

Ill I I I

IV IV 2+

Figure 28 Long term follow-up (F /U) for Group A and B patients according to New York Heart Association (NYHA) functional class. AU patients showed early post-operative (POSTOP) clinical improvemernt but only in Group A was this sustained long term. The two deaths occured in Group B. -165-

Discussion

The patient group in this study had evidence pre-operatively of severe

coronary artery disease and marked left ventricular dysfunction. There was no

operative mortality in this series reflecting the improvements in anesthetic

techniques and the use of cardioplegia for better myocardial protection

(Rahimtoola et al 1981). All patients had relief from their disabling angina and had experienced substantial symptomatic benefit when examined three months post-operatively.

Effect on Ventricular Performance

Most studies of patients with pre-operative normal or mildly abnormal ventricular function have not shown improvement in resting left ventricular performance after myocardial revascularisation (Barry et al 1976, Kent et al

1978, Bussman et al 1979 , Freeman et al 1981 a, Wolf et al 1977, Lim et al

1982). In this study of patients with depressed left ventricular performance, the resting left ventricular performance was unchanged three months after surgery.

There have been conflicting results in the few reported studies which have examined the effects of myocardial revascularisation on resting left ventricular function in patients with moderate or advanced left ventricular dysfunction.

Chatterjee et al (1973) studied 11 patients with previous myocardial infarction and showed an improvement in resting left ventricular ejection fraction from - 166-

44% pre-operatively to 59% following surgery. Hellman et al (1980) performed

post-operative radionuclide angiography on 19 patients with a pre-operative

L VEF of <40%; these investigators also demonstrated an improvement in resting

L VEF from 31% to 39% for the group. The differing results obtained in these

two studies compared to these results may be related partly to differences in

patient population and partly to the timing of the post-operative study. In the

series of both Chatterjee et al (1973) and Hellman et al (1980), the post­

operative studies were performed two weeks following surgery when chest wall

pain and anaemia are frequently present, resulting in increased sympathetic activity which possibly contributed to an early improvement in ventricular

function. In contrast, the post-operative studies reported by Hammermeister et al (1974) and Hung et al (1980) were performed at 4 and 19 months respectively following surgery. In patient subgroups similar to my study, these investigators showed no change in resting left ventricular performance followng successful myocardial revascularisation, which is in agreement with the findings of this study.

Measurement of ventricular performance at rest may not be sufficiently sensitive to detect the effects of surgical intervention and does not allow the assessment of changes in cardiac performance reserve. This study has shown that, in contrast to LVEF obtained at rest, L VEF measured at peak exercise increased after myocardial revascularisation in this patient group. The mechanism of the improvement in peak exercise LVEF can [J;3 understood when the changes in ventricular volumes in those patients who increased their peak

LVEF by at least 10% (Group A) are examined. With exercise there was an increase in both end-systolic and end-diastolic - 167- volumes in Group A patients but the magnitude of the increase in the end­ systolic volume was smaller following surgery. Since the changes in end­ diastolic volume with exercise were not altered, post-operative peak exercise

L VEF increased. The improvement in exercise ventricular function demonstrated in this study would be expected to result from increased myocardial perfusion to ischaemic segments during exercise (Kent et al 1978).

Radionuclide studies using either Rubidium 86 (Lurie et al 1976) or Thallium

201 (Ritchie et al 1977, Pfisterer et al 1982) have documented an increase in segmental myocardial perfusion to ischaemic areas following myocardial rev asc ularisa tio n.

Although there was no change in global resting left ventricular function after surgery, some improvement in regional myocardial function, as assessed by segmental wall motion, was demonstrated. Twelve (18%) of 66 left ventricular segments with abnormal wall motion pre-operatively showed an improvement in motion following surgery. This low incidence of resting reversible asynergic segments is less than reported by Rozansky et al (1981) and Bourassa et al

(1982), and reflects both the high incidence of previous myocardial infarction and the more severe grades of abnormal wall motion documented in our patients pre­ operatively.

There were no clinical differences between Groups A and B, but there were significant differences in their pre-operative ventricular performance. Group A patients had smaller ventricular volumes, significantly higher resting systolic ejection fractions and less regional wall abnormalities indicating that cardiac function was less severely impaired in this sub-group. Since ten of the 12 left - 168-

ventricular segments which, following surgery, showed improvement in exercise

induced abnormalities occured in Group A patients, it is likely that the Group A

patients had more potentially ischaemic myocardium and hence, relatively less

myocardial scarring than the Group 8 patients. The marked reduction in LVEF

with exercise in Group A would represent a greater degree of ischaemic

dysfunction than would be possible in Group 8 patients in whom there would be a

larger amount of myocardial scar tissue. This explanation is consistent with the

exercise data provided by Port et al 1981 who demonstrated that the magnitude of fall in LVEF with exercise in patients with coronary artery disease was greater in patients with a moderate reduction in LVEF than in those patients with more severely depressed ventricular performance. Therefore, patients with depressed ventricular function who show a marked ischaemic response to exercise, suggesting larger amounts of jeopardised myocardium, might be expected to improve their ventricular function during exercise following myocardial revascularisation to a much greater degree than those patients who had substantial amounts of myocardial scar and hence less potential for improving wall motion.

Early and Late Clinical Results

All patients in this series experienced substantial early symptomatic benefit in both their angina and symptoms of heart failure. None required diuretic therapy when examined three months post-operatively. Other workers also reported that patients with depressed ventricular function who survive surgery usually have relief or marked improvement in their anginal symptoms - 169-

(Yatteau et a11974, Mitchel et a11975, Manley et a11976, Spencer et a11971).

There is a paucity of information on long term follow-up of patients with marked ischaemic left ventricular dysfunction who undergo myocardial revascularisation. These earlier published studies which compared the survival

of surgically treated patients with medically treated patients were unduly influenced by the high operative mortality. More recently, there have been two

long term studies which have examined survival in these groups of patients.

Faulkner et al (1977) reported a low operative mortality and a two year survival of 83% in patients followed for a mean of 19 months. Coles et al (1981) followed 59 surgically treated patients with an average pre-operative LVEF of

28%. Their five year actuarial survival was 80% .:!:. 6%. These results are in agreement with the findings in this study of 89% survival after a mean follow-up of 27 months.

Despite the initial marked subjective clinical improvement in the patients there was significant attrition with time. After more than two years follow-up eight patients had developed clinical evidence of cardiac failure requiring diuretic therapy and five of these eight patients also had recurrence of angina.

Most of the poor long term clinical results, including the two late deaths, occurred in patients who failed to increase their peak exercise L VEF significantly following surgery (Group B). As previously discussed, this group had n.ore advanced resting left ventricular dysfunction pre-operatively. - 170-

Limitations of the Study

Surgical therapy was only undertaken in this group of patients following failure of maximum medical therapy and hence, a matched medical control group was not applicable. Since the aim of the study was to examine the effects of myocardial revascularisation on ventricular performance, patient IL, the only patient to have a proven peri-operative myocardial infarction, was excluded from the analysis. The diagnosis of peri-operative infarction may represent considerable difficulties in patients with previous myocardial infarction raising the possibility that ventricular performance may have been altered by undetected myocardial infarction in the remaining patients. Following surgery, patient JL demonstrated a large increase in ventricular volumes consistent with further myocardial damage, although this was not accompanied by clinical or electrocardiographic evidence of myocardial infarction.

This study was designed to examine post-operatively the effects of revascularisation surgery on left ventricular function. However,. it later became apparent that analys1s of subgroups was appropriate since a clear distinction existed bwtween those patients who demonstrated improvment and those in whom there was no improvement or a deterioration. Accordingly, retrospective analysis was made of the characteristics of these two subgroups.

Since most patients were receiving bata blocking drugs prior to surgery, it is possible that these drugs may have independently affected the documented changes in the ventricular performance. Beta blocking drugs have a small and - 171-

inconsistent effect on resting left ventricular ejection fraction (Marshall et al

1978, Battler et al 1979, Marshall et al1981), but have demonstrated a reduction

in the magnitude of fall in L VEF during exercise in patients with symptomatic coronary artery disease • It is possible that the magnitude of ischaemic response

pre-operatively was blunted by beta blocking drugs masking an even greater

beneficial effect of revascularisation on exercise performance.

Complete revascularisation was attempted in all patients. An average of

2.5 grafts were placed per patient in'dicating most patients received grafts to all major areas of vascular supply to the myocardium. Post-operative coronary graft angiography was not routinely performed to assess graft patency in this study. Most surgical units report a patency rate of 85-95% at three months

(Rahimtoola 1982) and we have assumed a similar figure for this series. In the interval between hospital discharge and the three month radionuclide study, no patient had a myocardial infarction or recurrence of angina, which might have suggested early graft closure. Later studies to assess ventricular function were not performed because of the wide variability in progression of coronary artery disease on patients with time.

Clinical Implications

It has been shown that patients with disabling angina who have depressed ven~.. icular function may undergo coronary artery bypass surgery with a low risk.

Those patients who demonstrate substantial ischaemic left ventricular dysfunction with exercise can be expected to show a significant improvement in exercise ventricular performance post-operatively and to have a good long term prognosis. - 172-

These findings would indicate that patients with the poorest resting left ventricular function (LVEF < 25%) in whom there is little change with exercise, have a high likelihood of recurrence of heart failure and angina long term, despite initial short term symptomatic benefit. - 173-

CHAPTER12

MYOCARDIAL VIABILITY

Improved regional ventricular function after successful myocardial revascularisation in patients with depressed ventricular performance

Anecdotal evidence suggests that individual patients demonstrate objective improvement in resting left ventricular function following coronary graft surgery. However, in the previous chapter, improvement in global resting left ventricular function was not demonstrated, but significant improvement in the motion of 17% of resting asynergic segments was shown. It possible these patients with markedly depressed left ventricular performance had such extensive areas of infarction that it was not surprising only a small percentage of resting segmental abnormalities did improve. Other studies evaluating the effects of myocardial revascularisation on segmental function have included a majority of patients with either normal or near normal left ventricular performance (Rozanski et al 1981, Gibson et al 1983). Consequently, there is little information about the effects of surgery on resting segmental motion and myocardial perfusion in patients with stable angina and moderately severe depression of left ventricular performance. It is in these patients that myocardial asynergy may not necessarily imply fibrosis, as segments bordering an area of infarction may be viable and revascularisation of these segments could be expected to improve their motion. Recently it has been suggested that e·ven at rest, a state of chronic ischaemic left ventricular dysfunction can exist in patients with stable angina (Braunwald and Kloner, 1982). The potential for improvement of wall segments with abnormal resting wall motion and reversible -174- ischaemia in patients with moderate depression of impaired global left ventricular function is unknown.

Accordingly, a group of patients with a prior history of myocardial infarction and moderate depression of global resting left ventricular function

(LV EF >25%) undergoing coronary artery bypass surgery for relief of angina were studied prospectively. The value of redistribution of thallium-201 to regions of resting segmental dysfunction in predicting improvement in these segments was examined. Results were analysed to determine the relationship between segmental revascularisation and post-operative changes in perfusion and resting left ventricular function. - 175-

Materials and Methods

Patient Population

Twenty consecutive patients with chronic stable angina with moderately severe reduction in angiographic left ventricular ejection fraction (>25%) who were undergoing elective coronary artery bypass surgery were studied prospectively. Patients requiring additional aneurysm resection or valve surgery were excluded.

Clinical details of these 20 patients are shown in Table 14. There were 19 males and one female, age 56 .::_ 6 years (range 42-68 years). All patients had at least one prior myocardial infarction diagnosed by the triad of typical history, development of greater than 0.04 second Q waves on the electrocardiogram and elevated cardiac enzymes. Two patients had New York Heart Association

(NYHA) functional class (FC) II, 11 had FC III and seven had FC IV angina.

Fifteen patients required chronic beta blockade therapy, 11 long acting nitrates as Isorbide Dinitrate (33 .::_ 17 mg/day, range 30-40 mg/day); 5 patients were receiving a calcium antagonist for anti-anginal therapy and 5 patients required

Frusemide for symptoms of heart failure.

