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Myocardial Perfusion and Viability Imaging in Coronary Artery Disease: Clinical Value in Diagnosis, Prognosis, and Therapeutic Guidance

  • Dan L. Li
    Affiliations
    Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn
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  • Marvin W. Kronenberg
    Correspondence
    Requests for reprints should be addressed to Marvin W. Kronenberg, MD, Vanderbilt Heart and Vascular Institute, Vanderbilt Medical Center East, Ste. 5209, 1215 21st Avenue. South, Nashville, TN, 37232.
    Affiliations
    Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn
    Search for articles by this author
Open AccessPublished:April 14, 2021DOI:https://doi.org/10.1016/j.amjmed.2021.03.011

      Highlights

      • Single photon emission computed tomography has extensive prognostic data for coronary artery disease.
      • Positron emission tomography offers higher accuracy over conventional scintigraphy.
      • Scintigraphic imaging demonstrates physiological significance, whereas coronary computed tomography primarily detects anatomic stenosis.
      • Myocardial viability tests reveal the likelihood of functional improvement following revascularization.
      • The choice of the best test depends on facility resources and individual patient characteristics.

      Abstract

      Coronary artery disease is a leading cause of morbidity and mortality worldwide. Noninvasive imaging tests play a significant role in diagnosing coronary artery disease, as well as risk stratification and guidance for revascularization. Myocardial perfusion imaging, including single photon emission computed tomography and positron emission tomography, has been widely employed. In this review, we will review test accuracy and clinical significance of these methods for diagnosing and managing coronary artery disease. We will further discuss the comparative usefulness of other noninvasive tests—stress echocardiography, coronary computed tomography angiography, and cardiac magnetic resonance imaging—in the evaluation of ischemia and myocardial viability.

      Keywords

      Clinical Significance
      • Single photon emission computed tomography has extensive prognostic data for coronary artery disease.
      • Positron emission tomography offers higher accuracy over conventional scintigraphy.
      • Scintigraphic imaging demonstrates physiological significance while coronary computed tomography primarily detects anatomic stenosis.
      • Myocardial viability tests reveal the likelihood of functional improvement following revascularization.
      • The choice of the best test depends on facility resources and individual patient characteristics.

      Introduction

      Coronary artery disease is a leading cause of mortality and morbidity worldwide.
      • Benjamin EJ
      • Blaha MJ
      • Chiuve SE
      • et al.
      Heart disease and stroke statistics-2017 update: A Report From the American Heart Association.
      Although coronary angiography remains the “gold standard” for diagnosing the presence and severity of coronary artery disease, various noninvasive imaging tests offer high sensitivity and specificity for diagnosis and risk stratification and provide guidance for revascularization. In this article, we will 1) review the clinical usefulness of myocardial perfusion imaging, single photon emission computed tomography and positron emission tomography, for the evaluation of coronary artery disease and myocardial viability; 2) compare the scintigraphic methods to other noninvasive tests, including stress echocardiography, coronary computed tomography angiography, and cardiac magnetic resonance imaging; and 3) demonstrate the role of imaging in evaluating myocardial viability.

      Myocardial Perfusion Imaging

      General Principles

      Myocardial perfusion imaging reflects relative differences in the distribution of blood flow in the myocardium at rest and during stress, which may be produced by exercise or by pharmacological means. Myocardial arterioles distal to a significant epicardial coronary stenosis are dilated by autoregulation to maintain myocardial blood flow at rest. Stress conditions cause significant vasodilation of normal vascular beds, but little additional dilation in vascular beds distal to significant coronary stenoses, leading to differences in perfusion, appearing as “defects” in myocardial perfusion images. This original method has been supplemented by images that demonstrate ventricular function.
      Standard displays of the poststress and rest images are demonstrated and compared in transverse (short axis), vertical long axis and horizontal long axis (Figure 1A). Perfusion defects are described by a standardized 17-segment model of the left ventricle (Figure 1B). An irreversible (fixed) defect (ie, seen on both at rest and stress images) indicates infarction, whereas a perfusion defect seen after stress but reversible (not seen) on resting images indicates myocardial ischemia (Figure 1B). Figure 1C demonstrates correlative angiographic findings.
      Figure 1
      Figure 1An example of myocardial perfusion imaging in correlation with coronary angiogram. (A) Perfusion scan showing anterior and septal ischemia. (B) A 17-segment model corresponding to perfusion imaging. (Severity denoted by numbers and colors.) Moderate-severe reduction of activity on poststress image, mostly reversible on rest image is consistent with ischemia. Mild reduction in activity at rest is due to prior nontransmural infarction. Poststress attenuation corrected image demonstrates that apparent inferior defect on poststress image is largely due to diaphragmatic attenuation. (C) Coronary angiogram demonstrates: 1) Focal 95% stenosis of proximal left anterior descending artery (arrowhead); 2) insignificant lesion of right coronary artery that sends collateral vessels to LAD (arrows); 3) widely patent anterior descending artery following stent placement. AC = attenuation correction; ANT = anterior; HLA = horizontal long axis; INF = inferior; LAT = lateral; SA = short axis; SEP = septal; VLA = vertical long axis.
      Exercise is the preferred stress method because it provides valuable prognostic information.
      • Stone PH
      • Turi ZG
      • Muller JE
      • et al.
      Prognostic significance of the treadmill exercise test performance 6 months after myocardial infarction.
      Pharmacological stress is indicated for 1) patients who are unable to achieve adequate exercise
      • Verzijlbergen JF
      • Vermeersch PH
      • Laarman GJ
      • Ascoop CA.
      Inadequate exercise leads to suboptimal imaging. Thallium-201 myocardial perfusion imaging after dipyridamole combined with low-level exercise unmasks ischemia in symptomatic patients with non-diagnostic thallium-201 scans who exercise submaximally.
      and 2) patients with left bundle branch block or ventricular pacing, which often show relative septal hypoperfusion accentuated by exercise and can be mistakenly interpreted as ischemia.
      • Vaduganathan P
      • He ZX
      • Raghavan C
      • Mahmarian JJ
      • Verani MS.
      Detection of left anterior descending coronary artery stenosis in patients with left bundle branch block: exercise, adenosine or dobutamine imaging?.
      Pharmacological stress tests (regadenoson is most commonly used at present) have similar sensitivity and specificity compared to exercise stress testing.
      • Underwood SR
      • Anagnostopoulos C
      • Cerqueira M
      • et al.
      Myocardial perfusion scintigraphy: the evidence.

