In the past three decades, a great body of literature has established the use of radionuclide myocardial perfusion imaging (MPI), for risk stratification in patients with known or suspected coronary artery disease (CAD). The early studies have been reinforced and enhanced with the use of novel stress agents, modern single-photon emission tomography (SPECT) technologies, and the evolution of the appropriate use criteria (AUC). This chapter will review the use of stress radionuclide SPECT MPI for risk stratification in a general population and among patients with chronic CAD. Risk stratification for specific applications is discussed elsewhere in this book, including prior to major noncardiac surgery (Chapter 16), after therapeutic intervention (Chapter 17), in heart failure patients (Chapter 18), and for a variety of unique populations (Chapter 19).

Risk Assessment

Risk stratification is of crucial importance for the practice of contemporary medicine. Appropriate management of CAD should include the assessment of the individual risk of future cardiac events, particularly cardiac death and myocardial infarction (MI).¹ Extending the paradigm of noninvasive cardiac testing beyond the detection of disease is especially important, as risk assessment permits patient management decisions to be formulated on an evidence-based approach. Patients who are identified as being at high risk for subsequent cardiac events should be considered for aggressive management, including cardiac catheterization and revascularization procedures that may improve their outcome. Conversely, the management of low-risk patients should be focused toward aggressive medical therapy and risk factor modification,^2,3 thus reserving invasive procedures for patients who fail medical management. Additional testing in this low-risk group should generally be avoided, thereby minimizing cost. An outcome-based risk assessment model strives for improved patient outcome and avoidance of complications from unnecessary procedures, and is cost-effective.

Risk strata are often defined in many ways; but when related to CAD events, specifically nonfatal MI and cardiac death, an annual event rate of <1% is accepted as a low risk, while an annual event rate of >3% is considered high risk and an annual event rate between 1% and 3% is an intermediate risk.⁴

Risk can be defined using clinical parameters, namely cardiac risk factors⁵ and symptoms characterization, such as chest pain⁴ or dyspnea.⁶ However, risk assessment based only on clinical findings and resting ECG is often limited. Exercise tolerance test (ETT) without imaging and related risk indices, such as the Duke Treadmill Score, provide substantial prognostic value.⁷ Unfortunately, in contemporary practice, many patients cannot undergo ETT due to aging, obesity, and other limiting comorbidities. Moreover, using clinical data and the Duke Treadmill Score, most patients with suspected CAD would fall in an intermediate-risk group which may necessitate additional risk stratification.⁸

While coronary angiography is considered the “gold standard” for the diagnosis of CAD, it does not provide information about the physiologic significance of atherosclerotic disease, especially in borderline lesions (50–70% stenosis) or when the culprit lesion cannot be determined by angiography data alone.⁹ In fact, disparity often exists when comparing anatomic findings with physiologic data obtained with SPECT or fractional flow reserve (FFR).^9–15 Importantly, angiographic data do often not provide a clear marker of risk of adverse events, especially in patients with moderate disease severity.¹¹ However, functional information related to a coronary stenosis, including both noninvasive physiologic testing as well as invasive determinants of hemodynamic significance, is highly predictive of outcomes in patients with ischemic heart disease.^11–15

SPECT MPI is ideally suited for risk stratification among patients with known or suspected CAD (Table 15-1). This method detects ischemia and the presence of a scar, but importantly provides the physiologic significance of a known stenosis. In addition, it permits the determination of the location, extent, and severity of perfusion defects, which has important implications in clinical decision making. There is a clear association between the type of perfusion abnormalities and cardiac events, with reversible defects being associated with acute coronary syndromes and fixed abnormalities being predictive of death and heart failure.¹⁶ SPECT MPI may also predict functional recovery of myocardial contractility as discussed in Chapter 21.