Wher significant coronary arterial obstruction was defined as greater than

50% luminal narrowing, 7 patients had triple vessel coronary artery disease, 9 two vessel disease and 4 patients single vessel disease. In all 20 patients, one or more significant lesions were present in the left anterior descending artery. The right coronary artery was dominant in 16 of the 20 patients (80%). A significant lesion of a dominant right coronary artery was present in 11 patients with -176-

Table 14.Pre-operative, clinical, haemodynamic and angiographic data in 20 patients

Pt Age FC LVEDP LVEF Coronary Drug Therapy (yrs) (NYHA) (mmltg) (%) Score (mg/day)

AA 56 III 16 47 10.6 Me 200, Nif 30, AmilS

AC 68 III 26 26 10.6 At 50, Isd 30

EK 62 IV 20 32 8._1 Me ZOO, Isd 20

KM 62 II 16 43 11.4 Me ZOO

EB 55 m. 24 29. 6-.0 At SO,Isd 40,F 40 vw 61 III 16 53 7.2 Isd 40 FT 55 IV 30 26 9.4 Ve 240, F 40

BP 59 II 12 54 9.8 Ve 240, Isd 40, Pr 40

KS 60 IV 17 39 11.2 Pr 160, F 40, Isd 30

JW 57 IV 15 40 11.6 Me 100

FT 54 IV 16 52 9.2 Isd 30

RH 53 IV 18 49 10.4 Nif 30,Isd 30

PM 42 III 16 26 10.0 Me 50, F 40

DR 58 III 26 38 11.0 Pr 120, Isd 30, F 80

MH 51 IV 12 49 5.0 PilO

KF 50 III 18 51 8.5 Me ZOO

HH 57 III 15 54 10.3 Pr 120

LW 47 III 11 47 7.4 At 50, lsd 30

FB 55 III 20 54 5.4 Pr 120, Isd 40 ww 52 III 12 26 10.2 Ve 240,Cl500,

Abbreviations: FC = NYHA Functional Class; L VEDP = left ventricular end diastoli( pressure; LVEF = left ventricular ejection fraction; Me= Metoprolol; Nif = Nifedipine; Ami

= Amiloride; At = Atenolol; Isd = Isorbide Dinitrate; Ve = Verapamil; F = Frusemide; Pr = Propranolol; Pi = Pindolol; Cl = Chlorothiazide; -177- significant lesions of the circumflex artery present in nine patients. Using the coronary artery scoring method of Brandt et al (1977), a mean score for the patient group was 9.1.!. 2, range 5-11.6 (a maximum score of 15 points represents the total occlusion of all three major vessels. For the 20 patients the mean angiographic left ventricular ejection fraction was 42 !. 11 o/o and le.ft ventricular end-diastolic pressure (LVEDP) 18 + 5 mmHg. In Table 15, the electrocardiographic site of myocardial infarction was related to the coronary disease present in each patient. -178-

Table 15. Relationship of coronary anatomy, site of previous infarction

and coronary arteries grafted

Coronary anatomy Site of previous Grafts (% luminal reduction) infarction

LAD DIAG RCA ex

AA 100 100(dom) inferior AC 100 100 40 inferiorI anterior LAD DIAG RCA EK 100 60 20 inferior/anterior RCA,LAD KM 50 50 100 100 inferior RCA,LAD,DIAG,CX EB 100 anterior LAD vw 50/100 60 60/100 anterior LAD,DIAG,CX FT 70 70 100 70/65(dom) anterior/inferior LAD,DIAG,CX BP 80 100 inferior LAD,PDA KS 40 100 95 anterior/inferior DIAG,C,PDA JW 60/100 100 40 inferior LAD,LM,RCA FJ 30/60 100 40 inferior LAD,DIAG RH 100 100 30 anterior/inferior LAD PM 100 anterior LAD DR 75 50 50/40 70/70 anterior LAD,RCA,CX MH 100 anterior LAD KF 70 50 100 inferior LAD HH 40 100 100(dom) inferior PDA,LAD LW 50 100 50 inferior LAD,RCA,LM FB 60/80 anterior LAD ww 100 100 anterior LAD Abbreviations: Where LAD = left anterior descending artery; DIAG = diagonal; RCA = right coronary artery; CX = circumflex artery; dom = dominant - 179-

Study Protocol

All patients underwent exercise and rest redistribution thallium-201

myocardial perfusion imaging and resting gated equilibrium ventriculography 5 !

3 days prior to surgery. No patient had angina at rest during the studies and at

least 24 hours was allowed between the exercise thallium study and radionuclide

angiography. Coronary artery surgery was performed using standard surgical

techniques with cold potassium cardioplegic arrest for myocardial protection.

At surgery, 2.2! 0.9 grafts were placed per patient.

The clinical course of the patients was closely followed post-operatively.

At three months after surgery (93 ! 8 days, range 86-112 days) all patients were reviewed clinically and underwent rest and exercise thallium-201 perfusion scintigraphy and on the following day, resting radionuclide ventriculography.

Radionuclide Techniques

Myocardial Perfusion Scintigraphy

For thallium exercise scintigraphy, patients were exercised on the treadmill

according to the Bruce protocol. All patients were monitored by a three channel electrocardiogram throughout exercise with modified bipolar chest leads.

Exercise end puints were limiting symptoms, fall in blood pressure greater than

10 mmHg, ventricular arrhythmias or ST segment depression greater than 4 mm.

At peak exercise, two mCl thallium-201 was administered intravenously and exercise was continued at the same level for a further minute. Scintigrams were - 180- then performed immediately following peak exercise with the patient supine using an Ohio Nuclear Mobile Gamma Camera and an all purpose high resolution parallel hole collimator. Images of the heart were obtained sequentially in the

45 ° left anterior oblique projection, right decubitus left lateral and anterior projection. The three views were repeated after four hours of rest (Fig. 29) i Imaging of all views was continued until 350,000 counts/image were obtained. In addition to recording on transparency film, all studies were acquired and displayed on computer. -181-

Anterior Left lateral (or 70' LAO)

lnferoapical Inferior

Figure 29 The relationship of the coronary circulation and coronary blood flow to

segments visualized by Thallium-201 scintigraphy (TL-201) scintigraphy in 3

projections : anterior, LAO = left anterior oblique, and left lateral view. - 182-

Resting Radionuclide Ventriculography

Resting gated blood pool imaging was performed according to the previously

described techniques.

Image Analysis

The left ventricular images by both radionuclide techniques were assessed

qualitatively by two independent blinded observers who had no knowledge of the

clinical, angiographic data or the results of the other radionuclide investigations.

For purposes of analysis, images of the left ventricle obtained by both

radionuclide techniques were divided into five segments; antero-lateral, apical,

inferior, septal and postero-lateral. Regional left ventricular wall motion was

assessed according to four grades according to the classification of Herman et al

(1967); normal, hypokinetic, akinetic and dyskinetic. Criteria for improvement in wall motion was defined as a change from a more severe grade of wall motion abnormality to a less severe grade of abnormality or to normal segmental motion.

A scan segment was designated as having abnormal perfusion on the basis of reduced thallium-201 uptake in the initial post-exercise images. The images therefore, were characterised ac9ording to three patterns. A normal pattern was defined as having both normal uptake of thallium-201 post-exerdse and at redistribution. An abnormal pattern was defined as either ·showing substantial redistribution of thallium-201 to the initial post-exercise defect or a fixed defect showing no redistribution or only partial redistribution of thallium-201 to -183- the initial post-exercise defect. There were no major disagreements between the two observers related to the presence or absence of perfusion or segmental motion abnormality. Minor disagreements related to the degree of these abnormalities and these disagreements were resolved by consensus. -184-

Results

All 20 patients survived surgery and were discharged from hospital. No

patient had symptomatic or electrocardiographic evidence of peri-operative

infarction. Eighteen of the 20 patients had no symptoms of angina or heart

failure at the time of their three month post-operative evaluation. One patient

reported no change in his angina after surgery and another noted significant, but

incomplete, relief of angina after surgery. At treadmill exercise pre-

operatively, 19 patients ":'ere limited by angina, and in one patient exercise was

terminated at the onset of multiple ventricular ectopic beats associated with

marked ST segment depression. Post-operatively, 16 patients were limited by

leg fatigue, two by dyspnoea, one by angina and one by claudication. The improved symptomatic status was corroborated by objective improvement of

exercise performance. Exercise capacity improved from a mean treadmill time of 7.9 .:!:. 2.4 minutes to 11.1 .:!:. 3 minutes (P <0.05). Peak exercise double product

also improved from 85.:!:. 20 x 102 to 96.:!:. 20 x 102 (P <0.05) following surgery.

Pre-operatively, 56 segments had abnormal motion (28 were hypokinetic, 25 akinetic and three were dyskinetic) (see Fig. 30). Pre-operatively using thallium-

201 scintigraphy, abnormalities of myocardial perfusion (Fig. 30) were demonstrated in 53 of the 56 segments with redistribution demonstrated in 20 segments and fixed defects in 33 segments. Of the 20 segments showing redistribution pre-operatively, 16 demonstrated an improvement in wall motion after surgery (11 hypokinetic and five akinetic or dyskinetic segments). Four of these segments remained unchanged, two being supplied by vessels unsuitable for revascularisation. -185-

PnLDJCTIVf V/\LUE OF PRC-OPERAfJVE TL 201 PlRFUSION IMAGING

SEGMENTS WITH ABNORMAL WALL MOTION

PRE-OP 20 33 THALLIUM NORMAL RED I STB I DUTI ON FIXED PERrus!oN DEFECT

PosT-DP WALL MoTION 3 16 4 2 31 UNCHANGED IMPROVED UNCHANGED IMPROVED UNCHANGED

Figure 30. The value of pre-operative TL-201 imaging of 56 left vetricular wall segments with abnormal preoperative (PREOP) motion in predicting postoperative (POSTOP) improvement following reva~cularization. -186-

Segmental myocardial perfusion after surgery was considered normal in those

16 segments which showed improved wall motion and in the remaining two persistingly abnormal segments that were revascularised. Of the 33 segments showing fixed defects, only two showed improvement in wall motion after revascularisation. Thirty-one segments failed to improve (nine hypokinetic, 22 akinetic or dyskinetic). Segmental myocardial perfusion remained absent in 28 of the 31 segments that failed to show improvement in motion, while two normalised perfusion and one developed a redistribution defect post-operatively.

Pre-operatively, 44 of the remaining segments had normal wall motion.

Thirty-six of 37 segments had normal motion and perfusion before and after surgery. Seven segments had normal resting function despite abnormalities of perfusion, either at rest or with exercise. Two of these segments showed redistribution pre-operatively and showed normal perfusion after surgery. Five had fixed defects prior to surgery, two becoming normally perfused and three remaining fixed.

The left anterior descending artery was grafted in 19 patients and the major diagonal branch in seven. Of the 39 segments with abnormal wall motion supplied by thi.s vessel, 38 were revascularised (Fig. 31). Of these, 12 showed improved motion following surgery, all showing redistribution of thallium to these segments pre-operatively. - 187-

LAD SEGMENTS WITH ABNOR~1AL MOTION

39 I 38 CORONARY BYPASS GRAFTS

PRE-OP TL 201 14 24 PERFUSION REDISTRIBUTION FIXED

Po sT-OP 12 2 2 22 WALL IMPROVED UNCHANGED IMPROVED UNCHANGED MoTION

Figure 31. The effects Qf grafting the left anterior descending artery (LAD) on

abnormal wall motion postoperatively (POSTOP) in segments showing

red.istribution and many with failure to show redistribution (FIXED)

preoperatively (PREOP)with Tl-201 imaging. - 188-

Two other abnormal segments with a similar pre-operative pattern of perfusion

were revascularised, but despite normalisation of perfusion, segmental function was not a!tered. Fixed defects were present in the remaining 24 segments of

which 22 showed no change in perfusion or function despite grafting. In the remaining two segments, both perfusion and function improved. Total occlusion

of the left anterior descending artery was associated with improvement in wall

motion in eight segments and lack of improvement in 13 segments.

