- Email: [email protected]
Nuclear Cardiology
CURRENT REVIEW
Current Review
Nuclear Cardiology Zita E. Ballok, FRACP ∗ Mayne Health Diagnostic Imaging Unit, Epworth Hospital, 89 Bridge Road, Richmond, Melbourne, Vic. 3121, Australia
Nuclear cardiology has shown double digit growth yearly over the last few years and remains the second most commonly performed noninvasive cardiac imaging investigation of choice. Approximately 9 million studies performed yearly in the U.S. alone. As cardiovascular disease remains the largest healthcare problem around the world despite increasing healthcare spending there is growing interest to enhance the use of cost effective diagnostic tools, such as nuclear cardiology. Recent development of technology has seen the addition of hybrid imaging tools such PET/CT and SPECT/CT into the armorial. More data is expected to become available on this subject within the next few years, and we also expect several molecular imaging tests to become available for clinical use. Despite easy availability of these diagnostic tools, cardiac mortality and morbidity in patients with long term diabetes and also in the postoperative setting remains unexpectedly high and emergency department physician are still being sued after patients being discharged with undiagnosed chest pain. The value of the use of nuclear cardiology studies is briefly reviewed in these clinical settings. (Heart Lung and Circulation 2005;14S:S27–S30) © 2005 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
Introduction
N
uclear medicine surpassed its old name of ‘‘hot spot imaging’’ since new generation hybrid scanners which combine functional imaging with anatomical details have become available for clinical use over the last few years. In the newest hybrid systems, CT scanners are attached either to a SPECT or to a PET camera. These are also available in small animal scanners for research application. SPECT cameras are available with the addition of a single, dual or a 6-slice CT scanner. The hybrid PET/CT (16-slice or 64-slice) scanners are considered currently the ‘‘best’’ one stop-shop for cardiac imaging by many experts (Figs. 1 and 2).1
Molecular Imaging in Cardiology The new and up to date name for nuclear medicine is molecular imaging. Even long-established international nuclear medicine journals recognized the rapid development by changing their names incorporating molecular imaging into their title after many years of stagnation. Large companies, which previously exclusively specialized in supplying equipment for imaging purposes have spent large amount of resources acquiring pharmaceutical companies engaged in development of radiopharmaceuti∗
Tel.: +61 3 92424848; fax: +61 3 92424830. E-mail address: [email protected].
cals for diagnostic and therapeutic purposes. Agents have been developed to image inflammation, atherosclerosis, and apoptosis just to list a few applications in the cardiology field. LDL can be labeled by a number of isotopes, e.g., I-123, Tc-99m, In-111. Macrophages take up oxidized LDL via scavenger receptor much more readily than native LDL. In a study of seven patients with symptomatic carotid artery lesions, uptake of Tc-99m oxidized LDL was seen in 10 out of 11 atheromatous lesions.2 Oxidised LDL has a rapid blood clearance which allows for imaging 1 h after tracer injection. Radiolabeled antibodies raised against epitopes on the LDL particles have also been studied. I125-MDA2, one of these antibodies shows 17 times higher concentration in hyperlipidaemic rabbits compared with normal rabbits.3 Peptids are even more promising as they clear from circulation much quicker than lipoproteins. A human pilot study showed Tc-99m label on a synthetic apo-B analog, P-215, and uptake into human carotid lesion.4 Endothelin production by smooth muscle and endothelial cells is upregulated in the presence of endothelial dysfunction, providing a potential target. Both iodinated and Tc-99m-labeled endothelin and its derivatives accumulate in atherosclerotic lesions in animal studies.5,6 Macrophages in atherosclerotic plaques express cell surface Fc receptors and they can also be imaged with F18FDG.7
© 2005 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
1443-9506/04/$30.00 doi:10.1016/j.hlc.2005.08.012
CURRENT REVIEW
S28
Ballok Nuclear cardiology
Heart Lung and Circulation 2005;14S:S27–S30
Figure 1. Courtesy of Professor Jim Corbett.
