Myocardial Perfusion Imaging With SPECT and PET

Definition and Clinical Purpose

Myocardial perfusion imaging (MPI) with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) is a radionuclide-based method for assessing regional myocardial blood flow, inducible ischaemia, myocardial scar, ventricular function, and, in selected circumstances, myocardial viability.

Both techniques rely on intravenous radiopharmaceuticals that are taken up by myocardial tissue. The distribution of retained tracer provides tomographic information about relative regional perfusion. Imaging is generally performed at rest and during exercise or pharmacological stress, allowing comparison between myocardial blood-flow states.

MPI is used principally to:

• Diagnose and quantify stress-induced myocardial ischaemia.

• Detect and characterize myocardial scar.

• Estimate the risk of major adverse cardiovascular events.

• Assess left ventricular volumes, regional wall motion, and ejection fraction using ECG-gated acquisitions.

• Quantify myocardial blood flow and myocardial flow reserve with PET.

• Evaluate myocardial viability, particularly when combined with metabolic imaging.

• Contribute to assessment of cardiac inflammation, infective endocarditis, and cardiac amyloidosis using appropriate radiopharmaceuticals.

Functional perfusion imaging primarily identifies haemodynamically important disease. Non-obstructive coronary atherosclerosis not associated with demonstrable ischaemia may therefore remain undetected unless CT-based coronary calcium assessment or another anatomical technique is added.

Pathophysiological Basis

Stress MPI is based on the principle that flow-limiting coronary disease limits the ability of a myocardial territory to augment blood flow during exercise or pharmacological vasodilation. Relative differences in regional tracer uptake during stress are compared with rest images or with a normally perfused reference region.

A stress-induced reduction in tracer uptake that improves at rest indicates reversible hypoperfusion and is consistent with inducible ischaemia. A persistent defect on stress and rest images may represent scar, although interpretation must account for attenuation and other technical factors.

Relative perfusion assessment has an important limitation: it requires a normally perfused reference territory. In diffuse coronary disease, balanced multivessel disease, or global impairment of microvascular vasodilation, regional differences may be underestimated. PET addresses this limitation by allowing absolute myocardial blood-flow quantification and calculation of myocardial flow reserve.

Myocardial flow reserve is the ratio of stress myocardial blood flow to resting myocardial blood flow. It provides an integrated measure influenced by epicardial stenosis, diffuse atherosclerosis, and coronary microvascular dysfunction. A reduced value may therefore identify clinically important vascular dysfunction even when regional perfusion images appear normal.

Radionuclide imaging can also assess viability. SPECT and PET perfusion imaging evaluate blood-flow-related tracer retention, whereas metabolic 18F-fluorodeoxyglucose (18F-FDG) PET assesses myocardial glucose metabolism. Areas with reduced perfusion but preserved 18F-FDG uptake represent a perfusion–metabolism mismatch and may indicate viable, hibernating myocardium.

Clinical Indications

Suspected or Known Chronic Coronary Syndrome

Stress SPECT or, preferably where available, PET MPI is recommended in individuals with suspected chronic coronary syndrome and a moderate or high pre-test likelihood of obstructive coronary artery disease, defined in the cited guidance as greater than 15% and up to 85%.

The examination may be used to:

• Establish the presence of ischaemia or scar.

• Quantify the extent of myocardial involvement.

• Estimate major adverse cardiovascular event risk.

• Quantify myocardial blood flow when PET is used.

SPECT is recommended in suspected chronic coronary syndrome with moderate or high pre-test likelihood or in known chronic coronary syndrome. PET is particularly valuable when absolute flow quantification is clinically important or when SPECT image quality is likely to be limited.

Patients Unable to Exercise Adequately

Exercise is generally preferred because it provides physiological information, including exercise duration, symptoms, haemodynamic response, functional capacity, and ST-segment behaviour. Submaximal exercise lowers diagnostic sensitivity and should be avoided when the purpose is initial diagnosis of coronary disease.