Of the 16 segments with a dominant right coronary artery, grafting was possible to this vessel in 10 patients and in two patients the anatomy was unsuitable despite significant disease (Fig. 32). No significant lesions of the vessels were present in the remaining four patients~ Of 10 abnormal wall motion segments supplied by the right coronary artery, six were revascularised. Of these, two showed improvement in wall motion followig surgery, both showing redistribution of thallium to these segments pre-operatively. Fixed defects were present in the remaining four segments, all of which showed no change in perfusion or function despite grafting of the right coronary artery.

A non-dominant right coronary artery was present in four patients.

Therefore, in the whole group, 20 postero-lateral and four inferior wall segments were supplied by the circumflex and its branches. Seven of these segments had abnormal restin~ wall motion pre-operatively, with coronary artery graft possible to five of these wall segments. Of these, two showed significant redistribution pre-operatively on thallium scintigraphy (Fig. 33). The remaining three segments showed no change in wall motion following surgery, with fixed defects present on both pre-operative and post-operative perfusion scans. -189-

RCA SEGMENTS WITH ABNORMAL MOTION

10 I 6 CORONARY BYPASS GRAFTS

PRE-OP TL 201 PERFUSION 2 4 REDISTRIBUTION FIXED Posr-op I WALL IMPROVED UNCHANGED MoTION

Figure 32. The effects of grafting the right coronary artery (RCA) on abnormal

wall motion post-operatively (POSTOP) in segments showing redistribution and

those with fa: '•Jre to redistribute (FIXED) preoperatively with Tl-201 imaging. - 190-

LCx SEGMENTS WITH ABNORMAL MOTION

7 I 5 CORONARY BYPASS GRAFTS

PRE-OP TL 201 2 3 PERFUSION REDISTRIBUTION FIXED

PosT-oP ~~ALL MOTION IMPROVED UNCHANGED

Figure 33. The effE:lpts of grafting the left circumflex artery (LCX) on abnormal

wall motion post, .:lperatively (postop) in segments showing redistribution and

those with failure to show redistribution (fixed) preoperatively (pre-op) with TL-

201 imaging. - 191-

Post-operatively, patients who showed normalisation of perfusion to the territory of at least one diseased vessel had a significantly greater improvement in resting LVEF. (47 .:_ 12%), than those who did not (37 .:_ 8%) (P <0.05), despite comparable pre-operative LVEF at rest (40 .:_ 11% versus 38 .:_ 8%).

Discussion

It has been shown that thallium scintigraphy can predict improvement in abnormal resting left ventricular function following coronary artery surgery in patients with stable angina and moderately impaired left ventricular performance. (Example patient EK. Figs. 34 & 35). Of 20 left ventricular segments with abnormal resting contraction, but evidence of significant thallium redistribution at exercise thallium scintigraphy, 17 (30% of abnormal segments) demonstrated an improvement in contraction following successful bypass surgery to the artery supplying that segment. Only four segments showing this pattern of thallium uptake failed to demonstrate improved function following surgery.

Conversely segments with a fixed defect at exercise thallium scintigraphy rarely showed improved function. Fixed defects were present in 33 segments with abnormal·motion and following bypass surgery to the vessel supplying these segments, only two segments showed any improvement in function after surgery.

In previous studies, (Rozansky et al1981, Gibson et al1983, and Iskandrian et al 1983) have shown the value of thallium-201 scintigraphy in predicting improvement in the function of asynergic left ventricular segments. However, these data were obtained in patients with normal or near normal global resting left ventricular function with most not having sustained a previous infarction. - 192-

Figure 34. Example. Patient EK. Effects of revascularization on regional wall motion visualised in th0 ant = anterior and LAO = left anterior oblique views before and after surgery at end _systole (ES) and end diastole (ED) showing a significant reduction of LV size and improvement of motion of the anterolateral, apical and septal segments. PRE-OPERATIVE E.S E.D

ANT.

LAO

POST-OPERATIVE E.S E.D

ANT.

LAO - 193-

Figure 35. Example. Patient EK. Effects of revascularization on regional

myocardial perfusion in the same views, anterior and left anterior oblique before

and after surgery with exercise and redistribution • Preoperatively the

redistribution is shown to the septum , apex and anterolateral wall segments with

abnormal motion. All of these segments show improved perfusion following surgery • STRESS

ANT

A - 194-

As it may become increasingly important to identify patients with impaired resting ventricular performance that may benefit most from revascularisation surgery, patients with stable angina pectoris and moderately depressed left ventricular function following myocardial infarction were specifically examined.

It is in these patients there is a paucity of evidence that improvement of perfusion after surgery results in the improvement in left ventricular function in segments that may have been regarded as permanently damaged.

Impaired resting left ventricular function observed in patients with stable angina has been regarded as evidence of previous myocardial necrosis. Patients with unstable angina frequently develop evidence of abnormal segmental ventricular contraction during symptoms, and this abnormality recovers after the symptoms are relieved (Wackers et al 1976). More recently, Braunwald and

Kloner (1982) have suggested in patients with coronary artery disease, myocardial ischaemia may be present in the absence of symptoms and this results in an abnormal left ventricular function. The patients that were examined in this study did not have unstable angina and were not symptomatic at rest. However, in these patients there was improved regional function in a majority (16 of 20) of segments having abnormal function pre-operatively in which there was evidenc.:J of significant thallium redistribution on exercise thallium scintigraphy before operation and normal thallium perfusion following surgery. These data suggest that the mechanism of this enhanced ventricular function may be due to relief of resting myocardial ischaemia. - 195-

The demonstration of contractile reserve of regional function has also been observed in patients with ischaemic heart disease following an inotropic intervention, post extra-systolic potentiation and immediately following exercise. If the myocardium was necrotic, its function should not be improved by any intervention. The concept of a lag in time of mechanical improvement following ischaemia is supported by data obtained by Ninomiya et al (1981) in an animal model. They showed that in a dog, repeated short episodes (five to 15 minutes) of myocardial ischaemia, which did not cause death of myocardial cells, may have a cumulative effect and produce myocardial contractile abnormalities indicating the recovery between episodes was not complete and the effects of intermittent ischaemia were persistent in maintaining mechanical dysfunction.

The exact mechanism of the contractile reserve of hypokinetic segments is unclear and could be due to non-ischaemic viable cells in a scarred area or as

Braunwald and Kloner (1982) have suggested, be due to chronic active ischaemia.

Berger et al (1979) have shown that with rest thallium scintigraphy, initial resting defects may not represent myocardial scar. Many of these resting defects showed substantial redistribution of thallium uptake, suggesting some defects seen on initial resting thallium images may be related to a chronic reduction of resting myocardial perfusion, even in the absence of clinical or electrocardiographic evidence of ischaemia. In their study, 77% of segments with this pre-operative pattern of perfusion reverted towards normal perfusion following coronary artery surgery. Gibson et al (1983) showed that many segments with persistent thallium defects pre-operatively, had improved perfusion following bypass surgery. However, redistribution images in their study were obtained at 2.5 hours after exercise. It is possible that many of these - 196- defects may have shown substantial redistribution if redistribution imaging was performed later than 2.5 hours after exercise, and this may explain a difference in data to that seen in my own study. Two segments which demonstrated persistent defects pre-operatively, but showed improved perfusion after surgery were noted. It is possible that in these patients severe myocardial ischaemia may have occurred and redistribution of thallium uptake may only have been noted if redistribution imaging had been obtained at an even greater interval than four hours.

Other workers have shown the pote~tial for reversal of resting asynergy in patients with stable angina and a reduced left ventricular ejection fraction using contrast angiography. Bourassa et al (1972) demonstrated that 19 of 37 (51%) of segmental wall motion abnormalities revascularised by patent grafts were improved after surgery. Chaterjee et al (1973) in a similar subgroup of 11 patients with documented previous infarction, showed a significant improvement after surgery of the motion of non-infarcted segments which were associated with a rise in global left ventricular ejection fraction. Wolf et al (1978), more recently, in seven patients, showed improvement of percentage shortening and mean velocity of circumferential shortening in previously asynergic segments supplied by patent grafts. In these studies, although graft patency to the effected segment was known, it was not possible to predict improved regional function. In our study, evid::Jnce of thallium redistribution was highly predictive of improved segmental function if vessels supplying that segment were revascularised. Normal thallium perfusion post-operatively was presumptive evidence of a patent graft. - 197-

Quantitative thallium imaging was not used in this study to define exercise and redistribution uptake in the thallium images, but only a qualitative analysis of these images. However, in our analysis, subtle changes were regarded as no change at all, ie. if there was· minimal redistribution of thallium, then this was regarded as evidence of no redistribution. Graft patency was not assessed by angiography but the incidence of graft closure at three months is very low in our experience and that of many published studies as stated by Rahimtoola (1981) in a review of the subject. Thallium imaging has been used extensively to determine blood flow to myocardial segments and hence, graft patency in post­ operative patients. Also, the aim of this study was to determine the effect of revascularising viable tissue, and thallium imaging indicates both myocardial viability and adequacy of blood flow to that segment.

Clinical Implications

This study suggests that in patients with stable angina and a past history of myocardial infarction, resting regional left ventricular dysfunction may be improved following revascularisation if there is evidence of thallium redistribution to the abnormal segment. This improvement can be predicted reliably if redistribution of thallium-201 occurs to a segment with abnormal contraction pre-operatively. Alternatively, if an abnormally functioning segment does not show a significant redistribution of thallium pre-operatively, it is unlikely that grafting a favourably appearing vessel supplying this area would improve contraction of this segment. With this pre-operative information, excessive ischaemic arrest time, as required to perform multiple grafts, may be avoided if abnormal and ·nan-viable segments of the left ventricle could be -198- identified correctly prior to surgery. Also in patients with any large wall motion abnormality at ventriculography, a decision as whether to perform aneurysm repair or bypass surgery or both can be made pre-operatively. -199-

CHAPTER 13

LEFT VENTRICULAR ANEURYSMECTOMY

Long term effects on ventricular function and clinical status. Preoperative

determinants of clinical outcome.

Left ventricular aneurysm is a common complication of myocardial infarction.

Many of these patients develop symptoms of left ventrict.:Jlar failure and require

medical therapy. Despite treatment of heart failure some patients continue to be

symptomatic and undergo aneurysmectomy. As symptomatic improvement

appears to occur more frequently however, in patients in whom the predominant

symptom was angina, it is possible that the improvement in symptomatic status

following aneurysmectomy may be largely due to associated myocardial revascularisation.

Several groups (Kitamura et al 1972, Hazan et al 1973, Cullhed et al 1975,

Schonbeck et al 1975, Aranda et al 1977, Le Femme et al 1977, Rivera et al

1979, Sesto et al 1979, Swan et al 1978 and Otterstad et al1981) have evaluated haemodynamic variables before and after aneurysmectomy. Despite symptomatic improvement in most patients, the results are conflicting, with some authors reporting an improvement in haemodynamics, some showing no change and others a deterioration. There are many difficulties in comparing results of these studies due to the various forms of surgery utilised, the variable effects of coronary artery graft surgery, the heterogenous indications for which surgery was performed and the timing and method of assessment of post­ operative left ventricular performance. - 200-

In patients without angina it is uncertain whether any preoperative features will indicate a good long term clinical outcome as the results of surgery in this group are variable and thus, the guidelines for selection of patients with symptoms of heart failure for aneurysmectomy are controversial.

Accordingly, the aim of this study was to examine the effect of left ventricular aneurysmectomy on left ventricular function and to determine if pre­ operative angiographic parameters of left ventricular performance could predict clinical outcome following left ventricular aneurysm resection performed in patients with intractable symptoms of heart failure but without angina. - 201-

Methods

Patient Population

Twenty-six consecutive patients with antero-apical aneurysms undergoing left ventricular aneurysmectomy (not plication) for symptoms of heart failure were included in the study. Patients in whom angina or arrhythmias were the major indications for surgery, were excluded, as were patients with significant mitral regurgitation.

