Appropriate Use Criteria for PET Myocardial Perfusion Imaging

Clinical Scenarios 1–15

The following scenarios address patients presenting a low pretest probability of CAD:

• Scenario 1: Low pretest probability for CAD, with an interpretable  electrocardiogram (ECG) and where the patient is able to undergo adequate exercise stress (Score 2 – Rarely Appropriate)

• Scenario 2: Low pretest probability of CAD, ECG uninterpretable  or unable to exercise (Score 3 – Rarely Appropriate)

• Scenario 3: Low pretest probability for CAD, with an uninterpretable  ECG (Score 3 – Rarely Appropriate)

• Scenario 4: Low pretest probability for CAD, where the patient  is unable to undergo adequate exercise stress (Score 3 – Rarely Appropriate)

The following scenarios address patients presenting an intermediate pretest probability of CAD:

• Scenario 5: In symptomatic patients with intermediate pretest  probability for CAD, where ECG is interpretable and where the patient is able to undergo adequate exercise stress (Score 7 – Appropriate)

• Scenario 6: Intermediate pretest probability for CAD, where  ECG is uninterpretable (Score 9 – Appropriate)

• Scenario 7: Intermediate pretest probability for CAD, where the  patient is unable to undergo adequate exercise stress (Score 9 – Appropriate)

The following scenarios address patients presenting a high pretest probability of CAD:

• Scenario 8: In symptomatic patients with high pretest probability  for CAD, where ECG is interpretable and where the patient is able to undergo adequate exercise stress (Score 8 – Appropriate)

• Scenario 9: High pretest probability for CAD, where ECG is  uninterpretable (Score 9 – Appropriate)

• Scenario 10: High pretest probability for CAD, where the patient  is unable to undergo adequate exercise stress (Score 9 – Appropriate)

The following scenarios address symptomatic patients presenting to the emergency department (ED) (or inpatients) with acute coronary syndrome (ACS) features:

• Scenario 11: Patients presenting to the ED (or inpatients) with  symptoms suspicious for CAD without (or with) known CAD who have features consistent with non–ST elevation myocardial infarction (non-STEMI)/ACS (increase in troponin (Tn) level(s) or dynamic ECG changes) (Score 1 – Rarely Appropriate)

• Scenario 12: Patients presenting to the ED (or inpatients) with symp toms suspicious for CAD without (or with) known CAD who have features consistent with unstable angina/ACS (no increase in Tn level(s), no dynamic ECG changes) (Score 7 – Appropriate)

The following scenario addresses patients presenting to the ED (or inpatients) with chest pain or equivalent symptoms without (or with) known CAD who have equivocal Tn level(s) or a temporal Tn pattern not consistent with ACS:

• Scenario 13: Patients presenting to the ED (or inpatients) with  chest pain or equivalent symptoms without (or with) known CAD who have equivocal Tn level(s) or a temporal Tn pattern not consistent with ACS (Score 8 – Appropriate)

The following scenario addresses patients presenting to the ED (or inpatients) with symptoms of chest pain that may be due to ACS, with normal Tn level(s) and no dynamic ECG changes:

• Scenario 14: Patients presenting to the ED (or inpatients) with  symptoms of chest pain that may be due to ACS, normal Tn level(s) and no dynamic ECG changes (Score 8 – Appropriate)

The following scenario addresses patients presenting to the ED (or inpatients) with symptoms of chest pain that is unlikely to be due to ACS, with normal Tn level(s) and no dynamic ECG changes:

• Scenario 15: Patients presenting to the ED (or inpatients) with symp toms of chest pain that is unlikely to be due to ACS, normal Tn level(s) and no dynamic ECG changes (Score 7 – Appropriate)

The preceding scenarios evaluate the role of MPI PET in the management of symptomatic patients with suspected or known CAD (scenarios 1–10) or who present to the ED (scenarios 11–15).

In symptomatic patients with suspected or known CAD, scintigraphic MPI such as with PET (PET MPI) is best performed for risk stratification with a clinically intermediate risk of subsequent cardiac events (1,4,5,26–28). This also relates to the optimal application of PET MPI to patients with an intermediate likelihood of having CAD. Critical determinants of outcome in patients with CAD can be determined by stress-related myocardial perfusion and function (26,27,29,30). Although indices that determine the extent of LV dysfunction (LVEF, the extent of infarcted myocardium, transient ischemic dilation of the left ventricle, and increased radiotracer uptake in the lungs) are relevant predictors of cardiac mortality, parameters related to ischemia induction (exertional symptoms, ECG alterations, extent and severity of reversible perfusion deficits, and ventricular wall motion abnormalities) are independent predictors of acute ischemic syndromes (26,28–32). PET MPI, in particular, affords the advantage of high diagnostic accuracy, concurrent evaluation of myocardial perfusion (radiotracer uptake) and regional MFR, and wall motion assessment at peak pharmacologic stress (2,8,10,26,33–39). This enables the accurate identification and description of the extent and severity of stress-induced ischemia in individuals with suspected CAD and intermediate and high pretest probability. In addition, the concurrent assessment of regional and global hyperemic MBF and MFR enables the detection and characterization of flow-limiting effects of each single vessel in multivessel disease (2,4–8,10,11,40–46), and reductions in global MFR also convey important and incremental prognostic information in patients with and without obstructive CAD (2,3,7,14,26,39,46–48).

In symptomatic patients with suspected CAD but low pretest probability in scenarios 1–4, the application of PET MPI in general is rarely appropriate after standard clinical practice guidelines (27,28). Conversely, for scenarios 5–7 in the category of intermediate pretest probability for CAD, the performance of PET MPI has been judged as appropriate in accordance with standard clinical practice in scintigraphic MPI (27,28). In patients with high pretest probability for CAD, who have an uninterpretable ECG and are able or unable to exercise, PET MPI was seen as appropriate (scenarios 8–10) according to standard clinical practice in MPI (27,28).

In symptomatic patients who present to the ED (or inpatients) with ACS features that are consistent with non-STEMI or ACS (increase in Tn levels or dynamic ECG changes) (scenario 11), MPI PET is not indicated, as these patients are at high risk and, thus, they are commonly referred to further triage with invasive coronary angiography and potential intervention according to standard clinical practice (49,50). In scenario 12, this group of patients with some type of unstable angina or ACS and with positive Tn results but with neither an increase in Tn levels later nor dynamic ECG changes, PET MPI was seen as appropriate for further cardiovascular risk stratification and triage of the patient (27,28,32,49–54).

Scenarios 13–15 address the role of PET MPI in patients who present to the ED (or inpatients) with chest pain or equivalent symptoms with or without known CAD who have equivocal Tn levels or a temporal Tn pattern not consistent with ACS (scenario 13); patients who present to the ED (or inpatients) with symptoms of chest pain that may be due to ACS, with normal Tn levels and no dynamic ECG changes (scenario 14); and patients who present to the ED (or inpatients) with symptoms of chest pain that are unlikely to be due to ACS, with normal Tn levels and no dynamic ECG changes (scenario 15). Given the clinical constellation and standard clinical practice (27,28,32,49–54), these scenarios were seen as appropriate.

Clinical Scenarios 16–25: Asymptomatic Patients (Without Symptoms or Ischemic Equivalent) by Pretest CAD Risk

• Scenario 16: Asymptomatic patients with a low ASCVD risk  (<7.5%) (Score 1 – Rarely Appropriate)

• Scenario 17: Asymptomatic patients with an intermediate ASCVD  risk (7.5%–20%), who have an interpretable resting ECG and are able to exercise (Score 2 – Rarely Appropriate)

• Scenario 18: Asymptomatic patients with an intermediate ASCVD  risk (7.5%–20%), who have an uninterpretable resting ECG or are unable to exercise (Score 5 – May be Appropriate)

• Scenario 19: Asymptomatic patients with a high ASCVD risk  (>20%) (Score 5 – May be Appropriate)

• Scenario 20: Asymptomatic patients with an intermediate ASCVD  risk (7.5%–20%), who have a calcium score of 400–1,000 (Score 6 – May be Appropriate)

• Scenario 21: Asymptomatic patients with a high ASCVD risk  (>20%), who have a calcium score of 400–1,000 (Score 8 – Appropriate)

• Scenario 22: Asymptomatic patients who have a calcium score  of >1,000 (Score 8 – Appropriate)

• Scenario 23: Asymptomatic patients with peripheral vascular  disease (Score 5 – May be Appropriate)

• Scenario 24: Asymptomatic patients with a family history of  premature CAD (Score 3 – Rarely Appropriate)

• Scenario 25: Asymptomatic patients with familial hyperlipidemia  (Score 5 – May be Appropriate)

PET was rated as rarely appropriate in asymptomatic patients with a low (<7.5%) or intermediate ASCVD risk (7.5%–20%) if they have an interpretable resting ECG (e.g., left bundle branch block [LBBB], paced rhythm, Wolff-Parkinson-White changes) and are able to exercise (scenarios 16 and 17). In keeping with other modalities, the use of PET was rated as may be appropriate in patients with an intermediate ASCVD risk who have an uninterpretable resting ECG or who are unable to exercise, as well as in those with a high ASCVD risk (>20%) (scenarios 18 and 19). Regarding asymptomatic patients with prior coronary artery calcium (CAC) scoring, the use of PET was rated as may be appropriate in patients with an intermediate ASCVD risk and a CAC score of 400–1,000 (scenario 20). However, PET MPI was rated as appropriate in patients with a high ASCVD risk (>20%) and a CAC score of 400–1,000 or a very high CAC score (>1,000) regardless of clinical risk (scenarios 21 and 22). This rating was based on the fact that the presence of an elevated CAC score (>400) increases the likelihood of obstructive CAD and risk of events, especially in patients with multiple coronary risk factors with a high ASCVD risk. The use of PET in patients with a history of peripheral vascular disease (e.g., stroke) or familial hyperlipidemia was rated as may be appropriate because their clinical ASCVD risk is high (scenarios 23 and 25). However, a family history of premature CAD without any other risk qualifier was rated as rarely appropriate (scenario 24) (28,56–66).

Clinical Scenarios 26–33: Asymptomatic Patients with Equivocal or Abnormal Prior Test Results

• Scenario 26: Asymptomatic patients with equivocal or abnormal  prior test results from coronary CT angiography (CCTA) or invasive coronary angiography (ICA) (Score 8 – Appropriate)

• Scenario 27: Asymptomatic patients with recent (<90 d) equivocal  or abnormal prior test results from stress testing (imaging or nonimaging) (Score 6 – May be Appropriate)

• Scenario 28: Asymptomatic patients with regional or global LV  systolic dysfunction (Score 8 – Appropriate)

• Scenario 29: Asymptomatic patients with new LBBB (Score 8 –  Appropriate)

• Scenario 30: Asymptomatic patients with atrial fibrillation (AF)  (Score 5 – May be Appropriate)

• Scenario 31: Asymptomatic patients with abnormal resting  ECG results that show abnormal or pathologic Q waves (Score 6 – May be Appropriate)

• Scenario 32: Asymptomatic patients with abnormal resting ECG  results that show ST-T segment abnormalities (Score 5 – May be Appropriate)

• Scenario 33: Asymptomatic patients with known stable CAD with out prior revascularization (Score 6 – May be Appropriate)

The use of PET was considered appropriate in patients with equivocal or abnormal coronary angiography (CCTA or ICA) results, regional or global LV dysfunction, or new LBBB (scenarios 26, 28, and 29). PET imaging was rated as may be appropriate in asymptomatic patients with recent (<90 d) abnormal or equivocal stress testing with or without imaging, as well as in those with atrial fibrillation (AF), abnormal resting ECG results showing pathologic Q waves or ST-T segment abnormalities, or stable CAD without prior revascularization (scenarios 27, 30–33) (28,67–71).

Clinical Scenarios 34–37: Asymptomatic Patients with Prior Revascularization (Percutaneous Coronary Intervention [PCI] or Coronary Artery Bypass Graft [CABG])

The following scenarios address asymptomatic patients with a history of PCI:

• Scenario 34: Asymptomatic patients with a history of PCI of  <2 y (Score 2 – Rarely Appropriate)

• Scenario 35: Asymptomatic patients with a history of PCI of  >2 y (Score 6 – May be Appropriate)

• The following scenarios address asymptomatic patients with a prior CABG.

• Scenario 36: Asymptomatic patients with a prior CABG of <5 y  (Score 2 – Rarely Appropriate)

• Scenario 37: Asymptomatic patients with a prior CABG of >5 y  (Score 6 – May be Appropriate)

In keeping with the prior multimodality AUC document, the use of PET in asymptomatic patients with a history of prior PCI (<2 y) or CABG (<5 y) was considered rarely appropriate. However, PET MPI was rated as may be appropriate for asymptomatic patients >2 y after PCI or >5 y after CABG (scenarios 34–37) (28,61).

Clinical Scenario 38: Asymptomatic Patients with Prior Heart Transplantation

• Scenario 38: Evaluation for CAV in asymptomatic patients with  prior heart transplantation (Score 8 – Appropriate)

Annual surveillance to assess the presence and severity of CAV is the current standard of care after orthotopic heart transplantation. Although the current standard for CAV screening is ICA, it is considered inadequate because of its low yield and limited sensitivity to detect diffuse CAV. In addition, it is a costly, invasive procedure with a low but measurable risk for complications that is associated with relative contraindications in many patients transferred from outside the hospital because of the high prevalence of renal dysfunction. Noninvasive imaging modalities such as dobutamine stress echocardiography and SPECT MPI are relatively insensitive for the detection of CAV. Recent evidence supports a unique role for quantitative PET imaging for CAV screening with high accuracy. In keeping with this evidence, the workgroup rated the use of PET MPI for CAV screening as appropriate (scenario 38) (68,72–75).

Clinical Scenario 39: Asymptomatic Patients Being Considered for Solid Organ Transplantation (Kidney, Lung, Liver)

• Scenario 39: Evaluation for CAD in patients being considered  for solid organ transplantation (e.g., kidney, lung, liver) (Score 8 – Appropriate)

Although coronary revascularization before noncardiac surgery has not been shown to reduce the risk of cardiac events, preoperative noninvasive screening for obstructive CAD is commonly performed among patients who are candidates for solid organ transplantation. The rationale for such testing in these candidates includes the need to determine the perioperative risk and whether the patient’s cardiovascular risk is high enough that organ transplantation would be futile and lead to an inappropriate use of a scarce organ. Given the high sensitivity of quantitative PET MPI for detection of obstructive CAD, the workgroup rated its use in this group of patients as appropriate (scenario 39) (76).

