Background

Myocardial Perfusion Imaging (MPI) is a non-invasive diagnostic technique used extensively for the detection and evaluation of coronary artery disease (CAD). It provides a visual representation of myocardial blood flow both at rest and under stress conditions, making it useful for assessing myocardial perfusion, ischemic areas, and the viability of cardiac tissues. MPI uses radiotracers in combination with imaging techniques, predominantly Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET).

The significance of MPI lies in its ability to detect areas of the myocardium that are at risk of ischemia or have undergone infarction. By comparing blood flow in the myocardium during rest and stress, it helps clinicians determine whether the blood flow to specific areas of the heart is adequate, enabling informed decisions regarding further interventions such as coronary angioplasty, bypass surgery, or medical therapy.

Methodology of Myocardial Perfusion Imaging

Principles of MPI

The principle behind MPI is based on the fact that myocardial blood flow can vary significantly between rest and stress conditions, especially in the presence of coronary artery stenosis. By using radioactive tracers that emit gamma radiation, MPI is able to detect disparities in blood flow that can indicate coronary artery disease. The images are typically obtained using SPECT or PET cameras, which capture gamma rays emitted from the tracer injected into the patient’s bloodstream. These images allow the visualization of perfusion across different regions of the myocardium.

The Physics of MPI

MPI imaging modalities such as SPECT and PET use gamma-ray emissions from radiotracers injected into the patient. SPECT relies on gamma cameras to detect photons and create tomographic images of the myocardium. PET imaging, on the other hand, uses positron-emitting tracers and benefits from higher spatial and temporal resolution. The PET tracers, such as rubidium-82 and nitrogen-13 ammonia, produce photons that travel in opposite directions upon annihilation, allowing for more precise localization of radiotracer uptake compared to SPECT.

Radiotracers Used in MPI

Radiotracers used in MPI can vary depending on the imaging modality. Each tracer has unique properties, including half-life, method of uptake, and redistribution capabilities:

• Technetium-99m (Sestamibi or Tetrofosmin): Technetium-99m is commonly used in SPECT MPI. It has a half-life of six hours, which allows for relatively high doses to be administered, leading to better image quality. This tracer passively diffuses into cardiomyocytes and binds to the mitochondria. Unlike thallium, technetium-99m has little to no redistribution, meaning delayed imaging can be performed without significant changes in tracer distribution.
• Thallium-201: Thallium-201 is a potassium analog that enters cardiomyocytes via the Na+/K+ ATPase pump. It has a longer half-life of 73 hours, resulting in higher radiation exposure to patients. Thallium-201 undergoes redistribution, making it ideal for assessing myocardial viability and hibernating myocardium. Thallium tends to produce images that appear blurrier compared to technetium due to its lower photon energy (80 keV). Thallium-201 is particularly useful for identifying viable myocardium since absent thallium uptake generally indicates non-viable tissue.
• PET Tracers (Rubidium-82 and Nitrogen-13 Ammonia): PET imaging typically uses rubidium-82 or nitrogen-13 ammonia as perfusion tracers. Rubidium-82 has a very short half-life of 76 seconds, necessitating an on-site generator, while nitrogen-13 ammonia has a half-life of 9.96 minutes and requires a cyclotron for production. Both tracers provide superior image quality compared to SPECT tracers and are capable of quantifying myocardial blood flow, which adds significant diagnostic value, especially in cases of balanced ischemia.
• 18F-Fluorodeoxyglucose (18F-FDG): For myocardial viability imaging, 18F-FDG is commonly used to assess myocardial metabolism. This glucose analog is taken up by metabolically active cells, allowing the identification of hibernating but viable myocardium. Under ischemic conditions, the myocardium preferentially uses glucose for energy, making 18F-FDG an effective tracer to identify areas of viable tissue that may benefit from revascularization.

Physiological Basis of Stress Testing in MPI

MPI stress testing is designed to increase myocardial blood flow, thereby identifying disparities between normal and ischemic myocardial territories. There are two main types of stressors used in MPI: exercise and pharmacologic agents.

Exercise Stress Testing

Exercise stress testing is the preferred method of stressing the myocardium, as it simulates physiological conditions where myocardial oxygen demand increases. Normal coronary arteries respond to exercise by dilating, allowing an increase in blood flow of three- to fivefold, while stenosed arteries demonstrate a blunted flow response. Maximal exercise, defined as achieving at least 85% of the age-predicted maximum heart rate, is ideal for an effective stress test.

Pharmacologic Stress Testing

Pharmacologic agents are used for patients who are unable to perform adequate exercise due to orthopedic limitations, neurologic conditions, or peripheral arterial disease. The pharmacologic agents used for MPI include:

• Adenosine, Dipyridamole, and Regadenoson: These are vasodilators that increase coronary blood flow by acting on adenosine A2A receptors, leading to vasodilation of normal coronary arteries. However, coronary arteries with significant stenosis are already maximally dilated at rest, which leads to reduced tracer uptake in ischemic regions during stress imaging. Adenosine and dipyridamole are contraindicated in patients with bronchospastic diseases due to the risk of inducing bronchospasm.
• Dobutamine: This agent is used as an alternative in patients with contraindications to vasodilators. Dobutamine increases myocardial oxygen demand by enhancing heart rate, contractility, and blood pressure, thereby mimicking the effects of exercise.