      Pitfalls in Study Interpretation

      First, myocardial perfusion imaging may underestimate the presence of 3-vessel or left main disease due to “balanced perfusion defects” during stress.
      • Lima RS
      • Watson DD
      • Goode AR
      • et al.
      Incremental value of combined perfusion and function over perfusion alone by gated SPECT myocardial perfusion imaging for detection of severe three-vessel coronary artery disease.
      ,
      • Berman DS
      • Kang X
      • Slomka PJ
      • et al.
      Underestimation of extent of ischemia by gated SPECT myocardial perfusion imaging in patients with left main coronary artery disease.
      The additional findings of transient ischemic left ventricular dilatation and reduced left ventricular ejection fraction during stress improve the diagnostic sensitivity in these scenarios.
      • Lima RS
      • Watson DD
      • Goode AR
      • et al.
      Incremental value of combined perfusion and function over perfusion alone by gated SPECT myocardial perfusion imaging for detection of severe three-vessel coronary artery disease.
      ,
      • Berman DS
      • Kang X
      • Slomka PJ
      • et al.
      Underestimation of extent of ischemia by gated SPECT myocardial perfusion imaging in patients with left main coronary artery disease.
      Second, disorders other than epicardial coronary disease may produce false-positive findings in patients with nonischemic, dilated cardiomyopathy.
      • Richardson TD
      • Kronenberg MW.
      Reversible myocardial perfusion abnormalities in nonischemic dilated cardiomyopathy.
      ,
      • Chan N
      • Litwok Y
      • Boutis L
      • Makaryus JN.
      SPECT myocardial perfusion imaging findings in a patient with hypereosinophilic myocarditis.
      Importantly, coronary microvascular disease
      • Crea F
      • Camici PG
      • Bairey Merz CN
      Coronary microvascular dysfunction: an update.
      can be associated with perfusion abnormalities. Third, attenuation artifact from the soft tissue can affect study accuracy, although the effect can be reduced by attenuation correction software. Attenuation from an elevated diaphragm can cause an apparent inferior defect, whereas persistent breast attenuation may simulate anterior infarction.
      • Burrell S
      • MacDonald A.
      Artifacts and pitfalls in myocardial perfusion imaging.
      ,
      • Doukky R
      • Rahaby M
      • Chawla D
      • Vashistha R
      • Alyousef T
      • Amin AP
      Soft tissue attenuation patterns associated with upright acquisition SPECT myocardial perfusion imaging: a descriptive study.
      Lateral wall defects may be observed in women and patients who are obese.
      • Doukky R
      • Rahaby M
      • Chawla D
      • Vashistha R
      • Alyousef T
      • Amin AP
      Soft tissue attenuation patterns associated with upright acquisition SPECT myocardial perfusion imaging: a descriptive study.

      Single Photon Emission Computed Tomography for Diagnosis and Prognosis in Coronary Artery Disease

