Myocardial Perfusion Imaging: From Diagnosis to Prognosis

Author: Arash Kardan, MD, Nuclear Medicine Physician, Kettering Healthcare Network, Kettering, OH.

Peer Reviewer: Michael H. Crawford, MD, Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco.

Myocardial perfusion imaging (MPI) refers to the utilization of radiotracers to image regional myocardial perfusion from coronary artery blood flow to the heart muscle. Used effectively, MPI can provide the clinician with a noninvasive technique that yields both important diagnostic and powerful prognostic information regarding the functional significance of anatomic coronary artery disease. MPI can help guide therapeutic decision-making by stratifying patients with respect to future risk for adverse outcomes.

Nuclear medicine is a medical specialty that uses radioactive substances in the diagnosis and treatment of disease. In nuclear medicine procedures, trace amounts of radioactive isotopes are combined with other elements or radiopharmaceuticals to form radioactive-labeled chemical compounds or “radiotracers.” These radiotracers localize to specific organs or cellular receptors within the body and mimic physiologic or biochemical pathways based on the inherent activity of the compound or pharmaceutical within the body’s functional pathways. This property of radiotracers gives nuclear medicine specialists the ability to image the extent of a disease process in the body based on the cellular function and physiology, rather than relying on physical changes in the tissue anatomy. In some diseases, nuclear medicine studies can identify medical problems at a much earlier stage than other diagnostic tests by demonstrating alterations in metabolism or physiology prior to the onset of changes in tissue anatomy. Nuclear medicine, in a sense, is radiology done inside out, or endo-radiology, because it images radiation emitted from within the body rather than radiation that is generated by external sources such as x-rays.

Nuclear cardiology employs the principles of nuclear medicine for the noninvasive study of the heart by using various radiotracers to evaluate different aspects of cardiac physiology. Some radiotracers are delivered via blood flow to the heart and then taken up by heart muscle, allowing the detection of blood flow-limiting stenosis in the coronary arteries and areas of abnormal blood flow in the heart muscle secondary to prior infarction. Other radiotracers are taken up by the heart muscle, which is alive but starved of blood flow secondary to coronary blockages and therefore not functioning actively, thereby allowing the detection of viable or “hibernating” heart muscle that will recover its function if normal blood flow is resumed via a revascularization procedure. Red blood cells can be radioactively labeled and imaged in the heart to give accurate and reproducible estimates of left ventricular ejection fraction for serial monitoring during potentially cardiotoxic chemotherapies for cancer. Alternatively, the technique can be used to map the contraction pattern of the left and right ventricle to help determine if the placement of a biventricular multi-lead cardiac pacemaker to resynchronize the contraction of the ventricles in the setting of congestive heart failure will be helpful.

Epidemiology of Cardiovascular Disease

Prevalence. An estimated 82.6 million American adults have one or more types of cardiovascular disease (CVD), defined as high blood pressure, coronary or peripheral atherosclerotic disease, heart failure, stroke, or congenital cardiovascular defects.1 Of these, 40.4 million are estimated to be ≥ 60 years of age.1

Mortality. Mortality data for 2007 show CVD accounted for 33.6% (813,804) of all 2,243,712 deaths in 2007, or 1 in 2.9 deaths in the United States.2 Using 2007 mortality data, more than 2200 Americans die of CVD each day, an average of 1 death every 39 seconds.2 CVD claims more lives each year than cancer, chronic lower respiratory disease, and accidents combined.2 More than 150,000 Americans killed by CVD in 2007 were < 65 years of age. Nearly 33% of deaths due to CVD occurred before the age of 75 years, which is well before the average life expectancy of 77.9 years.2 In every year since 1900, except 1918, CVD accounted for more deaths than any other major cause of death in the United States.3-6 (In 1918, the leading cause of death in the United States was due to the Spanish influenza epidemic). Coronary heart disease caused approximately 1 in 6 deaths in the United States in 2007 with a total mortality of 406,351.1 Each year, an estimated 785,000 Americans will have a new heart attack and an estimated 470,000 Americans will have a recurrent heart attack. An additional 195,000 silent first heart attacks occur each year.1 Approximately every 25 seconds, an American will have a coronary event, and approximately every minute, someone will die of one.1 In 2007, 1 in 9 death certificates (277,193) in the United States mentioned heart failure.1

Cost. The total number of inpatient cardiovascular operations and procedures increased 27%, from 5.382 million in 1997 to 6.846 million in 2007.1 The total direct and indirect cost of CVD and stroke in the United States for 2007 is estimated to be $286 billion. By comparison, the estimated cost of all cancer and benign neoplasms for 2008 was $228 billion.1

Coronary Anatomy

The heart muscle is about the size of one’s fist and weighs approximately 1 pound. It pumps about 5 quarts (4.7 liters) of blood per minute. Two coronary arteries branch from the main aorta just above the aortic valve. No larger than drinking straws, the aorta divide to encircle the heart, covering its surface with a lacy network that looks like a slightly crooked crown. Coronary comes from the Latin term coronaries, belonging to a crown or wreath. The coronary arteries carry out about 130 gallons of blood through the heart daily.7