Normal SPECT Imaging Study

The presence of a normal SPECT MPI study at a high level of stress (≥85% of maximum predicted heart rate) or adequate pharmacologic stress carries a benign prognosis, with mortality rate usually <1% per year. On the other hand, an abnormal perfusion study is associated with a multifold increase in the risk of nonfatal MI and/or cardiac death.^17,18 This finding has been reproduced in a multitude of studies in various clinical settings.^19–24 Pooling the results of SPECT imaging in >100,000 patients, Shaw and Iskandrian²⁴ demonstrated that the event rate (death or MI) for patients with normal MPI is 0.6% per year, whereas a moderate–severely abnormal study carries 5.9% per year event rate, an almost 10-fold increase in risk (Fig. 15-1). A meta-analysis of over 8000 patients demonstrated that a normal exercise SPECT MPI study had a negative predictive value of 98.8% and was associated with an annual event rate of 0.45%.²⁵ Moreover, a normal scan was associated with low rates of unstable angina and coronary revascularization.²⁵ Thus, a normal exercise stress SPECT MPI carries an excellent negative predictive value for adverse events.

The predictive value of SPECT MPI is independent of the radiopharmaceutical being used.^20,25 In a meta-analysis of published literature on prognostic value of normal SPECT MPI using various tracers (thallium-201 [Tl-201] and Tc-99m-sestamibi), Shaw et al.²⁰ confirmed similar excellent survival rates (99.3–99.7%) regardless of the radiopharmaceutical agent used. Similarly, the prognostic value of SPECT imaging is not dependent on the mode of stress. As with exercise SPECT, abnormal pharmacologic stress MPI is associated with several fold increase in risk compared to a normal scan. However, the risk of a cardiac event following a normal pharmacologic stress SPECT MPI is greater than the risk associated with normal exercise SPECT MPI^20,23,26; that is likely due to selection of patients with greater comorbidities and higher pretest likelihood of disease for pharmacologic stress.^27,28 In other high-risk groups, such as the elderly and patients with diabetes, established CAD, or end-stage renal disease, a normal MPI still predicts lower risk than abnormal MPI. However, a normal scan in these patient populations carries greater risk than a normal scan in patients without these comorbidities.^28–32

The favorable outcome associated with normal SPECT MPI has not only been demonstrated with exercise stress, but also with dipyridamole,^16,33,34 adenosine,^20,35,36 and dobutamine^26,37,38 stress modalities. Recent data with regadenoson (a selective A2A-adenosine receptor agonist), indicated that normal regadenoson SPECT MPI portrays low risk of adverse cardiac events, similar to normal adenosine MPI.³⁵ More recently, perfusion abnormalities produced by regadenoson has been shown to carry similar prognostic information to adenosine stress.^35,39 Furthermore, the excellent prognostic value of normal SPECT MPI has been demonstrated not only in tertiary care centers, but also in community-based cardiology and primary care office settings.^22,36

When stress methods are combined, such as vasodilator stress with symptom-limited exercise, SPECT imaging permitted stratification of >2000 patients into low-, intermediate-, and high-risk groups on the basis of their functional capacity, perfusion defects, left ventricular ejection fraction (LVEF), and the presence or absence of transient ischemic dilation (TID).⁴⁰ The benign prognosis associated with a normal SPECT study appears to persist even in patients with positive ETT or angiographically significant coronary disease.^41,42 However, if an abnormal ECG response is noted with the infusion of dobutamine, adenosine, or regadenoson; the risk associated with a normal study increases significantly, suggesting that such patients should not be considered low risk.^26,43–45 Despite this increase in risk, patients with abnormal ECG response to pharmacologic stress and normal MPI are generally at lower risk than those with abnormal MPI.⁴⁵

Most of the prognostic data for SPECT MPI were derived from conventional scintillation Anger cameras. However, the robust risk stratification value for SPECT MPI has been reproduced using modern SPECT cameras. A major recent advancement in SPECT technology has been the advent of cadmium-zinc-telluride (CZT) cameras, which implement semiconductors in photon detection. This and other recent advances in SPECT technology, such as modern attenuation correction methods (CT or fluorescence x-ray), cardiocentric collimation, and resolution recovery software, allow for marked improvement in count statistics, and special resolution. In a recent study in over 2000 patients, Oldan et al.⁴⁶ demonstrated that, compared to conventional Anger camera, images produced by modern CZT camera have a similar prognostic value in predicting events of death and MI. Therefore, the vast accumulated wealth of prognostic SPECT MPI data are applicable to CZT SPECT technology.^46,47