Clinical Scenarios 40 and 41: Asymptomatic Patients Undergoing Cancer Treatment

• Scenario 40: Asymptomatic patients during or after chemotherapy  or radiation therapy for cancer who have a reduced LVEF (Score 5 – May be Appropriate)

• Scenario 41: Asymptomatic patients during or after chemotherapy  or radiation therapy for cancer (Score 1 – Rarely Appropriate)

The use of PET MPI in patients with cancer before or during chemotherapy or radiation therapy was rated as may be appropriate in asymptomatic patients with new LV dysfunction (scenario 40). This was predicated on the fact that radiotherapy and newer chemotherapeutic drugs may cause accelerated progression of atherosclerosis. However, its use in patients with normal LV function was rated as rarely appropriate (scenario 41) (68).

Clinical Scenarios 42 and 43: Asymptomatic Patients with a History of Coronary Vasculitis or High-Risk Coronary Anomalies

• Scenario 42: Asymptomatic patients with a history of coronary  vasculitis and evidence of structurally abnormal coronary arteries (e.g., aneurysms) (Score 7 – Appropriate)

• Scenario 43: Asymptomatic patients with a history of high-risk  coronary anomalies (Score 5 – May be Appropriate)

The use of PET MPI in asymptomatic patients with a history of coronary vasculitis (e.g., Kawasaki disease) and evidence of structurally abnormal coronary arteries (e.g., coronary obstruction or aneurysms) was rated as appropriate (scenario 42). The use of PET MPI in patients with high-risk coronary anomalies was rated as may be appropriate, especially if it can be performed with exercise stress testing (scenario 43) (77–79).

Clinical Scenarios 44–46: Patients with Diagnosed Heart Failure with Reduced Ejection Fraction

• Scenario 44: Patients with diagnosed heart failure with reduced  ejection fraction, no established history of CAD, and a low clinical risk of CAD: stress and rest perfusion PET (Score 7 – Appropriate)

• Scenario 45: Patients with diagnosed heart failure with reduced  ejection fraction, no established history of CAD, and an intermediate clinical risk of CAD: stress and rest perfusion PET (Score 9 – Appropriate)

• Scenario 46: Patients with diagnosed heart failure with reduced  ejection fraction, no established history of CAD, and a high clinical risk of CAD: stress and rest perfusion PET (Score 8 – Appropriate)

Ischemic heart disease is an important cause of heart failure with reduced ejection fraction. Patients without established CAD may, in many cases, warrant workup for ischemic causes, although this will vary depending on the clinical risk of CAD, which includes the presence of angina (71). In some cases, stress testing has been felt to be insufficiently sensitive to rule out ischemic causes for heart failure in patients with a higher clinical risk (i.e., insufficient negative predictive value). However, the greater sensitivity of stress perfusion PET, which is always combined with some form of attenuation correction, leading to a higher specificity, led the panel to rate this test as appropriate across the entire spectrum of risk. Notably, the addition of quantification of MBF and flow reserve will further improve the sensitivity and negative predictive value.

Clinical Scenarios 47–49: Patients with Newly Diagnosed Heart Failure with Preserved Ejection Fraction (HFpEF)

• Scenario 47: Patients with diagnosed HFpEF, no established  history of CAD, and a low clinical risk of CAD: stress and rest perfusion PET (Score 5 – May be Appropriate)

• Scenario 48: Patients with diagnosed HFpEF, no established  history of CAD, and an intermediate clinical risk of CAD: stress and rest perfusion PET (Score 9 – Appropriate)

• Scenario 49: Patients with diagnosed HFpEF, no established  history of CAD, and a high clinical risk of CAD: stress and rest perfusion PET (Score 9 – Appropriate)

HFpEF is a complex syndrome with contributions from myocardial ischemia, LV hypertrophy and stiffening, vascular stiffening, renal dysfunction, and altered pulmonary and skeletal muscle function, among other systemic alterations. Several previous studies have demonstrated a link between abnormalities in microvascular function and myocardial strain, as well as with clinical HFpEF (84,85). In patients with low clinical risk of CAD, the yield of stress PET will generally be suboptimal, although in select patients, testing may be helpful. Conversely, in patients with intermediate to high clinical risk, evaluation for myocardial ischemia as a cause of or contributor to heart failure symptoms is appropriate.

Clinical Scenarios 50 and 51: Patients with Diagnosed Heart Failure Who Are Undergoing Assessment of Viability and Hibernation

• Scenario 50: Patients with diagnosed heart failure who are un dergoing assessment of viability and hibernation with ¹⁸F-FDG PET: rest perfusion PET (Score 9 – Appropriate)

• Scenario 51: Patients with diagnosed heart failure who are un dergoing assessment of viability and hibernation: rest or stress perfusion PET (Score 9 – Appropriate)

A detailed discussion of the role of rest and stress perfusion PET in the assessment of viability and hibernation can be found in scenario 164.

Clinical Scenarios 52–55: Evaluation of Patients with Known or Suspected Cardiac Sarcoidosis

• Scenario 52: Patients undergoing assessment of myocardial in flammation with ¹⁸F-FDG PET: rest perfusion PET (Score 9 – Appropriate)

• Scenario 53: Patients with suspected cardiac sarcoidosis who  have not been previously evaluated for CAD, in whom myocardial inflammation imaging with ¹⁸F-FDG PET is planned: stress and rest perfusion PET (Score 5 – May be Appropriate)

• Scenario 54: Patients with suspected cardiac sarcoidosis who  have been previously evaluated for CAD in whom myocardial inflammation imaging with ¹⁸F-FDG PET is planned: stress and rest perfusion PET (Score 1 – Rarely Appropriate)

• Scenario 55: Patients undergoing reevaluation for response to  therapy or recurrent inflammation with ¹⁸F-FDG PET: rest perfusion PET (Score 9 – Appropriate)

Rest MPI along with ¹⁸F-FDG PET imaging is essential for the evaluation of cardiac sarcoidosis. A pattern of perfusion metabolic mismatch may be seen in active myocardial sarcoidosis, as well as in hibernating myocardium. Hence, knowledge of the presence or absence of coronary artery obstruction is essential to the appropriate interpretation of the perfusion and metabolic patterns in patients with suspected sarcoidosis. For diagnosing CAD, imaging of the coronary arteries with either invasive or CT-based imaging is preferred over stress perfusion imaging; stress–rest MPI is an alternative to angiography. Some experts have expressed concern over same-day ¹⁸F-FDG and stress testing, as ischemia may promote glycolysis in noninflamed myocardium. Others, however, felt that this effect could be surmounted by use of vasodilator stress, careful comparison of inducible perfusion defects with ¹⁸F-FDG uptake, or temporal separation of stress testing and ¹⁸F-FDG injection.

Because of the variable success rates in the suppression of physiologic ¹⁸F-FDG uptake by normal myocardium, rest perfusion imaging is helpful and may improve specificity, especially during reevaluation for response to therapy. When myocardial ¹⁸F-FDG uptake is present on the follow-up scan (persistent inflammation), a decrease in perfusion defect size may indicate partial response. When myocardial ¹⁸F-FDG uptake is absent on the follow-up scan, the presence of a perfusion defect may indicate fibrosis (worsening), whereas the absence of a perfusion defect may indicate improvement with resolution of myocardial inflammation.

Detailed discussion of the role of rest and stress perfusion PET in the assessment of cardiac sarcoidosis can be found in scenarios 162 and 163.

Clinical Scenarios 56–59: Clinically Stable Patients with Sustained VT

• Scenario 56: Clinically stable patients with an episode of sus tained VT who have a low global clinical risk of CAD (Score 6 – May be Appropriate)

• Scenario 57: Clinically stable patients with an episode of sus tained VT who have an intermediate clinical risk of CAD (Score 9 – Appropriate)

• Scenario 58: Clinically stable patients with an episode of sus tained VT who have a high clinical risk of CAD (Score 8 – Appropriate)

• Scenario 59: Clinically unstable patients with an episode of sus tained VT (Score 1 – Rarely Appropriate)

Transient myocardial ischemia is more commonly a trigger of polymorphic rather than monomorphic sustained VT. Monomorphic VT in the setting of prior myocardial infarction (MI) is typically due to scar-related reentry and not to acute ischemia. For patients suspected of having myocardial ischemia, stress testing or coronary angiography along with subsequent revascularization should be performed before catheter ablation when possible to avoid significant ischemia during VT induction, mapping, and ablation. In clinically stable patients with an episode of sustained VT, the use of stress perfusion PET is thought to be dependent on the global clinical risk of CAD in the patient. Patients with a low global clinical risk are given an AUC score of 6, may be appropriate. However, in patients considered to be at intermediate or high clinical risk, stress perfusion PET is considered appropriate. It is important to realize that in clinically unstable patients, stress perfusion PET may occasionally contribute to assessment but is more likely to delay definitive clinical care. Consequently, it was considered rarely appropriate, irrespective of the clinical risk of CAD.

Clinical Scenarios 60 and 61: Patients with a Recent Episode of VF

• Scenario 60: Clinically stable patients with a recent episode of  VF who have a low clinical risk of CAD (Score 1 – Rarely Appropriate)

• Scenario 61: Clinically unstable patients with a recent episode  of VF (Score 1 – Rarely Appropriate)

In clinically stable and unstable patients with a recent episode of VF who have a low clinical risk of CAD, stress perfusion PET is thought to be rarely appropriate, as it may result in delay of definitive therapy and will only rarely change the clinical management.

Clinical Scenarios 62–67: Patients with Exercise-Induced VT or Nonsustained VT

• Scenario 62: Patients with nonsustained VT who have a low  clinical risk of CAD (Score 4 – May be Appropriate)

• Scenario 63: Patients with exercise-induced VT who have a low  clinical risk of CAD (Score 5 – May be Appropriate)

• Scenario 64: Patients with nonsustained VT who have an in termediate clinical risk of CAD (Score 7 – Appropriate)

• Scenario 65: Patients with exercise-induced VT who have an  intermediate clinical risk of CAD (Score 8 – Appropriate)

• Scenario 66: Patients with nonsustained VT who have a high  clinical risk of CAD (Score 8 – Appropriate)

• Scenario 67: Patients with exercise-induced VT who have a  high clinical risk of CAD (Score 4 – May be Appropriate)

Exercise-induced VT rarely occurs in the absence of structural heart disease. In its absence, idiopathic monomorphic VT has a relatively benign prognosis. The main aspect of the risk stratification process is recognizing subtle forms of organic heart disease such as arrhythmogenic right ventricular cardiomyopathy. Exercise-induced polymorphic VT is often malignant and may be related to myocardial ischemia. Exercise-induced polymorphic VT has also been seen in mitral valve prolapse (88). Patients with stable coronary disease may have short bursts of polymorphic VT during exercise tests that are not reproducible during repeated testing and that have unknown long-term clinical significance. Therefore, the appropriateness of stress perfusion PET increases with increasing risk of clinical CAD. However, among those with high clinical risk and exercise-induced VT, appropriateness is somewhat lower, as noninvasive testing may result in delay of definitive therapy.

Clinical Scenarios 68–70: Patients with Frequent PVCs

• Scenario 68: Patients with frequent PVCs who have a low clin ical risk of CAD (Score 7 – Appropriate)

• Scenario 69: Patients with frequent PVCs who have an inter mediate clinical risk of CAD (Score 8 – Appropriate)

• Scenario 70: Patients with frequent PVCs who have a high  clinical risk of CAD (Score 2 – Rarely Appropriate)

PVCs are the most common ventricular arrhythmia. Their prognostic significance cannot be interpreted without considering the presence or absence of any associated underlying cardiac condition. In the absence of structural heart disease, PVCs were generally considered to be benign. In the 1970s and 1980s, it was postulated that frequent PVCs could be a trigger for VT, VF, and sudden cardiac death after an MI, and therefore PVC suppression was thought to be warranted in this context. In a normal healthy population, PVCs have been observed in up to 75% of subjects during 48-h Holter monitoring (89), with >60 PVCs/h detected in up to 4% of individuals (90). This latter prevalence increases progressively with age, comorbidity burden, and duration of monitoring, ranging from 1% to 69% (91,92). The adverse impact of frequent PVCs on the prognosis in patients with underlying or structural cardiac disease, such as a previous MI, is well established (93). In the late 1990s, Duffee et al. demonstrated that pharmacologic suppression of PVCs in patients with presumed idiopathic dilated cardiomyopathy subsequently improved LVEF (94). Recent studies have demonstrated the potential detrimental effects of frequent PVCs in patients with structurally normal hearts and the development and reversibility of PVC-induced cardiomyopathy (95,96). Frequent PVCs can also worsen a preexisting cardiomyopathy, in which case PVC suppression may only lead to partial recovery of LV dysfunction (97). A PVC burden > 24% has been suggested to have the highest sensitivity and specificity (79% and 78%, respectively) in predicting the occurrence of PVC-induced cardiomyopathy (96). However, a recent study has shown that heart failure may be caused by a much lower PVC burden than that traditionally associated with PVC-induced cardiomyopathy (98). In the presence of LVEF impairment or regional wall motion abnormalities, stress imaging may be performed in patients with impaired LV systolic function, depending on their cardiovascular risk profile. Therefore, in patients with frequent PVCs with low or intermediate clinical risk of CAD, stress perfusion is appropriate. Stress perfusion in patients with frequent PVCs and a high clinical risk of CAD is rarely appropriate, as it may delay definitive therapy.

Clinical Scenarios 71–73: Patients with Infrequent PVCs

• Scenario 71: Patients with infrequent PVCs who have a low  clinical risk of CAD (Score 1 – Rarely Appropriate)

• Scenario 72: Patients with infrequent PVCs who have an  intermediate clinical risk of CAD (Score 5 – May be Appropriate)

• Scenario 73: Patients with infrequent PVCs who have a high  clinical risk of CAD (Score 5 – May be Appropriate)

As stated earlier, the prognostic significance of PVCs cannot be interpreted without considering the presence or absence of any associated underlying cardiac condition. However, a low PVC burden has no prognostic significance. Therefore, patients with infrequent PVCs are to be evaluated according their clinical risk of CAD; that is, stress PET perfusion in patients with infrequent PVCs and a low clinical risk of CAD is rarely appropriate, and stress PET perfusion in patients with an intermediate to high clinical risk may be appropriate in certain circumstances, depending on associated clinical factors.