Pathogenesis of Atherosclerosis and Myocardial Infarction

Current theories of the pathogenesis of the lesions of atherosclerosis relate back to early proposals made by Virchow, Rokitansky, and Duguid. Virchow believed that a form of low-grade injury to the artery wall resulted in a type of inflammatory response, which in turn caused increased passage and accumulation of plasma constituents in the intima of the artery.8 Rokitansky’s belief, subsequently elaborated upon by Duguid, was that an encrustation of small mural thrombi existed at sites of arterial injury, that these thrombi went on to organize by the growth of smooth muscle cells into them, and they would become incorporated into the lesions and thus serve as sites where the lesions would progress.9,10 In 1973, these two notions about atherogenesis were combined with new knowledge of the cellular and molecular biology of the artery wall in a hypothesis termed the “response to injury hypothesis of atherosclerosis.”11 This hypothesis has been modified as new data have come forth. It now takes into account many aspects of the behavior of arterial and blood cells described above, as well as the numerous risk factors that have been associated with atherogenesis, including hyperlipidemia, hormone dysfunction, hypertension, cigarette smoking, diabetes, and so on.11,12

Almost all myocardial infarctions (MIs) result from atherosclerosis of the coronary arteries, generally with superimposed coronary thrombosis. The genesis of the coronary atherosclerotic lesion is a complex and controversial issue, and a number of risk factors have been associated with the development of atherosclerosis. However, regardless of the etiology and pathogenesis of the atherosclerotic process, the end result is plaques that cause luminal narrowing of the coronary arterial tree. Below a certain critical level of blood flow, myocardial cells develop ischemic injury. When severe ischemia is prolonged, irreversible damage (i.e., MI) occurs.13

Myocardial Perfusion Imaging

Stress MPI with single photon emission computed tomography (SPECT) can detect perfusion abnormalities early in the ischemic cascade of events before metabolic, electrical, or anatomic disturbances occur.14 (See Figure 1.)

Figure 1


SPECT MPI uses radiotracers to provide information about regional blood flow, coronary artery perfusion, and ventricular function.17 The myocardial uptake of radiolabeled flow tracer is in proportion to the regional distribution of myocardial blood flow. The radiotracer is retained within the myocardium for some period of time depending on its pharmacokinetics. Images are acquired by scanners that register the gamma radiation (single photon) emitted from the radiotracer within heart muscle, converting it into digital data, which is then reconstructed in three dimensions (computed tomography) for viewing and analysis. A 17-segment model is used to evaluate the different coronary territories. The 17-segment model was developed in conjunction with, and is endorsed by, many professional associations, including the American Heart Association, the American Society of Nuclear Cardiology, the North American Society of Cardiac Imaging, and the American Society of Echocardiography.18 (See Figures 2 and 3.) Each segment is scored with respect to the degree of abnormality seen and these scores are then summed to provide an assessment of abnormality throughout the whole myocardium. This is performed for both the stress and rest studies, with the difference between the two scores being reflective of the burden of ischemia.19 (See Figure 4.)

Figure 2: The 17-Segment Model


Figure 3: The Bullseye Representation of the 17-Segment Model


Figure 4: Summed Stress Scores


Thallium behaves as a potassium analog and therefore can shift in and, subsequently, out of myocardiocytes.20,21 Thallium was the first medical radiotracer to be used for MPI after it was discovered to have high uptake in the heart and demonstrate a linear relationship to perfusion over a wide range of flows.22,23 It is likely due to its historical precedence as a myocardial perfusion agent that even today many physicians refer to all MPI studies as “thallium scans.” Due to its long half-life, which limits the dose that can be administered, and its low energy gamma radiation, which limits picture quality, thallium has largely been replaced by technetium-99m labeled radiotracers for evaluation of myocardial perfusion. However, due to its behavior as a potassium-like analog, thallium continues to be used as a cost effective radiotracer alternative in evaluation of myocardial viability in centers where a PET (positron emission tomography) scanner is not available.24

The lower energy thallium has largely been supplanted by the use of technetium-99m-based imaging agents, which have a substantially shorter half-life (6 hours vs 73 hours for thallium) allowing higher doses to be administered. Also, technetium-99m emits higher energy gamma radiation (140 keV vs 70-80 keV for thallium) meaning fewer photons are stopped by the body and, therefore, arrive at the camera, resulting in higher image quality.17,24 The two commercially available radiotracers using technetium-99m are sestamibi (Cardiolite) and tetrafosmin (Myoview). These are both cationic lipophilic molecules that diffuse through the cell membrane and subsequently localize in the mitochondria. Unlike thallium, which shifts back out of myocardial cells analogous to potassium transport, both the technetium radiotracers get permanently “locked” in the mitochondria and do not redistribute. This stability of localization, along with higher energy resulting in clearer imaging, allows for the acquisition of gated images utilizing electrocardiogram leads to take pictures of the heart during different stages of contraction. With this information, wall motion and ejection fractions can be evaluated. This was not possible with thallium.14,17,24