Although the excellent prognostic value of SPECT MPI has been established based on conventional rest–stress protocols, data published in the past decade clearly demonstrated that normal stress-only SPECT scan carries similar excellent prognostic value. Chang et al.⁴⁸ analyzed data from over 16,000 patients and found that the mortality rates for patients with normal stress-only versus rest–stress protocols are similar, but patients who underwent stress-only imaging had a 61% reduction in radiation dose. Similarly in a cohort of over 10,000 patients, Duvall et al.⁴⁹ demonstrated that in patients with low pretest probability for CAD, the prognostic value of a negative stress-only MPI was similar to that of a rest–stress MPI protocol. Based on these findings, a stress-only protocol for appropriate patients is an option to consider in an effort to reduce radiation exposure and improve patient experience with the test.

In summary, the excellent prognostic value of a normal or near-normal stress myocardial perfusion study has been confirmed in numerous investigations using various radiopharmaceuticals and differing stress modalities.^{10,16,17,19,20,26,36,38,50–56} These findings have been noted in different subsets of patients regardless of race,⁵⁷ clinical setting,^22,36 or CAD status,⁵⁸ and in important patient subgroups, including diabetics and women; these unique cohorts will be discussed in Chapter 19.

Abnormal SPECT Scan

An abnormal SPECT MPI study conveys a multifold increase in the risk of subsequent cardiac events compared to a normal scan. However, the presence of a perfusion defect is but one of the many variables that may provide important prognostic information (Table 15-2). The increased risk associated with abnormal MPI, compared to a normal scan, has been shown to be sustained for more than a decade after testing.^31,32,37,59

The value of radionuclide MPI comes from its ability to identify and quantify the size and severity of scintigraphic abnormalities during stress, and thus place patients in more defined risk categories. The size of the perfusion abnormality provides powerful prognostic information and has been shown to directly relate to outcome,^{21,50,60–63} as the larger the perfusion abnormality, the higher the mortality rate.^61–71 Ladenheim et al.⁶¹ have demonstrated that the magnitude of ischemia (severity and extent) correlates well with cardiac events, and this relationship is not linear, but exponential (Fig. 15-2). Vanzetto et al.⁵⁰ have also shown a correlation between event rate (death, nonfatal MI, and revascularization) and the extent of ischemia, quantified by the number of ischemic segments on SPECT scan. Hage et al.³⁹ replicated these findings with regadenoson, demonstrating a stepwise increase in cardiac event rates with increasing percent myocardium affected by perfusion abnormalities. Moreover, among patients with dyspnea, the defect size correlates with mortality, as patients with a normal MPI study had 80% fewer events of death than those with severe perfusion defect.⁶⁴

Even among asymptomatic patients without a prior diagnosis of ischemic heart disease, the presence of an ischemic defect of at least 7.5% of the myocardium identified a high-risk marker for cardiac death or MI.⁶⁵ This was confirmed in a second study of moderate-risk asymptomatic patients, which demonstrated a relationship between survival and the burden of perfusion abnormality by SPECT.⁶⁶