Clinical Scenarios 74–76: Patients with New-Onset AF

• Scenario 74: Patients with new-onset AF who have a low global  clinical risk of CAD (Score 2 – Rarely Appropriate)

• Scenario 75: Patients with new-onset AF who have an intermediate  global clinical risk of CAD (Score 5 – May be Appropriate)

• Scenario 76: Patients with new-onset AF who have a high global  clinical risk of CAD (Score 6 – May be Appropriate)

CAD is only one of many risk factors associated with the development of AF. Patients with recent-onset AF should be evaluated according to their clinical risk of CAD and in relation to their LVEF. Therefore, in patients with new-onset AF who have a low global clinical risk of CAD, stress perfusion PET is rarely appropriate. However, in patients with new-onset AF who have an intermediate to high global clinical risk of CAD, stress perfusion PET may be appropriate, depending on the presence of LV systolic or diastolic dysfunction (99).

Clinical Scenarios 77–79: Evaluation of Patients Before the Initiation of Antiarrhythmic Medications

• Scenario 77: Patients with a low global CAD risk before initiation  of antiarrhythmic medications (Score 5 – May be Appropriate)

• Scenario 78: Patients with an intermediate global CAD risk  before initiation of antiarrhythmic medications (Score 5 – May be Appropriate)

• Scenario 79: Patients with a high global CAD risk before initi ation of antiarrhythmic medications (Score 7 – Appropriate)

The safety of antiarrhythmic drug therapy typically determines the initial choice of antiarrhythmic drugs. The 2016 ESC Guidelines for the Management of Atrial Fibrillation (99) emphasize the assessment of risks of harm from ventricular arrhythmogenesis before initiation of long-term rhythm control therapy, the goal being to improve symptoms in AF safely. Appropriate options are related to specific patient characteristics, including the global clinical risk of CAD among others, with appropriateness of stress perfusion PET increasing with increasing clinical CAD risk (99).

Clinical Scenarios 80–82: Patients With Syncope Without an Ischemic Equivalent

• Scenario 80: Patients with syncope and a low global clinical  risk of CAD (Score 2 – Rarely Appropriate)

• Scenario 81: Patients with syncope and an intermediate global  clinical risk of CAD (Score 5 – May be Appropriate)

• Scenario 82: Patients with syncope and a high global clinical  risk of CAD (Score 7 – Appropriate)

Clinical Scenarios 83–87: Symptomatic Patients with Known Obstructive or Nonobstructive HCM

In patients with obstructive or nonobstructive HCM (scenarios 83–87), CMD is frequently encountered that accounts for angina or chest pain symptoms and that also conveys important prognostic information (13,102,104,105,115–117,119). PET-determined CMD is helpful here to identify those HCM patients who are likely to benefit, at least in part, from intensified medical treatment with vasoactive medications such as ACE-I, angiotensin type 2 receptor blocker (ARB), calcium-channel blockers, or ranolazine in order to reduce symptoms and improve outcome; this approach does, however, still require large-scale evaluation (3,121–124). Commonly, classic CAD is less likely to be present in this relatively young population with a lower burden of cardiovascular risk factors. Nonetheless, obstructive CAD lesions may be present in up to 26% of these patients, which may manifest as regional perfusion deficit on PET MPI images and require further evaluation with either noninvasive coronary angiography or ICA (125,126). Overall, from the available prevalence and outcome data for CMD in patients with HCM, and, in particular, from standard clinical practice regarding the clinical decision-making process and treatment options for controlling symptoms, these scenarios were commonly deemed appropriate.

The following scenarios address symptomatic patients with positive or negative results of an exercise ECG stress test.

• Scenario 83: Symptomatic patients with positive results of an  exercise ECG stress test (Score 8 – Appropriate)

Symptomatic patients with HCM and CMD have an increased risk for cardiac arrhythmia and for a worse outcome. Positive results of an ECG stress test are nonspecific because stress-related disturbances can be related not only to ischemia, but also to wall thickening or interstitial fibrosis. In these symptomatic patients with HCM, stress–rest perfusion PET can be performed to assess the presence of flow-limiting obstructive CAD and, at the same time, to identify CMD as a potential substrate for angina symptoms (102,105). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,85,121–124,126,127). From the available outcome data for CMD in this population (115,117,119) and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 8).

• Scenario 84: Symptomatic patients with negative results of an  exercise ECG stress test (Score 8 – Appropriate)

Symptomatic patients with HCM and CMD have an increased risk for cardiac arrhythmia and for a worse outcome. Negative results of an ECG stress test may not exclude ischemia or CMD in symptomatic patients with HCM. In these patients, stress–rest perfusion PET can be performed to assess the presence of flow-limiting obstructive CAD and, at the same time, to identify CMD as a potential substrate for angina symptoms (102,105). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,85,121–124,126,127). From the available outcome data for CMD in this population (115–117,119) and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 8).

• Scenario 85: Symptomatic patients with positive or negative  results of an exercise ECG stress test and exclusion of obstructive CAD by angiography (Score 8 – Appropriate)

Symptomatic patients with HCM and CMD have an increased risk for cardiac arrhythmia and for a worse outcome. In symptomatic patients with positive or negative results of an exercise ECG stress test and exclusion of obstructive CAD by invasive or noninvasive angiography, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms (102,105). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121–124,126,127). From the available outcome data for CMD in this population (115–117,119) and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 8).

• Scenario 86: Symptomatic patients with positive or negative  results of an exercise ECG stress test and normal SPECT perfusion findings (Score 7 – Appropriate)

Symptomatic patients with HCM and CMD have an increased risk for cardiac arrhythmia and for a worse outcome. In symptomatic patients with positive or negative results of an exercise ECG stress test and normal SPECT perfusion findings, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms (102,105). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121–124,126,127). From the available outcome data for CMD in this population (115–117,119) and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 7).

• Scenario 87: Asymptomatic patients with positive or negative  results of an exercise ECG stress test (Score 3 – Rarely Appropriate)

In asymptomatic patients with HCM and positive or negative results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess CMD for cardiovascular risk stratification. Nonetheless, no outcome studies are available and there is no diagnostic value with stress–rest myocardial perfusion studies in these patients. In certain high-risk constellations, for example, related to familial risk of sudden cardiac death, stress–rest perfusion PET may be indicated for cardiovascular risk stratification. Thus, this scenario was scored as rarely appropriate (score 3).

Clinical Scenarios 88–107: Symptomatic Patients with Known LV Hypertrophy Related to Arterial Hypertension, Diabetes Mellitus, or Obesity

In symptomatic patients with known LV hypertrophy related to adverse effects of arterial hypertension, diabetes mellitus, or obesity (scenarios 88–107), PET MPI affords concurrent assessment of the presence of hemodynamically obstructive CAD (perfusion imaging) and microvascular function (MBF quantification) (2,3,102,104,105). In a substantial number of these patients without obstructive CAD (normal perfusion images), PET-determined CMD (reduced hyperemic MBF and MFR) may account for reported angina symptoms, which also conveys important prognostic information (29,39,46,48,114,118,120). Thus, apart from the identification of hemodynamically obstructive CAD (stress-related regional perfusion deficit) with PET MPI, it also adds important diagnostic and prognostic information with the concurrent assessment of CMD (MBF quantification). Given the numerous outcome data on CMD in these individuals with cardiovascular risk, with the possibility of intensifying preventive medical care to improve or even normalize CMD with improved control of symptoms (2,3,121) and likely improved outcome, these scenarios were commonly deemed appropriate.

The following scenarios address patients with arterial hypertension.

• Scenario 88: Symptomatic patients with positive results of an  exercise ECG stress test (Score 9 – Appropriate)

In symptomatic patients with positive results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess the presence of flow-limiting obstructive CAD and, at the same time, to identify CMD as a potential substrate for angina symptoms (2,3,102,104,105). Positive results of an ECG stress test are nonspecific because stress-related disturbances can be related not only to ischemia, but also to wall thickening or interstitial fibrosis. The advantage of stress–rest perfusion PET is the concurrent evaluation of the presence of obstructive CAD (perfusion deficit) and of CMD. The concurrent assessment of CMD adds diagnostic and prognostic value in these high-risk populations (3,29,39,48,114,118,120). Such symptomatic patients without obstructive CAD but with CMD may also benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD and from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 9).

• Scenario 89: Symptomatic patients with negative results of an  exercise ECG stress test (Score 9 – Appropriate)

In symptomatic patients with negative results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess the presence of flow-limiting obstructive CAD and, at the same time, to identify CMD as a potential substrate for angina symptoms (2,3,102,104,105). Negative results of an ECG stress test may not exclude ischemia or CMD in these patients. The advantage of stress–rest perfusion PET is the concurrent evaluation of the presence of obstructive CAD (perfusion deficit) and of CMD. The concurrent assessment of CMD adds diagnostic and prognostic value in these high-risk populations (3,29,39,46,48,114,118,120). Such symptomatic patients without obstructive CAD but with CMD may also benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data of CMD and the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 9).

• Scenario 90: Symptomatic patients with positive or negative  results of an exercise ECG stress test without evidence of CAD by angiography (Score 9 – Appropriate)

In symptomatic patients with positive or negative results of an exercise ECG stress test without evidence of CAD by angiography, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms (2,3,102,104,105). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (3,29,39,46,48,114,118,120) and the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 9).

• Scenario 91: Asymptomatic patients with positive results of an  exercise ECG stress test (Score 4 – May be Appropriate)

In asymptomatic patients with positive results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess for macro- and microvascular CAD for cardiovascular risk stratification (2,3). Positive results of an ECG stress test are seen as nonspecific because stress-related disturbances of repolarization can be related not only to ischemia, but also to wall thickening or interstitial fibrosis. No outcome studies are available and there is no diagnostic value with stress–rest myocardial perfusion studies in these asymptomatic patients. Conversely, positive results of an ECG stress test may give rise to concern for silent ischemia that could affect the cardiovascular outcome. From the clinical point of view, stress–rest perfusion PET may be indicated for further diagnostic evaluation and cardiovascular risk stratification in such high-risk populations. Thus, this scenario was scored as may be appropriate (score 4).

• Scenario 92: Asymptomatic patients with negative results of an  exercise ECG stress test (Score 1 – Rarely Appropriate)

In asymptomatic patients with negative results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess for macro- and microvascular CAD for cardiovascular risk stratification. Nonetheless, no outcome studies are available and there is no added diagnostic value with stress–rest myocardial perfusion studies in these asymptomatic patients. Thus, this scenario was scored as rarely appropriate (score 1).

• Scenario 93: Symptomatic patients with positive or negative  results of an exercise ECG stress test and exclusion of coronary atherosclerosis as shown by angiography (Score 2 – Rarely Appropriate)

In symptomatic patients with positive or negative results of an exercise ECG stress test and exclusion of coronary atherosclerosis by angiography, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms. In such patients with completely normal coronary angiogram results, the presence of CMD is very unlikely. Thus, this scenario was scored as rarely appropriate (score 2).

• Scenario 94: Symptomatic patients with positive or negative  results of an exercise ECG stress test who have atherosclerosis and nonobstructive CAD as shown by angiography (Score 8 – Appropriate)

In symptomatic patients with positive or negative results of an exercise ECG stress test who have atherosclerosis and nonobstructive CAD as shown by angiography, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms. CMD may be present in up to 60% of such patients (102,104,105). Symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (29,39,46,48,114,118,120) and in particular from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 8).

The following scenarios address patients with diabetes mellitus.

• Scenario 95: Symptomatic patients with positive results of an  exercise ECG stress test (Score 8 – Appropriate)

In symptomatic patients with diabetes mellitus and positive results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess the presence of flow-limiting obstructive CAD and, at the same time, to identify CMD as a potential substrate for angina symptoms. Positive results of an ECG stress test are nonspecific because stress-related disturbances can be related not only to ischemia, but also to wall thickening or interstitial fibrosis. The advantage of stress–rest perfusion PET is the concurrent evaluation of the presence of obstructive CAD (perfusion deficit) and of CMD. The concurrent assessment of CMD adds diagnostic and prognostic value in these high-risk populations (3,48). Such symptomatic patients without obstructive CAD but with CMD may also benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (29,39,46,48,114,118,120) and the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 8).

• Scenario 96: Symptomatic patients with negative results of an  exercise ECG stress test (Score 8 – Appropriate)

In symptomatic patients with diabetes mellitus and negative results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess the presence of flow-limiting obstructive CAD and, at the same time, to identify CMD as a potential substrate for angina symptoms. Negative results of an ECG stress test may not exclude ischemia or CMD in these patients. The advantage of stress–rest perfusion PET is the concurrent evaluation of the presence of obstructive CAD (perfusion deficit) and of CMD. The concurrent assessment of CMD adds diagnostic and prognostic value in these high-risk populations (3,48). Such symptomatic patients without obstructive CAD but with CMD may also benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (29,39,46,48,114,118,120) and the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 8).

• Scenario 97: Symptomatic patients with positive or negative  results of an exercise ECG stress test who have atherosclerosis and nonobstructive CAD as shown by angiography (Score 8 – Appropriate)

In symptomatic patients with diabetes mellitus and positive or negative results of an exercise ECG stress test who have atherosclerosis and nonobstructive CAD as shown by angiography, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms. CMD may be present in up to 60% of such patients (102,104,105). Symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (29,39,46,48,114,118,120) and in particular from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 8).

• Scenario 98: Symptomatic patients with positive or negative  results of an exercise ECG stress test who have normal SPECT perfusion findings (Score 8 – Appropriate)

In symptomatic patients with diabetes mellitus and positive or negative results of an exercise ECG stress test who have normal SPECT perfusion findings, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms. CMD may be present in up to 60% of such patients (102,104). Symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (29,39,46,48,114,118,120) and in particular from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 8).