A meta-analysis of 33 studies, which included thallium-201 and technetium-99m tracers, found that SPECT MPI with treadmill exercise stress for the detection of significant coronary artery disease, defined as a stenosis of more than 50%, had an average sensitivity of 87% and specificity of 73%.17 SPECT MPI with pharmacologic stress using adenosine or dipyridamole — coronary vasodilators often employed when patients are incapable of adequate exercise — demonstrated similar results with an average sensitivity of 89% and specificity of 75%.17 With the addition of gated SPECT imaging in MPI with technetium-99m radiotracers in patients with symptoms suggestive of typical or atypical angina, exercise or pharmacologic stress SPECT MPI yielded a sensitivity of 85-90% and a specificity of 80-90%.17,25,26,27

A meta-analysis of 1405 patients compared stress echocardiography with stress MPI for detection of coronary artery disease. MPI yielded higher sensitivity (84% for MPI vs 80% for stress echo), but had lower specificity (77% for MPI vs 86% for stress echo).15 A comparison of the sensitivities and specificities for the different modalities is summarized in Figure 5. The studies included in this meta-analysis primarily utilized older techniques, whereas studies utilizing more contemporary techniques for MPI have yielded specificities similar to stress echocardiography.17,25,26,27

Figure 5: Sensitivity and Specificity of Noninvasive Tests for the Detection of Coronary Artery Disease28,29


Risk Stratification

In patients with stable coronary artery disease, it remained unclear whether an initial management strategy of percutaneous coronary intervention (PCI) with intensive pharmacologic therapy and lifestyle intervention (optimal medical therapy) is superior to optimal medical therapy alone in reducing the risk of cardiovascular events. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial was designed to determine whether PCI coupled with optimal medical therapy reduces the risk of death or nonfatal MI in patients with stable coronary artery disease, as compared with optimal medical therapy alone. Such a “strategy trial” had never been conducted since the advent of angioplasty in 1977. The trial investigators conducted a randomized trial involving 2287 patients who had objective evidence of myocardial ischemia and significant coronary artery disease at 50 U.S. and Canadian centers. Between 1999 and 2004, they assigned 1149 patients to undergo PCI with optimal medical therapy (PCI group) and 1138 to receive optimal medical therapy alone (medical-therapy group). The primary outcome was death from any cause and nonfatal MI during a follow-up period of 2.5 to 7.0 years (median, 4.6). There were 211 primary events in the PCI group and 202 events in the medical-therapy group. The 4.6-year cumulative primary-event rates were 19.0% in the PCI group and 18.5% in the medical-therapy group. There were no significant differences between the PCI group and the medical-therapy group in the composite of death, MI, and stroke (20.0% vs 19.5%); hospitalization for acute coronary syndrome (12.4% vs 11.8%); or MI (13.2% vs 12.3%). The authors concluded that as an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, MI, or other major cardiovascular events when added to optimal medical therapy.30

Advances in the understanding of the pathophysiologic basis for acute coronary syndromes and the important role that plaque rupture or fissure plays in the genesis of MI clearly indicate that non-flow-limiting coronary stenoses are the principal progenitors of most hard clinical events.31,32,33 It is well established that coronary occlusion following plaque rupture or fissuring is an emergency that cannot be optimally managed pharmacologically. Abundant data from clinical trials show that urgent or emergent PCI in patients with ST-segment elevation MI or high-risk non-ST-segment elevation MI reduces the rates of death or subsequent MI.34-39 The COURAGE trial does not challenge this fact. However, performing elective PCI in patients with chronic angina and stable coronary artery disease is virtually identical procedurally to that performed in patients with acute coronary syndromes. Thus, many have accepted the broader premise that PCI would confer a more durable clinical benefit (i.e., beyond angina relief or improved exercise performance) in patients with chronic angina and stable coronary artery disease as well. This belief system is rooted in a scientifically plausible clinical construct that dilating one or more flow-limiting coronary stenoses would be inherently superior to an approach that involved only pharmacologic and lifestyle interventions, but this premise was unproven.16

The application of prognostic testing is based on the premise that patients can be stratified with respect to risk for adverse outcomes and can receive intervention to change the natural history of their disease so that their subsequent risk is reduced. Several studies have historically shown that patients with stable coronary disease can be stratified into different risk groups based on demographics, exercise, MPI, and catheterization information.40-49 Schinkel and colleagues found that half of 650 patients with known or suspected CAD with normal exercise ECGs had abnormal SPECT myocardial perfusion studies. In 20% of these studies, the abnormalities were related to ischemia and, therefore, reversible. The degree of abnormality on myocardial perfusion SPECT was predictive of cardiovascular death or morbidity out to 10 years. The summed stress score (SSS), which measures both infarcted and ischemic myocardium, was an independent predictor of major adverse cardiac events. The summed rest score (SRS), which measures the amount of infarcted myocardium, was an independent predictor of death.

