Pulmonary thallium uptake: Correlation with systolic and diastolic left ventricular function at rest and during exercise Quantified pulmonary 201-thallium uptake, assessed as pulmonary/myocardial ratios (PM) and body surface area-corrected absolute pulmonary uptake (Pc), was determined from single photon emission computed tomography studies in 22 normal subjects and 46 consecutive patients with coronary artery disease (CAD). By means of equilibrium radionuclide angiography (ERNA), ejection fraction (EF), peak ejection rate (PER) in end-diastolic volume (EDV/sec) and peak filling rate (PFR) in EDV/sec and stroke volume (SV/sec) units, PFR/PER ratio, and time to peak filling rate (TPFR) in milliseconds were computed at rest and during exercise (n ~ 35). Left ventricular response to exercise was assessed as AEF, relative AEF, AEDV, and AESV. In normal subjects the PM ratios showed significant inverse correlation with PER at rest and with EF, PER, and PFRedv during exercise. For the left ventricular response to exercise, AESV showed significant correlation with the PM ratios. The body surface area-corrected pulmonary uptake values showed no correlation with any of the variables. In patients with CAD the PM ratios and Pc uptake showed significant inverse correlation with EF, PER, PFRedv and to exercise EF, exercise PER, and e x e r c i s e PFRedv. For the left ventricular response to exercise; AEF showed significant inverse correlation with the PM ratios but not with the Pc uptake. Neither in normal subjects nor in patients with CAD did any of the independent diastolic variables show significant correlation with the PM ratios or Pc values. Thus pulmonary thallium uptake is correlated with systolic left ventricular function at rest and during exercise in normal subjects and in patients with CAD but not with diastolic function. In normal subjects AESV and in patients with CAD, AEF showed correlation with pulmonary thallium uptake. (AM HEART J 1990;119:1137.)
Finn Mannting, MD. Uppsala, Sweden Increased pulmonary thallium-201 activity in patients with coronary artery disease (CAD) is related to the extent and severity of CAD, the number of initial thallium perfusion defects, redistribution of thallium, stress-induced increases in pulmonary capillary wedge pressure and end-diastolic pressure, achieved exercise level before injection of thallium, pea~Blouble product, and heart rate; these findings are documented in multiple studies3 -n Quite recently increased pulmonary thallium uptake was shown to be the most important thallium stress test variable for prediction of future major cardiac events, 12 an observation with considerable clinical impact. An inverse correlation with the ejection fraction (EF) at rest has been shown in several studFrom the Department of Clinical Physiology, Nuclear Medicine Section, University Hospital. Received for puhlication Aug. 21, 1989; accepted Dec. 4, 1989. Reprint requests: Finn Mannting, MD, Department of Clinical Physiology, Nuclear Medicine Section, University Hospital, 751 85 Uppsala, Sweden. 4/1/19095
ies,1, a, 5-8,13 but most investigators consider the up: take a marker of stress-induced left ventricular dysfunction. One study 6 examined the relationship between pulmonary uptake and left ventricular ejection fraction during exercise, and two studies 5' 6 examined the relationship between pulmonary uptake and left ventricular response (AEF) to exercise. The correlation with other variables of systolic or diastolic function at rest, and especially during exercise, or with other variables of left ventricular response to exercise, have to our knowledge not been disclosed. The aim of this study was to determine if and how pulmonary thallium uptake, assessed as pulmonary/ myocardial (PM) uptake ratios and as body surface area-corrected absolute pulmonary (Pc) uptake, correlates with systolic and diastolic left ventricular function at rest and during exercise and with variables of left ventricular response to stress in patients with CAD. METHODS Study population.