• Scenario 99: Asymptomatic patients with positive results of an  exercise ECG stress test (Score 7 – Appropriate)

In asymptomatic patients with diabetes mellitus and positive results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess for macro- and microvascular CAD for cardiovascular risk stratification (3,48). Positive results of an ECG stress test are nonspecific because stress-related disturbances of the repolarization can be related to ischemia and to interstitial fibrosis. The value of stress–rest myocardial perfusion studies in these asymptomatic but high-risk patients is controversial (128–133). Positive results of an ECG stress test may give rise to concern for silent ischemia that could affect the cardiovascular outcome (48,130,131). In particular, the presence of CMD may predict a worse cardiovascular outcome (29,39,46,48,114,118,120). From the clinical point of view, stress–rest perfusion PET may be indicated for further diagnostic evaluation and cardiovascular risk stratification in such a high-risk population. Thus, this scenario was scored as appropriate (score 7).

• Scenario 100: Asymptomatic patients with negative results of  an exercise ECG stress test (Score 1 – Rarely Appropriate)

In asymptomatic patients with diabetes mellitus and negative results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess for macro- and microvascular CAD for cardiovascular risk stratification (128–133). Nonetheless, no specific outcome studies are available and there is no added diagnostic value with stress–rest myocardial perfusion and flow studies in these asymptomatic patients. Thus, this scenario was scored as rarely appropriate (score 1).

The following scenarios address patients with obesity.

• Scenario 101: Symptomatic patients with positive results of an  exercise ECG stress test (Score 9 – Appropriate)

In symptomatic patients with positive results of an exercise ECG stress test, stress–rest perfusion PET can assess the presence of flow-limiting obstructive CAD and, at the same time, identify CMD as a potential substrate for angina symptoms. Positive results of an ECG stress test are nonspecific because stress-related disturbances can be related not only to ischemia, but also to wall thickening or interstitial fibrosis. The advantage of stress–rest perfusion PET is the concurrent evaluation of the presence of obstructive CAD (perfusion deficit) with high diagnostic accuracy and of CMD (29,114,120,134). The concurrent assessment of CMD adds diagnostic and prognostic value in these high-risk populations (114). Such symptomatic patients without obstructive CAD but with CMD may also benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for microvascular disease and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 9).

• Scenario 102: Symptomatic patients with negative results of an  exercise ECG stress test (Score 9 – Appropriate)

In symptomatic patients with negative results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess the presence of flow-limiting obstructive CAD and, at the same time, to identify CMD as a potential substrate for angina symptoms. Negative results of an ECG stress test may not exclude ischemia or CMD in these patients. The advantage of stress–rest perfusion PET is the concurrent evaluation of the presence of obstructive CAD (perfusion deficit) with high diagnostic accuracy and of CMD (29,114,120). The concurrent assessment of CMD adds diagnostic and prognostic value in these high-risk populations (114). Such symptomatic patients without obstructive CAD but with CMD may also benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 9).

• Scenario 103: Symptomatic patients with positive or negative  results of an exercise ECG stress test who have atherosclerosis and nonobstructive CAD as shown by angiography (Score 8 – Appropriate)

In symptomatic patients with positive or negative results of an exercise ECG stress test who have atherosclerosis and nonobstructive CAD as shown by angiography, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms. CMD may be present in up to 60% of such patients (102,104,105). Symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 8).

• Scenario 104: Symptomatic patients with positive or negative  results of an exercise ECG stress test who do not have atherosclerotic CAD as shown by angiography (Score 2 – Rarely Appropriate)

In symptomatic patients with positive or negative results of an exercise ECG stress test who do not have atherosclerotic CAD as shown by angiography, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms. In such patients with completely normal results of a coronary angiogram, the presence of CMD is very unlikely. Thus, this scenario was scored as rarely appropriate (score 2).

• Scenario 105: Symptomatic patients with positive or negative  results of an exercise ECG stress test who have normal SPECT perfusion findings (Score 8 – Appropriate)

In symptomatic patients with positive or negative results of an exercise ECG stress test who have normal SPECT perfusion findings, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms. The prevalence of CMD may be as high as 60% (102,104,105). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (114) and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 8).

• Scenario 106: Asymptomatic patients with positive results of an  exercise ECG stress test (Score 5 – May be Appropriate)

In asymptomatic patients with positive results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess for macro- and microvascular CAD. Positive results of an ECG stress test are nonspecific because stress-related disturbances of repolarization can be related not only to ischemia, but also to wall thickening or interstitial fibrosis. No outcome studies are available and there is no diagnostic value with stress–rest myocardial perfusion studies in these asymptomatic patients. Conversely, positive results of an ECG stress test may give rise to concern for silent ischemia that could affect the cardiovascular outcome (29,114,120). From the clinical point of view, stress–rest perfusion PET may be indicated for further diagnostic evaluation and cardiovascular risk stratification in such a high-risk population (114). Thus, this scenario was scored as may be appropriate (score 5).

• Scenario 107: Asymptomatic patients with negative results of  an exercise ECG stress test (Score 1 – Rarely Appropriate)

In asymptomatic patients with negative results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess for macro- and microvascular CAD for cardiovascular risk stratification. Nonetheless, no outcome studies are available and there is no added diagnostic value with stress–rest myocardial perfusion studies in these asymptomatic patients. Thus, this scenario was scored as rarely appropriate (score 1).

Clinical Scenarios 108–114: Postmenopausal Women

In symptomatic postmenopausal women (scenarios 108–114), the application of PET MPI may be critical, as it concurrently determines the presence of hemodynamically obstructive CAD (perfusion imaging) and microvascular function (MBF quantification) (2,3,102,104,105). Postmenopausal women in the presence of cardiovascular risk and significant reduction in estrogen plasma levels are apt to initiate and rapidly develop CAD or CMD. In particular, there is a high prevalence of CMD in women with recurrent chest pain but nonobstructive CAD. PET MPI offers a comprehensive assessment of the presence of both hemodynamically obstructive CAD and CMD, which conveys important diagnostic and prognostic information (39,108,113,135–143). From the available outcome data for CMD and standard clinical practice regarding the clinical decision-making process and treatment options (2,3,121), these scenarios were commonly deemed appropriate.

• Scenario 108: Symptomatic postmenopausal women with positive  results of an exercise ECG stress test (Score 9 – Appropriate)

In symptomatic postmenopausal women with positive results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess the presence of flow-limiting obstructive CAD and, at the same time, to identify CMD as a potential substrate for angina symptoms (2,85,102,104). Positive results of an ECG stress test are nonspecific because stress-related disturbances can be related not only to ischemia, but also to wall thickening or interstitial fibrosis. The advantage of stress–rest perfusion PET is the concurrent evaluation of the presence of obstructive CAD (perfusion deficit) and of CMD. The concurrent assessment of CMD adds important diagnostic and prognostic value in this population (34,108,113,135–143). Such symptomatic patients without obstructive CAD but with CMD may also benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,85,121,123,124,126,127,135–139). From the available outcome data for CMD and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 9).

• Scenario 109: Symptomatic postmenopausal women with negative  results of an exercise ECG stress test (Score 9 – Appropriate)

In symptomatic postmenopausal women with negative results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess the presence of flow-limiting obstructive CAD and, at the same time, to identify CMD as a potential substrate for angina symptoms (2,85,102,104,105). Negative results of an ECG stress test may not exclude ischemia or CMD in these patients. The advantage of stress–rest perfusion PET is the concurrent evaluation of the presence of obstructive CAD (perfusion deficit) and of CMD. The concurrent assessment of CMD adds important diagnostic and prognostic value in this population (2,85,121,123,124,126,127,135–139). Such symptomatic patients without obstructive CAD but with CMD may also benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,85,121,123,124,126,127). From the available outcome data of CMD and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 9).

• Scenario 110: Symptomatic postmenopausal women with positive  or negative results of an exercise ECG stress test and exclusion of coronary atherosclerosis by angiography (Score 1 – Rarely Appropriate)

In symptomatic postmenopausal women with positive or negative results of an exercise ECG stress test and exclusion of coronary atherosclerosis by angiography, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms (2,85,102,104). Because the presence of CMD in such patients without evidence of any atherosclerotic process in the coronary vessels is very unlikely, this scenario was scored as rarely appropriate (score 1).

• Scenario 111: Symptomatic postmenopausal women with positive  or negative results of an exercise ECG stress test who have atherosclerosis and nonobstructive CAD as shown by angiography (Score 9 – Appropriate)

In symptomatic postmenopausal women with positive or negative results of an exercise ECG stress test who have atherosclerosis and nonobstructive CAD as shown by angiography, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms (2,85,102,104). The prevalence of CMD may be as high as 60% (102,104,105). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,85,121,123,124,126,127). From the available outcome data for CMD and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 9).

• Scenario 112: Symptomatic postmenopausal women with positive  or negative results of an exercise ECG stress test and normal SPECT perfusion findings (Score 9 – Appropriate)

In symptomatic postmenopausal women with positive or negative results of an exercise ECG stress test and normal SPECT perfusion findings, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms (2,85,102,104). The prevalence of CMD may be as high as 60% (102,104). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 9).

• Scenario 113: Asymptomatic postmenopausal women with positive  results of an exercise ECG stress test (Score 5 – May be Appropriate)

In asymptomatic postmenopausal women with positive results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess for macro- or microvascular CAD (2,85,102,104). Positive results of an ECG stress test are nonspecific because stress-related disturbances of repolarization can be related not only to ischemia, but also to wall thickening or interstitial fibrosis. No outcome studies are available and there is no diagnostic value with stress–rest myocardial perfusion studies in these asymptomatic patients. Conversely, positive results of an ECG stress test may give rise to concern for silent ischemia that could affect the cardiovascular outcome (108,113,144). From the clinical point of view, stress–rest perfusion PET may be indicated for further diagnostic evaluation and cardiovascular risk stratification in such a high-risk population. Thus, this scenario was scored as may be appropriate (score 5).

• Scenario 114: Asymptomatic postmenopausal women with negative  results of an exercise ECG stress test (Score 1 – Rarely Appropriate)

In asymptomatic postmenopausal women with negative results of an exercise ECG stress test, stress–rest perfusion PET can be performed to assess CMD for cardiovascular risk stratification. Nonetheless, no outcome studies are available and there is no diagnostic value with stress–rest myocardial perfusion studies in these asymptomatic patients. Thus, this scenario was scored as rarely appropriate (score 1).

Clinical Scenarios 115–118: Patients with Syndrome X: No Obstructive CAD but Ongoing Chest Pain Syndrome

In patients with so-called syndrome X, implying nonobstructive CAD but ongoing chest pain syndrome with recurrent hospitalizations (scenarios 115–118), the application of PET MPI is pivotal in the identification of CMD as a potential substrate for recurrent chest pain (2,85,102,105,145–148) that may be amenable to intensified preventive and vasoactive medical care of cardiovascular risk factors with statins, ACE-I, or ARB. In the absence of cardiovascular risk factors, symptoms may be controlled with calcium antagonists or ranolazine medication (2,85,121). Flow outcome data are limited and controversial in this subset of patients with CMD (140,143,149,150). Previously, the clinical term syndrome X was reserved for symptomatic patients with normal results of coronary angiograms. The clinical classification of syndrome X has been extended today to include patients with classic cardiovascular risk factors and nonobstructive CAD. This may explain, at least in part, a certain variability in clinical outcome data in these patients. Overall, the identification of CMD as a potential substrate for recurrent symptoms is central to the diagnosis and clinical decision-making process and for the treatment options and medical care for these patients (2,3,13,121,148). Thus, these scenarios were commonly deemed appropriate.

• Scenario 115: Patients with ongoing chest pain syndrome and  positive results of an exercise ECG stress test who have nonobstructive CAD as shown by coronary angiography (Score 9 – Appropriate)

In patients with ongoing chest pain syndrome and with positive results of an exercise ECG stress test who have nonobstructive CAD as shown by coronary angiography, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms (2,85,102,105,145–148). Positive results of an ECG stress test are nonspecific because stress-related disturbances can be related not only to ischemia, but also to wall thickening or interstitial fibrosis. The advantage of stress–rest perfusion PET is the concurrent evaluation of the presence of obstructive CAD (perfusion deficit) and of CMD. The concurrent assessment of CMD adds important diagnostic and prognostic value in this population. The prevalence of CMD may be as high as 60% (102,105). Such symptomatic patients without obstructive CAD but with CMD may also benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,85,121,123,124,126,127). From the available outcome data for CMD and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 9).

• Scenario 116: Patients with ongoing chest pain syndrome and  negative results of an exercise ECG stress test who have no evidence of obstructive CAD as shown by coronary angiography (Score 8 – Appropriate)

In patients with ongoing chest pain syndrome and with negative results of an exercise ECG stress test who have no evidence of obstructive CAD as shown by coronary angiography, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms (2,85,102,105,145–148). Negative results of an ECG stress test may not exclude ischemia or CMD in these patients. The advantage of stress–rest perfusion PET is the concurrent evaluation of the presence of obstructive CAD (perfusion deficit) and of CMD. The concurrent assessment of CMD adds important diagnostic and prognostic value in this population. The prevalence of CMD may be as high as 60% (102,105). Such symptomatic patients without obstructive CAD but with CMD may also benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,85,121,123,124,126,127). From the available outcome data for CMD and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 8).

• Scenario 117: Patients with ongoing chest pain syndrome, positive  results of an exercise ECG stress test, and normal SPECT perfusion findings (Score 9 – Appropriate)

In patients with ongoing chest pain syndrome, positive results of an exercise ECG stress test, and normal SPECT perfusion findings, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms (2,85,102,105,145–148). The prevalence of CMD may be as high as 60% (102,105). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,85,121,123,124,126,127). From the available outcome data for CMD and, in particular, from the clinical point of view, decision-making process, and treatment consequences, this scenario was scored as appropriate (score 9).

• Scenario 118: Patients with ongoing chest pain syndrome, neg ative results of an exercise ECG stress test, and normal SPECT perfusion findings (Score 8 – Appropriate)

In patients with ongoing chest pain syndrome, negative results of an exercise ECG stress test, and normal SPECT perfusion findings, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms (2,85,102,105,145–148). Negative results of an exercise ECG stress test and normal SPECT findings may not exclude CMD. The prevalence of CMD may be as high as 60% (102,105). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,85,121,123,124,126,127). From the available outcome data of CMD and, in particular, from the point of view of the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 8).