      99mTc-based radiopharmaceuticals have largely replaced 201Tl because of improved dosimetry, better spatial imaging resolution, and less soft-tissue attenuation,
      • Burrell S
      • MacDonald A.
      Artifacts and pitfalls in myocardial perfusion imaging.
      leading to greater test accuracy.
      • Taillefer R
      • DePuey EG
      • Udelson JE
      • Beller GA
      • Latour Y
      • Reeves F.
      Comparative diagnostic accuracy of Tl-201 and Tc-99m sestamibi SPECT imaging (perfusion and ECG-gated SPECT) in detecting coronary artery disease in women.
      The sensitivity and specificity of 99mTc perfusion imaging are reported 68%-74% and 71%-79%, respectively
      • Danad I
      • Szymonifka J
      • Twisk JWR
      • et al.
      Diagnostic performance of cardiac imaging methods to diagnose ischaemia-causing coronary artery disease when directly compared with fractional flow reserve as a reference standard: a meta-analysis.
      ,
      • Takx RA
      • Blomberg BA
      • El Aidi H
      • et al.
      Diagnostic accuracy of stress myocardial perfusion imaging compared to invasive coronary angiography with fractional flow reserve meta-analysis.
      (Table 1). In studies of good quality, the sensitivity and specificity of visually assessed exercise stress 99mTc imaging are 73%-96% and 70%-89%, respectively.
      • Underwood SR
      • Anagnostopoulos C
      • Cerqueira M
      • et al.
      Myocardial perfusion scintigraphy: the evidence.
      Table 1Comparison of Noninvasive Tests (at Patient Level) for Diagnosing Coronary Artery Disease
      TestSensitivitySpecificityAdvantagesDisadvantages
      SPECT0.68-0.74
      • Hachamovitch R
      • Berman DS
      • Shaw LJ
      • et al.
      Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction.
      ,
      • Iskandrian AS
      • Chae SC
      • Heo J
      • Stanberry CD
      • Wasserleben V
      • Cave V.
      Independent and incremental prognostic value of exercise single-photon emission computed tomographic (SPECT) thallium imaging in coronary artery disease.
      0.71-0.79
      • Hachamovitch R
      • Berman DS
      • Shaw LJ
      • et al.
      Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction.
      ,
      • Iskandrian AS
      • Chae SC
      • Heo J
      • Stanberry CD
      • Wasserleben V
      • Cave V.
      Independent and incremental prognostic value of exercise single-photon emission computed tomographic (SPECT) thallium imaging in coronary artery disease.
      • 1)
        Inexpensive, and widely available
      • 2)
        Associated with prognosis
      • 1)
        Radiation exposure
      • 2)
        Higher false-negativity for multivessel disease
      • 3)
        Higher false-positivity due to attenuation
      PET0.84
      • Iskandrian AS
      • Chae SC
      • Heo J
      • Stanberry CD
      • Wasserleben V
      • Cave V.
      Independent and incremental prognostic value of exercise single-photon emission computed tomographic (SPECT) thallium imaging in coronary artery disease.
      0.87
      • Iskandrian AS
      • Chae SC
      • Heo J
      • Stanberry CD
      • Wasserleben V
      • Cave V.
      Independent and incremental prognostic value of exercise single-photon emission computed tomographic (SPECT) thallium imaging in coronary artery disease.
      • 1)
        Greater accuracy than SPECT
      • 2)
        Improved diagnosis of multivessel disease
      • 3)
        Anatomical information
      • 4)
        Associated with prognosis
      • 1)
        Limited by availability and expertise of facility
      • 2)
        Radiation exposure
      Stress echo0.39-0.77
      • Hachamovitch R
      • Berman DS
      • Shaw LJ
      • et al.
      Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction.
      ,
      • Iskandrian AS
      • Chae SC
      • Heo J
      • Stanberry CD
      • Wasserleben V
      • Cave V.
      Independent and incremental prognostic value of exercise single-photon emission computed tomographic (SPECT) thallium imaging in coronary artery disease.
      0.75-0.93
      • Hachamovitch R
      • Berman DS
      • Shaw LJ
      • et al.
      Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction.
      ,
      • Iskandrian AS
      • Chae SC
      • Heo J
      • Stanberry CD
      • Wasserleben V
      • Cave V.
      Independent and incremental prognostic value of exercise single-photon emission computed tomographic (SPECT) thallium imaging in coronary artery disease.
      • 1)
        No radiation or contrast exposure
      • 2)
        Structural information
      • 3)
        Higher specificity in female and obese patients
      • 1)
        Dependence on technical and imaging quality as well as reader experience
      • 2)
        Lower sensitivity for diagnosing single vessel coronary artery disease
      Coronary CT angiogram0.90-0.94
      • Hachamovitch R
      • Berman DS
      • Shaw LJ
      • et al.
      Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction.
      ,
      • Bateman TM
      • Heller GV
      • McGhie AI
      • et al.
      Diagnostic accuracy of rest/stress ECG-gated Rb-82 myocardial perfusion PET: comparison with ECG-gated Tc-99m sestamibi SPECT.


      CTP
      • Shreibati JB
      • Baker LC
      • Hlatky MA.
      Association of coronary CT angiography or stress testing with subsequent utilization and spending among Medicare beneficiaries.
      : 0.83

      FFTCT
      • Shreibati JB
      • Baker LC
      • Hlatky MA.
      Association of coronary CT angiography or stress testing with subsequent utilization and spending among Medicare beneficiaries.
      : 0.89
      0.39-0.48
      • Hachamovitch R
      • Berman DS
      • Shaw LJ
      • et al.
      Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction.
      ,
      • Bateman TM
      • Heller GV
      • McGhie AI
      • et al.
      Diagnostic accuracy of rest/stress ECG-gated Rb-82 myocardial perfusion PET: comparison with ECG-gated Tc-99m sestamibi SPECT.


      CTP
      • Shreibati JB
      • Baker LC
      • Hlatky MA.
      Association of coronary CT angiography or stress testing with subsequent utilization and spending among Medicare beneficiaries.
      : 0.79