Clinical details of these 26 patients are shown in Table 16. There were 19 males and seven females, aged 57 .:!:. 11 years (range 35-72 years). All patients had a history of prior myocardial infarction and subsequent clinical evidence of congestive cardiac failure. Twelve patients had New York Heart Association functional class III dyspnoea and 14 patients FC IV dyspnoea. All patients were receiving diuretics, 22 of the 26 patients (85%) frusemide (74 .:!:. 45 mg/day), 18 patients (69%) digoxin and 8 patients (31 %) vasodilator therapy for symptoms of heart failure. Before surgery all patients underwent left heart catheterisation with single plane ventriculography performed in the 30° RAO projection prior to coronary angiography and within one week, resting radionuclide angiography, as described in chapter 2. When significant coronary arterial obstruction was defined as greater than 50% luminal narrowing, 10 patients had single vessel disease, 12 two vessel disease and four patients triple vessel disease. The mean coronary artery score according to the methods of Brandt et al 1977 was 8.5. In this scoring system total occlusion of all three major vessels scores a total of 15.

The mean left ventricular end-diastolic pressure for the group was 25 .:!:. 9 mmHg. - 202-

Table 16.Pre-operative, clinical, haemodynamic and angiographic data in 26 patients

Pt Age FC LVEDP LVEF Coronary Drug Therapy (yrs) (NYHA) (mmHg) (%) Score (mg/day)

DI 35 IV 26 24 11.4 Di 0.5, F 160 JSt 35 IV 33 18 7.0 F 80, Id 80 PB 35 III 35 78- 8.4 Di 0.25, F 40 BH 40 III 43 30 10.4 Di 0.24, F 40, Id 60 FK 47 III 20 39 12.8 Di 0.25, F 40 MJ 50 IV 16 42 12.4 F 40, Hyd 100 KK 51 III 32 47 11.2 Di 0.25, Ch 500 RS 52 III 16 45 6.5 Di 0.25, F 40 J"s 56 IV 26 37 5.6 Di 0.25, F 40 KW 56 IV 18 16 11.2 Di 0.25, F 40 MA 57 IV 22 19 6.0 F 80 MH 58 IV 12 56 4.0 Di 0.25 ID 58 IV 18 23 13.8 Oi 0.25, F 40, Id 40, Praz 4 WL 58 IV 29 23 6.5 Di 0.25, F 160, Id 80, Praz 9 EB 61 III 22 16 6.6 F 80 JH 62 III 32 17 8.0 Di 0.25, Id 40 ER 63 III 20 22 8.2 Di 0.25 MT 65 IV 21 36 8.3 F 80, Id 80 BL 66 III 31 28 6.2 Di 0.25, F 40, Ami 5 MS 66 III 22 33 7.9 F 40 IH 68 IV 12 31 8.0 Di 0.125, F 80 BC 69 IV 36 11 11.8 F 160, Ami 10 IW 70 III 17 32 7.0 Di 0.25, F 80 EG 70 IV 28 34 4.8 Di 0.25, F 80, Hyd 150 PS 71 IV 36 11 8.6 F 80, Ami 10 NS 72 IV 34 32 8.0 Di 0.25, F 160, Hyd 200

Abbreviations: FC = Functional Class (New York Heart Association); LVEDP = left

ventricular end diastolic pressure; LVEF = left ventricular ejection fraction; Di = Digoxin; F

= Frusemide; Id = Isorbide Dinitrate; Hyd = Hydralazine; Ch = Chlorothiazide; Praz = Prazosin; Ami = Amiloride - 203-

Pre-Operative Data Derived

The total left ventricular end-diastolic and end-systolic volumes were calculated from the contrast ventriculogram using a prolate spheroid model and the area length method of Sandler and Dodge (1968). Using the method of

Watson et al (1975) a line of demarcation was drawn between the aneurysm and the remaining left ventricle, which was designated as the contractile segment

(Fig. 36).

The contractile segment (CS) was considered a hemi-spheroid for end-diastolic and end-systolic volume determination. With this model, the volume equation for the contractile segment (CS) was:

volume CS = 8A 2 /31\L x CF'

in which A = the area of the contractile segment determined by planimetry and L equals the longest length within the contractile segment perpendicular to the demarcation line.

Left ventricular volumes were calculated according to the methods described in chapter 8 from the contrast ventriculogram.

The respective ejection fractions for both total ventricular and contractile segment function were calculat.ed:

L VEF = EDV - ESV /EDV

EFcs = EDVCS- ESVCS/EDVCS - 204-

I Line of demarca!10'1

I I I

' \ '\ Aneurysma' '' 1 , sect1or. ' '' ' 'I ' ' .. I .. I' ...... ,I ' ..... , ~ ...... __ ,,

Hernispr.eroid Model

Volume of Each Hemispheroid V· 2/3·T· L· r2 · cf3 r• 2· A 'II'. I V • 8A2 • ct3 h 3'11'·L Figure 36. Upper panel. Schematic diagram showing the line of demarcation between the contractile and aneurysm s&ction.

Lower panel. Method of calculation of left ventricular volume of the contractile segment. - 205-

Where LVEF = total left ventricular ejection fraction, CSEF = contractile

segment ejection fraction, EDV = end-diastolic volume, ESV = end-systolic

volume.

The contractile segment fractional shortening was determined at the point of

maximal incursion of the contractile segment at end-systole. The fractional

,shortening was calculated according to the following formula:

FScs% = CSIDD - CSIDS/CSIDD

where FSCS = fractional shortening of the contractile segment, CSIDD = the contractile segment internal dimension at diastole, and CSIDs = the contractile segment internal dimension at end systole.

The outline of the left ventricular aneurysm was traced and perimeter

expressed as a percentage circumferential ratio of the left ventricular aneurysm

circumference to the total circumference at end-diastole in the right anterior

oblique projection.

Preoperative Radionuclide Data:

At the pre-operative radionuclide study, L VEF was calculated, regional wall

motion was assessed qualitatively in five left ventricular wall segments (Chapter

7); antero-lateral, apical, inferior, septal and postero-lateral. Regional wall

motion was scored according to the morphological classification of Herman et al

(1967): 0 = normal, 1 = hypokinesis, 2 = akinesis and 3 = dyskinesis. - 206-

Surgical Technique

After establishment of cardiopulmonary bypass if coronary graft surgery

was contemplated, an aortic cross-clamp was placed and the aortic root was

perfused with hypothermic cardioplegic solution. If graft surgery was not

contemplated, the aorta was not cross-clamped and cardioplegic solution was not

used.

Negative pressure was applied sufficient to suck all blood from the ventricle

through the aortic vent catheter in order to delineate the aneurysm. The thinned

aut myocardium was incised and the interior of the ventricle was explored by

palpation and thrombus removed. A margin of scar was retained on the perimeter

of the excised myocardium.

The edges of the myocardium were then approximated using interrupted

horizontal mattress sutures of 1 Tycron suture material tied over Teflon

bolsters, re-inforced by a second layer of 1 Tycron suture material inserted as

continuous simple sutures through the Teflon bolsters to achieve hemostasis.

Sixteen patients (62%) underwent left ventricular aneurysmectomy alone and

nine patients (38%) had additional coronary artery bypass surgery with amean of

1.8_:.75 grafts placed. - 207-

Follow-Up

At 15 i-ll months after surgery, I examined all surviving patients and immediately following this clinical assessment, all patients underwent repeat radionuclide angiography.

On the basis of this clinical evaluation, the patients were divided into those who were considered as improvers: defined as those patients in whom there was an improvement of at least one functional class according to the New York

Heart Association classification and a reduction in heart failure therapy, or non­ improvers: those patients who had died, had no change, or a deterioration in functional class and/or increased heart failure therapy.

Data Analysis.

Data are expressed as a mean ± SO. Statistical analysis was done using a

Student's paired or unpaired t- test where appropriate. Multivariate analysis was performed using step-wise linear discriminant analysis to determine the strongest pre-operative angiographic predictors of longterm clinical outcome.

Results were considered significant at a value of p < 0.05. - 208-

Results

Clinical Assessment

Two patients (MA and MF) died peri-operatively. Both patients required parenteral inotropic and intra- aortic balloon counterpulsation support in the initial post-operative phase. Despite this intensive therapy both died of intractable low cardiac output states. Two patients (AS and IH) died suddenly two and three months after surgery respectively, and one patient (KW) suffered a further myocardial infarction complicated by severe cardiac failure and died 13 months after surgery. Of the 21 surviving patients, 13 had an improvement of at least one functional class with reduction in heart failure therapy. The remaining eight patients were clinically unchanged or had deteriorated at follow­ up with no reduction or an increase in heart failure therapy. Thus on clinical assessment there were 13 improvers, and 13 non-improvers of whom 8 were survivors and evaluated at follow up. Three of the improvers and 6 of the non improvers underwent additional coronary artery graft surgery.

Effect of Left Ventricular Aneurysmectomy on Left Ventricular Function

Pre and post-operative global left ventricular function measured by radionuclide angiography are shown in Fig. 37, for both improvers and non- improvers. Although patients who showed long term clinical improvement had an increase in LVEF from 29+8%- to 34+11- %, this change was not statistically significant. There was no significant change in LVEF after surgery for the non­ improvers. Mean regional wall motion score fell for both groups, largely due to - 209-

RADIONUCLIDE LVEF BEFORE AND AFTER LV ANEURYSMECTOMY LVEF (%) 70

P=NS P=NS 50

30

10

· PRE-QP POST -OP PRE-OP POST -OP

NON ---- IMPROVERS 13 --IMPROVERS r8

Figure 37. Left ventricular ejection fraction (LVEF) preoperatively (PREOP) and postoperatively (POSTOP) fallowing aneurysmectamy far the improvers (---)and non improvers(-). - 210- resection of dyskinetic segments, although this change was significant only for the improvers, 5.8.! 1.7 to 4.9.! 1.6 (P <0.05), and 7.5.! 1.1 to 6.1.! 1.9 (NS) for the non-improvers.

Five of the improvers (38%) were considered by both observers to have a significant residual left ventricular aneurysm despite resection and one to have a false aneurysm. Four of the survivors in the non-improvers (50%) had evidence of a significant residual left ventricular aneurysm.

Pre-Operati-ve Angiographic Data

The pre-operative global angiographic data for both improvers and non­ improvers are shown in Fig. 38. Significant mean differences in all angiographic variables reflecting total left ventricular size or aneurysm size were found between the two groups. End-diastolic volume was significantly smaller in the improvers, 145 .! 56 ml/m 2 than in the non-improvers, 199 .! 65 ml/m 2 (P <0.05) as was end-systolic volume 94 .! 47 ml/m 2 versus 154 .! 51 ml/m 2 (P

The pre-operative angiographic data for the contractile segments for both the improvers and non-improvers are compared in Fig. 39. There was no significant difference in contractile segment volumes, ejection fraction and fractional shortening between the two groups. ~ 211 ~

PRE-OPERATIVE GLOBAL ~IMPROVERS (13l

DATA NON D IMPROVERS (131

LVEF EDV ESV (%) (mls) (mls) 300 300

200 200

100 100

P<0.05 P<0.05 P<0.01 P

Figure 38. Preoperative angiographic left ventricular ejection fraction (L VEF), end diastolic volume (EDV), end systolic volume (ESV) and ratio of the circumference of the aneurysm to total LV size ( CAN/LV ) for the improvers compared with the non improvers. - 212-

PRE-OPERATIVE CONTRACTILE ~ IMPROVERS (13) SEGMENT DATA NON D IMPROVERS (13)

CSEF CSEDV CSESV CSFS (%j (mls) (mls) (%) 150 150

70 70 100 100 50 50

30 30 50 50

10 10

P=NS P=NS P=NS P=NS

Figure 39 Pre-operative angiogr'aphic contractilE. segment ejection fraction

(CSEF), end-diastolic volume (CSEDV), end systolic volume (CSESV), for the

improvers compared with the non improvers. - 213-

All pre-operative angiographic variables for the improvers and the non­ improvers were subjected to a multi-variate stepwise linear discriminate analysis. The circumferential ratio of the perimeter of the left ventricular aneurysm to the total left ventricle and the end-systolic volume were the two strongest independent predictors of long term clinical outcome. The relationship between these two variables is shown in Fig. 40. A combination of these variables provided an accurate predictor of surgical survival and functional class improvement. Specifically, eight of the 13 (65%) improvers had a circumferential ratio of aneurysm to total left ventricle of <45% and an end­