Clinical Scenarios 119–133: Patients with Advanced Obesity or Women with Large Breasts or Dense Breast Tissue

In symptomatic patients with advanced obesity (BMI > 35 kg/m²) and women with large breasts or dense breast tissue (scenarios 119–133), PET MPI offers the highest diagnostic accuracy for CAD detection and the lowest radiation exposure in scintigraphic MPI (2,144,151). In addition, the identification of CMD as a potential substrate for recurrent chest pain may be amenable to intensified preventive and vasoactive medical care of cardiovascular risk factors with statins, ACE-I, or ARB (2,3,121). In the absence of cardiovascular risk factors, symptoms may be controlled with calcium antagonists (121) or ranolazine medication (126,127). Recent large-scale PET MPI investigations in obesity (29,39,114,120) also emphasize incremental adverse outcomes in the presence of CMD in obesity. Given the high diagnostic accuracy of CAD detection, the relatively low radiation exposure in these 2 specific populations, the concurrent assessment of CMD that conveys important diagnostic and prognostic information, and the possibility of intensifying preventive medical care to improve or even normalize CMD with improved control of symptoms and likely improved outcome, these scenarios were commonly deemed appropriate.

The following scenarios address advanced obesity (BMI > 35 kg/m²).

• Scenario 119: Symptomatic patients with advanced obesity  (BMI > 35 kg/m2) (Score 9 – Appropriate)

In symptomatic patients with advanced obesity (BMI > 35 kg/m²), stress–rest PET MPI can be performed to assess macro- and microvascular CAD disease. The reasoning behind this is that it has the highest diagnostic accuracy in the detection of flow-limiting CAD among all noninvasive imaging modalities (134,144,151). In addition, the concurrent assessment of MFR provides important information about the presence of CMD as a potential substrate for angina symptoms (2,3,102,104). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (29,39,114,120) and, in particular, from the point of view of the clinical decision-making process and treatment consequences, this scenario was scored as appropriate (score 9).

• Scenario 120: Symptomatic patients with advanced obesity  (BMI > 35 kg/m2) who have atherosclerosis or nonobstructive CAD as shown by coronary angiography (invasive or noninvasive) (Score 8 – Appropriate)

In symptomatic patients with advanced obesity (BMI > 35 kg/m²) who have atherosclerosis or nonobstructive CAD as shown by coronary angiography (invasive or noninvasive), stress–rest PET MPI can be performed to identify CMD as a potential substrate for angina symptoms (2,3,102,104). The prevalence of CMD may be as high as 60% (102,104). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (39,114) and, in particular, from the point of view of the clinical decision-making process and treatment consequences, this scenario was scored as appropriate (score 8).

• Scenario 121: Symptomatic patients with advanced obesity (BMI  > 35 kg/m2) and normal coronary angiography results (invasive or noninvasive) (Score 7 – Appropriate)

In symptomatic patients with advanced obesity (BMI > 35 kg/m²) and normal coronary angiography results (invasive or noninvasive), stress–rest PET MPI can be performed to identify CMD as a potential substrate for angina symptoms (2,3,102,104). The prevalence of CMD in such patients appears to be marked (102,104), even without evidence of any atherosclerotic process in the coronary vessels, which conveys important prognostic information (114). From the available outcome data for CMD (39,114), the high diagnostic accuracy of PET perfusion imaging in this specific population (29,144), and the point of view of the clinical decision-making process and treatment consequences, this scenario was scored as appropriate (score 7).

• Scenario 122: Symptomatic patients with advanced obesity (BMI  > 35 kg/m2) and equivocal findings on stress–rest myocardial perfusion SPECT (Score 9 – Appropriate)

In symptomatic patients with advanced obesity (BMI > 35 kg/m²) and equivocal findings on stress–rest myocardial perfusion SPECT, an additional stress–rest PET MPI can be performed for definitive evaluation of the presence or absence of obstructive CAD because PET has the highest diagnostic accuracy in the detection of flow-limiting CAD in this specific population (29,134,144). The concurrent assessment of MFR provides important information about the presence of CMD as a potential substrate for angina symptoms (2,3,102,104). From the available outcome data (39,114), clinical decision-making process, and treatment consequences, this scenario was scored as appropriate (score 9).

• Scenario 123: Asymptomatic patients with advanced obesity  (BMI > 35 kg/m2) who are at high cardiovascular risk when undergoing noncardiac surgery (Score 7 – Appropriate)

In asymptomatic patients with advanced obesity (BMI > 35 kg/m²) who are at high cardiovascular risk when undergoing noncardiac surgery, stress–rest cardiac perfusion PET can be seen as the best noninvasive perfusion imaging modality for preoperative cardiac risk stratification. From the available outcome data (39,114), standard clinical practice (28), and treatment consequences, this scenario was scored as appropriate (score 7).

• Scenario 124: Asymptomatic patients with advanced obesity (BMI  > 35 kg/m2) who are at intermediate cardiovascular risk when undergoing noncardiac surgery (Score 5 – May be Appropriate)

In asymptomatic patients with advanced obesity (BMI > 35 kg/m²) who are at intermediate cardiovascular risk when undergoing noncardiac surgery, stress–rest cardiac perfusion PET can be seen as the best noninvasive perfusion imaging modality for preoperative cardiac risk stratification. From the available outcome data (39,114), standard clinical practice (28), and treatment consequences, this scenario was scored as may be appropriate (score 5).

• Scenario 125: In asymptomatic patients with advanced obesity  (BMI > 35 kg/m2) who are at low cardiovascular risk when undergoing noncardiac surgery (Score 2 – Rarely Appropriate)

In asymptomatic patients with advanced obesity who are at low cardiovascular risk when undergoing noncardiac surgery, stress–rest cardiac perfusion PET can be seen as the best noninvasive perfusion imaging modality for preoperative cardiac risk stratification but is rarely appropriate (score 2).

The following scenarios address women with large breasts or with dense breast tissue that causes attenuation artifacts.

• Scenario 126: Symptomatic women with large breasts or dense  breast tissue (Score 8 – Appropriate)

In symptomatic women with large breasts or dense breast tissue, stress–rest PET MPI can be performed, as it has the highest diagnostic accuracy in the detection of flow-limiting CAD among all noninvasive imaging modalities and the lowest radiation exposure, in particular for the breast (29,144). In addition, the concurrent assessment of MFR provides important information about the presence of CMD as a potential substrate for angina symptoms. From the available outcome data (39,108,113,135–143), clinical decision-making process, and treatment consequences (2,3,121,123,124,126,127), this scenario was scored as appropriate (score 8).

• Scenario 127: Symptomatic women with large breasts or dense  breast tissue who have atherosclerosis or nonobstructive CAD as shown by angiography (invasive or noninvasive) (Score 8 – Appropriate)

In symptomatic women with large breasts or dense breast tissue who have atherosclerosis or nonobstructive CAD as shown by angiography (invasive or noninvasive), stress–rest PET MPI and PET/CT can be performed, as the concurrent assessment of MFR provides important information about the presence of CMD as a potential substrate for angina symptoms (2,3,102,104). The prevalence of CMD may be as high as 60% (102,104). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data of CMD (39,108,113,135–143) and in view of the clinical decision-making process and treatment consequences, this scenario was scored as appropriate (score 8).

• Scenario 128: Symptomatic women with large breasts or dense  breast tissue and normal coronary angiography results (invasive or noninvasive) (Score 7 – Appropriate)

In symptomatic women with large breasts or dense breast tissue and normal coronary angiography results (invasive or noninvasive), stress–rest PET MPI and PET/CT can be performed, as the concurrent assessment of MFR provides important information about the presence of CMD as a potential substrate for angina symptoms (2,3,102,104). Microvascular disease in postmenopausal women is common, even with completely normal coronary angiogram results. Such symptomatic patients with normal coronary angiogram results but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (39,108,113,135–143) and in view of the clinical decision-making process and treatment consequences, this scenario was scored as appropriate (score 7).

• Scenario 129: Symptomatic women with large breasts or dense  breast tissue who have normal results on stress–rest myocardial perfusion SPECT (Score 7 – Appropriate)

In symptomatic women with large breasts or dense breast tissue who have normal results on stress–rest myocardial perfusion SPECT, an additional stress–rest PET MPI/CT can be performed, as the concurrent assessment of MFR provides important information about the presence of CMD as a potential substrate for angina symptoms (2,3,102,104). Normal results on perfusion SPECT cannot rule out CMD. Given the outcome data (39,108,113,135–143), clinical decision-making process, and treatment options (2,3,121,123,124,126,127), this scenario was scored as appropriate (score 7).

• Scenario 130: Symptomatic women with large breasts or dense  breast tissue who have equivocal findings on stress–rest myocardial perfusion SPECT (Score 9 – Appropriate)

In symptomatic women with large breasts or dense breast tissue who have equivocal findings on stress–rest myocardial perfusion SPECT, an additional stress–rest PET MPI can be performed for definitive evaluation of the presence or absence of obstructive CAD because PET has the highest diagnostic accuracy in the detection of flow-limiting CAD in such conditions (29,144). The concurrent assessment of MFR provides important information about the presence of CMD as a potential substrate for angina symptoms (2,3,102,104). Given the outcome data (39,108,113,135–143), clinical decision-making process, and treatment options (2,3,121,123,124,126,127), this scenario was scored as appropriate (score 9).

• Scenario 131: Asymptomatic women with large breasts or dense  breast tissue who are at high cardiovascular risk when undergoing noncardiac surgery (Score 7 – Appropriate)

In asymptomatic women with large breasts or dense breast tissue who are at high cardiovascular risk when undergoing noncardiac surgery, stress–rest cardiac perfusion PET can be seen as the best noninvasive perfusion imaging modality for preoperative cardiac risk stratification. From the available outcome data (39,108,113,135–143), standard clinical practice (28), and treatment consequences, this scenario was scored as appropriate (score 7).

• Scenario 132: Asymptomatic women with large breasts or dense  breast tissue who are at intermediate cardiovascular risk when undergoing noncardiac surgery (Score 5 – May be Appropriate)

In asymptomatic women with large breasts or dense breast tissue who are at intermediate cardiovascular risk when undergoing noncardiac surgery, stress–rest cardiac perfusion PET can be seen as the best noninvasive perfusion imaging modality for preoperative cardiac risk stratification. From the available outcome data (39,108,113,135–143), standard clinical practice (28), and treatment consequences, this scenario was scored as may be appropriate (score 5).

• Scenario 133: Asymptomatic women with large breasts or dense  breast tissue who are at low cardiovascular risk when undergoing noncardiac surgery (Score 2 – Rarely Appropriate)

In asymptomatic women with large breasts or dense breast tissue who are at low cardiovascular risk when undergoing noncardiac surgery, stress–rest cardiac perfusion PET can be seen as the best noninvasive perfusion imaging modality for preoperative cardiac risk stratification. From the available outcome data (39,108,113,135–143), standard clinical practice (28), and treatment consequences, this scenario was scored as rarely appropriate (score 2).

Clinical Scenarios 134–140: Symptomatic Young Women and Young Men

In symptomatic young women (age < 45 y) and young men (age < 40 y) (scenarios 134–140), the application of PET MPI may be seen as helpful for the identification of CMD in the absence of obstructive and flow-limiting CAD. In such patients who have undergone a traditional exercise ECG stress test in conjunction with a SPECT or echocardiography stress test or noninvasive CTA without evidence of obstructive CAD, PET MPI seems to be appropriate for the identification of CMD as a potential substrate for recurrent chest pain that may be amenable to intensified preventive and vasoactive medical care of cardiovascular risk factors with statins, ACE-I, or ARB (2,3,121). In the absence of cardiovascular risk factors, symptoms may be controlled with calcium antagonists (121) or ranolazine (125,127). Given the outcome data for CMD about cardiovascular risk in individuals at this younger age (3,29,39,46,48,114,118,120), the relatively low radiation burden with PET MPI, and the possibility of intensifying preventive medical care to improve or even normalize CMD with improved control of symptoms and likely improved outcome, these scenarios were commonly deemed appropriate but only when obstructive CAD has been excluded. A specific assessment of CMD appears to be needed in the appropriate clinical context.

The following scenarios address young women (age < 45 y).

• Scenario 134: Symptomatic young women (age < 45 y) with  positive or negative results of an exercise ECG stress test or negative results of stress imaging testing with SPECT or echocardiography, but persistent chest pain syndrome (Score 8 – Appropriate)

In symptomatic young women (age < 45 y) with positive or negative results of an exercise ECG stress test or negative results of stress imaging testing with SPECT or echocardiography but persistent chest pain syndrome, stress–rest MPI is seen as the first choice for the evaluation of CAD because PET is commonly done with pharmacologic vasodilator stress or, in rare instances, with dobutamine stress provocation. In the case of normal perfusion findings on SPECT images and persistent chest pain syndrome, an additional stress–rest PET MPI can be done to assess MFR and thus the presence of CMD as a potential substrate for angina symptoms (2,3,102,104). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms. From the available outcome data for CMD (39,108,113,135–143), clinical decision-making process, and treatment consequences (2,3,121,123,124,126,127), this scenario was scored as appropriate (score 8).

• Scenario 135: Symptomatic young women (age < 45 y) with  positive or negative results of an exercise ECG stress test, who have atherosclerosis or nonobstructive CAD as shown by angiography, but persistent chest pain syndrome (Score 8 – Appropriate)

In symptomatic young women (age < 45 y) with positive or negative results of an exercise ECG stress test, who have atherosclerosis or nonobstructive CAD as shown by angiography but persistent chest pain syndrome, stress–rest PET MPI can be performed to assess MFR and thus the presence of CMD as a potential substrate for angina symptoms (2,3,102,104). Such symptomatic patients without evidence of CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (39,108,113,135–143), clinical decision-making process, and treatment consequences, this scenario was scored as appropriate (score 8).

• Scenario 136: Symptomatic young women (age < 45 y) with  positive or negative results of an exercise ECG stress test and normal coronary angiography results, but persistent chest pain syndrome (Score 7 – Appropriate)

In symptomatic young women (age < 45 y) with positive or negative results of an exercise ECG stress test and normal coronary angiography results but persistent chest pain syndrome, stress–rest PET MPI can be performed to assess MFR and thus the presence of CMD as a potential substrate for angina symptoms (2,3,102,104). Despite normal coronary angiogram results, CMD in this population is frequently encountered (102,104). Such symptomatic patients may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (39,108,113,135–143), clinical decision-making process, and treatment consequences, this scenario was scored as appropriate (score 7).