      FFRCT
      • Shreibati JB
      • Baker LC
      • Hlatky MA.
      Association of coronary CT angiography or stress testing with subsequent utilization and spending among Medicare beneficiaries.
      : 0.76
      • 1)
        Anatomical details including plaque characteristics
      • 2)
        High sensitivity; also detects atherosclerosis without critical stenosis
      • 1)
        Radiation & contrast exposure
      • 2)
        Relatively low specificity improved with CT-FFRCT or CTP
      • 3)
        Affected by calcium-related artifacts
      Cardiac MRI0.89-0.90
      • Hachamovitch R
      • Berman DS
      • Shaw LJ
      • et al.
      Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction.
      ,
      • Iskandrian AS
      • Chae SC
      • Heo J
      • Stanberry CD
      • Wasserleben V
      • Cave V.
      Independent and incremental prognostic value of exercise single-photon emission computed tomographic (SPECT) thallium imaging in coronary artery disease.
      0.87-0.94
      • Hachamovitch R
      • Berman DS
      • Shaw LJ
      • et al.
      Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction.
      ,
      • Iskandrian AS
      • Chae SC
      • Heo J
      • Stanberry CD
      • Wasserleben V
      • Cave V.
      Independent and incremental prognostic value of exercise single-photon emission computed tomographic (SPECT) thallium imaging in coronary artery disease.
      • 1)
        High sensitivity and specificity
      • 2)
        Detailed structural information
      • 1)
        Expensive and not universally available
      • 2)
        Contraindicated in advanced renal disease
      • 3)
        Affected by arrhythmia, tachycardia and breath-holding skills
      CT = computed tomography; CTP = (coronary) computed tomography perfusion; FFR = (coronary) fractional flow reserve; MRI = magnetic resonance imaging; PET = positron emission tomography; SPECT = single photon emission computed tomography.
      The sensitivity and specificity data are obtained from multiple meta-analyses (see reference), with invasive serving as gold standard. The analyses were performed at patient level to determine the test accuracy in ischemia detection, without localization to a specific vessel.
      Decades of experience with single photon scintigraphy has contributed to abundant data, demonstrating its prognostic role. In a study of 5183 patients, the annual risks of cardiac death and myocardial infarction were 0.3% and 0.5%, respectively, in 2946 patients with normal perfusion images, in contrast to 6% and 9.8%, respectively, in 2237 patients with abnormal images.
      • Murthy VL
      • Naya M
      • Foster CR
      • et al.
      Improved cardiac risk assessment with noninvasive measures of coronary flow reserve.
      In patients with known coronary artery disease, the physiological information obtained by myocardial perfusion imaging improves risk stratification beyond the anatomical information of coronary angiography.
      • Hachamovitch R
      • Berman DS
      • Shaw LJ
      • et al.
      Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction.

      Positron Emission Tomography for Diagnosis of Coronary Artery Disease

      These images are of better quality than single photon computed tomographic images due to better resolution and attenuation correction,
      • Iskandrian AS
      • Chae SC
      • Heo J
      • Stanberry CD
      • Wasserleben V
      • Cave V.
      Independent and incremental prognostic value of exercise single-photon emission computed tomographic (SPECT) thallium imaging in coronary artery disease.
      leading to a greater accuracy in localizing disease to individual coronary arteries.
      • Andrew M
      • John H
      The challenge of coronary calcium on coronary computed tomographic angiography (CCTA) scans: effect on interpretation and possible solutions.
      Importantly, positron emission tomography can quantify myocardial blood flow and myocardial flow reserve, which significantly enhances the diagnosis of coronary artery disease.
      • Andrew M
      • John H
      The challenge of coronary calcium on coronary computed tomographic angiography (CCTA) scans: effect on interpretation and possible solutions.
      The sensitivity and specificity of positron emission imaging was reported 84% and 87%, respectively, in a meta-analysis
      • Takx RA
      • Blomberg BA
      • El Aidi H
      • et al.
      Diagnostic accuracy of stress myocardial perfusion imaging compared to invasive coronary angiography with fractional flow reserve meta-analysis.
      (Table 1).

      Other Methods for Diagnosis of Coronary Artery Disease

      Coronary computed tomography angiography, stress echocardiography, and cardiac magnetic resonance imaging are all useful for the diagnosis of coronary artery disease. Table 1 displays the results of selected, high-quality meta-analyses. The most significant advantages and disadvantages, plus sensitivity and specificity of these methods, are summarized.

      Coronary Computed Tomography Angiography

      The main advantage of coronary tomography angiography is the anatomical detection of coronary lesions with high sensitivity. On the other hand, its specificity is relatively low, largely due to blooming effects from heavy coronary calcification.
      • Danad I
      • Szymonifka J
      • Twisk JWR
      • et al.
      Diagnostic performance of cardiac imaging methods to diagnose ischaemia-causing coronary artery disease when directly compared with fractional flow reserve as a reference standard: a meta-analysis.
      ,
      • Takx RA
      • Blomberg BA
      • El Aidi H
      • et al.
      Diagnostic accuracy of stress myocardial perfusion imaging compared to invasive coronary angiography with fractional flow reserve meta-analysis.
      ,
      • Pontone G
      • Baggiano A
      • Andreini D
      • et al.
      Stress computed tomography perfusion versus fractional flow reserve CT Derived in suspected coronary artery disease: the PERFECTION study.
      Therefore, this method has been more commonly used in younger patients with low to intermediate risk. Recent techniques, including stress perfusion and calculated coronary fractional flow reserve, increase the overall test specificity to 87% and 85%, respectively,
      • Celeng C
      • Leiner T
      • Maurovich-Horvat P
      • et al.
      Anatomical and functional computed tomography for diagnosing hemodynamically significant coronary artery disease: a meta-analysis.
      ,
      • Driessen RS
      • Danad I
      • Stuijfzand WJ
      • et al.
      Comparison of coronary computed tomography angiography, fractional flow reserve, and perfusion imaging for ischemia diagnosis.
      compared to 54% by computed tomography angiography alone
      • Celeng C
      • Leiner T
      • Maurovich-Horvat P
      • et al.
      Anatomical and functional computed tomography for diagnosing hemodynamically significant coronary artery disease: a meta-analysis.
      (Table 1). The coronary fractional flow reserve by computed tomography angiography has better performance than positron emission imaging in identifying vessel-specific lesions;
      • Fihn SD
      • Gardin JM
      • Abrams J
      • et al.
      2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      but on a per-patient level, the specificity is lower.
      • Fihn SD
      • Gardin JM
      • Abrams J
      • et al.
      2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      The current North American guidelines favor noninvasive functional imaging over coronary computed tomography angiography as a first-line diagnostic tool for most patients with suspected myocardial ischemia.
      • Hecht HS
      • Shaw L
      • Chandrashekhar YS
      • Bax JJ
      • Narula J.
      Should NICE guidelines be universally accepted for the evaluation of stable coronary disease? A debate.
      However, the 2016 guideline from the National Institute for Health and Care Excellence (NICE) in the United Kingdom favors coronary computed tomography angiography as the first test in patients without known coronary artery disease.
      • Foy AJ
      • Dhruva SS
      • Peterson B
      • Mandrola JM
      • Morgan DJ
      • Redberg RF.
      Coronary computed tomography angiography vs functional stress testing for patients with suspected coronary artery disease a systematic review and meta-analysis.
      A meta-analysis of randomized clinical trials comparing coronary computed tomography angiography to other imaging methods showed that former was associated with a lower incidence of subsequent myocardial infarction.
      • Douglas PS
      • Hoffmann U
      • Patel MR
      • et al.
      Outcomes of anatomical versus functional testing for coronary artery disease.
      This may be due to detection of nonobstructive disease that prompted more aggressive medical therapy and increased referral for angiography and revascularization.
      • Douglas PS
      • Hoffmann U
      • Patel MR
      • et al.
      Outcomes of anatomical versus functional testing for coronary artery disease.
      The disadvantages of computed tomography angiography include radiation and contrast exposure, the lack of physiological exercise data, and greater expense than myocardial perfusion imaging. This process can increase the number of subsequent cardiac catheterizations
      • Shreibati JB
      • Baker LC
      • Hlatky MA.
      Association of coronary CT angiography or stress testing with subsequent utilization and spending among Medicare beneficiaries.
      and the “downstream costs.”
      • Bateman TM
      • Heller GV
      • McGhie AI
      • et al.
      Diagnostic accuracy of rest/stress ECG-gated Rb-82 myocardial perfusion PET: comparison with ECG-gated Tc-99m sestamibi SPECT.
      This controversy will continue, with more results to follow. The overarching issue will be deciding the best strategy for treating stable coronary artery disease as outlined in recent publications from the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial.
      • Maron DJ
      • Hochman JS
      • Reynolds HR
      • et al.
      Initial invasive or conservative strategy for stable coronary disease.
      ,
      • Spertus JA
      • Jones PG
      • Maron DJ
      • et al.
      Health-status outcomes with invasive or conservative care in coronary disease.
      This controversy highlights the evolution in the choice of diagnostic test from aiming at the “best accuracy” to the “best outcome.”