Nuclear Cardiology Versus Other Modalities Nuclear medicine methods, especially PET, remains the gold standard for viability imaging despite the advances in MRI and echocardiography. PET has overcome obstacles commonly seen with MRI, such as negative contrast, unclear labeling. Also, absolute quantifications to measure blood flow with PET8 have been established long ago, but not yet clearly established with MRI.9 CT calcium score screening is not endorsed by the AHA or by any other cardiac societies.10 CT angiography has made a long progress, however, it fails where it should be the most accurate. Severity of the coronary artery stenosis is difficult to assess with CT angiography at sites with significant calcifications.11 Patients with high probability of coronary artery disease in a recent study designed to assess the technology of a 16-slice MDCT against the gold standard coronary angiography showed significant false positive results due to calcifications within central coronary artery segments. This disappointing result makes it clear that additional functional imaging either with echocardiography, SPECT, or PET studies remains invaluable for risk stratification. CT angiography has also been promoted for screening in patients with low probability for coronary artery disease, however, CT angiography does deliver a relatively
large dose of radiation to the patient, which is usually higher than a nuclear medicine SestaMIBI SPECT perfusion study or conventional coronary angiography.
Imaging of the Asymptomatic Diabetic Patients Age-adjusted mortality rate for coronary artery disease has fallen by 60% since the 1960s, but the prevalence of CAD is increasing. This increased prevalence results from the increase of average life span, the increased number of elderly patients, and the epidemics of obesity and Type 2 diabetes. Diabetes is one of at least three areas where nuclear cardiology studies could be utilized more aggressively and more extensively to help our population and referring doctors to assess the risk of significant coronary artery disease early and diagnose the disease more accurately and cost effectively. This could lead for early referral for appropriate cardiac intervention and more aggressive risk factor modification, and even to the increase in productivity in general as diabetes and obesity-related illnesses are accepted by large insurance companies and employers as productivity reducing factors. Stress myocardial perfusion imaging has proven valuable in both diagnostic and prognostic evaluation
Ballok Nuclear cardiology
S29
Figure 2. Reprinted with permission from J Nucl Med 2004;45(9):14N.
of diabetic patients who are at increased risk of CAD. Myocardial perfusion imaging provides major incremental value for risk stratification in this patient group.12 In fact, several developed countries, e.g., Japan and France are already using myocardial perfusion imaging as a screening tool to assess high-risk asymptomatic diabetic subgroups. The Detection of Ischaemia in Asymptomatic Diabetic patients (DIAD) study is the first amongst those which predicts that this approach will be more widely accepted practice in the developed world in the near future.13 A large proportion of diabetic patients are unable to complete the minimum 5METs exercise for an interpretable exercise stress study, and pharmacological stress test in combination with perfusion imaging is often necessary for accurate risk stratification. These pharmacological studies are safe, well accepted and reproducible, and have the same predictive value14 for future major cardiac events as exercise perfusion imaging.
Nuclear Cardiology in the Emergency Department The second patient group at need for more aggressive early noninvasive cardiac investigations, primarily with myocardial perfusion imaging is the one who presents to the Emergency Department with chest pain, normal baseline ECG and normal troponine level. A significant number of the discharged patients from this group carry a high risk for further cardiac events. In fact, missed acute coronary syndrome is the number one on the list
of medical liability suits among emergency department physicians. Large studies have shown that coronary angiogram often not performed on the right patients as clinical variables may not classify the patients adequately, causing a significant amount of patient with intermediate to high risk for coronary event misclassified to the low risk group and missing out on further evaluation. Acute ‘‘hot MIBI’’ nuclear medicine perfusion imaging is a very useful tool in the assessment of patients presenting to the emergency departments. Abnormal perfusion studies identify patients at high risk for major cardiac events, while patient with normal studies remain at low risk.15 Patient with abnormal studies need further evaluation with coronary angiogram while those with a normal ‘‘hot MIBI’’ perfusion pattern usually return for a stress perfusion study within a few days.
Preoperative Cardiac Risk Assessment The third area where wider screening with myocardial perfusion studies is recommended is preoperative assessment before major orthopedic and vascular intervention. Data from the Netherlands show that postoperative cardiac complications have not reduced to low levels, as previously predicted, despite significant advancement in anesthetic care.16 The goal is not just to detect occlusive vascular disease;17 preoperative assessment has two major goals: the patients not just need to survive the operation, she or he also needs to enjoy the benefit of the operation.