2 systolic volume of <120 ml/m • Conversely, if one or both these criteria were not met, a poor outcome could be correctly predicted in 12 of the 13 (92%) non­ improvers. - 214-

PRE-OPERATIVE PREDICTORS OF LONG TERM e IMPROVERS CAN CLINICAL OUTCOME CLV NOI\4 (%) X IMPROVERS 70 )(

)( )( GO X • )( )( )( • )()( 50 • )( ------.---.~-1(-i 40 •• I .: )( . I I •• I I 30 I • I I I I I I I I I I I o!-n' 40 80 120 160 200 240

Fig 40. The relationship between the two strongest preC.::ctors of long term

outcome CAN/LV and ESV for the improvers compared with the non improvers. - 215-

Discussion

In patients with left ventricular aneurysms without angina, this study has shown that 50% of patients undergoing aneurysmectomy for intractable heart failure can expect to sustain a clinical improvement. As expected, a favourable clinical result was more likely in patients if global parameters of left ventricular function were only moderately impaired and the aneurysm involved relatively less of the total left ventricular circumference. Those patients with a poor pre­ operative ejection fraction, with extensive less discrete aneurysms and massive dilatation, aneurysmectomy does not appear to provide a successful therapeutic alternative. Between these two extremes however, I found a critical point where a favourable long term outcome becomes less likely. Specifically, the best independent predictors of long term outcome were a combination of pre­ operative angiographic variables. If the end-systolic volume was less than 120 ml/m 2 and the circumferential ratio of aneurysm to ventricle less than 45%, a good outcome was correctly predicted in eight (62%) of patients sustaining a clinical improvement. None of these patients underwent coronary artery bypass graft surgery and thus improvement cannot be attributed to revascularisation. A reversal of ischaemic dysfunction may have been the mechanism of improvement in three of the remaining five improvers who did not fulfill these criteria however, because in these patients additional revascularisation surgery was performed. It is unlikely in patients with such advanced ischaemic heart disease any greater predictive accuracy of long term outcome could be achieved as there are so many variables known to affect prognosis including the extent of coronary disease and the electrical stability of the left ventricle. - 216-

Although clinical symptoms were improved in 13 patients in this series, no significant change of left ventricular ejection fraction could be demonstrated in this group. The mechanism for improvement of symptoms in these patients was therefore, not answered in this study. However these patients had a higher mean resting left ventricular ejection fraction, smaller ventricular volumes and smaller ventricular aneurysms and thus the left ventricles in the improvers had suffered less damage and repair to near normal ventricular geometry was possible. It is likely that "splinting" of the left ventricle and reduction of the volume of the left ventricle led to a decrease in wall stress and a resultant normalisation of motion of hyperkinetic residual contractile segments. As a result global ventricular performance as measured by ejection fraction was unlikely to change. Although my analysis of regional wall motion did not distinguish hyperkinetic from normal motion and this mechanism is only hypothetical there was a significant reduction in wall motion score in these patients.

The large ventricles were more extensively damaged and therefore it was likely that repair by aneurysmectomy was incomplete. As a result regional wall motion score was unchanged, and wall stress was likely to have remained high in the non-improvers with maintenance of increased myocardial oxygen requirements and possible ischaemic dysfunction in residual non-aneurysmal segments perfused by diseased coronary" arteries. However, the ideal balanc'"' between the benefits derived from wall tension reduction by decreasing end-diastolic volume and the necessity of maintaining an adequate preload varies from person to person.

Therefore, aneurysmectomy is likely to be associated with variable results as shown in this study, and symptomatic improvement not necessarily linked to - 217-

favourable changes in ejection fraction. It is interesting that end-systolic

volume was independently such a good predictor of long term clinical outcome.

Some workers have proposed that end systolic volume is an important indicator

of intrinsic contractility independent of loading conditions (Slutsky et al1980(c)).

Most aneurysms in the improvers had evidence of some contractile function and

were not either totally dyskinetic or akinetic. As left ventricular volume

increased, it appeared that adequate contractile function associated with an

improved symptomatic state could only be preserved following surgery if the

end-systolic volume did not exceed 120 ml/m 2 (4-5 times normal end-systolic

volume). In addition, Sesto et al (1979) has also postulated that failure of

aneurysmectomy to improve systolic ventricular function in patients with

isolated left anterior descending disease is due to the destruction of transitional

zone contractility at the time of surgery. Results of my study are similar to

that of Froehlich et al (1980) who were unable, using radionuclide techniques in a

smaller group of patients, to demonstrate an improvement in ejection fraction

before and after surgery. They described a greater improvement in functional

class following surgery than in my study. Fifteen of 18 patients had significant

angina, and in all these patients the angina was lessened post-operatively. Thus,

relief of angina rather than dyspnoea secondary to coronary artery bypass

grafting, could be responsible for their finding of a higher incidence of

improvement in functional class.

Some authors (Kluge et al 1971, Arthur et al 1972 and Kiefer et a! 1983),

have suggested that good contractile segment function is predictive of

favourable long term clinical outcome. The presence of excellent contractile segment function in my study did not reliably predict long term clinical outcome. - 218-

Certain patients in this study with large discrete left ventricular aneurysms and grossly dilated left ventricles did poorly in both the short and long term despite excellent residual contractile segment function. Many of these earlier studies have included patients with angina and it is possible that revascularisation of vessels to these contractile segments may have improved exercise left ventricular function and symptom status independent of the aneurysm resection.

In order to examine the effects of aneurysmectomy, this study was restricted to a homogenous group of patients in whom coronary artery grafting was not performed in 16 and only sparingly in the remaining patients, so that the effects of complete revascularisation were unlikely to significantly effect the interpretation of these data.

Interestingly, despite surgery, many patients continued to have significant wall motion abnormalities. This highlights the difficulties faced by the surgeon at operation in defining those areas of the myocardium which are viable and which are not, recognising that the surgeon is limited by anatomical restraints such as the mitral valve apparatus and the interventricular septum, with additional difficulties in maintaining stable sutures in contractile viable myocardium. However, none of the surviving patients were compromised by having their left ventricular volume reduced to such an extent as to impede function.

Clinical Implications

Patients undergoing left ventricular aneurysmectomy for symptoms of heart failure without angina, have a much poorer long term clinical outcome than previously reported patients, whose predominant symptom was angina. Although - 219- left ventricular ejection fraction was not increased by aneurysmectomy, repair of the left ventricle in patients with discrete ventricular aneurysms and reasonably well preserved systolic function, led to a better long term prognosis than those patients with large ventricular aneurysms and markedly depressed ejection fractions. - 220-

CHAPTER 14

IRON OVERLOAD AND THE HEART

Early left ventricular dysfunction and chelation therapy in thalassaemia major

Thalassaemia major is usually a profound anemia inherited in a Mendelian

recessive manner. Although it characteristically occurs in persons of

Mediterranean origin, patterns of migration in recent years have resulted in a

world-wide distribution of the disease. Previously, most patients died from

severe anaemia during the first decade, but with modern transfusion therapy

many now survive beyond childhood (Weatherall et al 1981). Because of such

therapy, however, excessive iron deposition occurs in the myocardium, resulting in death between 20 and 30 years of age from refractory cardiac failure or arrhythmias (Engle et al1964). Leon et al (1979) using radionuclide angiography, have shown that abnormal left ventricular function at rest and during exercise is associated with heavy iron loads due to recurrent transfusion. Chelation therapy has been used in an attempt to minimise iron deposition and many patients now receive an intensive chelation regimen. Nevertheless, the ability to detect cardiac complications remains a major problem in the management. It is essential that these complications be identified at an early stage, because clinical evidence of cardiac dysfunction is a late and usually poor prognostic event. The recognition of subclinical abnormalities could indicate a need for more aggressive treatment. - 221-

In a group of asymptomatic patients with thalassaemia major, the aim of the first part of the study ( Study one ) was to examine the incidence of cardiac dysfunction in unchelated patients or patients who had received only a short period of chelation and relate this to the degree of iron load from transfusion.

Buja and Roberts (1971) have shown iron causes the cell to hypertrophy so that the ventricular walls become thickened. Patchy death of individual muscle fibres occurs as a terminal event and as a result there is minimal fibrosis. Therefore, it is possible that normal function may be retained or recovered if iron could be removed. Barry et al (1974) have shown that the liver iron concentration can be reduced and the progress to hepatic fibrosis prevented by chelation with effective infusions of subcutaneous desferrioxamine. No previous study, however has examined left ventricular performance in patients with thalassaemia major undergoing regular intensive chelation with desferrioxamine. The aim of the second part of this study ( Study two ) was therefore, to examine the effect of long term chelation therapy on left ventricular function and to determine if this therapy would result in preservation or improvement of left ventricular performance. - 222-

STUDY ONE.

Methods

Patient Population

Twenty-three patients with thalassaemia major and no cardiac symptoms were studied. The group consisted of all asymptomatic patients who regularly attended a specialised hematologic unit at this hospital. These patients had been referred at different ages but subsequently had been under regular supervision for a mean (.:!:_ SO) of 5.1 .:!:. 6 years. The group comprised 14 males and nine females, with a mean age of 13.2 .:!:. 5.3 years (range, 6 to 23 years). No patient had clinical, radiologic, or electrocardiographic evidence of cardiac disease at the time of the study. A past episode of cardiac failure secondary to severe anaemia had occurred in three patients, two of whom remained on digitalis therapy. All three patients were asymptomatic at the time of this study. No other patient was receiving cardiac drugs.

Haematologic Protocol

According to the policy of this unit, a hypertransfusion regi :nen is used to maintain a haemoglobin level greater than 10 g/dL and chelation therapy is introduced as soon as practical after diagnosis. Only twelve patients had received prior chelation (3.6 .:!:. 1.9 years), and 11 no chelation therapy at all. The duration of anaemia before the initiation of adequate transfusion - 223-

therapy and total iron load in grams received from blood transfusions was

estimated from the patients' records. The patients had regular transfusions of

185 2:_129 units of blood over 6.3 2:. 5 years at the unit, or before referral. Total iron load in grams, was calculated assuming 200 mg of iron per unit of blood (450

ml of whole blood or 250 ml of packed cells). The haemoglobin level and serum

ferritin concentration were determined at the time of each radionuclide study.

No patient was anaemic at the time of the study, (haemoglobin, 12.9 2:. 1.4 g/dL).

Serum ferritin was estimated using a commercial radioimmunoassay kit

(Diagnostic Products Corporation, Los Angeles, California; normal range, 20 to

400 ng/mL).

Radionuclide Data

Resting and peak exercise radionuclide data, using previously described techniques in chapter 3, were examined and related to the clinical, haematologic, and exercise characteristics. To avoid the effects of sudden changes in intravascular volume on left ventricular function, all patients were transfused seven to 14 days before the radionuclide study. ADDENDUM P224 para 1

To be inserted after II mean LVEF of 50% +1- 8%."

"Although the study in normal children suggested

that an LVEF of under 50% was abnormal, it did not

seem appropriate, because of the limited number in

the control group, to apply such a strict parameter

to this study of children with Thalassaemia Major.

Accordingly, only values under 45% were considered abnormal. " - 224-

Results

Left ventrieular function at the inital study

The results of the initial measurements of rest and exercise ejection fraction

for each of the 23 patients are shown in Table 17. Resting left ventricular ejection fraction (LVEF) was normal in 18 of the 23 patients studied, with a

mean LVEF of 50 + 8%. At peak exercise the mean LVEF was 51% .:!: 11%.