Twenty-two subjects (group 1), six women (mean age 44.0 _+ 8.1, range 30 to 53 years) and 16
1137
May 1990
1138 Mannting men (mean age 39.9 _+ 9.2, range 23 to 61 years), comprised the reference population. The patients were referred for evaluation of chest pain, abnormal resting ECG, or inconclusive stress test results. Ten patients were judged normal according to results of coronary angiography, contrast ventriculography, and quantitative thallium single photon emission computed tomography (SPECT), whereas 12 patients were determined to be normal based on results of stress tests, quantified thallium SPECT, and equilibrium radionuclide angiography (ERNA). Sixty-six consecutive patients (group 2) referred for stress thallium SPECT imaging were studied. Sixty-three patients were investigated for chest pain, ECG changes suggestive of ischemic heart disease, or both (Group 2A). Two patients had dilated cardiomyopathy, clinical heart failure, and chest pain, and one patient had high-degree aortic regurgitation, clinical heart failure, and chest pain (group 2B). Exercise testing. All subjects performed upright, symptom-limited, maximum bicycle stress testing according to a standard protocol. All tests were performed in the morning after patients had fasted overnight. ECG, heart rate, blood pressure, and respiration rate were recorded at rest (baseline), immediately before the start of exercise with patients in position on the bicycle, and every 2 minutes during exercise. Work load was increased 20 W every 2 minutes. At the end of each stage the patients were asked to grade work load, dyspnea, and chest pain on a 10-point scale. The test was terminated when maximum tolerable fatigue, dyspnea, or chest pain occurred or when significant ventricular arrhythmia or a decrease in blood pressure was detected. Patients were advised not to take any medication on the day of the examination, and no medication was allowed between the thallium stress test and the ERNA study. Myocardial perfusion imaging. At peak exercise90 MBq (2.4 mCi) 201-thallium (DuPont Company, London, England) was injected into an antecubital vein through an indwelling intravenous catheter that was carefully flushed with 10 ml saline solution. The patient was encouraged to continue exercising for an additional 90 to 120 seconds. The injected arm was examined for residual thallium-201 activity. Acquisition of SPECT data (SPETS-TSX, Nuclear Diagnostics, Stockholm, Sweden) was begun less than 10 minutes after injection of thallium according to our standard protocol: 180-degree body contour rotation mode from left posterior oblique 45 degrees to right anterior oblique 45 degrees, 32 angles, 30 seconds per angle (step and shoot mode), in a 64 • 64 matrix with no zoom. The same digital gamma camera (Picker SX-300, Digital Dyna Camera, Cleveland, Ohio) equipped with the same high-resolution, hexagonal, parallel-hole collimator was used for all patients. Two symmetrical 20 % windows centered at the 75 keV and 167 keV peaks were used. For evaluation and quantification of the myocardial SPECT studies a previously described technique was applied. 14 Briefly the method simultaneously displays the sagittal reference images from the stress and redistribution studies and reconstructed coronal slices corresponding to
AmericanHeartJournal
a movable level selector. The heart is divided into three equally sized portions (basal, middle, and apical thirds) by adding slices. The apex, defined as the most distal portion without an identifiable cavity, is considered as a separate fourth part. Corresponding portions of the heart are selected and displayed side by side for evaluation on a high-resolution monitor connected to an eight-bit video board. Quantification of thallium-201 distribution is done after definition of the epicardial and endocardial borders. The area between the borders is defined as the myocardium and is divided into sectors. In this study 30-degree sectors were used, that is, the coronal slice is divided into twelve 30-degree sectors. The mean counts/pixel and sector are calculated and compared with integrated data bases for men and women. Sectors with values below the lower limit of normal (mean minus two standard deviations for that specific sector and part of the heart) for the stress and the late study are automatically identified and highlighted. Pulmonary thallium uptake. Quantification of pulmonary thallium activity, expressed as PM ratios and absolute pulmonary uptake, was computed as follows: the raw SPECT acquisition data were used. The eight acquired frames from anterior to right anterior oblique 45 degrees were added to one composite image representing 240 seconds of data acquisition. A region of interest was placed over the heart, and a 1-pixel wide heart background region of interest was drawn three pixels outside the heart region of interest from 10 o'clock to 3 o'clock (Fig. 1). Next a region of interest was placed over the right lung, and finally a region of interest was placed over the upper part of the left lung clearly separated from the heart by the