• Scenario 137: Symptomatic young women (age < 45 y) with  positive or negative results of an exercise ECG stress test and normal SPECT perfusion findings, but persistent chest pain syndrome (Score 8 – Appropriate)

In symptomatic young women (age < 45 y) with positive or negative results of an exercise ECG stress test and normal SPECT perfusion findings but persistent chest pain syndrome, stress–rest perfusion PET can be performed to identify CMD as a potential substrate for angina symptoms (2,3,102,104). Findings of the exercise ECG stress test are nonspecific and normal perfusion findings with SPECT do not rule out CMD. Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (39,108,113,135–143) and in view of the clinical decision-making process and treatment consequences, this scenario was scored as appropriate (score 8).

The following scenarios address young men (age < 40 y).

• Scenario 138: Symptomatic young men (age < 40 y) with  negative results of stress–rest imaging testing with SPECT or echocardiography, but persistent chest pain syndrome (Score 8 – Appropriate)

In symptomatic young men (age < 40 y) with negative results of stress–rest imaging testing with SPECT or echocardiography but persistent chest pain syndrome, an additional stress–rest PET MPI is seen as first choice for the evaluation of CAD. An additional stress–rest PET MPI to assess MFR enables the identification of CMD that may reflect a functional substrate for chest pain amenable to medical treatment (2,3,102,104). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (29,39,46,48,114,118,120) and in view of the clinical decision-making process and treatment consequences, this scenario was scored as appropriate (score 8).

• Scenario 139: Symptomatic young men (age < 40 y) with  positive or negative results of an exercise ECG stress test, who have atherosclerosis, nonobstructive CAD, and persistent chest pain syndrome (Score 8 – Appropriate)

In symptomatic young men (age < 40 y) with positive or negative results of an exercise ECG stress test, who have atherosclerosis, nonobstructive CAD, and persistent chest pain syndrome, stress–rest PET MPI can be performed to assess MFR and thus the presence of CMD as a potential substrate for angina symptoms (2,3,102,104). The prevalence of CMD may be as high as 60% (102). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (29,39,46,48,114,118,120), and in view of the clinical decision-making process and treatment consequences, this scenario was scored as appropriate (score 8).

• Scenario 140: Symptomatic young men (age < 40 y) with  positive or negative results of an exercise ECG stress test and normal results on a coronary angiogram, but persistent chest pain syndrome (Score 7 – Appropriate)

In symptomatic young men (age < 40 y) with positive or negative results of an exercise ECG stress test and normal coronary angiogram results, but persistent chest pain syndrome, stress–rest PET MPI can be performed to assess MFR and thus the presence of CMD as a potential substrate for angina symptoms (2,85,102,104,105). Despite normal coronary angiogram results (102), CMD may be frequently encountered in this population. Such symptomatic patients without any evidence of CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD (29,39,46,48,114,118,120), and in view of the clinical decision-making process and treatment consequences, this scenario was scored as appropriate (score 7).

Clinical Scenario 141: Children and Adolescents with Congenital Heart Disease

In symptomatic children and adolescents patients with congenital heart disease (scenario 141), exercise stress testing with imaging is seen as a first option to verify whether the congenital heart disease may affect blood flow to the heart during daily activities and exercise (152–154). If the patient cannot exercise or the congenital heart disease may compromise the blood flow supply independent of exercise stress, then stress-only or stress–rest perfusion PET was seen as a viable option because of its low radiation exposure, and the indication for PET MPI was deemed appropriate.

• Scenario 141: Symptomatic children and adolescents with con genital heart disease (Score 8 – Appropriate)

In symptomatic children and adolescents with congenital heart disease that could compromise the blood flow supply to the heart, exercise echocardiography should be given preference because of the absence of any radiation exposure. If exercise echocardiography is not feasible, then exercise and rest perfusion SPECT is an option. If the patient cannot exercise or the congenital heart disease may compromise the blood flow supply independent of exercise stress, then stress-only or stress–rest perfusion PET is a viable option because of its low radiation exposure (score 8).

Clinical Scenarios 142–147: Patients with Familial Hypercholesterolemia

In symptomatic patients with familial hypercholesterolemia (scenarios 142–146) without evidence of obstructive CAD by imaging, no specific outcome data are available. Nonetheless, the application of PET MPI was deemed appropriate to identify CMD as a potential substrate for angina symptoms in persistent chest pain syndrome (2,85,102,105,145–148) amenable to intensified preventive and vasoactive medical care with statins or ranolazine (2,3,121,126,127) to control symptoms and to potentially improve outcome, respectively.

Conversely, in asymptomatic individuals with familial hypercholesterolemia (scenario 147), the application of PET MPI was deemed rarely appropriate. In rare instances, however, despite the absence of symptoms, PET MPI may be indicated for cardiovascular risk stratification if there is a positive family history of CAD.

• Scenario 142: Symptomatic individuals with familial hypercho lesterolemia and negative stress–rest imaging findings but persistent chest pain syndrome (Score 7 – Appropriate)

In symptomatic individuals with familial hypercholesterolemia and negative stress–rest SPECT imaging or echocardiographic findings, but persistent chest pain syndrome, an additional stress–rest PET MPI can be performed to assess MFR and thus the presence of CMD as a potential substrate for angina symptoms (2,85,102,104,105) and cardiovascular risk stratification (29,39,46,48,114,118,120). Such symptomatic patients without evidence of obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD, clinical decision-making process, and treatment consequences, this scenario was scored as appropriate (score 7).

• Scenario 143: Symptomatic individuals with familial hypercho lesterolemia and positive or negative results of an exercise ECG stress test, who have atherosclerosis and nonobstructive CAD, but persistent chest pain (Score 8 – Appropriate)

In symptomatic individuals with familial hypercholesterolemia and positive or negative results of an exercise ECG stress test, who have atherosclerosis and nonobstructive CAD, but persistent chest pain, stress–rest PET MPI can be performed to assess MFR and thus the presence of CMD as a potential substrate for angina symptoms (2,85,102,104,105) and cardiovascular risk stratification (29,39,46,48,114,118,120). The prevalence of CMD may be as high as 60% (102). Such symptomatic patients without obstructive CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD and in view of the clinical decision-making process and treatment consequences, this scenario was scored as appropriate (score 8).

• Scenario 144: Symptomatic individuals with familial hypercho lesterolemia and positive or negative results of an exercise ECG stress test and normal results on a coronary angiogram, but persistent chest pain (Score 7 – Appropriate)

In symptomatic individuals with familial hypercholesterolemia and positive or negative results of an exercise ECG stress test and normal coronary angiogram results, but persistent chest pain, stress–rest PET MPI can be performed to assess MFR and thus the presence of CMD as a potential substrate for angina symptoms (2,85,102,104,105) and cardiovascular risk stratification (29,39,46,48,114,119,120). Despite normal coronary angiogram results, CMD in this population is frequently encountered (102). Such symptomatic patients with normal coronary arteries but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD, clinical decision-making process, and treatment consequences, this scenario was scored as appropriate (score 7).

• Scenario 145: Symptomatic individuals with familial hypercho lesterolemia and positive or negative results of an exercise ECG stress test, who have no coronary artery calcifications on noncontrast cardiac CT (CCT) (Score 7 – Appropriate)

In symptomatic individuals with familial hypercholesterolemia and positive or negative results of an exercise ECG stress test, who have no coronary artery calcifications on noncontrast CCT, stress–rest PET MPI can be performed to assess obstructive CAD (albeit this is less likely with the absence of coronary artery calcifications) and to measure MFR and thus the presence of CMD as a potential substrate for angina symptoms (2,85,102,104,105) and cardiovascular risk stratification (29,39,46,48,114,118,120). Despite the absence of coronary artery calcifications on noncontrast CCT, CAD may be present and CMD in this population is frequently encountered (102). Such symptomatic patients without apparent CAD but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD, clinical decision-making process, and treatment consequences, this scenario was scored as appropriate (score 7).

• Scenario 146: Symptomatic individuals with familial hypercho lesterolemia and positive or negative results of an exercise ECG stress test, who have coronary artery calcifications on noncontrast CCT (Score 8 – Appropriate)

In symptomatic individuals with familial hypercholesterolemia with positive or negative results of an exercise ECG stress test, who have coronary artery calcifications on noncontrast CCT, stress–rest PET MPI can be performed to identify obstructive CAD and, if perfusion results are normal, to assess CMD as a potential substrate for angina symptoms (2,85,102,104,105) and for cardiovascular risk stratification (29,39,46,48,114,118,120). Cardiac perfusion PET may be given preference over stress–rest SPECT because of its low radiation exposure and added value of CMD assessment. CMD in this population is frequently encountered (102). Such symptomatic patients with coronary artery calcifications but with CMD may benefit from ACE-I, ARB, or ranolazine to improve hyperemic flow and symptoms (2,3,121,123,124,126,127). From the available outcome data for CMD, clinical decision-making process, and treatment consequences, this scenario was scored as appropriate (score 8).

• Scenario 147: Asymptomatic individuals with familial hyper cholesterolemia and positive or negative results of an exercise ECG stress test (Score 2 – Rarely Appropriate)

In asymptomatic individuals with familial hypercholesterolemia and positive or negative results of an exercise ECG stress test, stress–rest PET MPI may be used in rare instances for cardiovascular risk stratification if a positive familial history of CAD is present. In the absence of outcome data, given the clinical-decision making process and treatment options, this scenario was scored as rarely appropriate (score 2).

Clinical Scenarios 148–150: Symptomatic Patients with CAD with Known Left Main or Multivessel Disease

In symptomatic CAD patients with known left main or multivessel disease (scenarios 148–150), the application of PET MPI affords the advantage of high diagnostic accuracy, concurrent evaluation of myocardial perfusion (radiotracer uptake) and regional MFR, and wall motion assessment at peak pharmacologic stress (2,8,10,29,35,37,39). Given these advantages of stress–rest perfusion PET over other imaging modalities that may profoundly affect the diagnostic accuracy, decision-making process, and treatment options, its application was deemed appropriate.

• Scenario 148: Symptomatic patients with known left main or  multivessel disease as shown by ICA (Score 9 – Appropriate)

In symptomatic patients with known left main or multivessel disease as shown by ICA, stress–rest perfusion PET not only determines the relative radiotracer uptake (perfusion distribution) of the left ventricle, but it also quantifies MFR and determines LV wall motion at peak stress. Alternatively, dobutamine echocardiography is a viable option if patients have normal LV function and are suitable for this technique. Stress–rest myocardial perfusion SPECT may miss diffuse ischemia induced by left main or multivessel disease, as the relative radiotracer uptake may be homogeneous and ischemia-induced hypokinesis or akinesis may have resolved 40 min after stress at image acquisition of ^99mTc SPECT. Given the advantages of stress–rest perfusion PET over other imaging modalities that may profoundly affect the diagnostic accuracy (2,8,10,29,35,37,39), decision-making process, and treatment options, this scenario was scored as appropriate (score 9).

• Scenario 149: Symptomatic patients with CAD in the left main  segment or in all 3 vessels as shown by noninvasive CTA (Score 9 – Appropriate)

In symptomatic patients with CAD in the left main segment or in all 3 vessels as shown by noninvasive CTA (56,155,156), stress–rest perfusion PET can be performed, as it may be seen as the most accurate and cost-effective noninvasive imaging modality in this condition. Given the advantages of stress–rest perfusion PET over other imaging modalities (as mentioned in scenario 148) that may profoundly affect the diagnostic accuracy (2,8,10,29,35,37,39), decision-making process, and treatment options, this scenario was scored as appropriate (score 9).

• Scenario 150: Symptomatic patients with coronary artery calci fications in the left main segment or in all 3 vessels as shown on noncontrast CCT (Score 9 – Appropriate)

In symptomatic patients with coronary artery calcifications in the left main segment or in all 3 vessels as shown on noncontrast CCT (56,155,156), stress–rest perfusion PET can be performed, as it may be seen as the most accurate and cost-effective noninvasive imaging modality in this condition. Given the advantages of stress–rest perfusion PET over other imaging modalities (as mentioned in scenario 148) that may profoundly affect the diagnostic accuracy (2,8,10,29,35,37,39), decision-making process, and treatment options, this scenario was scored as appropriate (score 9).

Clinical Scenarios 151–153: Asymptomatic Patients with CAD with Known Left Main or Multivessel Disease

Conversely, in asymptomatic patients with known left main or multivessel disease (scenarios 151–153), the application of PET MPI may be justified in view of the possibility of advanced CAD-induced repetitive silent ischemia that may eventually lead to heart failure or sudden cardiac death. Given the appropriate clinical context, PET MPI may be indicated for this scenario.

• Scenario 151: Asymptomatic patients with known left main or  multivessel disease as shown by coronary angiography (Score 6 – May be Appropriate)

In asymptomatic patients with known left main or multivessel disease as shown by coronary angiography (56,155,156), stress–rest perfusion PET can be performed to identify silent macro- or microvascular CAD that could lead to heart failure or sudden cardiac death. Although the patient is asymptomatic, the risk constellation shown from coronary morphologic features with left main or multivessel disease may necessitate further risk stratification with evaluation for ischemia with stress–rest perfusion PET. Given this scenario, stress–rest perfusion PET may be most helpful for further risk stratification (2,8,10,29,35,37,39) that potentially affects the decision-making process and treatment options. Thus, this scenario was scored as may be appropriate (score 6).

• Scenario 152: Asymptomatic patients with pronounced coronary  calcifications in the left main or in all 3 main vessels as shown by noncontrast CCT (Score 7 – Appropriate)

In asymptomatic patients with pronounced coronary calcifications in the left main or in all 3 main vessels as shown on noncontrast CCT (56,155,156), stress–rest perfusion PET can be performed to identify silent macro- or microvascular CAD that could lead to heart failure or sudden cardiac death. Although the patient is asymptomatic, the risk constellation of pronounced coronary calcifications in the left main or in all 3 main vessels necessitates further risk stratification by evaluation for ischemia with stress–rest perfusion PET (2,8,10,29,35,37,39). Given the outcome data, decision-making process, and treatment options, this scenario was scored as appropriate (score 7).