Patients with normal left ventricular performance were defined as having normal resting LVEF with an increase of at least 5% LVEF units at peak exercise as shown in chapter 6. The LVEF rose normally with exercise in only five of the 18 patients with a normal resting LVEF. As shown in Figure 41, 18 of the 23 asymptomatic patients had evidence of abnormal ventricular function, shown either at rest or by a failure of ventricular function to improve during exercise.

Haematologic Correlates of Ventricular Function

The haematologic and exercise data for the patients (mean age, 14 :r 6years) with normal ventricular function were compared with those for patients (mean age, 13.5 .:!: 5 years) who had abnormal left ventricular function (Table 18). The mean LVEF for the five patients with normal ventricular function W2"' 55%.:!: 8% at rest, increasing to 63% .:!: 8% at peak exercise (P <0.05). The LVEF of the 18 patients with evidence of abnormal left ventricular function was 48% + 7% at rest and 48% .:!:. 8% at peak exercise (P = ns). Although there was a significant difference in peak exercise LVEF response, there was no significant difference in - 225-

Table 17. Results Obtained in 23 Patients with Thalassemia Major

Patient Age Rest Exercise Exercise Work Iron Serum Anemia LVEF LVEF DP.10-2 Load Load Ferritin Duration yrs % % HR.mmHg watts gms ng/rJ?l yrs 1 6 47 40 248 25 0 470 5 2 6 51 64 234 50 8 880 4 3 7 44 44 173 50 23 4770 2 4 7 59 57 192 50 16 3100 1 5 8 42 46 119 75 18 2060 5 6 9 42 42 252 50 30 3200 1 7 9 49 47 302 75 14 4500 2 8 9 60 65 169 25 17 900 1 9 10 45 43 218 50 20 2880 5 10 12 48 45 286 50 39 3100 3 11 12 48 48 173 75 9 2780 10 12 13 46 50 235 50 38 4400 3 13 13 48 47 338 25 49 3300 2 14 14 58 60 170 100 42 1990 7 15 14 68 77 190 125 40 456 3 16 17 38 36 284 175 65 8300 7 17 17 55 57 329 100 59 6390 3 18 17 45 56 240 150 8 1420 15 19 19 47 51 319 175 83 2700 10 20 19 50 50 210 150 69 3760 5 21 21 67 64 195 100 101 5880 0 22 22 49 55 167 100 8 1560 20 23 23 37 30 208 175 16 3600 17

LVEF = Left Ventricular Ejection Fraction - 226-

'Normal' response 'Abnormal' response

(n=5) (n=18) 80 8

7 ~ 70

60 60

*Li.. 50 50 w I~I ~ 35¢~ 40 40 I I * 30 LL.w 30 ~ >..J i!! 20 2

10 10

0 0 Rest Ex Rest Ex

Figure 41. Left ventricular ejection fraction (LVEF) at rest and peak exercise (EX) for 23 patients with thalassaemia major showing only 5 patients able to augment LVEF normally with exercise prior to .Jr after only a limited period of chelation therapy. - 227-

Table 18. Comparison of Data (Mean+ SO) in Patients with Normal and Abnormal Left Ventricular Function

Normal LV Abnormal LV p Function Function Value*

Patients, (n) 5 18

Age (yrs) 14 ± 6 13 * 5 ns

Ejection fraction, (%) 55 ;1: 5 48.7 ns

Exercise ejection fraction, (%) 63 ± 8 48 =8 <0.05 Exercise double product0 .10! 200 .. 31 236.61 ns

Work Load, (watts) 90 :i- 46 86 =49 ns

Iron load, (gm) 16 i-12 38 =27 <0.05

Serum ferritin, (ng/m 1) 1043 ;1: 400 3732 •1749 <0.05

Anemia duration, (yrs) 9;~:7 5 •4 ns

*ns = not significant 0 J. Systolic blood pressure x heart rate (mm Hg x beats/min). - 228- workload (watts) or double product (systolic blood pressure X heart rate) achieved between the two patient groups. The mean iron load from transfusion was estimated at 16 ,:t 12 g in the group with normal ventricular function, and at 38 ,:t 27 g in the group with abnormal ventricular function (P<0.05). Similarly the mean serum ferritin level was 1043 ,:t 400 ng/ml in patients with normal ventricular function and 3752 ,:t 1500 ng/ml in patients with abnormal ventricular function (p<0.05). The mean duration of anaemia before the optimal transfusion therapy was 9 ,:t 8 years in the group with normal left ventricular function and 5

,:t 4 years in the group with abnormal ventricular function (P = ns). - 229-

STUDY TWO.

M~thods

Patient Population

All 23 patients with thalassaemia major described previously continued to form the study group. All patients were managed according to the policy of this unit and kept under regular, careful clinical surveillance with maintenance of haemoglobin levels greater than 10 gm/dl by regular transfusion.

Chelation Therapy

Chelation therapy was continued in 12 patients and begun in a further 11 patients and was administered subcutaneously by infusion pump 5 days/week, by an intensive regime 1-4 gm/day, (642:_18 mgm/kg body weight/day). All patients and parents, where possi(?le, were instructed on the use of the subcutaneous infusion pump via hospital staff. Compliance with the infusion regime was checked randomly by a measure of 24 hr. urinary iron excretion in all patients at various times during the study period. In one patient (patient 19), in whom left ventricular function data suggested progress was not adequate, 12 gms of desferrioxamine was given intravenously for 16 hours on an additional day each week. To increase the mobilisation of iron and increase the effectiveness of chelation, ascorbic acid was started in all patients. In an attempt to reduce the initial toxic effect of released iron, ascorbic acid ( 2-10 mg/kg) was only started in all patients when clinically stable at least six months after institution of chelation therapy. Total iron load in grams received in blood transfusions was recorded and calculated as previously described. - 230-

Radionuclide Studies

Radionuclide studies were performed at rest and during semi-supine bicycle

exercise using exactly the same protocol as previously described. As in the

original study, all patients were transfused 7-14 days before the radionuclide

study to avoid the effects of sudden changes in intravascular volume. All

studies were performed annually over the subsequent 4 years. Haemoglobin and

serum ferritin concentrations were determined at the time of each radionuclide study.

Data Analysis

For each patient, each variable (resting LVEF, change in LVEF, peak exercise

LVEF and serum ferritin levels) was plotted against time for the value obtained at the initial study and from the data each year for the subsequent four years.

The slope of this line was taken to be the calculated yearly increase or decrease of that variable for each patient. Significant changes in the slopes of each of these variables over time were examined using the one sample Wilcoxon rank test. Differences between variables measured at the initial and final study were examined using the Student's paired or unpaired t test. - 231-

Results

Clinical Data

Patients 21 and 23 died from progressive refractory congestive cardiac failure

at 8 and 12 months after the initiation of the study. Patient 12 developed

clinical pericarditis after cholecystectomy, patient 18 transient asymptomatic

A-V nodal conduction abnormality which has not recurred and patient 26

frequent atrial extra-systoles and recurrent paroxysmal atrial tachycardia

requiring digitalis and later beta blockade therapy. The remaining 18 patients

showed no clinical evidence of cardiac dysfunction during the four years follow

up period. All prepubertal children maintained a steady, although below average

growth pattern and were able to increase their work load from the initial to the

final study. For the total group, however, there was no significant increase in

work load over the four year period as is shown in Table 19 and Fig 42.

Effects of chelation therapy on iron load.

All patients were adequately transfused and at the time of each study the

mean haemoglobin of all patients was greater than 10.0 gm/dl. As can be seen in

Table 20 and Fig 43 the iron load from transfusion rose from 34.!_27gms to 63_::

28gms over fot1r years. Despite this, serum ferritin level fell from 3,14~_::1,956

at the initial study to 2,228_::1,825 ng/ml at the final study. Although this

difference was not statistically significant, the calculated yearly fall of serum ferritin levels over the four year period was significant (p<0.05). - 232-

Table 19. Initial iron load, exercise and haemodynamic data with the average yearly

change ever the 4 year period of chelation.

Yearly change

Initial study Average + SD p

REST LVEF (%) 50+8- 2.2 2.2 < 0.01 EXERCISE EF (%) 51+11- 3.7 2.9 < 0.001 % change L VEF 2+6- 1.6 1.8 < 0.001 WORK LOAD (watts) 86+49- 2.4 9.7 NS DP* .10-2 (mmHg.HR) 218+75- -1.7 25 NS FERRITIN (ng/mJ) 3148+1956- -295 562 < 0.05 - 233-

EXERCISE DATA MEASURED OVER STUDY PERIOD 32

c: 30 :J:' biJ :J: 28 E .,.-E 10 26 .-! a.X c 24

22 I I I I Initial yrl yr2 yr3 yr4

100 en P=NS -ctl ~ 80 "'C ctl 0 -I 60 ,I, ..:.::,_ 0 ... ,I, . ~ 40 ... I I I I I Initial yrl yr2 yr3 yr4

Figure 42 • Double Product (DP) and Watt Load achieved with maximal semi-

supine bicycle exercise at the inital study and over the following 4 years. -234

Table 20. Mean values of iron load, exercise performance and ventricular function

data for the 21 patients with Thalassaemia Major.

Initial Study YRI YR2 YR3 YR4

IRON LOAD (gms) 34+27-- 39+24 46+26- 55+27- 63+28 FERRITIN (ng/ml) 3148+1956- 2808+2063- 2552+1145-- 2427+1812 2024+1286 DP .10-2 (mmHg.HR) 218+75 272+49- 226+40--- 234+52 248+58 WORK LOAD (watts) 86+49- 86+42---- 85+39 89+43 90+29 REST LVEF (%) 50+8- 51+11- 56+8--- 55+9 57+6 EXERCISE L VEF (%) 51+11 56+14--- 62+9 64+12 65+7- - 235-

EFFECT OF CHELATION ON HAEMATOLOGICAL DATA

Se Fer Fe load (n=21) 9,000 90

7.000 70 . 1

5,000 50

3,000 30 P<0.05 1.000 10 I I I I 1 I I I I Initial yrl yr2 yr3 yr4

Figure 43. Iron Load received from obligatory blood transfusion and Serum Ferritin levels

(Se Fer) at the inital study and after 4 y,ears of chelation therapy with subcutaneous infusions of desferrioxamine. - 236-

Effects of Chelation on Left Ventricular Function

In Table 19 and Fig 44 are shown the sequential effects of chelation on left

ventricular performance in the 21 surviving patients over the 4 year period of

chelation. There was a significant annual increase in resting L VEF from 50+8%

to 5 7~6% (p<0.01). Peak exercise LVEF rose significantly from 51~11% to 65~ 7%

(p

Figure 44, prior to treatment was 2~6% rising each year over the study period to

10_!6% (p<0.001) after 4 years.

Figure 45 shows the individual left ventricular function data for the 21

survivors at the end of the 4 year study period divided into those with normal and

abnormal left ventricular performance in a similar format to the initial data (Fig

41). As shown previously, patients with normal left ventricular performance were

defined as having normal resting LVEF with an increase of at least 5% ejection

fraction units at peak exercise. Figure 45 shows that 16 of the 21 (76%) surviving patients now have normal left ventricular function compared to 5 patients (22%)

at the start of the study. The mean resting LVEF for those patients with normal rest and exercise left ventricular function was 56~4% rising to mean peak

exercise LVEF of 67+6%. In those patients with abnormal left ventricular performance the mean resting LVEF was 58~ll% and peak exercise LVEF of 62~ 10%.

Of the 18 patients at the start of the study with abnormal left ventricular performance 5 continued to have abnormal left ventricular function, with 2 as - 237-

shown previously dying from cardiac failure and 11 at the final study showing improvement. The 5 patients with normal left ventricular function at the start of the study were again normal at the final study. Four of these 5 were already receiving subcutaneous chelation treatment.

Only one patient, (patient 19) however, despite chelation, showed a progressive deterioration in left ventricular function with a steady fall in resting LVEF from

47% to 29% and peak exercise LVEF from 29% to 25% after three years.