Several studies have demonstrated that defect reversibility is an important predictor of type of cardiac events, as fixed perfusion defects are associated with cardiac death, whereas reversible perfusion defects are associated with nonfatal MI.^16,18,62,67 An examination of 7849 patients confirmed that the extent of ischemia correlated with event rates.⁶⁷ Moreover, Shaw et al.⁶⁷ demonstrated that resting perfusion defects also convey important prognostic information, as for each 1% defect on a rest study, there was a corresponding 3% increase in cardiac events. Rest defects also inversely correlated with LVEF. Overall, there is a synergy between rest and reversible defects, with both contributing to risk for subsequent cardiac events. Therefore, stress perfusion studies should be reported documenting defect severity (mild, moderate, and severe), size (small, moderate, and large), and reversibility in order to provide essential risk stratification information.⁷² Moreover, Hachamovitch et al.⁶² demonstrated a difference in the type of events predicted based on varying severity/extent of perfusion defects. As shown in Figure 15-3, a mildly abnormal study was associated with a very low mortality rate (0.8%) but a slightly higher risk of nonfatal MI (2.7%) than a normal scan (0.5%). In contrast, the most common event in patients with severe perfusion abnormalities was found to be cardiac death, not MI. These findings have important management implications, as coronary artery bypass grafting and percutaneous coronary intervention have not been shown to reduce the rates of nonfatal MI, whereas statins effectively reduce event rate of death and MI. Thus, medical therapy such as statins and angiotensin-converting enzyme inhibitors, rather than revascularization procedures, should be the mainstay in the management of patients with mildly abnormal MPI.^68,73,74

Hachamovitch et al.⁶⁹ further extended the predictive value of SPECT MPI by demonstrating that the burden of inducible ischemia is not only predictive of event-free survival, but may also indicate whether medical therapy or coronary revascularization should be undertaken. A survival advantage was shown in patients with no or mild ischemia (<10% ischemic myocardium) undergoing medical therapy while those with moderate or severe ischemia (>12.5% ischemic myocardium) had a survival benefit with coronary revascularization, as compared with medical therapy alone (Fig. 15-4).

The use of optimal medical therapy as the mainstay of management in patients with mild perfusion abnormality is supported by the COURAGE trial which did not demonstrate an overall benefit from PCI beyond optimal medical therapy.⁶⁸ However, the nuclear substudy of the COURAGE trial suggests that among patients with moderate–severe ischemia on SPECT MPI, those treated with PCI in addition to optimal medical therapy had a greater reduction of ischemic events (33%) than medical therapy alone (19%).⁷⁵ The ISCHEMIA trial, which is an ongoing multicenter, randomized controlled trial planning to enroll 8000 patients with at least moderate ischemia on stress imaging, will compare a routine invasive strategy with complete revascularization when feasible versus optimal medical therapy only; it is the hope that this trial will provide evidence to help guide management in patients with stable ischemic heart disease.

Incremental Prognostic Value

The prognostic value of the SPECT scan is not simply a substitute but a valuable addition to prognostic data derived from clinical findings or stress testing. Iskandrian et al.⁷⁰ and others^{50,71,76–78} have shown the additive value of SPECT MPI to clinical data and ETT, especially if the burden of perfusion abnormalities is taken into account.⁵⁰ The incremental prognostic value has been confirmed using various stress modalities, radiopharmaceutical agents, and protocols.^8,58,79–84 In a cohort of 2200 patients, Hachamovitch et al.⁸ demonstrated that gated SPECT provided additional prognostic information irrespective of Duke Treadmill Score risk category (high, intermediate, and low). The added prognostic value of SPECT was most notable in the intermediate Duke Treadmill Score (55% of the cohort), in whom MPI effectively separated between low-risk patients with normal perfusion and high-risk patients with abnormal perfusion.⁸ However, the added prognostic value of MPI in patients with low-risk Duke Treadmill Score was modest, as most of these patients had normal- or low-risk scan with low event rates. On the other hand, the added prognostic value of MPI in patients with high-risk Duke Treadmill Score was also limited, as these patients had increased event rates, irrespective of MPI.⁸ Thus, MPI provides the highest incremental prognostic value in patients who are not fully risk stratified by ETT. Based on these observations, Bourque et al.⁸⁵ prospectively examined the incremental diagnostic yield of MPI in a cohort of 1056 patients on the basis of workload achieved during ETT. Among 430 patients who reached a workload of ≥10 METs without exercise-induced ST-segment depression, none had ≥10% left ventricular (LV) ischemia. In contrast, the prevalence of ≥10% LV ischemia was highest in the patients achieving <10 METs with ST-segment depression (19.4%).⁸⁵ In a separate investigation, the same group demonstrated that in patients at intermediate risk for CAD or with known CAD, achieving ≥10 METs is associated with very low rates of cardiac mortality (0.1% per year) and nonfatal MI (0.3% per year), irrespective of heart rate achieved. These results suggest that patients who attain ≥10 METs during ETT have an excellent intermediate-term prognosis, regardless of peak exercise heart rate achieved. Thus, the added value of MPI to standard exercise ECG testing in this population is limited.⁸⁶ Based on the aforementioned findings, these investigators proposed a provisional SPECT MPI imaging protocol, in which patients undergoing exercise stress MPI would receive the stress radiotracer injection only if they fail to achieve ≥10 METs or if they develop ischemic ST-segment changes.⁸⁷ However, deploying such protocol in the clinical setting possesses some logistic and financial challenges.