      Stress Echocardiography

      Similar to perfusion scanning, stress echocardiography, either with exercise or dobutamine stimulation, is commonly employed for evaluating myocardial ischemia by producing ischemic wall motion abnormalities.
      • Armstrong WF
      • Zoghbi WA.
      Stress echocardiography: current methodology and clinical applications.
      The sensitivity of stress echocardiography is lower than 99mTc perfusion imaging, but specificity is greater.
      • Danad I
      • Szymonifka J
      • Twisk JWR
      • et al.
      Diagnostic performance of cardiac imaging methods to diagnose ischaemia-causing coronary artery disease when directly compared with fractional flow reserve as a reference standard: a meta-analysis.
      ,
      • Takx RA
      • Blomberg BA
      • El Aidi H
      • et al.
      Diagnostic accuracy of stress myocardial perfusion imaging compared to invasive coronary angiography with fractional flow reserve meta-analysis.
      This is likely owing to a greater extent of ischemia needed to produce a wall motion abnormality than needed to produce a perfusion abnormality.
      • Danad I
      • Szymonifka J
      • Twisk JWR
      • et al.
      Diagnostic performance of cardiac imaging methods to diagnose ischaemia-causing coronary artery disease when directly compared with fractional flow reserve as a reference standard: a meta-analysis.
      ,
      • Takx RA
      • Blomberg BA
      • El Aidi H
      • et al.
      Diagnostic accuracy of stress myocardial perfusion imaging compared to invasive coronary angiography with fractional flow reserve meta-analysis.
      On the other hand, stress echocardiography has greater specificity than 99mTc perfusion imaging in females and patients with left ventricular hypertrophy.
      • Geleijnse ML
      • Elhendy A.
      Can stress echocardiography compete with perfusion scintigraphy in the detection of coronary artery disease and cardiac risk assessment?.

      Stress Cardiac Magnetic Resonance Imaging

      Magnetic resonance imaging may employ pharmacological vasodilation or dobutamine, each with similar sensitivity and specificity for diagnosing coronary artery disease.
      • Nandalur KR
      • Dwamena BA
      • Choudhri AF
      • Nandalur MR
      • Carlos RC.
      Diagnostic performance of stress cardiac magnetic resonance imaging in the detection of coronary artery disease: a meta-analysis.
      ,
      • Manka R
      • Jahnke C
      • Gebker R
      • Schnackenburg B
      • Paetsch I.
      Head-to-head comparison of first-pass MR perfusion imaging during adenosine and high-dose dobutamine/atropine stress.
      The sensitivity and specificity of stress cardiac magnetic resonance imaging with myocardial perfusion are 89%-90% and 87%-94%, respectively, in meta-analyses.
      • Danad I
      • Szymonifka J
      • Twisk JWR
      • et al.
      Diagnostic performance of cardiac imaging methods to diagnose ischaemia-causing coronary artery disease when directly compared with fractional flow reserve as a reference standard: a meta-analysis.
      ,
      • Takx RA
      • Blomberg BA
      • El Aidi H
      • et al.
      Diagnostic accuracy of stress myocardial perfusion imaging compared to invasive coronary angiography with fractional flow reserve meta-analysis.
      Dobutamine is more often employed when gadolinium is contraindicated. In randomized trials, the sensitivity of stress magnetic resonance imaging was greater than perfusion imaging, but the specificity of perfusion imaging was greater.
      • Schwitter J
      • Wacker CM
      • Wilke N
      • et al.
      MR-IMPACT II: Magnetic Resonance Imaging for Myocardial Perfusion Assessment in Coronary artery disease Trial: perfusion-cardiac magnetic resonance vs. single-photon emission computed tomography for the detection of coronary artery disease: a comparative multicentre, multivendor trial.
      • Schwitter J
      • Wacker CM
      • van Rossum AC
      • et al.
      MR-IMPACT: comparison of perfusion-cardiac magnetic resonance with single-photon emission computed tomography for the detection of coronary artery disease in a multicentre, multivendor, randomized trial.
      • Greenwood JP
      • Maredia N
      • Younger JF
      • et al.
      Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial.
      • Hamon M
      • Fau G
      • Nee G
      • Ehtisham J
      • Morello R
      • Hamon M.
      Meta-analysis of the diagnostic performance of stress perfusion cardiovascular magnetic resonance for detection of coronary artery disease.
      There are several important limitations of cardiac magnetic resonance imaging, including a lack of information about exercise capacity, contraindication in patients with incompatible cardiovascular implantable electronic devices, relatively limited availability of devices, and imaging expertise compared to other methods.