• Scenario 153: Asymptomatic patients with mild coronary cal cifications in the left main or in all 3 main vessels as shown on noncontrast CCT (Score 3 – Rarely Appropriate)

In asymptomatic patients with mild coronary calcifications in the left main or in all 3 main vessels as shown on noncontrast CCT (56,155,156), stress–rest perfusion PET can be performed to assess silent macro- or microvascular CAD. Patients who are asymptomatic and have mild coronary artery calcifications do not necessarily have an increased risk for silent ischemia. Given the outcome data, low influence on the decision-making process, and treatment options, this scenario was scored as rarely appropriate (score 3).

Clinical Scenarios 154–157: Patients Who Have Undergone CABG

In symptomatic patients with CAD who have undergone CABG, the application of PET MPI was deemed appropriate if exercise SPECT cannot be performed (scenario 154), or if exercise SPECT findings are equivocal (scenario 155) (27,28).

Conversely, in asymptomatic patients with CAD who have undergone CABG, the application of PET MPI within 5 y of CABG (scenario 156) was deemed as rarely appropriate (low diagnostic yield), whereas for a ≥5-y period after CABG (scenario 157) PET MPI may be appropriate for the detection of silent ischemia due to the increased likelihood of occlusion of single bypass grafts (27,28).

• Scenario 154: Symptomatic patients after undergoing CABG:  stress–rest perfusion PET if exercise SPECT cannot be performed (Score 8 –Appropriate)

In symptomatic patients who have undergone CABG, stress–rest perfusion PET can be performed if exercise SPECT is not feasible. From the outcome data (29,39,46,48,114,118,120), advantages of stress–rest perfusion PET that may affect the decision-making process (evaluation of each lesion for its hemodynamic consequences with regional MFR assessment) (2,8,9,39), and treatment options (redo CABG or PCI), this scenario was scored as appropriate (score 8).

• Scenario 155: Symptomatic patients after undergoing CABG:  stress–rest perfusion PET if exercise SPECT is equivocal (Score 8 – Appropriate)

In symptomatic patients who have undergone CABG, stress–rest perfusion PET can be performed if exercise SPECT is equivocal. Given the advantages of stress–rest perfusion PET, leading to the highest diagnostic accuracy (2,8,9,39), this scenario was scored as appropriate (score 8).

• Scenario 156: Asymptomatic patients within 5 y of undergoing  CABG (Score 2 – Rarely Appropriate)

In asymptomatic patients within 5 y of undergoing CABG, the diagnostic yield of stress–rest perfusion PET would be low or nonexistent (27,28). Thus, this scenario was scored as rarely appropriate (score 2).

• Scenario 157: Asymptomatic patients ≥5 y after undergoing  CABG (Score 6 – May be Appropriate)

In asymptomatic patients ≥5 y after undergoing CABG, stress–rest perfusion PET can be performed, as there is a certain probability of silent ischemia because of the potential occlusion of single bypass grafts. Given the severity of CAD and the numbers of left internal mammary artery and saphenous vein graft bypasses (27,28), this scenario was scored as may be appropriate (score 6).

Clinical Scenarios 158–161: Patients Who Have Undergone PCI in Multivessel Disease

In symptomatic patients with CAD who have undergone PCI in multivessel disease, the application of PET MPI was deemed appropriate if exercise SPECT cannot be performed (scenario 158), or if exercise SPECT findings are equivocal (scenario 159) (27,28).

Conversely, in asymptomatic patients with CAD who have undergone PCI in multivessel disease, the application of PET MPI within 2 y of PCI (scenario 160) was deemed rarely appropriate (low diagnostic yield), whereas at ≥2 y after PCI (scenario 161), PET MPI may be appropriate for the detection of silent ischemia because of the increased likelihood of silent ischemia from a novel stenosis in the arterial vessels (27,28).

• Scenario 158: Symptomatic patients with known multivessel  disease who have undergone PCI in whom exercise SPECT cannot be performed (Score 8 – Appropriate)

In symptomatic patients with known multivessel disease who have undergone PCI, stress–rest perfusion PET can be performed if exercise SPECT is not feasible. From the outcome data (29,39,46,48,114,118,120), the advantages of stress–rest perfusion PET that may affect the decision-making process (evaluation of each lesion for its hemodynamic consequences, with regional MFR assessment) (2,8,9,39), and the treatment options (redo CABG or PCI), this scenario was scored as appropriate (score 8).

• Scenario 159: Symptomatic patients with known multivessel  disease who have undergone PCI and who have equivocal exercise SPECT results (Score 9 – Appropriate)

In symptomatic patients with known multivessel disease who have undergone PCI, stress–rest perfusion PET can be performed if exercise SPECT is equivocal. Given the advantages of stress–rest perfusion PET, leading to the highest diagnostic accuracy (2,8,9,39), this scenario was scored as appropriate (score 9).

• Scenario 160: Asymptomatic patients within 2 y of undergoing  PCI (Score 2 – Rarely Appropriate)

In asymptomatic patients within 2 y of undergoing PCI, the diagnostic yield of stress–rest perfusion PET would be low or nonexistent (27,28). Thus, this scenario was scored as rarely appropriate (score 2).

• Scenario 161: Asymptomatic patients ≥2 y after undergoing  PCI (Score 6 – May be Appropriate)

In asymptomatic patients at ≥2 y after undergoing PCI, stress–rest perfusion PET can be performed, as there is a certain probability of silent ischemia because of novel stenosis in the arterial vessels. Given the complexity of CAD and number of PCIs that include stents (27,28), this scenario was scored as may be appropriate (score 6).

Clinical Scenarios 162–163: Use of Rest or Stress–Rest PET Perfusion in Patients in Conjunction with ¹⁸F-FDG PET to Assess Cardiac Sarcoidosis

In patients with suspected cardiac sarcoidosis (scenario 162), resting PET MPI is an integral part of the ¹⁸F-FDG PET protocol in the detection and characterization of cardiac sarcoidosis and thus this scenario was deemed appropriate (86,157,158).

In patients with suspected cardiac sarcoidosis with angina or chest pain symptoms or dyspnea that raises the suspicion for concomitant CAD (scenario 163), adding stress MPI PET to rest MPI and ¹⁸F-FDG PET was deemed appropriate (86,157–159).

• Scenario 162: Patients with suspected cardiac sarcoidosis: rest  perfusion PET as an integral part of the ¹⁸F-FDG PET protocol in the detection and characterization of cardiac sarcoidosis (Score 8 – Appropriate)

In patients with suspected cardiac sarcoidosis, resting perfusion PET is an integral part of the ¹⁸F-FDG PET protocol in the detection and characterization of cardiac sarcoidosis (86,157–159). The presence of a relative perfusion abnormality may signify old cardiac sarcoid activity as scarring or severe fibrosis, or it may reflect severe edema in the acute setting. In addition, a so-called mismatch between reduced perfusion and abnormal ¹⁸F-FDG uptake with a typical location (basal segments of the LV wall) is highly diagnostic for active inflammatory cardiac sarcoidosis. Overall, adding rest MPI to ¹⁸F-FDG PET increases the diagnostic yield, specificity, and reader confidence in the detection and characterization of cardiac sarcoidosis (86,157,158). Thus, this scenario was scored as appropriate (score 8).

• Scenario 163: Patients with suspected cardiac sarcoidosis and  concurrent chest pain symptoms or dyspnea who are undergoing rest perfusion and the ¹⁸F-FDG PET protocol: addition of stress perfusion PET (Score 8 – Appropriate)

In patients with suspected cardiac sarcoidosis who are undergoing rest perfusion and the ¹⁸F-FDG PET protocol, stress perfusion can be added in those with angina, chest pain symptoms, or dyspnea that raises the suspicion for concomitant CAD (86,157–159). Exercise or CAD-induced ischemia may lead to regional ¹⁸F-FDG-uptake and thus false-positive findings in sarcoid detection. False-positive findings on ¹⁸F-FDG PET images can be avoided by acquiring stress (-rest) perfusion images the day after ¹⁸F-FDG PET image acquisition to prevent interference with the ¹⁸F-FDG PET examination (86,158). From the clinical decision-making process and treatment options, this scenario was scored as appropriate (score 8).

Clinical Scenario 164: Use of Stress–Rest Perfusion in Patients in Conjunction with ¹⁸F-FDG PET to Assess Myocardial Viability

• Scenario 164: Patients with assessment of myocardial viability  in ischemic cardiomyopathy: rest or stress perfusion PET as an integral part of the ¹⁸F-FDG PET protocol in the detection and characterization of myocardial viability (Score 9 – Appropriate)

In patients with assessment of myocardial viability in ischemic cardiomyopathy, rest or stress perfusion PET is an integral part of the ¹⁸F-FDG PET protocol in the detection and characterization of myocardial viability. Concurrent resting perfusion assessment is an integral part of the diagnostic process. ¹⁸F-FDG uptake may exceedingly increase in regions with ischemically compromised viable or hibernation-stunned myocardium. Within the normalization process of the ¹⁸F-FDG signal, the excessive uptake of ¹⁸F-FDG may be upscaled (100%) and the remaining viable regions therefore may be downscaled pretending regions with reduced (albeit normal) viability. In some instances, the ¹⁸F-FDG uptake may only occur in regions with viable but ischemically compromised myocardium. Resting perfusion in these regions with low or no ¹⁸F-FDG uptake will be normal and thus indicate normal viability (26,27). Adding stress perfusion assessment with PET may add diagnostic value, as the hemodynamic effects of each CAD lesion in multivessel disease can be evaluated by the concurrent assessment of MFR, which may help in the decision-making process for complete or incomplete revascularization (9). Thus, this scenario was scored as appropriate (score 9).

Clinical Scenario 165: Patients Who Are Apparent Nonresponders to Pharmacologic Vasodilation with a Need to Change to Dobutamine Stress Testing

• Scenario 165: Symptomatic patients with an intermediate prob ability of CAD who are undergoing functional testing with myocardial perfusion SPECT or PET during pharmacologic stimulation and rest: repeat imaging test with PET but with dobutamine stimulation if there is no hemodynamic response (change in arterial blood pressure or no heart rate increase) during pharmacologic vasodilator stress (Score 3 – Rarely Appropriate)

This issue is controversial, but given the results of the Rampart trial (160) without a correlation among hyperemic coronary flow increases and hemodynamic response during pharmacologic vasodilator stress, this scenario was deemed rarely appropriate (score 3).

Clinical Scenario 166: Patients with Transplant Vasculopathy

• Scenario 166: Symptomatic patients or patients with suspected  cardiac graft rejection (Score 8 – Appropriate)

In symptomatic patients or in those with suspected cardiac graft rejection, PET MPI is unique, as it provides concurrent information about the presence of epicardial obstructive lesions and potential reductions in MFR, reflecting diffuse transplant vasculopathy and CMD (72,73,84,161). In addition, the identification of the severity of CMD may provide critical information about subclinical graft rejection (72). Given these advantages, PET MPI was deemed appropriate (score 8).

Clinical Scenario 167: Patients with Vasculitis and Arteritis (Kawasaki and Takayasu Disease)

• Scenario 167: Symptomatic patients with suspected vasculitis  and arteritis (Score 8 – Appropriate)

In symptomatic patients with suspected vasculitis and arteritis, PET MPI is unique, as it provides concurrent information about the presence of epicardial obstructive lesions and potential reductions in MFR, reflecting diffuse CMD. These patients have a poor outcome if the coronary vessels are affected, leading to ischemia and CMD (152,162). Although no specific outcome data are available related to cardiac perfusion PET, given the advantage of PET MPI to concurrently assess CMD, this clinical scenario was deemed appropriate (score 8).

Clinical Scenarios 168–173: Abnormal Results of a Prior Exercise ECG Test

• Scenario 168: Abnormal results of a prior exercise ECG test <  90 d ago with no intervening revascularization or sequential testing (Score 1 – Rarely Appropriate)

PET MPI < 90 d after abnormal results of a prior exercise ECG test without intervening revascularization is considered rarely appropriate (score 1). A goal-directed lifestyle and medical therapeutic intervention with or without revascularization appears to be appropriate without additional perfusion imaging (163). Serial MPI can identify a reduction in stress perfusion defects and ischemia consistent with a therapeutic response shown by using SPECT MPI or PET MPI (164–166). Although studies have shown incremental risk assessment with quantitative assessment of global myocardial perfusion reserve (MPR) of PET MPI (46,167), reclassification of patients is unlikely to affect clinical management in this group with PET MPI < 90 d after an abnormal prior exercise ECG test without intervening revascularization. If the abnormality on the prior ECG is nondiagnostic of ischemia, for example, with nonspecific t-wave abnormalities or a conduction abnormality such as LBBB, the test would be considered indeterminate for ischemia, and PET MPI would be categorized as appropriate. PET MPI is considered appropriate after equivocal or nondiagnostic categorization of the abnormality on the stress SPECT MPI or prior exercise ECG stress test.

• Scenario 169: Abnormal results of a prior exercise ECG test  (Score 5 – May be Appropriate)

• Scenario 170: Abnormal results of a prior exercise ECG test  with a low-risk Duke treadmill score (DTS) (≥5) (Score 6 – May be Appropriate)

• Scenario 171: Abnormal results of a prior exercise ECG test  with an intermediate-risk DTS (−10 to +4) (Score 8 – Appropriate)

• Scenario 172: Abnormal results of a prior exercise ECG test  with a high-risk DTS (> +4) (Score 8 – Appropriate)

PET MPI after abnormal results of a prior exercise ECG test may be appropriate (score 5). The degree of abnormality of the DTS (168) influences the likelihood that SPECT MPI or PET MPI can provide incremental risk assessment (169). DTS is calculated as follows: (number of minutes of Bruce protocol exercise time) – (5 × mm of ST segment deviation from baseline) – (4 × exercise treadmill test [ETT] angina index [0 for none, 1 for some, 2 for limiting angina during ETT]). With normal and severely abnormal MPI results, patients with intermediate-risk DTS (fatal and nonfatal MI risk 2.5%) are reclassified to low-risk (<0.1%–0.4%) and high-risk (8.9% per year) categories, respectively, and the relative risk of these hard coronary events within intermediate-risk DTS is amplified by more than 22-fold (169,170). The high diagnostic and prognostic accuracy of PET MPI (29,171,172) can be expected to reliably reclassify the risk assignment in this intermediate-risk DTS group. SPECT MPI and PET MPI are appropriate (score 8) in the intermediate-risk (DTS: −10 to +4) and high-risk (DTS: < −10) groups, and may be appropriate (score 6) in the low-risk group (DTS: > 4), similar to that for SPECT MPI (29,171,172).