CURRENT REVIEW
Heart Lung and Circulation 2005;14S:S27–S30
CURRENT REVIEW
S30
Ballok Nuclear cardiology
References 1. Schweiger M. EANM Annual Scientific Meeting, Helsinki, Finland, September 2004. 2. Iuliano L, Signore A, Vallabajosula S, Colavita AR, Camastra C, Ronga G, et al. Preparation and biodistribution of 99m-technetium labeled oxidized LDL in man. Atherosclerosis 1996;126:131–41. 3. Tsimikas S, Palinski W, Halpern SE, Yeung DW, Curtiss LK, Witztum JL. Radiolabeled MDA2, an oxidation-specific, monoclonal antibody, identifies native atherosclerotic lesions in vivo. J Nucl Cardiol 1999;6:41–53. 4. Lees R, Lees A. Radiopharmaceutical imaging of atherosclerosis. In: Fuster V, editor. Syndromes of atherosclerosis: correlations of clinical imaging and pathology. Armonk, NY: Future Publishing Co. Inc.; 1996. p. 385–401. 5. Dinkelborg L, Hingler C, Semmier W. Endothelin derivatives for imaging atherosclerosis. J Nucl Med 1995;36(Suppl.):102. 6. Prat L, Torres G, Carrio I, Roca M, Riambau V, Berna L, et al. Polyclonal In111-IgG, I125-LDL and I125-endothelin-1 accumulation in experimental arterial wall injury. Eur J Nuc Med 1993;20(12):1141–5. 7. Ben-Haim S, Kupzov E, Tamir A, Israel O. Evaluation of F18FDG uptake and arterial wall calcifications using 18F-FDG PET/CT. J Nucl Med 2004;45(11):1816–21. 8. Herrero P, Markham J, Bergmann SR. Quantitation of myocardial blood flow with H2 O and PET: assessment and error analysis of a mathematical approach. J Comput Assist Tomogr 1989;13:62–73. 9. Demer LL, Gould KL, Goldstein RA, Kirkeeide RL. Noninvasive assessment of coronary collaterals in man by PET perfusion imaging. JNM 1990;3:259–70.
Heart Lung and Circulation 2005;14S:S27–S30
10. Loscalzo J, Bonow RO, Jacobs AK. Coronary calcium screening and the American Heart Association News Embargo. Circulation 2004;110:3504–5. 11. Hoffman U, Moselewski F, Cury RC, Ferencik M, Jang IK, Diaz LJ, et al. Predictive value of 16-slice MDCT to detect significant obstructive coronary artery disease in patients with high risk for CAD. Circulation 2004;110:2638–43. 12. Giri S, Shaw LJ, Murthy DR, Travin MI, Miller DD, Hachamovitch R, et al. Impact of diabetes on the risk stratification using stress SPECT myocardial perfusion imaging in patients with symptoms suggestive of coronary artery disease. Circulation 2002;105(1):32–40. 13. Wackers FJ, Young LH, Inzucchi SE, Chyun DA, Davey JA, Barrett EJ, et al. Detection of silent myocardial ischaemia in asymptomatic diabetic subjects: DIAD Study. Diabetes Care 2004;27(8):1061–954. 14. Navare SM, Mather JF, Shaw LJ, Fowler MS, Heller GV. Comparison of risk stratification with pharmacologic and exercise stress myocardial perfusion imaging: a meta-analysis. J Nucl Cardiol 2004;11(5):551–61. 15. Udelson JE, Beshansky JR, Ballin DS, Feldman JA, Griffith JL, Handler J, et al. Myocardial perfusion imaging for evaluation and triage of patients with suspected acute cardiac ischaemia: a randomized controlled trial. JAMA 2002;288(21):2693–700. 16. Kertai MD, Boersma E, Westerhout CM, van Domburg R, Klein J, Bax JJ, et al. Association between long-term statin use and mortality after successful abdominal aortic aneurysm surgery. Am J Med 2004;116:96–103. 17. Bach DS, Eagle KA. Dobutamine stress echocardiography: stressing the indications for preoperative testing David S Bach and Kim A. Eagle. Circulation 1997;95:8–10.