      Limitations of Analyses

      Myocardial ischemia may be due to both epicardial obstructive coronary artery disease and microvascular dysfunction.
      • Crea F
      • Camici PG
      • Bairey Merz CN
      Coronary microvascular dysfunction: an update.
      All tests that are based on physiology demonstrate the summed effects of macrovascular and microvascular causes of ischemia. Thus, they are valuable in this regard but also will not solely reflect epicardial coronary artery disease.
      The extensive literature regarding sensitivity, specificity, and other measures of test validity is subject to potential errors.
      • Hachamovitch R
      • Di Carli MF.
      Methods and limitations of assessing new noninvasive tests: part I: Anatomy-based validation of noninvasive testing.
      ,
      • Hachamovitch R
      • Di Carli MF.
      Methods and limitations of assessingnew noninvasive tests: Part II: outcomes-based validation and reliability assessment of noninvasive testing.
      In addition, the field of analyzing the value of a specific test is evolving toward outcomes evaluation, rather than simply establishing a diagnosis of coronary artery disease. Here, we will discuss the value of scintigraphic imaging and other imaging modalities in predicting revascularization outcomes for patients with ischemic cardiomyopathy.

      Evaluation of Myocardial Viability

      Myocardial stunning and hibernation were defined in 1970s and 1980s. “Myocardial stunning” is the condition of myocardial contractile dysfunction after brief ischemia followed by the relief of ischemia, without irreversible tissue damage.
      • Heyndrickx GR
      • Millard RW
      • McRitchie RJ
      • Maroko PR,
      • Vatner SF.
      Regional myocardial functional and electrophysiological alterations after brief coronary artery occlusion in conscious dogs.
      In contrast, “myocardial hibernation” refers to the condition of chronic contractile dysfunction in the setting of persistent hypoperfusion, with the potential for improved contractility after revascularization.
      • Rahimtoola SH.
      The hibernating myocardium.
      ,
      • Braunwald E
      • Rutherford JD.
      Reversible ischemic left ventricular dysfunction: evidence for the "hibernating myocardium".
      Both stunned and hibernating myocardium are considered viable.
      Revascularization in patients with ischemic cardiomyopathy can reduce long-term mortality.
      • Killip T
      • Passamani E
      • Davis K
      Coronary-Artery Surgery Study (Cass) - a randomized trial of coronary-bypass surgery - 8 years follow-up and survival in patients with reduced ejection fraction.
      • Chaitman BR
      • Ryan TJ
      • Kronmal RA
      • Foster ED
      • Frommer PL
      • Killip T.
      Coronary-Artery Surgery Study (Cass) - comparability of 10 year survival in randomized and randomizable patients.
      • Velazquez EJ
      • Lee KL
      • Jones RH
      • et al.
      Coronary-artery bypass surgery in patients with ischemic cardiomyopathy.
      However, cardiac performance improves in some but, not all, patients.
      • Rizzello V
      • Poldermans D
      • Biagini E
      • et al.
      Prognosis of patients with ischaemic cardiomyopathy after coronary revascularisation: relation to viability and improvement in left ventricular ejection fraction.
      Selection of the patients with ischemic and viable myocardium who will benefit from revascularization has been the goal of myocardial viability studies. Hibernating or stunned myocardium can be detected by multiple imaging modalities, including scintigraphic imaging, dobutamine stress echocardiography, and cardiac magnetic resonance imaging.

      Single Photon Emission Computed Tomography

      Both 201Tl and 99mTc-based imaging has been studied, but 201Tl has been more commonly employed for detecting hibernating myocardium.
      • Bonow RO
      • Dilsizian V.
      Assessing viable myocardium with thallium-201.
      Bonow et al
      • Bonow RO
      • Dilsizian V.
      Assessing viable myocardium with thallium-201.
      showed generally good correlation for detecting viable myocardium between 201Tl imaging and 18F-flurodeoxyglucose positron emission tomography imaging. However, with severe, irreversible 201Tl defects, positron imaging was superior.
      • Bonow RO
      • Dilsizian V.
      Assessing viable myocardium with thallium-201.