background region of interest (Fig. 1). Two uptake ratios were calculated in each study, one for the right lung and one for the upper left lung, PM-rl and PM-ull, respectively, according to: Mean pulmonary counts/(mean myocardial counts - mean background counts). The absolute pulmonary thallium uptake (P) (mean counts/pixel) for the right lung (P-rl) and upper left lung (P-ull) was computed and corrected for dependency of body surface area (BSA) by means of: P c - - P + b (1-BSA), where Pc is the BSAcorrected uptake and b is the regression coefficient for pulmonary thallium uptake versus BSA obtained fror== data base of 32 normal subjects (b =-56.9 for rl uptake and b -- -56.1 for ull). The images and regions of interest used for assessing the PM ratios were established and saved before the ERNA data were processed, but the ratios were not computed until after the results of the ERNA studies had been evaluated. In this way the ratios and results of the ERNA studies were unknown at the time of active evaluation of each. Equilibrium radionuclide angiography. All ERNA studies were performed in the afternoon of the same day as the thallium SPECT studies. The patients were allowed a very light meal no less than 3 hours before the study. The patients' red blood cells were labeled with 740 MBq (20 mCi) 99m-technetium by means of a semi-in vitro technique. 15 Data were collected with the use of a 20% window at 140 keV on a large field-of-view camera (Picker SX-300, Digital Dyna Camera, Cleveland, Ohio) equipped with a low-
VoJume 119
Number 5
Pulmonary thallium uptake and left ventricular function
energy, general purpose, hexagonal, parallel-hole collimator. Six million counts were acquired in the best septal left anterior obligue projection with 15 degree caudal tilt. Software zoom x 2 was used to minimize counts from noncardiac structures. A gate interval of _+10% was set, and the studies were acquired in frame mode, 32 frames/cycle, in 64 x 64 word mode. The studies were spatially filtered frame by frame with a two-dimensional fast Fourier transformation (FFT) count-adaptive Metz filter 16 using an array processor (AP 400, Analogic Corp., Wakefield, Mass.). An algorithm 17 with automatic edge detection and automatic cycle-dependent background correlation, working according to the multiple regions of interest principle, was used for computing the volume-equivalent left ventricular time-activity curve. The resulting time-activity curve was temporally filtered by fitting a four-harmonic series. EF = (EDV - ESV/EDV) x 100%, peak ejection rate (PER) in EDV/sec units, peak filling rate (PFR) in both EDV/sec and SV/sec units, P F R / P E R ratio, and time to peak filling rate (TPFR) in milliseconds were computed (Fig. 2). ERNA during stress was performed immediately after the resting study with the patient supine and the camera maintained in the same position. Every 2 minutes the work load was increased by 20 W, and the study was performed at the maximum tolerable work load guided by what the patients achieved during the upright exercise test earlier the same day and by the patients grading of fatigue, dyspnea, and chest pain at the end of each stage. Heart rate and blood pressure were recorded at the end of each stage. ERNA data were acquired for at least 120 seconds or for a minimum of four million counts. Exercise ERNA variables of systolic and diastolic function were computed by means of the same methods as those used for ERNA at rest. The relative change in EDV and ESV (AEDV and AESV) from rest to exercise was computed by means of the enddiastolic frame and the end systolic frame according to: (exercise counts - r e s t counts/rest count) x 100 (% change), both corrected for frame duration and number of acquired heart cycles. The change in EF (AEF) was calculated as: AEF = exercise EF - rest EF (% units) and the relative change in EF (relative AEF) as: relative A E F - ((exercise EF - rest EF)/rest EF) X 100 (% change). In group 1 ERNA at rest was performed in all 22 patients and ERNA during exercise in 16 patients. In group 2A ERNA at rest was performed in 51 of the 63 patients; in 12 instances ERNA was not performed because of significant arrhythmia or because of practical reasons (space/ time). In 36 of the 51 patients exercise ERNA was performed. For the remaining patients exercise ERNA was not possible because of significant arrhythmia during exercise, lack of cooperation, inability to perform adequate exercise in 120 seconds, or for practical reasons (space/time). In group 2B three patients had ERNA at rest, whereas none was able to perform the necessary work load for exercise ERNA. Statistical analysis. Values are expressed as mean + standard deviation. Variables were compared by the paired t test. Correlations between variables were evalu-
1139
Fig. 1. Illustration of method used for defining regions of
interest for quantification of pulmonary thallium (TL) uptake. Regions of interest over myocardium (M), background (BKG), right lung (RL), and upper left lung (ULL) on composite, raw, nonreconstructed thallium SPECT image.