Although he was not symptomatic this deterioration in ventricular function, detected only by serial estimation of ventricular function led to this patient's chelation dose being increased to 20 gms/week. As a result, left ventricular function was shown to be improved at the final study to a resting LVEF of 57% and a peak exercise L VEF of 48%. Of the two patients who died within the first year of study, patient 21 had a no~ mal resting L VEF of 67% falling to 64% and patient 22, the oldest in the group, had the lowest resting L VEF of 37% and 30% at peak exercise. Despite the arrythmias noted in patients 18 and 26 at no time after recognition of these arryhtmias has LV dysfunction been demonstrated in these patients. - 238-

EFFECT OF CHELATION THERAPY ON LV PERFORMANCE 70 LL. tn=211 UJ >....1 ...... 60 en Q) 0::: 50 80

LL. UJ >....1 70 Q) ·uen ~ 60 X UJ 50

~ 10] LL.JI___..J....I ...... -! ___JP

~~ OJ ,.------~----~------~-----I I I I Initial yrl yr2 yr3 yr4

Figure 44. The ef'f.::.~cts of chelation therapy on LV ejection fraction (LVEF) at rest, peak exercise and percentage change in LVEF with exercise over 4 years - ZJ9-

100 100 'Normal' response 'Abnormal' response (n=161 ln=51 90 90

80 80

70 70 :::::=- .==::: 60 60 .. ,., u:. Li. UJ Ul 1 50 50 > ..J 3 I 40 40 ><

30 30

20 20

10 10

0 0 Rest Ex Rest Ex

Figure 45. Left ventricular ejection fraction (LVEF) at rest and peak exercise (EX) for 21 surving patients after 4 years of chelation therapy. - 240-

Discussion

Previous clinical studies (Engle et al 1964) have shown that in unchelated patients with transfusion dependent thalassaemia major, cardiac dysfunction is usually not clinically apparent until the patient accumulates up to 20 gms of iron. Systolic left ventricular function at rest is well preserved until late in the course of the disease, and deterioration, is felt to be rapid and unpredictable.

Cardiac arrhythmias become more frequent in the late teens and herald the onset of symptomatic arrhythmias or congestive cardiac failure. Death due to intractable arrhythmias or a congestive cardiomyopathy was common by the ages of 18 to 20 (Ehlers et al1980, Nienhuis et al1980).

Buja and Roberts (1971) demonstrated the pathology of iron overload of the heart. They showed that iron within the cell causes hypertrophy so that initially the left ventricular walls become thickened. In some patients with increasing cellular dysfunction, presumably due to the toxic effects of iron, subsequent progressive dilatation of the left ventricle occurred with thinning of the hypertrophied free wall of the left ventricle and death due to congestive cardiomyopathy. A transfusion burden of greater than 100 units (containing 20 gms of iron) was highly associated with grossly visible myocardial iron deposits and symptomatic heart failure in contrast to less extensive iron deposition in individuals free of cardiac symptoms. Maximal iron was found in "working" myocardium, while less extensive deposits were present in conduction tissue.

Ventricular myocardium generally contained more iron then atrial myocardium; atrial deposition was closely related to the presence of supraventricular - 240-

Discussion

Buja and Roberts (1971) demonstrated the pathology of iron overload of the heart. Small amounts of iron accumulated in the perinuclear zone of cardiac muscle cells but with increasing iron deposition, more myofibrils were affected and large number of fibres were laden with deposits. With moderate or even extensive iron deposition, the histological architecture was preserved. Cellular degeneration and fibrosis were noted only in areas of maximal iron deposition.

They showed that iron within the cell causes hypertrophy so that initially the left ventricular walls become thickened. In some patients subsequent progressive dilatation of the left ventricle occurred, possibly as a result of chronic anaemia, with thinning of the hypertrophied free wall of the left ventricle and death due to congestive cardiomyopathy. A transfusion burden of greater than 100 units

(containing 20 gms of iron) was highly associated with grossly visible myocardial iron deposits and symptomatic heart failure, in contrast to less extensive iron deposition in individuals free of cardiac symptoms. Maximal iron was found in ventricular myocardium, while less extensive deposits were present in the atrium and in conduction tissue.

Engle et al (1964) have also shown that in unchelated patients with transfusion dependent thalassaemia major, cardiac dysfunction was usually not clinically apparent uncil the patient accumulated up to 20 gms of iron. Systolic left ventricular function at rest was well preserved until late in the course of the disease, and deterioration, was felt to be rapid and unpredictable. Before transfusion regimes were widely accepted many of the older children were exposed to long periods of anaemia resulting in an enlarged vigorously - 241- contracting left ventricle. This explains why the resting left ventricular ejection fraction was often well preserved until late in the course of the disease because of the haemodynamic compensation for chronic anaemia. Cardiac arrhythmias became more frequent in the late teens and heralded the onset of symptomatic arrhythmias or congestive cardiac failure. Death due to intractable arrhythmias or a congestive cardiomyopathy was common by the ages of 18 to 20 (Ehlers et al' 1980, Nienhuis et al1980).

In patients with severe thalassaemia major who have been regularly transfused since diagnosis, many show mild ST-T wave abnormalities on the resting electrocardiogram but heart size estimated by chest x-ray is normal until late in the course of the disease. Echocardiography has been used to examine left ventricular function in this disorder. Henry et al (1978) noted normal resting systolic ventricular function as shown by M mode echocardiographic examination in most patients, but increased left ventricular mass and wall thickness can occur early in the disease and progresses with increased iron burden. Despite these early changes noted by Henry et al (1978), no study of diastolic left ventricular function has been performed in unchelated patients with transfusional iron overload. However, Valder-Cruz et al (1982) studied asymptomatic patients who had received chelation therapy from the time of diagnosis and noted abnormal contraction and relaxation of the posterior ventricular wall. Interestingly, the left ventricular posterior wall in their patients was thinner than in normal controls possibly reflecting an effect of intensive chelation. The use of M mode echocardiography for the serial evaluation of left ventricular function is limited in this disorder however, because small changes in left ventricular wall thickness are difficult to -242-

quantitate and the complex evaluation of diastolic function described by Valder­

Cruz et al (1982) has not been validated in a serial study. In addition the data

are acquired in only one plane and when M-mode imaging is employed, the motionless echo beam images a different portion of the ventricular cavity at each instant as the three-dimensional left ventricle moves through the beam during the cardiac cycle. A simple, more sensitive technique, which could

measure exercise ventricular performance was required to detect subclinical left ventricular dysfunction, and to evaluate the effects of chelation on the heart.

In the first part of my study using exercise radionuclide angiography it has been shown that in patients with thalassaemia major, who were unchelated or who had received a relatively short period of chelation, subclinical abnormalities of systolic ventricular function were not uncommon at rest and occurred in most patients (71 %) during exercise. Although none of the patients studied had cardiac symptoms and clinically all were considered to have normal cardiac function, these abnormalities were seen with equal frequency in young and old patients and had occurred much earlier than had previously been recognised. It is possible that an increased incidence of abnormalities of resting left ventricular function may have been found if diastolic function had been examined. Although measures of left ventricular compliance have been described using the gated equilibrium technique, this has yet to be validated in our laboratory.

The systolic abnormalities of left ventricular function observed were related to the iron load from transfusion and were most likely to occur in patients with high serum ferritin levels. This finding has been confirmed by Leon et al (1979) also using exercise radionuclide angiography. They found that - 243-

abnormalities of systolic left ventricular function during exercise were more

likely to be associated with a heavy iron load from transfusion, especially when

the burden exceeded 100 units of blood (ie. 20 gms of iron). However, in my

study, unlike Leon et al (1979), not all patients in whom impaired ventricular

function was demonstrated had received large numbers of blood transfusions.

One patient (patient 23) was the oldest in the group and had received less than

100 units of blood. This patient had a long period of anaemia before starting his

transfusion regime and had a previous episode of cardiac failure; increased

gastrointestinal tract absorption of iron and prolonged anaemia may have resulted in excessive myocardial iron deposition.

Some of the patients had long periods of anaemia before referral to our

unit but because the duration of anaemia differed, the effects of the anaemia on ventricular function could not be assessed accurately. However, none of the patients were anaemic at the time of the study, all being transfused within one week. As the policy of the unit was to maintain haemoglobin levels above 10 gms/dl, the patients had not been anaemic for an average period of 5.1 years before left ventricular function was assessed.

Internal Distribution of Excess Iron.

Man conserves iron and has little or no ability to excrete any excess quantity of this metal. Iron overload may therefore occur whenever excessive iron enters the body, either by increased absorption or by blood transfusion. The pattern of organ dysfunction is similar in patients with iron over load whether due to excess absorption or to blood transfusions. Regular blood transfusions are the mainstay of therapy for thalassaemia major • Since each unit of blood contains - 244-

200mgs of iron, and since daily iron excretion is limited to one mgm or less, a regimen of regular transfusions soon leads to marked iron overload.

In the iron overloaded state all storage compartments in liver cells and reticulo-endothelial cells (RE) of the spleen and bone marrow are saturated. Iron then appears in other organs where it usually not found, pituitary, eyes, teeth, thyroid, parathyroid, lungs, heart, liver, pancreas, spleen, adrenals, kidneys, skin, muscle, lymph nodes and gastric mucosa.

Transfused red cells, once senescent, find their way into the RE cells of the spleen, liver, bone marrow and lymph nodes (Finch et al 1970) where iron is released and then stored • The ability of the RE cells to store iron can easily be exceeded however and they release iron to transferrin. After administration of only 10-15 units of blood, transferrin becomes saturated with iron and increasing amounts are taken up by parenchymal cells. Genetic factors and the number of transferrin receptors on an individual cell may then influence iron uptake by that cell. Hepatic and cardiac parenchymal cells often adversely affected by excess iron may normally have a high demand for iron. To achieve adequate iron uptake, transferrin receptor density may be correspondingly high on these cells causing proportionally greater iron uptake in the face of iron overload. Iron may also be present in the plasma in a non-transferrin bound form (Hershko et al 1978 ). This non-protein bound iron may be ~irectly available to parenchymal cells for uptake and retention : iron in this form may be directly toxic to parenchymal cells.

After entry into. the cell (Fig 46) by way of speci fie membrane receptors, the iron enters an ill-defined labile iron pool which has been studied in cell - 245-

CELL MEMBRANE

FeTRANSFEP.RIN Fe

POFERRITIN

.1:I ~ TRANSFERR~--~ -;; 1. FERRITIN, FREE

~\NON-TRANSFERRIN MEMBRANE-BOUND~. PlASMA IRON

~DTPA~ FeDTPA

Figure 46. This is a schematic diagram of the different cellular iron

compartments indicating the manner iron enters the cell and is subseqently

stored. - 246- culture (White et a! 1976). The size of this pool is proportional to the rate at which iron enters the cell and stimulates production of apoferritin by directly controlling synthesis at the DNA level, so that the amount of apoferritin available to receive iron to become ferritin is proportional to the labile iron pool. As the amount of iron load increases within the cell, membrane bound ferritin particles are increasingly associated with lysosomes, eventually forming dense intracellular aggregates of haemosiderin.

Mechanism of iron toxicity.

Massive deposition of iron may occur without apparent damage either to cells or to organs. Liver function may well be preserved with 50 times more iron than normal. Resistance of cells to damage by iron must depend on their ability to sequester this substance in a non-toxic form. Indirect evidence suggests that lysosomal aggregates of haemosiderin may play a role in iron mediated cellular toxicity. Lysosomal sequestration of ferritin and haemosiderin may initially protect the cell from excess iron. However, Peters et al (1966) has shown that iron loaded lysosomes are more fragile than normal and thus damaged lysosomes could leak their contents into the cyt~plasm or pericellular space causing cellular damage or exaggerated collagen deposition. The defect causing lysosomal fragility has not yet been defined but iron in the form of haemosiderin is thought to damage the lipid membrane of lysosomes by peroxidation of unsaturated fatty acids • - 247-

The Effects of Chelation Therapy on Left Ventricular function

No previous study has examined the effects of intensive long term

chelation therapy on left ventricular function in this disorder. The data

presented in study 2 suggests, that abnormalities of myocardial function are in

fact reversible before extensive myocardial degeneration has occurred. Normal

left ventricular function was shown in Study 1 in only 5 of the 23 patients, 4 of

whom were receiving subcutaneous chelation treatment. After a further four

years of intensive chelation therapy, 11 additional patients showed a normal left

ventricular response to exercise and 4 of the remaining 5 patients maintained

both their resting and peak exercise left ventricular ejection fraction. Only 1

patient showed a steady deterioration in left ventricular function over 3 years of

therapy. Although he remained asymptomatic (patient 19), his resting LVEF fell from 47% to 29% which was associated with a rise in serum ferritin. As a result his dosage of chelation was increased to 2Dgms of desferrioxamine/week.