Pharmacological stress is an alternative when exercise is impossible or inadequate. Vasodilators such as adenosine, dipyridamole, and regadenoson are commonly used. Dobutamine, a β1-receptor agonist that increases contractility, heart rate, blood pressure, and myocardial oxygen demand, is another option and may be used when vasodilator stress is unsuitable, including in selected patients with chronic pulmonary disease.

Special Situations Favouring PET

PET MPI is particularly useful when:

• Prior stress imaging was poor quality, equivocal, inconclusive, or affected by attenuation artefact.

• Imaging findings are discordant with the clinical assessment or coronary angiography.

• Obesity, large breasts, or breast implants are likely to compromise image quality.

• Diagnostic error carries particular clinical consequences, including in diabetes, chronic kidney disease, or high-risk coronary disease.

• Repeated radiation exposure is anticipated, especially in younger patients with established coronary disease.

• Quantitative myocardial blood-flow measurement is required.

• Multivessel disease or diffuse flow impairment is suspected.

• More specific physiological assessment is needed in known coronary disease.

• Heart-transplant vasculopathy is suspected.

Myocardial Viability

In patients with severe left ventricular dysfunction and angiographic coronary disease, stress perfusion imaging may be combined with metabolic imaging to distinguish viable from nonviable myocardium.

PET provides a comprehensive approach by combining perfusion, quantitative flow assessment, ventricular function, and 18F-FDG metabolic imaging. Where PET is unavailable, thallium-201 SPECT may be used as an alternative for viability assessment, particularly in settings of severe resting hypoperfusion.

Other Applications

Radionuclide imaging also has roles in:

• Cardiac amyloidosis, using bone-seeking technetium-labelled agents.

• Myocardial and vascular inflammation, including 18F-FDG PET.

• Suspected infective endocarditis, particularly prosthetic valve endocarditis when echocardiography is inconclusive.

• Identification of septic emboli and distant infectious foci in infective endocarditis.

• Assessment of response to antimicrobial therapy in selected patients with established infective endocarditis who cannot undergo indicated surgery and remain on suppressive antibiotic treatment.

Clinical Presentation and Symptoms

The source material focuses on the imaging evaluation of patients with suspected or known coronary disease rather than on a distinct symptom complex. MPI may be performed in patients with symptoms suspicious for myocardial ischaemia, including patients unable to complete diagnostic-level exercise testing.

In suspected acute coronary syndrome, a normal radionuclide perfusion study in a patient with low-level troponin elevation, no typical symptoms or ECG changes, and intermediate clinical risk is associated with very low short-term cardiac mortality. Conversely, an abnormal study identifies a higher-risk group, and the extent of stress-induced ischaemia can help determine the need for coronary angiography and possible revascularization.

Evaluation and Physical Examination

The source material does not provide a dedicated physical-examination framework for MPI. Clinical assessment before testing should therefore be understood primarily in terms of determining:

• The likelihood of obstructive coronary disease.

• The patient’s ability to exercise adequately.

• The presence of factors likely to impair image quality.

• The clinical question: ischaemia, scar, viability, ventricular function, flow quantification, inflammation, infection, or amyloidosis.

• Whether stress should be exercise-based or pharmacological.

Exercise testing additionally supplies information about symptoms, exercise duration, functional status, haemodynamic responses, and ST-segment changes.

Radiopharmaceuticals

SPECT Agents

Technetium-99m (99mTc)-sestamibi and 99mTc-tetrofosmin are the principal SPECT perfusion tracers. They emit 140-keV gamma rays and have a physical half-life of approximately 6 hours. After intravenous injection, they enter cardiomyocytes in proportion to blood flow and become associated with mitochondria within approximately 60–90 seconds. They demonstrate minimal redistribution, allowing imaging to be delayed for several hours and permitting use with either exercise or pharmacological stress.

Thallium-201 has a longer physical half-life, approximately 72–73 hours, and emits lower-energy photons. It enters cardiomyocytes through the Na+/K+ ATPase pump and redistributes over time. Although redistribution can assist viability assessment, its greater radiation exposure means that it is no longer recommended routinely for perfusion imaging. It remains an alternative for viability evaluation when PET or CMR is unavailable.