LV TAC
VOL
EDV
.................
ESV
i
,'
P E R EOV/S
;-~!~
=
', ~"
P F R EDV/s
i TPFRms
PFR SV/s
i~
PFR/ PER
i =
I
ED
ES
Fig. 2. Left ventricular time-activity curve
TIME (LV TAC)
and variables computed. ED, end diastole; ES, end systole; EDV, end-diastolic volume; ESV, end-systolic volume; PER, peak ejection rate; PFR, peak filling rate; TPFR, time to peak filling rate.
ated by simple linear regression analysis or by stepwise multiple correlation analysis when more than two variables significantly correlated with the variable under evaluation and were not considered interrelated. A p value of
Finn Mannting, MD. Uppsala, Sweden Increased pulmonary thallium-201 activity in patients with coronary artery disease (CAD) is related to the extent and severity of CAD, the number of initial thallium perfusion defects, redistribution of thallium, stress-induced increases in pulmonary capillary wedge pressure and end-diastolic pressure, achieved exercise level before injection of thallium, pea~Blouble product, and heart rate; these findings are documented in multiple studies3 -n Quite recently increased pulmonary thallium uptake was shown to be the most important thallium stress test variable for prediction of future major cardiac events, 12 an observation with considerable clinical impact. An inverse correlation with the ejection fraction (EF) at rest has been shown in several studFrom the Department of Clinical Physiology, Nuclear Medicine Section, University Hospital. Received for puhlication Aug. 21, 1989; accepted Dec. 4, 1989. Reprint requests: Finn Mannting, MD, Department of Clinical Physiology, Nuclear Medicine Section, University Hospital, 751 85 Uppsala, Sweden. 4/1/19095
ies,1, a, 5-8,13 but most investigators consider the up: take a marker of stress-induced left ventricular dysfunction. One study 6 examined the relationship between pulmonary uptake and left ventricular ejection fraction during exercise, and two studies 5' 6 examined the relationship between pulmonary uptake and left ventricular response (AEF) to exercise. The correlation with other variables of systolic or diastolic function at rest, and especially during exercise, or with other variables of left ventricular response to exercise, have to our knowledge not been disclosed. The aim of this study was to determine if and how pulmonary thallium uptake, assessed as pulmonary/ myocardial (PM) uptake ratios and as body surface area-corrected absolute pulmonary (Pc) uptake, correlates with systolic and diastolic left ventricular function at rest and during exercise and with variables of left ventricular response to stress in patients with CAD. METHODS Study population.
Twenty-two subjects (group 1), six women (mean age 44.0 _+ 8.1, range 30 to 53 years) and 16
1137
May 1990
1138 Mannting men (mean age 39.9 _+ 9.2, range 23 to 61 years), comprised the reference population. The patients were referred for evaluation of chest pain, abnormal resting ECG, or inconclusive stress test results. Ten patients were judged normal according to results of coronary angiography, contrast ventriculography, and quantitative thallium single photon emission computed tomography (SPECT), whereas 12 patients were determined to be normal based on results of stress tests, quantified thallium SPECT, and equilibrium radionuclide angiography (ERNA). Sixty-six consecutive patients (group 2) referred for stress thallium SPECT imaging were studied. Sixty-three patients were investigated for chest pain, ECG changes suggestive of ischemic heart disease, or both (Group 2A). Two patients had dilated cardiomyopathy, clinical heart failure, and chest pain, and one patient had high-degree aortic regurgitation, clinical heart failure, and chest pain (group 2B). Exercise testing. All subjects performed upright, symptom-limited, maximum bicycle stress testing according to a standard protocol. All tests were performed in the morning after patients had fasted overnight. ECG, heart rate, blood pressure, and respiration rate were recorded at rest (baseline), immediately before the start of exercise with patients in position on the bicycle, and every 2 minutes during exercise. Work load was increased 20 W every 2 minutes. At the end of each stage the patients were asked to grade work load, dyspnea, and chest pain on a 10-point scale. The test was terminated when maximum tolerable fatigue, dyspnea, or chest pain occurred or when significant ventricular arrhythmia or a decrease in blood pressure was