Studies that utilized planar thallium imaging techniques with treadmill exercise stress found that a normal study was a significant predictor of lower risk for MI of death at 1 year.42-44 Compared with planar thallium imaging, SPECT thallium imaging has better image quality, improved sensitivity in detecting individual diseased vessels, and is more quantitative in nature with respect to describing the severity or extent of disease.50,51 Iskandrian and colleagues examined the independent and incremental prognostic value of exercise SPECT thallium imaging in patients with angiographically defined coronary artery disease. Data were obtained in 316 medically treated patients with coronary artery disease who underwent coronary angiography over a mean follow-up time of 28 months. The primary endpoints were cardiac death or non-fatal MI. Univariate analysis showed that gender, exercise work load, extent of coronary artery disease and left ventricular ejection fraction, and thallium SPECT variables were prognostically important. Multivariate analysis demonstrated that thallium SPECT data provided incremental prognostic value to catheterization data, with the extent of the perfusion abnormality being the single best predictor of prognosis (See Figure 6).52 Nallamothu and colleagues examined predictors of outcome after coronary bypass grafting in 255 patients over mean time of 5 years after surgery. All patients underwent coronary angiography and SPECT thallium imaging after coronary artery bypass grafting. Again SPECT thallium MPI demonstrated independent and incremental prognostic information to clinical, stress, and angiographic variables with respect to predicting cardiac death or non-fatal MI in this patient population.53

Figure 6: Independent and Incremental Prognostic Value of Exercise SPECT Imaging in Patients with Angiographically Defined Coronary Artery Disease52


Although a number of previous studies have demonstrated the incremental prognostic value of myocardial perfusion SPECT over clinical and exercise data, they all used either combined hard events (cardiac death or non-fatal MI) or total events (cardiac death, non-fatal MI, and early revascularization) as endpoints.52,54-57 As the treatment of patients for each of these outcomes may differ, applying the prognostic information of nuclear myocardial perfusion testing to patient management is difficult. Revascularization has been demonstrated to reduce the rate of cardiac death in selected high-risk subsets of patients, but has never been shown to reduce the rate of MI.58-61 Trials of medical therapy have demonstrated reductions in both fatal and nonfatal MI rates and cardiac death.62-65 Shaw and colleagues enrolled 4728 consecutive patients who underwent SPECT MPI with technetium-99m tetrofosmin with either exercise or pharmacologic stress. The observed annualized survival rate for those patients with a normal study was 0.6%.66 Numerous other investigators have demonstrated that event rates associated with normal or low-risk myocardial perfusion SPECT with thallium or technetium agents is less than 1% per year of follow-up.55,67-73 The annual mortality rate associated with revascularization is at least 1%.61 Therefore, patients with a normal or low-risk SPECT myocardial perfusion study do not warrant revascularization for purposes of improving survival.

Hachamovitch and colleagues performed the first study to be sufficiently powered to examine differences in the rates of MI and cardiac death after SPECT myocardial perfusion testing. They identified 5183 consecutive patients who underwent stress/rest SPECT and were followed up for the occurrence of cardiac death or MI. Over a mean follow-up of 642 ± 226 days, 119 cardiac deaths and 158 MIs occurred (3.0% cardiac death rate, 2.3% MI rate). Patients with normal scans were at low risk (0.5% per year), and rates of both outcomes increased significantly with worsening scan abnormalities. They found that after consideration of all prescan patient information, nuclear MPI provided statistical incremental prognostic value toward the prediction of both MI and cardiac death. Statistically significant and clinically relevant risk stratification was achieved by the nuclear test even after initial stratification by prescan information. Patients with normal scans had low rates of both outcomes, whereas patients with mildly abnormal scans who underwent exercise stress were at intermediate risk for MI but low risk of cardiac death, and patients with moderately or severely abnormal scans were at intermediate to high risk of both MI and cardiac death (See Figure 7). A risk-adjusted comparison of post-nuclear testing referral to early revascularization vs medical therapy suggested a survival advantage to the former in patients with severely abnormal scans. Finally, cost analysis reveals that referral to catheterization only in those patients with moderately to severely abnormal scans rather than all abnormal scans after exercise stress would result in a 33.5% cost savings.74

Figure 7: Rates of Cardiac Death and Myocardial Infarction as Function of Scan Result74


Recommended Uses for Nuclear MPI

The appropriate use of nuclear MPI may benefit patients; however, inappropriate use of MPI may be potentially harmful to patients and generate unwarranted costs to the health care system. Therefore, it is essential that the health care community knows how to effectively integrate and utilize MPI in daily clinical care and takes a proactive role in ensuring best practices.

The Appropriate Use Criteria (AUC) for Cardiac Radionuclide Imaging (the term “radionuclide imaging” in the AUC is synonymous with radionuclide MPI) were developed by the American College of Cardiology Foundation (ACCF), along with key cardiology societies, to serve as a guide for the responsible use of radionuclide MPI. The AUC were updated in 2009 to reflect changes in test utilization and new clinical data based on a broad range of clinical experiences and available evidence-based information. The indications were drawn from common applications, anticipated uses, and current clinical practice guidelines. Sixty-seven clinical scenarios were developed by a writing group and scored by a separate technical panel to designate various clinical indications for which radionuclide MPI is appropriate, inappropriate, or uncertain. Together with sound clinical judgment, the AUC can help practitioners determine whether radionuclide MPI is appropriate in individual patient cases.

The objective of the AUC is to improve patient care and health outcomes in a cost-effective manner but is not intended to ignore ambiguity and nuance intrinsic to clinical decision-making. The recommendations are intended as a practical guide for practitioners who order radionuclide MPI and should be considered in conjunction with clinical experience and judgment.