PET Agents

Common PET perfusion tracers include 13N-ammonia, 15O-water, and rubidium-82. Their short half-lives, ranging from seconds to minutes, generally require production or preparation close to the time of imaging. PET perfusion is therefore most often paired with pharmacological stress, although exercise is possible with longer-lived agents such as 13N-ammonia.

18F-flurpiridaz is a newer 18F-labelled PET perfusion tracer that binds mitochondrial complex I and has rapid myocardial uptake. Its approximately 110-minute half-life permits distribution as unit doses and allows use with exercise stress. In the cited phase III study, it demonstrated higher sensitivity than SPECT for detecting obstructive coronary disease and had non-inferior specificity, with better image quality and lower radiation exposure than the compared SPECT protocols.

SPECT Myocardial Perfusion Imaging

Acquisition Principles

SPECT images regional myocardial tracer retention, which reflects relative regional myocardial blood flow. Imaging is obtained at rest and during stress, using exercise or pharmacological agents.

Protocols may be stress-only, single-day, or two-day studies, depending on the clinical question, patient characteristics, and local practice. Technetium-labelled agents are preferred because of their image quality, availability, and lower radiation burden compared with thallium-201.

Newer cadmium-zinc-telluride detector systems can reduce acquisition time and radiation exposure while improving diagnostic accuracy. Some advanced SPECT systems can also quantify myocardial blood flow.

Interpretation

Important SPECT findings include:

• Reversible perfusion defects, indicating inducible ischaemia.

• Fixed defects, suggesting scar or persistent hypoperfusion.

• The size and severity of the perfusion abnormality.

• Transient ischaemic dilation.

• Post-stress reduction in ejection fraction.

• Left ventricular volumes and regional wall-motion abnormalities from gated images.

• Coronary artery calcium when the accompanying CT permits calcium assessment.

A normal rest study obtained after tracer injection during active chest pain has a high negative predictive value for myocardial ischaemia as the cause of the symptoms.

Limitations

SPECT depends on a normally perfused reference region. This can reduce sensitivity for balanced multivessel disease and diffuse impairment of microvascular vasodilation. SPECT also provides relative rather than routinely absolute measurements of myocardial blood flow.

Functional testing in general may fail to identify non-obstructive coronary atherosclerosis that is not associated with demonstrable ischaemia. Additional calcium scoring or anatomical imaging may therefore provide clinically important complementary information.

PET Myocardial Perfusion Imaging

Acquisition and Stress

PET perfusion imaging is generally performed at rest and during pharmacological stress with a vasodilator or, in selected protocols, dobutamine. PET is faster than SPECT but more expensive and less widely available. Exercise is technically difficult with many short-lived PET tracers.

PET/CT routinely includes low-dose non-contrast CT for attenuation correction. The CT component may also permit coronary artery calcium scoring. CT coronary angiography can be performed in hybrid systems, although routine combination of PET or SPECT MPI with coronary CT angiography is not recommended because of the higher radiation burden. Sequential testing may be useful in complex cases.

Relative Perfusion

PET generates relative perfusion images analogous to SPECT but generally with superior spatial and contrast resolution and lower radiation exposure. Relative perfusion identifies regional differences in tracer retention during stress and rest.

Quantitative Myocardial Blood Flow

The distinctive strength of PET is the ability to quantify absolute myocardial blood flow, including:

• Resting myocardial blood flow.

• Hyperaemic or stress myocardial blood flow.

• Myocardial flow reserve.

• Relative myocardial flow reserve.

Dynamic PET acquisition tracks tracer passage through the blood pool and myocardium. Compartmental analysis uses an arterial input function and myocardial time–activity curves, with corrections for tracer extraction, decay, and limited spatial resolution.

Myocardial flow reserve is calculated from rest and stress flow measurements. It provides diagnostic and prognostic information beyond relative perfusion imaging and is particularly useful in suspected diffuse coronary disease, multivessel disease, and microvascular dysfunction.