Moreover, SPECT perfusion imaging is a better predictor of cardiac events than cardiac catheterization.^60,70 SPECT MPI, when added to stress and clinical data, has shown a greater incremental prognostic value than cardiac catheterization, which in fact failed to produce incremental information beyond MPI.⁷⁰ In fact, multiple studies have demonstrated excellent correlation between MPI and invasive assessment of coronary physiology, such as coronary flow reserve, relative coronary flow velocity reserve, and FFR.^88–93 Even when angiographically insignificant disease is noted, the presence of an abnormal perfusion study is associated with a worse outcome, suggesting that these findings do not necessarily indicate a “false-positive” result, but rather a dissociation between anatomy and physiology.^12,94 On the other hand, Yokota et al.⁹⁵ investigated “false-negative” SPECT MPI in selected patients who underwent coronary angiography after normal MPI; of those, 36% had significant CAD (≥70% or ≥50% left main stenosis). The majority of patients with significant CAD had single vessel disease. Left main or three vessel disease, causing “balanced ischemia,” is a less common cause of false-negative MPI. Irrespective of the underlying coronary anatomy, the prognostic value of normal SPECT MPI remains excellent. The patients analyzed in the report by Yokota et al. were selected to undergo coronary angiography despite normal MPI, likely due to ominous clinical presentation.

The incremental value of physiologic assessment in predicting outcome and guiding revascularization decisions has been confirmed in the FAME trials.^9,11,14 In these trials, the physiologic significance of coronary lesions was assessed using FFR, which is a calculated ratio of the measured pressure distal to a coronary lesion to the pressure proximal to the lesion during vasodilator-induced hyperemia (typically with adenosine). An FFR ≤0.8 is considered to represent significant ischemia. In the FAME trial, patients who were randomized to undergo an FFR-guided PCI had a significant reduction in the composite end point of death, nonfatal MI, and repeat revascularization compared to patients randomized to PCI guided by angiography alone.^9,14 In the FAME II trial, patients with CAD and significant coronary stenosis (FFR ≤0.80), FFR-guided PCI plus best medical therapy decreased the composite end point of death, nonfatal MI, or urgent revascularization, as compared with the best medical therapy alone. In patients without significantly reduced FFR (>0.80), the outcome appeared to be favorable with the best medical therapy alone.¹¹ These trials confirmed the incremental prognostic and decision-making value of physiologic data derived from MPI which were established nearly two decades earlier. These studies and others indicate that, in patients with stable CAD, physiologic information, such as MPI, remains the main gatekeeper to coronary revascularization rather than purely anatomic data derived from invasive and noninvasive coronary angiography.^{12,69,96–98}

SPECT MPI delivers incremental prognostic value even when used in conjunction with vasodilator stress testing.^94,99 The prognostic value of vasodilator MPI can be further enhanced by incorporating MPI data into a risk score that encompasses patient’s age, heart rate, ECG findings, the presence of dyspnea, and the percentage of ischemic and scarred myocardium.⁹⁹ In a study of 5873 subjects undergoing adenosine stress SPECT MPI, this prognostic score successfully placed patients into low-, intermediate-, and high-risk categories, with observed cardiac death rates of 0.9%, 3.3%, and 9.5%, respectively. This score was superior to SPECT data alone and is likely useful in subsequent decision making.⁹⁹ The aforementioned score has not been validated for other vasodilator stress agents.