detected. Patients were advised not to take any medication on the day of the examination, and no medication was allowed between the thallium stress test and the ERNA study. Myocardial perfusion imaging. At peak exercise90 MBq (2.4 mCi) 201-thallium (DuPont Company, London, England) was injected into an antecubital vein through an indwelling intravenous catheter that was carefully flushed with 10 ml saline solution. The patient was encouraged to continue exercising for an additional 90 to 120 seconds. The injected arm was examined for residual thallium-201 activity. Acquisition of SPECT data (SPETS-TSX, Nuclear Diagnostics, Stockholm, Sweden) was begun less than 10 minutes after injection of thallium according to our standard protocol: 180-degree body contour rotation mode from left posterior oblique 45 degrees to right anterior oblique 45 degrees, 32 angles, 30 seconds per angle (step and shoot mode), in a 64 • 64 matrix with no zoom. The same digital gamma camera (Picker SX-300, Digital Dyna Camera, Cleveland, Ohio) equipped with the same high-resolution, hexagonal, parallel-hole collimator was used for all patients. Two symmetrical 20 % windows centered at the 75 keV and 167 keV peaks were used. For evaluation and quantification of the myocardial SPECT studies a previously described technique was applied. 14 Briefly the method simultaneously displays the sagittal reference images from the stress and redistribution studies and reconstructed coronal slices corresponding to
AmericanHeartJournal
a movable level selector. The heart is divided into three equally sized portions (basal, middle, and apical thirds) by adding slices. The apex, defined as the most distal portion without an identifiable cavity, is considered as a separate fourth part. Corresponding portions of the heart are selected and displayed side by side for evaluation on a high-resolution monitor connected to an eight-bit video board. Quantification of thallium-201 distribution is done after definition of the epicardial and endocardial borders. The area between the borders is defined as the myocardium and is divided into sectors. In this study 30-degree sectors were used, that is, the coronal slice is divided into twelve 30-degree sectors. The mean counts/pixel and sector are calculated and compared with integrated data bases for men and women. Sectors with values below the lower limit of normal (mean minus two standard deviations for that specific sector and part of the heart) for the stress and the late study are automatically identified and highlighted. Pulmonary thallium uptake. Quantification of pulmonary thallium activity, expressed as PM ratios and absolute pulmonary uptake, was computed as follows: the raw SPECT acquisition data were used. The eight acquired frames from anterior to right anterior oblique 45 degrees were added to one composite image representing 240 seconds of data acquisition. A region of interest was placed over the heart, and a 1-pixel wide heart background region of interest was drawn three pixels outside the heart region of interest from 10 o'clock to 3 o'clock (Fig. 1). Next a region of interest was placed over the right lung, and finally a region of interest was placed over the upper part of the left lung clearly separated from the heart by the background region of interest (Fig. 1). Two uptake ratios were calculated in each study, one for the right lung and one for the upper left lung, PM-rl and PM-ull, respectively, according to: Mean pulmonary counts/(mean myocardial counts - mean background counts). The absolute pulmonary thallium uptake (P) (mean counts/pixel) for the right lung (P-rl) and upper left lung (P-ull) was computed and corrected for dependency of body surface area (BSA) by means of: P c - - P + b (1-BSA), where Pc is the BSAcorrected uptake and b is the regression coefficient for pulmonary thallium uptake versus BSA obtained fror== data base of 32 normal subjects (b =-56.9 for rl uptake and b -- -56.1 for ull). The images and regions of interest used for assessing the PM ratios were established and saved before the ERNA data were processed, but the ratios were not computed until after the results of the ERNA studies had been evaluated. In this way the ratios and results of the ERNA studies were unknown at the time of active evaluation of each. Equilibrium radionuclide angiography. All ERNA studies were performed in the afternoon of the same day as the thallium SPECT studies. The patients were allowed a very light meal no less than 3 hours before the study. The patients' red blood cells were labeled with 740 MBq (20 mCi) 99m-technetium by means of a semi-in vitro technique. 15 Data were collected with the use of a 20% window at 140 keV on a large field-of-view camera (Picker SX-300, Digital Dyna Camera, Cleveland, Ohio) equipped with a low-