A low myocardial flow reserve may independently predict mortality and may identify patients who derive survival benefit from early revascularization with percutaneous coronary intervention or coronary artery bypass grafting, beyond the extent of visually assessed ischaemia.

Limitations

PET limitations include:

• Restricted availability.

• Higher cost.

• Methodological variation, particularly in thresholds used to define abnormal quantitative measurements.

• Difficulty performing physical exercise.

• Dependence on suitable radiopharmaceutical production or supply.

ECG-Gated Imaging and Ventricular Function

SPECT and PET data can be acquired in ECG-gated mode. The cardiac cycle is commonly divided into 8–16 frames. Gated imaging permits assessment of:

• Regional wall motion.

• Left ventricular end-diastolic and end-systolic volumes.

• Left ventricular ejection fraction.

• Ventricular dyssynchrony with specialized software.

The ejection fraction is derived from the relationship between end-diastolic and end-systolic volume:

Ejection fraction = (left ventricular end-diastolic volume − left ventricular end-systolic volume) ÷ left ventricular end-diastolic volume × 100

Gated perfusion imaging therefore integrates perfusion and ventricular function in a single examination. The extent of scar, the severity of stress-induced ischaemia, ventricular dilatation, and reduced ejection fraction are major determinants of prognosis.

Hybrid CT Imaging

Attenuation Correction

Attenuation-correction CT is a low-dose, non-contrast, ungated chest acquisition performed during free tidal breathing. It corrects for inhomogeneous attenuation caused by overlying soft tissues and improves interpretation of SPECT or PET images.

Coronary Calcium Scoring

A dedicated calcium-score CT is non-contrast and prospectively ECG-gated, usually acquired during an inspiratory breath-hold. Coronary artery calcium scoring can also be assessed from the attenuation-correction CT in some systems.

Calcium scoring adds information about both non-obstructive and obstructive coronary atherosclerosis, including in patients whose perfusion study does not demonstrate flow-limiting disease. In individuals undergoing SPECT or PET MPI, measuring coronary artery calcium from the unenhanced CT used for attenuation correction is recommended to improve detection of coronary disease.

CT Coronary Angiography

Coronary CT angiography is prospectively ECG-gated, uses iodinated contrast, and is performed during an inspiratory breath-hold. It may be combined with PET or SPECT in selected complex cases, but routine combination is discouraged because of the associated radiation burden.

Other Nuclear Imaging Applications

Infective Endocarditis

18F-FDG PET/CT and white blood cell SPECT/CT are recommended in suspected prosthetic valve endocarditis when echocardiography is inconclusive.

18F-FDG PET/CT is particularly useful for detecting prosthetic-valve infection, periprosthetic complications, septic emboli, mycotic aneurysms outside the brain, and the portal of entry of infection. Whole-body imaging may identify lesions in the spleen, lungs, kidneys, vertebral structures, muscles, joints, and liver.

Its performance is less favourable in native-valve endocarditis, where sensitivity is low despite high specificity. A negative scan therefore does not exclude native-valve infection. White blood cell SPECT/CT provides an alternative when PET/CT is unavailable or local experience is limited.

Combining PET with CT angiography can provide metabolic and anatomical information in a single examination and may be especially helpful in complex congenital heart disease or aortic graft settings.

Cardiac Amyloidosis

Bone-seeking technetium-labelled tracers, including 99mTc-PYP, 99mTc-HMDP, and 99mTc-DPD, are used in the evaluation of cardiac amyloidosis. These scans are more frequently positive in transthyretin amyloidosis but may also show modest positivity in light-chain amyloidosis.

Cardiac Sarcoidosis and Inflammation

18F-FDG PET may aid diagnosis, prognosis, and management of cardiac sarcoidosis. A heterogeneous myocardial uptake pattern may occur in cardiac sarcoidosis, contrasting with the diffuse uptake described in dilated cardiomyopathy and normal subjects. Following successful immunosuppressive treatment, myocardial 18F-FDG uptake may normalize.