      Positron Emission Tomography for Assessing Myocardial Viability

      Metabolic imaging with 18F-fluorodeoxyglucose reflects myocardial glucose uptake, consistent with viability and has the highest sensitivity among the viability tests
      • Schinkel AF
      • Bax JJ
      • Poldermans D
      • Elhendy A
      • Ferrari R
      • Rahimtoola SH.
      Hibernating myocardium: diagnosis and patient outcomes.
      (Table 2). A comprehensive meta-analysis of pooled studies
      • Schinkel AF
      • Bax JJ
      • Poldermans D
      • Elhendy A
      • Ferrari R
      • Rahimtoola SH.
      Hibernating myocardium: diagnosis and patient outcomes.
      showed a sensitivity and specificity in predicting segmental wall motion improvement after revascularization of 87% and 54% by 201TI-based protocols and 92% and 63% for 18F-fluorodeoxyglucose positron emission tomography
      • Schinkel AF
      • Bax JJ
      • Poldermans D
      • Elhendy A
      • Ferrari R
      • Rahimtoola SH.
      Hibernating myocardium: diagnosis and patient outcomes.
      (Table 2). It is preferred in facilities with this technology and experience.
      Table 2Comparison of Myocardial Viability Tests for Predicting Recovery of Contractility Following Coronary Revascularization
      • Maddahi J
      • Schelbert H
      • Brunken R
      • Di Carli M.
      Role of thallium-201 and PET imaging in evaluation of myocardial viability and management of patients with coronary artery disease and left ventricular dysfunction.
      TestStudies (N)Patients (N)Sensitivity (%)Specificity (%)PPV (%)NPV (%)
      201Tl SPECT40111987546779
      99mTc SPECT2572183657476
      PET2475692637487
      DSE41142180787583
      Dobutamine CMR927274827878
      CMR with gadolinium517884637278
      CMR = cardiac magnetic resonance; DSE = dobutamine stress echocardiography; NPV = negative predictive value; PET = positron emission tomography; PPV = positive predictive value; SPECT = single photon emission computed tomography.
      Data are summarized from the meta-analysis by Schinkel et al.
      • Maddahi J
      • Schelbert H
      • Brunken R
      • Di Carli M.
      Role of thallium-201 and PET imaging in evaluation of myocardial viability and management of patients with coronary artery disease and left ventricular dysfunction.
      Four principal patterns of perfusion and metabolism may be observed on perfusion and metabolism images
      • Anselm DD
      • Anselm AH
      • Renaud J
      • et al.
      Altered myocardial glucose utilization and the reverse mismatch pattern on rubidium-82 perfusion/F-18-FDG PET during the sub-acute phase following reperfusion of acute anterior myocardial infarction.
      (Figure 2). 1) Normal perfusion and metabolism suggest normal myocardium or ischemic stunning in the setting of reduced contractility; 2) reduced perfusion with preserved metabolism (perfusion-metabolism mismatch) suggests hibernating myocardium; 3) the combination of reduced perfusion and metabolism (matched defects) indicates nonviable, infarcted myocardium; and 4) rarely, a “reverse mismatch pattern” is found where normal perfusion coexists with reduced metabolism. This has been observed early after revascularization
      • Fukuoka Y
      • Nakano A
      • Uzui H
      • et al.
      Reverse blood flow-glucose metabolism mismatch indicates preserved oxygen metabolism in patients with revascularised myocardial infarction.
      and reflects a shift of metabolic substrate to free fatty acids.
      • Birnie D
      • de Kemp RA
      • Tang AS
      • et al.
      Reduced septal glucose metabolism predicts response to cardiac resynchronization therapy.
      Other rare instances have also been reported.
      • Maddahi J
      • Schelbert H
      • Brunken R
      • Di Carli M.
      Role of thallium-201 and PET imaging in evaluation of myocardial viability and management of patients with coronary artery disease and left ventricular dysfunction.
      ,
      • Hansen AK
      • Gejl M
      • Bouchelouche K
      • Tolbod LP
      • Gormsen LC.
      Reverse mismatch pattern in cardiac 18F-FDG Viability PET/CT is not associated with poor outcome of revascularization: a retrospective outcome study of 91 patients with heart failure.
      Figure 2
      Figure 2Patterns of myocardial viability on positron emission tomographic images.

      Other Methods: Dobutamine Stress Echocardiography and Cardiac Magnetic Resonance Imaging

      Dobutamine stress echocardiography and dobutamine stress cardiac magnetic resonance imaging examine myocardial contractile reserve. An improvement of wall motion in hypokinetic/akinetic regions with low-dose dobutamine followed by deterioration with higher-dose dobutamine signifies hibernating myocardium. These tests predict functional recovery after revascularization with higher specificity than nuclear viability tests but lower sensitivity.
      • Schinkel AF
      • Bax JJ
      • Poldermans D
      • Elhendy A
      • Ferrari R
      • Rahimtoola SH.
      Hibernating myocardium: diagnosis and patient outcomes.
      ,
      • Bax JJ
      • Poldermans D
      • Elhendy A
      • Boersma E
      • Rahimtoola SH.
      Sensitivity, specificity, and predictive accuracies of various noninvasive techniques for detecting hibernating myocardium.
      Magnetic resonance imaging with gadolinium assesses the extent of infarction. Segments with significant wall thinning (<6 mm) and ≥50% transmural scar have a low likelihood of improvement after revascularization and are considered nonviable.
      • Schinkel AF
      • Bax JJ
      • Poldermans D
      • Elhendy A
      • Ferrari R
      • Rahimtoola SH.
      Hibernating myocardium: diagnosis and patient outcomes.
      ,
      • Kim RJ
      • Wu E
      • Rafael A
      • et al.
      The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction.
      A sensitivity and specificity of 84% and 63%, respectively, was reported for this method
      • Schinkel AF
      • Bax JJ
      • Poldermans D
      • Elhendy A
      • Ferrari R
      • Rahimtoola SH.
      Hibernating myocardium: diagnosis and patient outcomes.
      (Table 2).