Physiological Rationale for MPI

The ischemic cascade describes the sequence of events that occur when myocardial oxygen supply is inadequate to meet demand. The earliest manifestation is a perfusion abnormality, followed by diastolic dysfunction, systolic dysfunction, electrocardiographic changes, and finally, angina. MPI is capable of detecting perfusion abnormalities, which occur earlier in the ischemic cascade compared to ECG changes or the onset of symptoms, making it a highly sensitive modality for detecting ischemia.

In the presence of a coronary stenosis, resting myocardial blood flow may remain normal due to compensatory vasodilation. However, during stress, the stenotic vessel cannot further dilate, resulting in a flow disparity between normal and stenosed regions. This difference in perfusion is detected by MPI, which reveals areas of relative hypoperfusion, indicative of ischemia.

Coronary Steal Phenomenon

Vasodilator stress agents can also cause coronary steal, a phenomenon that occurs when blood is redirected from a region supplied by a stenotic artery to a region with better perfusion. This occurs because the diseased arteries are already maximally dilated at rest, whereas the healthy arteries can still dilate in response to pharmacologic agents. This redistribution of blood flow can exacerbate ischemia in already compromised areas.

Indications for MPI

MPI is primarily indicated for:

1. Diagnosis of Coronary Artery Disease (CAD): MPI helps confirm or rule out the presence of CAD in patients with symptoms like chest pain or dyspnea, especially when initial tests such as ECG and echocardiography are inconclusive.
2. Risk Stratification: MPI is valuable for assessing the risk of future cardiac events in patients with known CAD or after myocardial infarction.
3. Assessing Myocardial Viability: MPI can determine whether dysfunctional myocardium is viable and would benefit from revascularization.
4. Evaluating the Success of Revascularization: MPI can be used to assess the effectiveness of procedures such as coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).

Contraindications for MPI

Contraindications for MPI depend on the type of stress used. Exercise stress testing is contraindicated in patients with acute myocardial infarction, unstable angina, severe aortic stenosis, decompensated heart failure, and uncontrolled arrhythmias. Pharmacologic stress agents have specific contraindications:

• Adenosine, Dipyridamole, Regadenoson: Should be avoided in patients with active bronchospasm, severe hypotension, or advanced AV block. Caffeine and other methylxanthines, which antagonize adenosine receptors, should be avoided for at least 12 hours before testing.
• Dobutamine: Contraindicated in patients with severe hypertension, unstable angina, and significant arrhythmias.

Performing the Test

MPI can be conducted in a variety of protocols depending on the clinical indication and patient characteristics. Protocols can be one-day or two-day, starting with either stress or rest imaging depending on patient-specific factors like body habitus and prior test results.

Exercise and Pharmacologic Stress Testing

The choice of stress modality depends on the patient’s ability to exercise. Exercise is preferred due to the additional prognostic information obtained from exercise duration, heart rate response, and symptomatic status. If the patient cannot exercise adequately, pharmacologic agents are used. Rapid heart rates can cause decreased septal blood flow in the absence of coronary artery disease in paced patients or those with left bundle branch block, making adenosine preferable to avoid excessive heart rate increase.

Radiotracers and Imaging Protocols

SPECT Tracers: Technetium-99m vs. Thallium-201

• Technetium-99m: Produced by a molybdenum generator, technetium-99m emits 140-keV gamma rays and has a half-life of 6 hours. It passively diffuses into cardiomyocytes and binds to the mitochondria. Its lack of significant redistribution makes delayed imaging possible, and its shorter half-life allows for higher doses, leading to improved image quality. Technetium is more suitable for pharmacologic and exercise stress testing but is less ideal for viability imaging due to the absence of redistribution.
• Thallium-201: Produced by a cyclotron, thallium-201 emits lower energy photons (80 keV) and has a longer half-life of 73 hours. Thallium is taken up into the myocardium via active transport (Na+/K+ ATPase pump) and redistributes over time, making it ideal for viability assessment. However, it provides a lower image quality due to fewer counts and higher susceptibility to scatter. Thallium is also associated with higher radiation exposure, which limits its use in repeated imaging.

PET Tracers: Rubidium-82 and Nitrogen-13 Ammonia

PET tracers, such as rubidium-82 and nitrogen-13 ammonia, are preferred for their superior image quality and ability to quantify myocardial blood flow.

• Rubidium-82: Produced by a strontium-82 generator, rubidium-82 has a very short half-life of 76 seconds. It enters cardiomyocytes through the Na+/K+ ATPase pump and allows for rapid sequential imaging due to its short half-life. However, exercise stress is not feasible with rubidium-82 due to its rapid decay. The need for an on-site generator limits its accessibility.
• Nitrogen-13 Ammonia: This tracer is produced by a cyclotron and has a half-life of 9.96 minutes. It passively enters cardiomyocytes and converts to 13N-glutamine. Nitrogen-13 ammonia allows for high-resolution imaging and quantification of myocardial blood flow, though logistical challenges exist due to its short half-life and need for a cyclotron. It can be used for exercise or pharmacologic stress testing.