Biomarkers and Laboratory Findings

The source material does not provide a laboratory panel or biomarker protocol specific to MPI. It does describe the relationship between low-level cardiac troponin elevation and PET findings.

In patients without typical symptoms or diagnostic ECG changes, low-level troponin elevation may reflect heterogeneous mechanisms. Impaired global myocardial flow reserve in the absence of obstructive coronary disease has been associated with troponin elevation, supporting a possible relationship between chronic microvascular ischaemia, diffuse atherosclerosis, and myocardial injury.

Quantitative PET flow assessment may therefore provide prognostic information beyond conventional clinical markers in intermediate- to high-risk patients with low-level troponin elevation.

Artificial Intelligence and Machine Learning

Machine-learning approaches have been investigated for:

• Predicting obstructive coronary disease from fast myocardial perfusion SPECT.

• Guiding prognostically safe stress-only SPECT protocols.

• Combining clinical and myocardial perfusion data to improve prognostic assessment.

The source material identifies these applications but does not provide sufficient information to define a routine clinical implementation strategy.

Guideline Recommendations

The cited European guideline recommendations can be summarized as follows:

Prognosis and Risk Stratification

MPI provides robust prognostic information. Risk is determined by the combined burden of:

• Stress-induced ischaemia.

• Myocardial scar.

• Left ventricular dilation.

• Reduced ejection fraction.

• Regional and global perfusion abnormalities.

• Quantitative myocardial blood flow and flow reserve when PET is used.

A normal or low-risk rest/stress MPI study is associated with a low annual risk of major adverse cardiovascular events, although the cited material emphasizes that this low-risk implication is not uniform across all populations. Patients with diabetes, chronic kidney disease, advanced age, hypertension, obesity, or other comorbidities may retain increased risk despite visually normal perfusion.

In higher-risk patients, preserved PET myocardial flow reserve can help identify individuals with genuinely low risk, whereas markedly reduced flow reserve identifies additional risk not apparent from relative perfusion alone.

The risk associated with an abnormal study rises with the extent and severity of the perfusion defect. Fixed defects, especially when accompanied by ventricular dilation and reduced ejection fraction, are associated particularly with cardiac death. Reversible defects are more closely related to subsequent nonfatal myocardial infarction. The combination of extensive scar, adverse ventricular remodelling, and reduced ejection fraction represents the highest-risk pattern.

In patients with suspected acute coronary syndrome, low-risk, intermediate-risk, and high-risk perfusion findings are associated with progressively greater risks of death and myocardial infarction. The magnitude of residual stress-induced ischaemia can assist decisions regarding coronary angiography and revascularization.

Follow-Up and Management Implications

MPI results should be integrated with symptoms, clinical risk, ventricular function, coronary calcium burden, and—when available—quantitative PET flow measurements.

A normal or low-risk study may support conservative management when the overall clinical context is consistent with low risk. An abnormal study, particularly one showing extensive ischaemia, scar, ventricular dilation, reduced ejection fraction, or severely impaired myocardial flow reserve, identifies patients who may require further anatomical assessment and consideration of revascularization.

PET myocardial flow reserve can provide additional follow-up information in patients whose relative perfusion images are normal but whose clinical risk remains high. It is especially relevant in diabetes, chronic kidney disease, diffuse atherosclerosis, suspected microvascular dysfunction, and known coronary disease requiring more specific physiological assessment.

For patients with infective endocarditis who cannot undergo surgery and require prolonged suppressive antibiotic treatment, serial 18F-FDG PET/CT may be used to monitor response to antimicrobial therapy. In cardiac sarcoidosis, normalization of myocardial 18F-FDG uptake may accompany successful immunosuppressive treatment.

The source material does not specify fixed intervals for repeat MPI or a universal surveillance schedule. Follow-up should therefore be individualized according to the clinical question, the severity and extent of imaging abnormalities, ventricular function, quantitative flow findings, and subsequent clinical status.