In general, the use of MPI is appropriate for the diagnosis and risk assessment of intermediate- and high-risk CAD patients, according to the AUC. MPI testing for low-risk patients, routine repeat testing, and general screening in certain clinical scenarios are considered less appropriate.75

Figures 8, 9, 10, and 11 demonstrate an algorithmic approach for evaluating the appropriateness of MPI for the detection of CAD in symptomatic patients, asymptomatic patients, patients with prior MPI testing, and patients undergoing preoperative evaluation for noncardiac surgery.

Figure 8: Detection of CAD: Symptomatic


Figure 9: Detection of CAD/Risk Assessment for Asymptomatic Patients


Figure 10: Risk Assessment with Prior Test Results and/or Known Chronic Stable CAD*


Figure 11: Risk Assessment: Preoperative Evaluation for Noncardiac Surgery Without Active Cardiac Conditions**


Radiation from Nuclear Myocardial Perfusion Imaging

The powerful diagnostic and risk-stratification data provided by these procedures play a central role in clinical cardiology and have contributed to the decrease in morbidity and mortality from coronary heart disease. Nevertheless, performance of any diagnostic test requires a careful assessment of the risks and benefits of the test and optimization of protocols to minimize risks to patients, staff members, and the public. Procedures that utilize ionizing radiation should be performed in accordance with the As Low As Reasonably Achievable (ALARA) philosophy. Thus, physicians ordering and performing cardiac imaging should be very familiar with the dosage of radiation from cardiac diagnostic tests and ways in which dose can be minimized.

Radiation dosimetry from a study using a radiopharmaceutical is typically estimated on the basis of a mathematical biokinetic model that quantifies the distribution and metabolism of that agent in the body. Such models incorporate biokinetic data from animal and human models.

Effective doses of MPI procedures are nontrivial and vary greatly between protocols. Substantial differences exist between procedures with the use of different radiopharmaceuticals and between different procedures with the use of the same agent. While the typical effective dose of a posteroanterior chest x-ray is 0.02 mSv, and the annual background radiation in the United States is 3.0 mSv, typical values for MPI studies range from 2.2-31.5 mSv. Of the most commonly performed studies, a rest-stress 99mTc sestamibi study averages 11.3 mSv, and a rest-stress 99mTc tetrofosmin study averages 9.3 mSv. Single-injection protocols are associated with a dose that is approximately 30% lower. Doses are much higher for studies using 201Tl. A single-injection 201Tl MPI study has an average value of 22 mSv. Dual isotope studies have the highest effective doses with an average value of 29.2 mSv for a 201Tl-99mTc sestamibi study or approximately three times that of a single-injection protocol using a 99mTc-containing agent.76

Dosimetric considerations have important implications for the selection of MPI protocols. In 2002, 35% of the 9.3 million MPI studies performed in the United States used 201Tl, with 86% of these being dual isotope studies. The use of these high-dose protocols appears to be increasing, with 30% of studies in 2002 being dual isotope compared with 19% in 1997. Dual isotope studies are particularly common in the outpatient setting, in which they are used in 36% of all MPI studies, perhaps because of the relatively fast patient throughput. However, the radiation dose of studies employing 201Tl, especially dual isotope MPI, is among the highest of all medical diagnostic tests. Thus, ALARA considerations appear to favor the use of 99mTc agents rather than 201Tl.76

Biological effects of ionizing radiation can be classified as deterministic or stochastic. Deterministic effects such as skin injuries and cataract formation occur predictably when dose exceeds a certain threshold, whereas stochastic effects such as cancer incidence and germ cell mutations occur with a probability that increases with dose.

The significance of measuring radiation doses comes from the relationships between dose and risks of deterministic and stochastic effects. In cardiac imaging, the only deterministic effect that occurs with any frequency in patients is skin injury. Stochastic risks of potential concern include heritable genetic effects and cancer. Risks for all classes of genetic diseases occur at a rate estimated at 0.30% to 0.47% per Gy per first-generation progeny. Even with the highest gonadal doses found in cardiac imaging, in 201Tl scintigraphy with a testicular absorbed dose of approximately 60 mGy, this would correspond to a risk of genetic diseases of only 0.02% to 0.03% per first-generation progeny.76

Physicians’ major radiation-related concern relating to cardiac imaging is iatrogenic malignancy. Ionizing radiation causes numerous types of DNA damage and it is hypothesized that damaged sites such as double-strand breaks are oncogenic. For the type of radiation used in cardiac imaging, i.e., low levels (≤ 100 mSv) of low linear energy transfer ionizing radiation, the relationship between dose and lifetime attributable risk of cancer is a controversial one. Many but not all organizations offering expert opinions maintain that the linear no-threshold model, whereby the risk of cancer proceeds in linear fashion with no lower threshold, provides the most reasonable description of this relationship. A National Academies committee affirming this position has developed risk models to estimate radiation-attributable cancer risk as a function of age and gender. Risk falls off with age and is typically higher in women. Although aspects of these models may be contentious, their underlying idea that cancer risk from radiation is dependent not just on dose but also on nonmodifiable person-specific factors such as age is well agreed on. A thorough discussion of the linear no-threshold model, cancer risk estimation, and their applications to cardiac imaging is beyond the scope of this article, but these subjects remain important areas of investigation.76

Case Studies

Case 1

The patient is a 74-year-old male with complaint of exertional chest pain that has developed over the last month. The patient also reports he gets pain in his legs while going up a flight of stairs. This has been occurring for several months. Both the chest pain and leg pain resolve with rest. Past medical history is significant for hypertension, hyperlipidemia, and carotid endarterectomy 4 years ago.