Current Review
Nuclear Cardiology Zita E. Ballok, FRACP ∗ Mayne Health Diagnostic Imaging Unit, Epworth Hospital, 89 Bridge Road, Richmond, Melbourne, Vic. 3121, Australia
Nuclear cardiology has shown double digit growth yearly over the last few years and remains the second most commonly performed noninvasive cardiac imaging investigation of choice. Approximately 9 million studies performed yearly in the U.S. alone. As cardiovascular disease remains the largest healthcare problem around the world despite increasing healthcare spending there is growing interest to enhance the use of cost effective diagnostic tools, such as nuclear cardiology. Recent development of technology has seen the addition of hybrid imaging tools such PET/CT and SPECT/CT into the armorial. More data is expected to become available on this subject within the next few years, and we also expect several molecular imaging tests to become available for clinical use. Despite easy availability of these diagnostic tools, cardiac mortality and morbidity in patients with long term diabetes and also in the postoperative setting remains unexpectedly high and emergency department physician are still being sued after patients being discharged with undiagnosed chest pain. The value of the use of nuclear cardiology studies is briefly reviewed in these clinical settings. (Heart Lung and Circulation 2005;14S:S27–S30) © 2005 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
Introduction
N
uclear medicine surpassed its old name of ‘‘hot spot imaging’’ since new generation hybrid scanners which combine functional imaging with anatomical details have become available for clinical use over the last few years. In the newest hybrid systems, CT scanners are attached either to a SPECT or to a PET camera. These are also available in small animal scanners for research application. SPECT cameras are available with the addition of a single, dual or a 6-slice CT scanner. The hybrid PET/CT (16-slice or 64-slice) scanners are considered currently the ‘‘best’’ one stop-shop for cardiac imaging by many experts (Figs. 1 and 2).1
Molecular Imaging in Cardiology The new and up to date name for nuclear medicine is molecular imaging. Even long-established international nuclear medicine journals recognized the rapid development by changing their names incorporating molecular imaging into their title after many years of stagnation. Large companies, which previously exclusively specialized in supplying equipment for imaging purposes have spent large amount of resources acquiring pharmaceutical companies engaged in development of radiopharmaceuti∗
Tel.: +61 3 92424848; fax: +61 3 92424830. E-mail address: [email protected].
cals for diagnostic and therapeutic purposes. Agents have been developed to image inflammation, atherosclerosis, and apoptosis just to list a few applications in the cardiology field. LDL can be labeled by a number of isotopes, e.g., I-123, Tc-99m, In-111. Macrophages take up oxidized LDL via scavenger receptor much more readily than native LDL. In a study of seven patients with symptomatic carotid artery lesions, uptake of Tc-99m oxidized LDL was seen in 10 out of 11 atheromatous lesions.2 Oxidised LDL has a rapid blood clearance which allows for imaging 1 h after tracer injection. Radiolabeled antibodies raised against epitopes on the LDL particles have also been studied. I125-MDA2, one of these antibodies shows 17 times higher concentration in hyperlipidaemic rabbits compared with normal rabbits.3 Peptids are even more promising as they clear from circulation much quicker than lipoproteins. A human pilot study showed Tc-99m label on a synthetic apo-B analog, P-215, and uptake into human carotid lesion.4 Endothelin production by smooth muscle and endothelial cells is upregulated in the presence of endothelial dysfunction, providing a potential target. Both iodinated and Tc-99m-labeled endothelin and its derivatives accumulate in atherosclerotic lesions in animal studies.5,6 Macrophages in atherosclerotic plaques express cell surface Fc receptors and they can also be imaged with F18FDG.7
© 2005 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand. Published by Elsevier Inc. All rights reserved.
1443-9506/04/$30.00 doi:10.1016/j.hlc.2005.08.012
CURRENT REVIEW
S28
Ballok Nuclear cardiology
Heart Lung and Circulation 2005;14S:S27–S30
Figure 1. Courtesy of Professor Jim Corbett.