VoJume 119
Number 5
Pulmonary thallium uptake and left ventricular function
energy, general purpose, hexagonal, parallel-hole collimator. Six million counts were acquired in the best septal left anterior obligue projection with 15 degree caudal tilt. Software zoom x 2 was used to minimize counts from noncardiac structures. A gate interval of _+10% was set, and the studies were acquired in frame mode, 32 frames/cycle, in 64 x 64 word mode. The studies were spatially filtered frame by frame with a two-dimensional fast Fourier transformation (FFT) count-adaptive Metz filter 16 using an array processor (AP 400, Analogic Corp., Wakefield, Mass.). An algorithm 17 with automatic edge detection and automatic cycle-dependent background correlation, working according to the multiple regions of interest principle, was used for computing the volume-equivalent left ventricular time-activity curve. The resulting time-activity curve was temporally filtered by fitting a four-harmonic series. EF = (EDV - ESV/EDV) x 100%, peak ejection rate (PER) in EDV/sec units, peak filling rate (PFR) in both EDV/sec and SV/sec units, P F R / P E R ratio, and time to peak filling rate (TPFR) in milliseconds were computed (Fig. 2). ERNA during stress was performed immediately after the resting study with the patient supine and the camera maintained in the same position. Every 2 minutes the work load was increased by 20 W, and the study was performed at the maximum tolerable work load guided by what the patients achieved during the upright exercise test earlier the same day and by the patients grading of fatigue, dyspnea, and chest pain at the end of each stage. Heart rate and blood pressure were recorded at the end of each stage. ERNA data were acquired for at least 120 seconds or for a minimum of four million counts. Exercise ERNA variables of systolic and diastolic function were computed by means of the same methods as those used for ERNA at rest. The relative change in EDV and ESV (AEDV and AESV) from rest to exercise was computed by means of the enddiastolic frame and the end systolic frame according to: (exercise counts - r e s t counts/rest count) x 100 (% change), both corrected for frame duration and number of acquired heart cycles. The change in EF (AEF) was calculated as: AEF = exercise EF - rest EF (% units) and the relative change in EF (relative AEF) as: relative A E F - ((exercise EF - rest EF)/rest EF) X 100 (% change). In group 1 ERNA at rest was performed in all 22 patients and ERNA during exercise in 16 patients. In group 2A ERNA at rest was performed in 51 of the 63 patients; in 12 instances ERNA was not performed because of significant arrhythmia or because of practical reasons (space/ time). In 36 of the 51 patients exercise ERNA was performed. For the remaining patients exercise ERNA was not possible because of significant arrhythmia during exercise, lack of cooperation, inability to perform adequate exercise in 120 seconds, or for practical reasons (space/time). In group 2B three patients had ERNA at rest, whereas none was able to perform the necessary work load for exercise ERNA. Statistical analysis. Values are expressed as mean + standard deviation. Variables were compared by the paired t test. Correlations between variables were evalu-
1139
Fig. 1. Illustration of method used for defining regions of
interest for quantification of pulmonary thallium (TL) uptake. Regions of interest over myocardium (M), background (BKG), right lung (RL), and upper left lung (ULL) on composite, raw, nonreconstructed thallium SPECT image.
LV TAC
VOL
EDV
.................
ESV
i
,'
P E R EOV/S
;-~!~
=
', ~"
P F R EDV/s
i TPFRms
PFR SV/s
i~
PFR/ PER
i =
I
ED
ES
Fig. 2. Left ventricular time-activity curve
TIME (LV TAC)
and variables computed. ED, end diastole; ES, end systole; EDV, end-diastolic volume; ESV, end-systolic volume; PER, peak ejection rate; PFR, peak filling rate; TPFR, time to peak filling rate.
ated by simple linear regression analysis or by stepwise multiple correlation analysis when more than two variables significantly correlated with the variable under evaluation and were not considered interrelated. A p value of