Is myocardial rest/stress perfusion imaging appropriate for this patient?

The patient is symptomatic and has multiple risk factors for coronary artery disease including age, sex, hypertension, and hyperlipidemia. A history of prior carotid endarterectomy is consistent with known atherosclerotic disease making this patient higher risk for CAD. The exertional leg pain is suspicious for claudication from PVD. Stress/rest MPI would be an appropriate non-invasive assessment for obstructive CAD.

MPI results

Stress/rest MPI performed with adenosine stress due to the patient’s inability to perform sufficient exercise on a treadmill secondary to his leg pain. The ECG portion of the study is nondiagnostic due to resting nonspecific ST-T wave abnormalities. Post-stress myocardial perfusion images demonstrate decreased perfusion in the inferior wall which normalizes on the resting images which are otherwise normal without evidence of prior infarct. The SSS is 10, the SRS is 0, making the SDS also 10.


MPI demonstrates evidence of moderate ischemia involving the inferior wall, most likely correlating with obstruction of the right coronary artery. An SSS score of 10 means the patient is at higher risk for both future MI and cardiac death. The patient should be referred for invasive coronary angiography and revascularization based on the higher risk of cardiac death.

Case 2

The patient is a 66-year-old female with complaint of occasional chest pressure accompanied by dyspnea when she takes her evening walk. The symptoms seem to occur with more regularity when she takes the path that includes an inclined portion. Past medical history is significant for type 2 diabetes for 11 years, hypertension, and hyperlipidemia. Her father died of a heart attack at the age of 54.

Is myocardial rest/stress perfusion imaging appropriate for this patient?

The patient is symptomatic and has multiple risk factors for coronary artery disease including age, diabetes, hypertension, and hyperlipidemia. She also has a family history of CAD. Overall, the patient has at least an intermediate risk for CAD. Stress/rest MPI would be an appropriate non-invasive assessment for the diagnosis of obstructive CAD.

MPI results

Stress/rest MPI performed with treadmill exercise stress recreates the patient’s symptoms of chest pressure and dyspnea. The patient exercised for 4 minutes and achieved 88% of maximum predicted heart rate. The ECG portion of the study is negative for ischemia with occasional premature ventricular contractions during recovery. Post-stress myocardial perfusion images demonstrate a mild decrease in perfusion in the lateral/inferolateral wall, which normalizes on the resting images that are otherwise normal without evidence of prior infarct. The SSS is 5, the SRS is 0, making the SDS also 5.


MPI demonstrates evidence of mild ischemia involving the inferior wall, most likely correlating with a lesion in the left circumflex coronary artery or one of its branches. An SSS score of 5 means the patient is at higher risk for future MI, but her risk for cardiac death remains very low. The patient should receive aggressive medical therapy to reduce to risk of MI, but should not be referred for invasive coronary angiography and revascularization based on the low risk of cardiac death.


1. Roger VL, et al. Heart disease and stroke statistics—2011 update: A report from the American Heart Association. Circulation 2011;123:e18-e209.

2. Xu J, et al. Deaths: Final data for 2007. Hyattsville, Md: National Center for Health Statistics. Natl Vital Stat Rep 2010;58:1-135.

3. National Center for Health Statistics. Health Data Interactive. Available at: Accessed Dec. 14, 2012.

4. National Center for Health Statistics. HIST290A: Deaths for selected causes by 10-year age groups, race, and sex: Death registration states, 1900-32, and United States, 1933-98. Available at: Accessed Dec. 14, 2012.

5. National Center for Health Statistics. GMWK292F: Deaths for 358 selected causes by 5-year age groups, race, and sex: United States, 1999-2007. Available at: Accessed Dec. 14, 2012.

6. National Center for Health Statistics. Health, United States, 2009: With Special Feature on Medical Technology. Hyatsville, Md: National Center for Health Statistics; 2010. Available at: Accessed Dec. 14, 2012.

7. Clark J. A Visual Guide to the Human Anatomy: A Comprehensive Atlas of the Structures of the Human Body. New York: Sterling Publishing; 2001:119.

8. Virchow R. Phlogose und Thrombose in Gefasssystem, Gesammelte Abhandlungen zur Wissenschaftlichen Medicin. Frankfurt-am-Main, Meidinger Sohn and Co. 1856; p.458.