Nuclear Cardiology Versus Other Modalities Nuclear medicine methods, especially PET, remains the gold standard for viability imaging despite the advances in MRI and echocardiography. PET has overcome obstacles commonly seen with MRI, such as negative contrast, unclear labeling. Also, absolute quantifications to measure blood flow with PET8 have been established long ago, but not yet clearly established with MRI.9 CT calcium score screening is not endorsed by the AHA or by any other cardiac societies.10 CT angiography has made a long progress, however, it fails where it should be the most accurate. Severity of the coronary artery stenosis is difficult to assess with CT angiography at sites with significant calcifications.11 Patients with high probability of coronary artery disease in a recent study designed to assess the technology of a 16-slice MDCT against the gold standard coronary angiography showed significant false positive results due to calcifications within central coronary artery segments. This disappointing result makes it clear that additional functional imaging either with echocardiography, SPECT, or PET studies remains invaluable for risk stratification. CT angiography has also been promoted for screening in patients with low probability for coronary artery disease, however, CT angiography does deliver a relatively
large dose of radiation to the patient, which is usually higher than a nuclear medicine SestaMIBI SPECT perfusion study or conventional coronary angiography.
Imaging of the Asymptomatic Diabetic Patients Age-adjusted mortality rate for coronary artery disease has fallen by 60% since the 1960s, but the prevalence of CAD is increasing. This increased prevalence results from the increase of average life span, the increased number of elderly patients, and the epidemics of obesity and Type 2 diabetes. Diabetes is one of at least three areas where nuclear cardiology studies could be utilized more aggressively and more extensively to help our population and referring doctors to assess the risk of significant coronary artery disease early and diagnose the disease more accurately and cost effectively. This could lead for early referral for appropriate cardiac intervention and more aggressive risk factor modification, and even to the increase in productivity in general as diabetes and obesity-related illnesses are accepted by large insurance companies and employers as productivity reducing factors. Stress myocardial perfusion imaging has proven valuable in both diagnostic and prognostic evaluation
Ballok Nuclear cardiology
S29
Figure 2. Reprinted with permission from J Nucl Med 2004;45(9):14N.
of diabetic patients who are at increased risk of CAD. Myocardial perfusion imaging provides major incremental value for risk stratification in this patient group.12 In fact, several developed countries, e.g., Japan and France are already using myocardial perfusion imaging as a screening tool to assess high-risk asymptomatic diabetic subgroups. The Detection of Ischaemia in Asymptomatic Diabetic patients (DIAD) study is the first amongst those which predicts that this approach will be more widely accepted practice in the developed world in the near future.13 A large proportion of diabetic patients are unable to complete the minimum 5METs exercise for an interpretable exercise stress study, and pharmacological stress test in combination with perfusion imaging is often necessary for accurate risk stratification. These pharmacological studies are safe, well accepted and reproducible, and have the same predictive value14 for future major cardiac events as exercise perfusion imaging.
Nuclear Cardiology in the Emergency Department The second patient group at need for more aggressive early noninvasive cardiac investigations, primarily with myocardial perfusion imaging is the one who presents to the Emergency Department with chest pain, normal baseline ECG and normal troponine level. A significant number of the discharged patients from this group carry a high risk for further cardiac events. In fact, missed acute coronary syndrome is the number one on the list
of medical liability suits among emergency department physicians. Large studies have shown that coronary angiogram often not performed on the right patients as clinical variables may not classify the patients adequately, causing a significant amount of patient with intermediate to high risk for coronary event misclassified to the low risk group and missing out on further evaluation. Acute ‘‘hot MIBI’’ nuclear medicine perfusion imaging is a very useful tool in the assessment of patients presenting to the emergency departments. Abnormal perfusion studies identify patients at high risk for major cardiac events, while patient with normal studies remain at low risk.15 Patient with abnormal studies need further evaluation with coronary angiogram while those with a normal ‘‘hot MIBI’’ perfusion pattern usually return for a stress perfusion study within a few days.
Preoperative Cardiac Risk Assessment The third area where wider screening with myocardial perfusion studies is recommended is preoperative assessment before major orthopedic and vascular intervention. Data from the Netherlands show that postoperative cardiac complications have not reduced to low levels, as previously predicted, despite significant advancement in anesthetic care.16 The goal is not just to detect occlusive vascular disease;17 preoperative assessment has two major goals: the patients not just need to survive the operation, she or he also needs to enjoy the benefit of the operation.