• Scenario 173: ETT of ≥10 metabolic equivalents (METs)  with no ischemic ST depression (Score 4 – May be Appropriate)

Bourque et al. reported that patients at intermediate risk for CAD or known CAD who achieve ≥10 METs have a very low prevalence of ≥10% LV ischemia and very low rates of cardiac mortality, nonfatal MI, and late revascularization, irrespective of the heart rate achieved (173). Cardiac events did not correlate with abnormalities on the index MPI study. This study suggested that patients who attain ≥10 METs during exercise stress have an excellent prognosis over an intermediate follow-up period, regardless of the peak exercise heart rate achieved. The added value of radionuclide MPI with standard exercise ECG testing in this population is questionable. However, radionuclide MPI demonstrated a 26-fold incremental risk assessment for hard coronary events in similar low-risk DTS patients in a study by Hachamovitch et al. (169). Thus, PET MPI may be appropriate (score 4) in this low-risk group without ST depression at high aerobic capacity of >10 METs during ETT.

Clinical Scenarios 174–179: Abnormal or Uncertain Results of a Prior Stress Imaging Study

• Scenario 174: Abnormal results of a prior stress imaging study  (Score 3 – Rarely Appropriate)

PET MPI after abnormal results of a prior stress imaging study is considered rarely appropriate (score 3). The rationale for this assessment was stated in scenario 168, as a goal-directed lifestyle and medical therapeutic intervention with or without revascularization appears to be appropriate without additional perfusion imaging (163).

• Scenario 175: Equivocal or discordant results of a prior stress  test with or without imaging (Score 8 – Appropriate)

PET MPI after equivocal or discordant results of a prior stress test with or without imaging is appropriate (score 8). PET provides improved image quality and diagnostic accuracy associated with attenuation correction, coincident detection, and higher sensitivity detectors, which provide higher count rate statistics to help resolve equivocal or discordant results of prior imaging or nonimaging stress tests (171,172).

• Scenario 176: CAD of uncertain clinical significance on prior  CCTA or ICA (Score 8 – Appropriate)

PET MPI to assess CAD of uncertain clinical significance on prior CCTA or ICA is appropriate (score 8). Similar to SPECT MPI, PET MPI provides favorable clinical value in the diagnosis, prognosis, and cost-effective management of known or suspected ischemic heart disease.

• Scenario 177: Abnormal prior CCT calcium results (Agatston  score < 100) (Score 2 – Rarely Appropriate)

PET MPI after prior abnormal low CCT calcium results (Agatston score < 100) is rarely appropriate (score 2). The likelihood of morbid coronary events over 10 y in this group of asymptomatic patients with multiple coronary risk factors is very low (<10%) and is affected by sex and Framingham risk profile.

• Scenario 178: Abnormal prior CCT calcium results (Agatston  score 100–400) (Score 5 – May be Appropriate)

PET MPI after prior abnormal intermediate CCT calcium results (Agatston score 100–400) may be appropriate (score 5). The likelihood of morbid coronary events over 10 y in this group of asymptomatic patients with multiple coronary risk factors is significant (10%–20%).

• Scenario 179: Abnormal prior CCT calcium results (Agatston  score 400–1,000 or >1,000) (Score 8 – Appropriate)

PET MPI after prior abnormal high CCT calcium results (Agatston score 400–1,000 or >1,000) is appropriate (score 8). The likelihood of morbid coronary events over 10 y in this group of asymptomatic patients with multiple coronary risk factors is substantial (>20%) (174,175).

ACC/AHA guidelines acknowledge that measurement of CAC can be useful for cardiovascular risk assessment in asymptomatic adults at intermediate or higher risk (10-y risk) (176). PET MPI may be appropriate to provide further incremental risk assessment of CAD, depending on the level of coronary calcium observed.

Clinical Scenarios 180–183: Follow-up Testing (>90 Days): Asymptomatic Patients

The following scenarios address abnormal results of a prior exercise ECG test.

• Scenario 180: Last test <2 y ago (Score 1 – Rarely Appropriate)

• Scenario 181: Last test ≥2 y ago (Score 1 – Rarely Appropriate)

The following scenarios address abnormal results of a prior stress imaging study (non-PET).

• Scenario 182: Last test <2 y ago (Score 2 – Rarely Appropriate)

• Scenario 183: Last test ≥2 y ago (Score 1 – Rarely Appropriate)

PET MPI is rarely appropriate in asymptomatic patients with abnormal results of a prior exercise ECG test performed <2 y or ≥2 y ago. By this time, if indicated, guideline-directed lifestyle and medical therapy would be expected to have been implemented (163). Additional testing is unlikely to change the diagnosis or therapeutic management. However, it is recognized that in certain circumstances of delayed referral to a PET center, PET MPI may be appropriate (score 4).

Clinical Scenarios 184–194: Follow-up Testing (>90 Days): Patients with Stable Symptoms or Asymptomatic Patients

The following scenarios address abnormal results of a prior cardiovascular imaging test in patients with stable symptoms.

• Scenario 184: Last test <2 y ago (Score 1 – Rarely Appropriate)

PET MPI is rarely appropriate (score 1) in patients with stable symptoms lasting >90 d and <2 y. By this time, if indicated, guideline-directed lifestyle and medical therapy would be expected to have been implemented (163). Additional testing is unlikely to change the diagnosis or therapeutic management. However, it is recognized that in certain circumstances of delayed referral to a PET center, PET MPI may be appropriate (score 4).

• Scenario 185: Last test ≥2 y ago (Score 4 – May be Appropriate)

PET MPI may be appropriate (score 4) in patients with abnormal results of a prior non-PET imaging study performed ≥2 y ago. By this time, if indicated, guideline-directed lifestyle and medical therapy would be expected to have been implemented (163), but disease progression may have occurred. Additional testing in these patients with stable symptoms long after initial evaluation might change the diagnosis or therapeutic management.

The following scenarios address abnormal results of a prior stress PET in asymptomatic patients without clinical change.

• Scenario 186: Abnormal results of PET MPI 3–6 mo ago (Score  1 – Rarely Appropriate)

• Scenario 187: Abnormal results of PET MPI > 6 mo ago (Score  2 – Rarely Appropriate)

PET MPI is rarely appropriate in asymptomatic patients without clinical change with abnormal results of stress PET MPI 3–6 or >6 mo ago. By this time, if indicated, guideline-directed lifestyle and medical therapy would be expected to have been implemented. Additional testing is unlikely to change the diagnosis or therapeutic management.

The following scenarios address obstructive CAD on prior coronary angiography (invasive or noninvasive) in asymptomatic patients without clinical change.

• Scenario 188: Last test <2 y ago (Score 6 – May be Appropriate)

• Scenario 189: Last test ≥2 y ago (Score 6 – May be Appropriate)

PET MPI may be appropriate (score 6) in patients with obstructive CAD on prior coronary angiography (invasive or noninvasive) performed <2 y ago and ≥2 y ago, depending on clinical circumstances.

The Economics of Noninvasive Diagnosis study and the PROMISE trial demonstrated the ability of functional imaging with MPI to enhance the diagnostic and prognostic accuracy and the cost-effectiveness of CAD management (177–180). Classic studies on the prognostic value of MPI compared with that of ICA in men (181) and women (108,182,183) demonstrate similar or higher prognostic assessment of MPI compared with that of angiographic stenoses. In the nuclear cardiology substudy of the COURAGE trial, scintigraphic reduction of ischemia associated with guideline-directed medical therapy (GDMT) with or without revascularization was associated with improved outcomes (166). Global ischemic burden can be optimally defined in patients with extensive or multivessel CAD by using dynamic flow analysis, which permits calculation of LV regional and global MFR with PET MPI (29,46,118,167). Women tend to have greater risk of morbid coronary events without the degree of obstructive CAD noted in men, which can be attributable to impaired MPR (108,183). Patients with stable ischemic heart disease on GDMT within 2 y of diagnosis of obstructive coronary disease by angiography would be expected to have a reduced risk of major adverse cardiac events. However, in high-risk patients with multivessel CAD, diabetes, chronic kidney disease, or statin intolerance for which more intensive GDMT may be considered, such as proprotein convertase subtilisin/kexin type 9 inhibitors, follow-up PET MPI may be appropriate to consider. New symptoms or ECG changes may prompt consideration of PET MPI in this group of patients with obstructive angiographic CAD.

The following scenarios address normal results of a prior exercise ECG test in patients with stable symptoms.

• Scenario 190: Low global CAD risk (<7.5%) (Score 1 – Rarely  Appropriate)

PET MPI is rarely appropriate (score 1) in patients with normal results of a prior exercise ECG test with stable symptoms and a low global CAD event risk of <7.5% per decade. In these patients, further testing is highly unlikely to identify CAD that would require treatment.

• Scenario 191: Intermediate CAD risk (7.5%–20%) when tested < 2 y ago (Score 2 – Rarely Appropriate)

• Scenario 192: Intermediate CAD risk (7.5%–20%) when tested ≥ 2 y ago (Score 3 – Rarely Appropriate)

PET MPI is rarely appropriate (score 2) in patients with normal results of a prior exercise ECG test with stable symptoms for <2 y or an intermediate CAD event risk of 7.5%–20% per decade. In these patients, further testing is unlikely to identify CAD that would require treatment. PET MPI continues to be considered rarely appropriate (score 3) ≥2 y after exercise ECG testing in these patients.

• Scenario 193: High global CAD risk (≥20%) when tested <2 y  ago (Score 4 – May be Appropriate)

PET MPI may be appropriate (score 4) in patients with normal results of a prior exercise ECG test with stable symptoms for <2 y and with a high CAD event risk of ≥20% per decade. The global event risk of these patients indicates the need for GDMT (176), and PET MPI may identify angiographic CAD that would benefit from revascularization.

• Scenario 194: High global CAD risk (≥20%) when tested ≥2 y  ago (Score 5 – May be Appropriate)

PET MPI may be appropriate (score 5) in patients with normal results of a prior exercise ECG test with stable symptoms for ≥2 y and with a high CAD event risk of ≥20% per decade. The global event risk of these patients indicates the need for GDMT (176), and PET MPI may identify angiographic CAD that would benefit from revascularization.

Clinical Scenarios 195–197: Preoperative Evaluation of Patients for Noncardiac Surgery

The following scenarios address the preoperative evaluation of patients for noncardiac surgery.

• Scenario 195: Patients with moderate to good functional capacity  (≥4 METs) or no clinical risk factors (history of ischemic heart disease, history of compensated or prior heart failure, history of cerebral vascular disease, diabetes mellitus, renal insufficiency) (Score 1 – Rarely Appropriate)

Patients with moderate to good functional capacity or no clinical risk factors are at low risk of cardiac complications (60) and PET MPI would be rarely appropriate.

• Scenario 196: Asymptomatic patients <1 y after normal func tional stress testing results (Score 1 – Rarely Appropriate)

Patients seen 1 y after normal results of a functional stress test and who remain asymptomatic are unlikely to have abnormal results of a functional stress test on repeat evaluation. These patients are at low risk and PET MPI is rarely appropriate.

• Scenario 197: Asymptomatic patients <2 y after normal coronary  morphology results by either CT or invasive angiogram (Score 1 – Rarely Appropriate)

Patients seen <2 y after invasive or noninvasive angiography that shows normal coronary morphology results and who remain asymptomatic are unlikely to develop significant coronary stenosis. These patients are at low risk and PET MPI is rarely appropriate.

Clinical Scenarios 198–206: Patients with Poor (<4 METs) or Unknown Functional Capacity

The following scenarios address patients with poor (<4 METs) or unknown functional capacity.

• Scenario 198: Low-risk surgery and no clinical risk factors  (Score 1 – Rarely Appropriate)

• Scenario 199: Low-risk surgery and ≥1 clinical risk factor  (Score 2 – Rarely Appropriate)

For patients undergoing low-risk surgery, complications are low, despite poor or unknown functional capacity and with or without clinical risk factors. For these patients, PET MPI is rarely appropriate.

• Scenario 200: Intermediate-risk surgery and no clinical risk  factors (Score 4 – May be Appropriate)

• Scenario 201: Intermediate-risk surgery and ≥ 1 clinical risk  factor (Score 5 – May be Appropriate)

For patients undergoing intermediate-risk surgery, complications are increased compared with those for low-risk surgery and vary with the presence of clinical risk factors. Thus, PET MPI may be appropriate in these patients if it is expected to change management.

• Scenario 202: Vascular surgery with no clinical risk factors (Score  7 – Appropriate)

• Scenario 203: Vascular surgery with ≥1 clinical risk factor (Score  8 – Appropriate)

For patients undergoing vascular surgery, complications are increased compared with those in patients undergoing intermediate-risk surgery and vary with the presence of clinical risk factors. Thus, PET MPI is appropriate in these patients if it is expected to change management.

• Scenario 204: Evaluation for CAD in patients being considered  for kidney transplantation (Score 8 – Appropriate)

• Scenario 205: Evaluation for CAD in patients being considered  for liver transplantation (Score 8 – Appropriate)

• Scenario 206: Evaluation for CAD in patients being considered  for lung transplantation (Score 8 – Appropriate)

For patients undergoing assessment for kidney, liver, or lung transplantation, preoperative screening for CAD with stress MPI is frequently used. Several studies have demonstrated the prognostic value of stress MPI for cardiac events in patients with end-stage renal failure who are being considered for renal transplantation (198–201).

Clinical Scenarios 207–210: Exercise Level Before Exercise Prescription or Cardiac Rehabilitation

• Scenario 207: Exercise prescription (Score 1 – Rarely Appropriate)

• Scenario 208: Determination of exercise level before initiation  of exercise prescription (Score 1 – Rarely Appropriate)

• Scenario 209: Before initiation of cardiac rehabilitation in pa tients able to exercise (Score 1 – Rarely Appropriate)

• Scenario 210: After revascularization (PCI or CABG) (Score 1 –  Rarely Appropriate)

For these scenarios, exercise testing is preferred and stress PET MPI is rarely appropriate.