9. Rokitansky C. A Manual of Pathological Anatomy. Translated by: Day GE. London: The Sydenham Society; 1852:vol 4.

10. Duguid JB. Thrombosis as a factor in the pathogenesis of coronary atherosclerosis. J Pathol Bacteriol 1946;58:207.

11. Ross R, et al. The Pathogenesis of atherosclerosis. In: Braunwald E (ed.) Heart Disease: A Textbook of Cardiovascular Medicine. 4th ed. Philadelphia: WB Saunders Company; 1992:1113.

12. Ross R, et al. The Pathogenesis of atherosclerosis. In: Braunwald E (ed.) Heart Disease: A Textbook of Cardiovascular Medicine. 4th ed. Philadelphia: WB Saunders Company; 1992:1106.

13. Pasternak, et al. Acute myocardial infarction. In: Braunwald E (ed.) Heart Disease: A Textbook of Cardiovascular Medicine. 4th ed. Philadelphia: WB Saunders Company; 1992:1201.

14. Mieres JH, et al. Noninvasive cardiac imaging. Am Fam Physician 2007;75:1219-1228.

15. Schinkel AF, et al. Noninvasive evaluation of ischemic heart disease: Myocardial perfusion imaging or stress echocardiography? Eur Heart J 2003;24:789-800.

16. Schuif J, et al. Cardiac imaging in coronary artery disease: Differing modalities. Heart 2005;91:1110-1117.

17. Klocke FJ, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radio-nuclide imaging—Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging). Circulation 2003;108:1404-1418.

18. Cerqueira MD, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539-542.

19. American Society of Nuclear Cardiology. Imaging guidelines for nuclear cardiology procedures: Part 2. J Nucl Cardiol 1999;6:G47-G84.

20. Kawana M, et al. Use of 199-thallium as a potassium analog in scanning. J Nuc Med 1970;11:333.

21. Britten J, Blank M. Thallium activation of Na-K ATPase of rabbit kidney. Biochem Biophys Acta 1968;159:160-166.

22. Bradley-Moore PR, et al. Thallium-201 for medical use. II. Biological behavior. J Nuc Med 1976;16:156-160.

23. Strauss HW, et al. Thallium-201 for myocardial imaging-relationship of Thallium-201 to regional myocardial perfusion. Circulation 1975;51:641.

24. Zeissman HA, et al. Cardiac system. In: Thrall J (ed.) Nuclear Medicine: The Requisites in Radiology. 3rd ed. Philadelphia: Elsevier Mosby; 2006:450-507.

25. Taillefer R, et al. Comparative diagnostic accuracy Tl-201 and Tc-99m Sestamibi SPECT imaging (perfusion and ECG-Gated SPECT) in detecting coronary artery disease in women. J Am Coll Cardiol 1997;29:69-77.

26. Amanullah AM, et al. Identification of severe or extensive coronary artery disease in women by adenosine Technetium-99m Sestamibi SPECT. Am J Cardiol 1997;80:132-137.

27. Santana-Boado C, et al. Diagnostic accuracy of Technetium-99m SPECT in women and men. J Nucl Med 1998;39:751-755.

28. Garber AM, Solomo NA. Cost-effectiveness of alternative test strategies for the diagnosis of coronary artery disease. Ann Intern Med 1999;130:719-728.

29. Gianrossi R, et al. Exercise-induced ST depression in the diagnosis of coronary artery disease: A meta-analysis. Circulation 1989;80:87-98.

30. Boden WE, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;35:1503-1516.

31. Naghavi M, et al. From vulnerable plaque to vulnerable patient: A call for new definitions and risk assessment strategies: Part I. Circulation 2003;108:1664-1672.

32. Ambrose JA, et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988;12:56-62.

33. Little WC, et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation 1988;78:1157-1166.

34. Antman EM, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation 2004;110:588-636.

35. Keeley EC, et al. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomized trials. Lancet 2003;361:13-20.

36. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Lancet 1999;354:708-715.

37. Cannon CP, et al. Comparison early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofibian. N Engl J Med 2001;344:1879-1887.

38. Fox KA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: The British Heart Foundation RITA 3 randomised trial. Randomised Intervention Trial of unstable Angina. Lancet 2002;360:743-751.

39. Mehta SR, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: A collaborative meta-analysis of randomized trials. JAMA 2005;293:2908-2917.

40. Bobbio M, et al. Comparative accuracy of clinical tests for diagnosis and prognosis of coronary artery disease. Am J Cardiol 1988;62:896-900.

41. Morris CK, et al. The prognostic value of exercise capacity: A review of the literature. Am Heart J 1991;122:1423-1431.

42. Brown KA, et al. Prognostic value of exercise Thallium-201 imaging in patients presenting for evaluation of chest pain. J Am Coll Cardiol 1983;1:994-1001.

43. Abraham RD, et al. Prediction of multivessel coronary disease and prognosis early after acute myocardial infarction by exercise electrocardiography and Thallium-201 myocardial perfusion scanning. Am J Cardiol 1986;58:423-427.

44. Ladenheim ML, et al. Extent and severity of myocardial infarction as predictors of prognosis in patients with suspected coronary artery disease. J Am Coll Cardiol 1986;7:464-471.

45. Kemp HG, et al. Participants in the coronary artery surgery study. Seven year survival in patients with normal or near normal coronary arteriograms: A CASS registry study. J Am Coll Cardiol 1986;7:479-483.