      Clinical Value of Viability Tests

      A large body of observational nonrandomized studies suggested the value of myocardial viability tests for estimating the prognosis of patients with ischemic cardiomyopathy treated with revascularization compared to medical therapy.
      • Rizzello V
      • Poldermans D
      • Biagini E
      • et al.
      Prognosis of patients with ischaemic cardiomyopathy after coronary revascularisation: relation to viability and improvement in left ventricular ejection fraction.
      ,
      • Allman KC
      • Shaw LJ
      • Hachamovitch R
      • Udelson JE.
      Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: A meta-analysis.
      ,
      • Gerber BL
      • Rousseau MF
      • Ahn SA
      • et al.
      Prognostic value of myocardial viability by delayed-enhanced magnetic resonance in patients with coronary artery disease and low ejection fraction: impact of revascularization therapy.
      Here we will discuss 2 important studies that call into question the benefit of myocardial viability tests and the caveats within.
      A landmark trial to study the clinical impact of viability tests was the PET And Recovery following Revascularization 2 (PARR-2) study, which randomized 430 patients with ischemic cardiomyopathy into a positron emission tomography guided-therapy group and a standard care group. Overall, there was no difference in the cardiac outcome at 1 year.
      • Beanlands RS
      • Nichol G
      • Huszti E
      • et al.
      F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2).
      However, recommendations from the radionuclide study were not followed in 25.7% of the patients in the imaging-guided arm.
      • Beanlands RS
      • Nichol G
      • Huszti E
      • et al.
      F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2).
      A post hoc analysis (Ottawa-FIVE) included the subset of 111 patients enrolled at the University of Ottawa Heart Institute, in which the imaging guidance was followed. This analysis showed a significant reduction of composite cardiac events in the imaging-guided arm (hazard ratio [HR] = 0.37, P = .009).
      • Abraham A
      • Nichol G
      • Williams KA
      • et al.
      18F-FDG PET imaging of myocardial viability in an experienced center with access to 18F-FDG and integration with clinical management teams: the Ottawa-FIVE substudy of the PARR 2 trial.
      This study remains the only randomized study to date that has used positron emission tomography to guide revascularization strategy.
      The Surgical Treatment for Ischemic Heart Failure (STICH) Trial tested the survival benefit of coronary artery bypass grafting for patients with ischemic cardiomyopathy.
      • Velazquez EJ
      • Lee KL
      • Deja MA
      • et al.
      Coronary-artery bypass surgery in patients with left ventricular dysfunction.
      A total of 601 patients from the 1212 patients enrolled in the trial underwent single photon myocardial perfusion imaging or dobutamine stress echocardiography to test for myocardial viability after randomization. Surgical revascularization plus medical therapy offered a survival benefit over medical therapy alone, but the myocardial viability results had no significant impact on the benefit of revascularization.
      • Panza JA
      • Ellis AM
      • Al-Khalidi HR
      • et al.
      Myocardial viability and long-term outcomes in ischemic cardiomyopathy.
      This study has met criticism for several reasons.
      • Redfors B
      • Stone GW.
      Myocardial viability and CABG surgery: a Bayesian appraisal of STICH.
      ,
      • Beller GA.
      More evidence for the survival benefit of coronary revascularization versus medical therapy in patients with ischemic cardiomyopathy and hibernating myocardium.
      The STICH viability study was observational and potentially affected by selection bias because viability imaging was nonrandomized and performed in only half of the 1212 enrollees. Further, because 81% of patients had positive viability tests, the study was judged to be underpowered to address the importance of viability testing.
      • Redfors B
      • Stone GW.
      Myocardial viability and CABG surgery: a Bayesian appraisal of STICH.
      Finally, the methods for assessing viability did not include positron emission tomography or magnetic resonance imaging, which are more sensitive methods. Recent but nonrandomized studies using positron emission tomography have lent support to the concept of testing ischemia and viability in ischemic cardiomyopathy.
      • Gerber BL
      • Rousseau MF
      • Ahn SA
      • et al.
      Prognostic value of myocardial viability by delayed-enhanced magnetic resonance in patients with coronary artery disease and low ejection fraction: impact of revascularization therapy.
      ,
      • Ling LF
      • Marwick TH
      • Flores DR
      • et al.
      Identification of therapeutic benefit from revascularization in patients with left ventricular systolic dysfunction: inducible ischemia versus hibernating myocardium.
      Thus, the weight of evidence supports the value of viability testing for defining the likelihood of major adverse cardiac events and functional recovery following revascularization in ischemic cardiomyopathy.

      Conclusion

      Scintigraphic methods play pivotal roles in the clinical diagnosis and management of coronary artery disease. 99mTc-based myocardial perfusion imaging is widely available and has ample data for judging prognosis, whereas positron emission imaging offers greater accuracy for diagnosing coronary artery disease and myocardial viability. Scintigraphic methods and others, such as stress echocardiography, cardiac computed tomography angiography, and cardiac magnetic resonance imaging, have different profiles of advantages and disadvantages. The choice of a specific diagnostic test should be tailored to the individual patient as well as facility resources. The field of test interpretation has evolved from simply detecting the presence of obstructive coronary artery disease to the evaluation of patient outcomes. Illustrating this are 2 issues: 1) the selection between functional stress testing versus anatomic definition (using coronary computed tomography angiography) for the diagnosis of coronary artery disease and 2) the use of myocardial viability testing in predicting outcomes following revascularization.

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