Twelve gms of this was given once weekly as an intravenous infusion over 16 hours. The remainder was given by a subcutaneous infusion of 2 gms for four nights each week. He also began an intensive transfusion regime with red cell exchanges at 2 to 3 weekly intervals, with minimal excursions of haemoglobin

levels and reduced red cell loading. After increasing the dose of desferrioxamine his left ventricular function improved. He maintained throughout that he complied with his chelation regime and it is possible that in this patient and in the four who did not improve ventricular performance, that an effective chelation dosage may have been greater than used routinely in this study. - 248-

Two patients (patient 21 and 23) died during the first year of the second

study, they were aged 21 and 23 years, the latter (patient 23) was the oldest in

the group. Both had been exposed to large amounts of iron, patient 21 had

received over 500 units of blood while patient 23 had a very long period of

anaemia prior to starting therapy and presumably had massive gastrointestinal

absorption of iron. These patients were siblings, late referrals to our unit and

had received less than a year of chelation therapy and it is likely irreparable

damage to left ventricular function had occurred.

Desferrioxamine

Desferrioxamine (Desferal) is a compound derived from Streptomyces pilosis and owes its ability to chelate iron to three hydroxamine acid groups. The iron -

Desferal chelate is called ferrioxamine, a compound which is excreted into the

urine without modification. Unfortunately it is poorly absorbed from the gastrointestinal tract (Keberle, 1964). Parenteral administration is thus required to obtain adequate levels of iron excretion in iron overloaded patients. The half

life of Desferal in man is only 5-10 minutes when administered intravenously and it requires up to twelve hours continuous intravenous administration to achieve a steady state plasma level. The chelate ferrioxamine is rapidly excreted by the kidneys but it is also actively reabsorbed and therefore has a prolonged half life in plasma (Sumners et al 1979). Chelate continues to be excreted for prolonged periods after an infusion of Desferal has ended.

Urinary iron excretion by iron overloaded patients may be as much as 150-

200 mgm/day when 3-4 gm of Desferal are given continuously by intravenous - 249- infusion (Modell and Beck, 1974). Propper et al (1977) first demonstrated continuous subcutaneous infusions of Desferal were nearly as effective as intravenous Desferal. Furthermore, they demonstrated that iron balance can be achieved by giving Desferal subcutaneously. A number of small, portable and convenient infusion pumps have been designed to facilitate administration of

Desferal by the subcutaneous route and were used in my study. However, great variability in Desferal induced urinary iron excretion exists from patient to patient (Pippard et al 1978). Iron balance was not measured in my study as faecal excretion of desferrioxamine also occurs and repeated collections of urine and faeces was not practical. Desferal induced stool iron excretion is proportionally greater in thalassaemia patients who have been transfused up to a normal haematocrit.

Estimation of the Total Iron Burden

An estimation of total iron stores may be obtained by calculating the amount of blood transfused. Obviously, this offers little help in evaluating the clinical benefits of chelation. The most accurate way of estimating iron burden is by direct measurement of iron concentration in biopsied liver tissue. This measurement correlates well with the total amount of blood given and the extent of hepatic fibrosis (Risdon et al1975). Letsky et al (1974) showed that the serum ferritin concentration correlated well with transfusional iron burden in thalassaemia major patients with no liver damage. De Virgilis et al (1980) showed that ferritin levels were useful in assessing iron load only in patients with no evidence of acute or chronic hepatitis. Serum ferritin levels were used to assess the efficacy of chelation therapy in reducing iron stores in my patients - 250-

only if hepatocellular markers of liver function were normal. An active search

for a non-invasive measure of iron stores continues, and although computerised

tomography and nuclear magnetic resonance show promise, serum ferritin levels

remain the only currently available non-invasive method to assess the effects of

chelation on iron load.

Other evidence of the effects of chelation therapy have been provided by

Barry et al (1974) who showed that regular administration of intramuscular

Desferal may reduce the hepatic liver iron concentration and markedly retard hepatic fibrosis. In their study serum ferritin levels were significantly lower in

treated patients and pubertal growth rate significantly improved. Eight of the 9 regularly chelated patients were still alive, while 10 of the controls had died of cardiac disease when reported by Modell et al in 1981. Serial liver biopsies were not performed in my patients and thus the effects of chelation on the liver were not assessed in my study.

Source of Chelated Iron

Iron in haemoglobin and transferrin are inaccessible for chelation.

Although Desferal can remove iron from ferritin and haemosiderin in vitro

(Keberle, 1964) there is little evidence that these storage forms are directly accessible either to chelation in vivo. Jacobs (1977) evolved the concept that there is a chelatable pool of iron present in cells in low molecular weight forms.

Using radiolabelled intravenous administered 59 Fe transferrin complexes,

Hershko et al (1979) showed that Desferal induced urinary iron excretion from reticuloendothelial cells in addition to excretion from parenchymal cells of the - 251-

liver. At present there are no data bearing on the ability of Desferal to retard

or reverse myocardial iron deposition.

Ascorbic Acid

Ascorbic acid has been shown to have several effects on iron metabolism.

A deficiency of ascorbate occurs in individuals with iron overload. This deficiency appears to increase retention of metabolically inactive iron in reticuloendothelial cells. In vitro evidence suggests that ascorbic acid may promote the iron-mediated peroxidation of membrane lipids thereby damaging cells (Wills, 1972). Nienhuis et al (1976) has shown that vitamin C administration to deficient patients will markedly increase the urinary excretion of iron in response to Desferal, promoting release of iron from storage forms into the chelatable iron pool. Clinical and echocardiographic observation by Nienhuis et al (1979) has shown cardiac deterioration following vitamin C administration, presumably due to the expansion of the chelatable iron pool and failure of

Desferal to remove this excess iron released from stores. In my study to minimise potentially deleterious effects of iron released by vitamin C, the smallest dose of vitamin C was given after Desferal infusions had been begun.

Clinical Implications

Before the introduction of chelation therapy, patients with transfusion dependent thalassaemia major died between the second and third decades from progressive cardiac failure or arrhythmias due to iron overload. This study has identified that in asymptomatic patients with this disorder there is a very high - 252- hitherto unknown incidence of subclinical abnormalities of left ventricular function in younger patients prior to a regular chelation regime. This suggests that optimal management directed towards reducing the iron load be started as soon as possible after diagnosis.

Serial measurement by radionuclide techniques offers a sensitive method to assess the combined effects of iron load and toxicity on ventricular performance and, provides a guide to therapy in individuals, allowing tailoring of chelation regimes to the particular patient needs. As a result, it appears that radionuclide angiography at rest and with exercise is a reliable non-invasive indicator of the extent of myocardial load in patients receiving chelation and compares favourably with less specific measures such as serum ferritin levels.

This study suggests iron can be recovered from the myocardium, a fact never previously demonstrated and that this removal of iron is associated with progressive improvement or maintenance of ventricular function. This occurred not only in older patients, who had suffered left ventricular dysfunction due to additional affects of long periods of anaemia and increased absorption of iron, but in younger patients who had been transfused from the time of diagnosis.

In the light of this experience certain principles of management of severe iron overload have emerged. Symptomless individuals should have regular non­ invasive assessment of cardiac function, preferably by radionuc.lide angiography.

Cardiac damage is reversible with standard desferrioxamine dosages although clinicians should be prepared to increase the dosage if left ventricular function begins to deteriorate. - 253-

Chapter 15

EPILOGUE

"Functional assessment of known disease represents one of the major areas of potential growth for nuclear cardiology. The extent of disease and its functional consequences can be quantified. This may include indices of global and regional systolic performance, as well as diastolic measurements. These data may provide insight to prognosis, as well as a means of selecting patients for surgical or medical therapy and monitoring the effects of such interventions." This quotation came from a recent review by Berger and Zaret in

1984. Later in this review, they stated "Stratification of patients based on exercise left ventricular performance before therapy may result in more appropriate therapeutic decisions for individual patients and prediction of subsequent clinical course."

Following the initial description of radionuclide equilibrium angiography by

Strauss et al in 1971 much attention was focused on this aspect of nuclear medicine. By 1980, when the investigations described in this thesis were initiated, the literature had grown rapidly, indicating the enormous potential of the procedure. Nevertheless, many aspects of the performance and application of the technique remained controversial. This thesis was designed to elucidate some of these problems. In order to perform the gated equilibrium technique most accurately, various methods of red cell labelling, acquisition and processing of data were examined. The optimal method for the assessment of exercise - 254-

performance, assessment of regional wall motion and measurement of

ventricular volumes were also examined. It was shown that, with care and

attention to detail, great precision could be achieved in providing further

parameters other than left ventricular ejection fraction in the evaluation of left

ventricular function.

The growth of nuclear cardiology resulted from its atraumatic nature and

its sensitivity in the detection of the presence and extent of cardiac disease.It

has therefore achieved a critical role in routine diagnostic investigation of many

cardiac problems. The further potential both in predicting prognosis and in the

serial evaluation of therapy has, as shown by the 1984 statement by Berger and

Zaret, quoted above, remained unproved. The studies which have comprised the

clinical section of this thesis proved that such stratification as postulated by

Berger and Zaret can indeed be provided by radionuclide angiography.

It was shown that revascularisation may improve exercise ventricular function

in patients, despite markedly depressed ventricular performance. Improved

resting segmental function may also result in patients with depressed ventricular

performance, suggesting the presence of reversible resting ischaemic

dysfunction. Those patients with previous infarction and angina who

demonstrated the. greatest amount of exercise induced ischaemic dysfunction or

who had evidence of viable myocardium with thallium 201 perfusion imaging, were likely to show the greatest benefit in ventricular performance and hence

long term prognosis. These studies suggested, using these techniques, that these patients can be predicted pre-operatively Conversely,if these features were not demonstrated in the preoperative radionuclide assessment, left ventricular - 255-

performance both at rest and exercise, and long term prognosis did not appear to

be improved despite revascularisation. This suggested that these patients who

may have shown some short term symptomatic improvement, did not ultimately

benefit from a hazardous costly surgical procedure. Further,it was shown that

aneurysmectomy, a procedure performed increasingly in patient with heart

failure, secondary to previous extensive myocardial infarction, does not improve

global parameters of left ventricular function. Half of the patients examined

did, however, show long term symptomatic benefit and certain pre-operative

ventriculographic features could be related to this improvement.

In the second group of patients studied, it was shown that in patients with

thalassaemia major, who had received mandatory routine blood transfusion

regimes but who were unchelated or who had a relatively short period of

chelation, subclinical abnormalities of ventricular function were not uncommon.

Although none of these patients studied had cardiac symptoms and clinically all

were considered to have normal cardiac function, these abnormalities were seen

with equal frequency in young and old patients and had occurred much earlier

than had previously been recognised. Serial measurement by radionuclide

techniques offered a sensitive method to assess the combined effects of iron load

and toxicity on ventricular performance and provided a guide to therapy in

individuals, allowing adaption of chelation regimes to the needs of particular

patients. This investigation suggested that chelation therapy did result in

removal of iron from the myocardium, and that this removal of iron was

associated with progressive improvement or maintenance of ventricular performance a fact never previously demonstrated. - 256-

It is postulated that this study of two quite different populations undergoing totally dissimilar therapeutic approaches exemplifies the value of nuclear cardiological procedures, in particular, that of the gated equilibrium technique to assess patients serially and to provide information about prognosis.

These procedures can, therefore now be applied as the means to reach the most appropriate therapeutic decision for each individual. - 257-

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