46. Mock MB, et al. Participants in the coronary artery surgery study: Survival of medically treated patients in the Coronary Artery Surgery Study (CASS) registry. Circulation 1982;66:562-568.

47. Defeyter PJ, et al. Prognostic value of exercise testing, coronary angiography, and left ventriculography 6-8 weeks after myocardial infarction. Circulation 1982;66:527-536.

48. Califf RM, et al. Prognostic value of a coronary artery jeopardy score. J Am Coll Cardiol 1985;5:1055-1063.

49. Proudfit WJ, et al. Fifteen year survival study of patients with obstructive coronary artery disease. Circulation 1983;68:986-997.

50. Heo J, et al. Stress Thallium imaging. Am J Noninvasive Cardiol 1991;5:173-184.

51. Iskandrian AS, et al. Thallium imaging with single photon emission computed tomography. Am Heart J 1987;114:852-865.

52. Iskandrian AS, et al. Independent and incremental prognostic value of exercise single-photon emission computed tomographic (SPECT) Thallium imaging in coronary artery disease. J Am Coll Cardiol 1993;3:665-670.

53. Nallamothu N, et al. Utility of stress single-photon emission computed tomography (SPECT) perfusion imaging in predicting outcome after coronary artery bypass grafting. J Am Coll Cardiol 1997;80:1517-1521.

54. Berman DS, et al. Incremental prognostic value of and cost implications of normal exercise Tc-99m Sestamibi myocardial perfusion SPECT. J Am Coll Cardiol 1995;26:639-647.

55. Hachamovitch R, et al. Exercise myocardial perfusion SPECT in patients without known coronary artery disease: Incremental prognostic value and impact on subsequent patient management. Circulation 1996;93:905-914.

56. Ladenheim ML, et al. Incremental prognostic power of clinical history, exercise, electrocardiography, and myocardial perfusion scintigraphy in suspected coronary artery disease. Am J Cardiol 1987;59:270-277.

57. Pollock SG, et al. Independent and incremental prognostic value of tests performed in hierarchical order to evaluate patients with suspected coronary artery disease. Circulation 1992;85:237-248.

58. CASS Principle Investigators and their associates. Myocardial infarction and mortality in the coronary artery surgery study randomized trial. N Engl J Med 1984;310:750-758.

59. Alderman EL, et al. Ten-year follow-up of survival and myocardial infarction in the randomized coronary artery surgery study. Circulation 1990;82:1629-1646.

60. Detre KM, et al. Long term mortality and morbidity results of the veterans administration randomized trial of coronary artery bypass surgery. Circulation 1985;72(suppl V) V-84-V-89.

61. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996;335:217-225.

62. Manson JE, et al. A prospective trial of aspirin use and primary prevention of cardiovascular disease in women. JAMA 1991;265:521-527.

63. The Steering Committee of the Physicians’ Health Study Research Group. Preliminary eeport: Findings from the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1988;318:262-264.

64. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389.

65. Shepard J, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-1307.

66. Shaw LJ, et al. Prognostic value of normal exercise and adenosine 99mTc-Tetrofosmin SPECT imaging: Results from the multicenter registry of 4,728 patients. J Nucl Med 2003;44:134-139.

67. Berman DS, et al. Nuclear cardiology. In: Fuster V, et al. (eds.) Hurst’s: The Heart. 10th ed. New York: McGraw Hill; 2001:525-565.

68. Berman DS, et al. Risk stratification in coronary artery disease: Implications for stabilization and prevention. Am J Cardiol 1997;79:10-16.

69. Berman DS, et al. Separate acquisition rest Thallium-201/stress Technetium-99m Sestaimibi dual-isotope myocardial persusion single-photon emission computed tomography: A clinical validation study. J Am Coll Cardiol 1993;22:1455-1464.

70. Berman DS, et al. Incremental value of prognostic testing in patients with known or suspected ischemic heart disease: A basis for optimal utilization of exercise Technetium-99m Sestamibi myocardial perfusion single-photon emission computed tomography. J Am Coll Cardiol 1995;26:639-647.

71. Shaw LJ, et al. Noninvasive strategies for the estimation of cardiac risk: An observational assessment of outcome in stable chest pain patients. Am J Cardiol 2000;86:1-7.

72. Gibbons RJ, et al. Long-term outcome of patients with intermediate-risk exercise electrocardiograms who do not have myocardial perfusion defects on radionuclide imaging. Circulation 1999;23:2140-2145.

73. Iskander S, et al. Risk assessment using single-photon emission computed tomographic Technetium-99m Sestaimibi imaging. J Am Coll Cardiol 1998;32:57-62.

74. Hachamovitch R, et al. Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: Differential stratification for risk of cardiac death and myocardial infarction. Circulation 1998;97:535-543.

75. Fromer L. Appropriate use criteria for cardiac radionuclide imaging: Part I. J Fam Pract online Cardiowatch Issue 1. Available at: Accessed Dec. 14, 2012.

76. Einstein AJ, et al. Contemporary reviews in cardiovascular medicine: Radiation dose to patients from cardiac diagnostic imaging. Circ 2007;116:1290-1305.