Left Ventricular Dysfunction

The availability of Tc-99m–based agents (i.e., Tc-99m sestamibi and Tc-99m tetrofosmin) has facilitated the widespread use of ECG-gated acquisition of myocardial perfusion studies. Gated SPECT allows the evaluation of global and regional wall motion and an accurate computation of LVEF.^78,100 The assessment of global and regional myocardial contractility not only increases the specificity of SPECT MPI,^101–103 but also provides incremental prognostic value.^71,104 Sharir et al.⁷¹ demonstrated an incremental prognostic value of LVEF when added to SPECT perfusion imaging data. In this study, LVEF <45% or an end-systolic volume of >70 mL was independently predictive of adverse outcome irrespective of the severity of perfusion abnormalities (Fig. 15-5). Similarly, in an evaluation of gated SPECT imaging in a community setting, for every 1% decrease in LVEF, there was an increase in the cardiac event rate.²² Furthermore, Emmett et al.⁵⁶ demonstrated that reversible regional wall motion abnormalities in patients undergoing exercise stress Tc-99m–gated SPECT MPI were highly specific for severe coronary stenosis and correlated well with CAD anatomy. Even when the LVEF is preserved, poststress regional wall motion abnormalities are incrementally predictive of cardiac death and MI to reversible perfusion defects alone.¹⁰⁵ The drop in poststress LVEF is considered to represent myocardial stunning or severe and extensive subendocardial ischemia.^106,107 This phenomenon has been observed not only with exercise but also with vasodilator stress.^56,108–112 The mechanism of myocardial stunning with vasodilator stress is not entirely understood, as these agents do not increase myocardial oxygen demand.^107,113,114 It is likely that ischemia with vasodilator stress is mediated by coronary steal phenomenon, since it is often associated with ST-segment shifts.⁴⁵ Irrespective of the mechanism, a drop in LVEF or stress-induced regional wall motion abnormalities has been generally correlated with extensive CAD and poor outcome.

A recent software innovation in gated SPECT applications has been the advent of phase analysis for the assessment of LV mechanical dyssynchrony. The degree of heterogeneity in the distribution of these time intervals (phase standard deviation) and the time during which 95% of the LV pixels initiate contraction (phase bandwidth) serve as measures of LV dyssynchrony.¹¹⁵ Measures of LV mechanical dyssynchrony have been shown to provide additional prognostic value in patients with heart failure as well as asymptomatic patients with end-stage renal disease under evaluation for renal transplant.^116,117

Transient Ischemic Dilation (also known as Transient Cavity Dilation)

TID is the appearance of a larger LV cavity volume on the poststress perfusion images when compared with the resting study. TID is expressed as a ratio of the stress-to-rest LV volumes. It is thought to be predominantly due to stress-induced subendocardial myocardial hypoperfusion leading to the appearance of cavity dilation (Fig. 15-6).¹¹⁸ Other proposed mechanisms include poststress myocardial stunning and actual LV dilation.¹¹⁸ However, a true stress-induced cavity dilation is rare, as the stress scan is acquired 20 to 60 minutes poststress (with Tc-99m radiotracers), by which time true ischemic dilation typically resolves.^118,119 Notably, TID can be produced by several disease processes other than CAD, as it has been reported with conditions associated with elevated end-diastolic pressure such as hypertensive heart disease, aortic stenosis, and hypertrophic cardiomyopathy. It is hypothesized that elevated LV end-diastolic pressure is a culprit for subendocardial ischemia (without CAD) leading to the appearance of TID.^112,118,120 Thus, some experts prefer using the term “transient cavity dilation,” as not all cases of “TID” are due to ischemia or CAD.