CURRENT REVIEW
Heart Lung and Circulation 2005;14S:S27–S30
CURRENT REVIEW
S30
Ballok Nuclear cardiology
References 1. Schweiger M. EANM Annual Scientific Meeting, Helsinki, Finland, September 2004. 2. Iuliano L, Signore A, Vallabajosula S, Colavita AR, Camastra C, Ronga G, et al. Preparation and biodistribution of 99m-technetium labeled oxidized LDL in man. Atherosclerosis 1996;126:131–41. 3. Tsimikas S, Palinski W, Halpern SE, Yeung DW, Curtiss LK, Witztum JL. Radiolabeled MDA2, an oxidation-specific, monoclonal antibody, identifies native atherosclerotic lesions in vivo. J Nucl Cardiol 1999;6:41–53. 4. Lees R, Lees A. Radiopharmaceutical imaging of atherosclerosis. In: Fuster V, editor. Syndromes of atherosclerosis: correlations of clinical imaging and pathology. Armonk, NY: Future Publishing Co. Inc.; 1996. p. 385–401. 5. Dinkelborg L, Hingler C, Semmier W. Endothelin derivatives for imaging atherosclerosis. J Nucl Med 1995;36(Suppl.):102. 6. Prat L, Torres G, Carrio I, Roca M, Riambau V, Berna L, et al. Polyclonal In111-IgG, I125-LDL and I125-endothelin-1 accumulation in experimental arterial wall injury. Eur J Nuc Med 1993;20(12):1141–5. 7. Ben-Haim S, Kupzov E, Tamir A, Israel O. Evaluation of F18FDG uptake and arterial wall calcifications using 18F-FDG PET/CT. J Nucl Med 2004;45(11):1816–21. 8. Herrero P, Markham J, Bergmann SR. Quantitation of myocardial blood flow with H2 O and PET: assessment and error analysis of a mathematical approach. J Comput Assist Tomogr 1989;13:62–73. 9. Demer LL, Gould KL, Goldstein RA, Kirkeeide RL. Noninvasive assessment of coronary collaterals in man by PET perfusion imaging. JNM 1990;3:259–70.
Heart Lung and Circulation 2005;14S:S27–S30
10. Loscalzo J, Bonow RO, Jacobs AK. Coronary calcium screening and the American Heart Association News Embargo. Circulation 2004;110:3504–5. 11. Hoffman U, Moselewski F, Cury RC, Ferencik M, Jang IK, Diaz LJ, et al. Predictive value of 16-slice MDCT to detect significant obstructive coronary artery disease in patients with high risk for CAD. Circulation 2004;110:2638–43. 12. Giri S, Shaw LJ, Murthy DR, Travin MI, Miller DD, Hachamovitch R, et al. Impact of diabetes on the risk stratification using stress SPECT myocardial perfusion imaging in patients with symptoms suggestive of coronary artery disease. Circulation 2002;105(1):32–40. 13. Wackers FJ, Young LH, Inzucchi SE, Chyun DA, Davey JA, Barrett EJ, et al. Detection of silent myocardial ischaemia in asymptomatic diabetic subjects: DIAD Study. Diabetes Care 2004;27(8):1061–954. 14. Navare SM, Mather JF, Shaw LJ, Fowler MS, Heller GV. Comparison of risk stratification with pharmacologic and exercise stress myocardial perfusion imaging: a meta-analysis. J Nucl Cardiol 2004;11(5):551–61. 15. Udelson JE, Beshansky JR, Ballin DS, Feldman JA, Griffith JL, Handler J, et al. Myocardial perfusion imaging for evaluation and triage of patients with suspected acute cardiac ischaemia: a randomized controlled trial. JAMA 2002;288(21):2693–700. 16. Kertai MD, Boersma E, Westerhout CM, van Domburg R, Klein J, Bax JJ, et al. Association between long-term statin use and mortality after successful abdominal aortic aneurysm surgery. Am J Med 2004;116:96–103. 17. Bach DS, Eagle KA. Dobutamine stress echocardiography: stressing the indications for preoperative testing David S Bach and Kim A. Eagle. Circulation 1997;95:8–10.