Myocardial Viability Imaging

Assessing myocardial viability is crucial for identifying patients who may benefit from revascularization. Myocardial viability imaging helps distinguish between viable and non-viable myocardial tissue in patients with ischemic cardiomyopathy.

• 18F-FDG PET: The gold standard for assessing myocardial viability, 18F-FDG PET is based on the premise that ischemic but viable myocardium switches its metabolism from fatty acid to glucose utilization. 18F-FDG is a glucose analog that enters cardiomyocytes through glucose transporters (GLUT1 and GLUT4) and is phosphorylated by hexokinase, trapping it within the cell. Viable myocardium will show increased 18F-FDG uptake, whereas non-viable scarred myocardium will show little or no uptake.
• Thallium-201: Thallium-201 is also used for viability imaging due to its redistribution properties. The absence of thallium uptake indicates non-viable myocardium, while redistribution into initially hypoperfused regions suggests viability. Thallium is particularly effective for assessing hibernating myocardium.
• Dobutamine Echocardiography and Cardiac MRI (CMR): Dobutamine stress echocardiography can be used to assess myocardial contractile reserve, which is an indicator of viability. Cardiac MRI with late gadolinium enhancement can also identify myocardial scar tissue, with the transmural extent of enhancement correlating inversely with the likelihood of functional recovery after revascularization.

Reverse Redistribution in MPI

Reverse redistribution refers to a phenomenon where a perfusion defect seen during stress imaging appears to worsen or is new on rest images. This pattern is sometimes seen with technetium-99m sestamibi and is thought to be an artifact rather than an indication of true pathology. Reverse redistribution is more common in obese patients (often affecting the RCA territory) and women with large breasts (typically in the LAD territory). It has no direct correlation with obstructive coronary artery disease and is generally considered a benign artifact.

Interpretation of MPI

Normal Variants and Artifacts

It is important to distinguish true perfusion abnormalities from normal variants or artifacts in MPI. Common normal variants include:

• Apical Thinning: Seen as a fixed perfusion defect in the apical inferior wall or septum with normal wall motion, often observed in both SPECT and PET imaging.
• Basal Lateral Perfusion Defect: Seen as a fixed defect in the basal lateral wall, particularly on nitrogen-13 ammonia PET/CT, with normal wall motion. This can be a normal finding and should not be misinterpreted as pathology.
• Breast and Diaphragmatic Attenuation: Breast tissue or diaphragmatic attenuation can result in fixed perfusion defects in the anterior or inferior walls, respectively. These artifacts can often be differentiated by repeating the imaging in a prone position or using attenuation correction methods.

High-Risk Features in MPI

MPI provides significant prognostic information based on the presence of high-risk features. According to Table 18.4, high-risk features in MPI include:

• Large Perfusion Defects: Large single or multiterritorial fixed and/or reversible perfusion defects involving more than 15% of the left ventricular (LV) mass suggest extensive coronary artery disease.
• Transient Ischemic Dilation (TID): An apparent increase in the size of the LV cavity during stress compared to rest indicates extensive subendocardial ischemia and is a marker of multivessel or left main disease.
• Stress-Induced Myocardial Stunning: A drop in left ventricular ejection fraction (LVEF) post-stress suggests significant ischemia and is considered a high-risk finding.
• Increased Pulmonary or RV Tracer Uptake: This indicates elevated left ventricular filling pressures during stress, reflecting significant ischemia and increased risk.

High-Risk Features of the Stress Test

In addition to imaging findings, certain clinical features observed during stress testing also indicate high risk:

• ST-Segment Changes: Significant ST-segment depression (>3 mm), multilead ST depression, prolonged ST depression, or ST elevation (>1 mm) are all markers of severe ischemia.
• Exercise-Induced Hypotension: A drop in systolic blood pressure of more than 10 mmHg during exercise is an indicator of significant ischemia.
• Sustained Ventricular Tachycardia: The occurrence of sustained ventricular tachycardia during stress testing is a marker of poor prognosis and requires further evaluation.

Quantification of Myocardial Blood Flow

One of the significant advantages of PET MPI over SPECT is its ability to quantify myocardial blood flow in absolute terms (mL/min/g of tissue). Quantitative myocardial blood flow provides additional diagnostic and prognostic information, particularly in patients with multivessel disease where balanced ischemia might mask flow disparities. A flow reserve of less than 2.0 is typically associated with adverse outcomes and suggests limited coronary vasodilatory capacity.

Quantitative PET MPI is particularly useful in the following scenarios:

• Assessment of Multivessel CAD: Quantitative flow measurements can unmask balanced ischemia by demonstrating uniformly reduced flow reserve in all coronary territories.
• Evaluation of Microvascular Disease: In patients with angina but no obstructive CAD (commonly known as microvascular angina), reduced flow reserve can be detected by PET.
• Risk Stratification: Lower myocardial blood flow and flow reserve are associated with worse outcomes and provide valuable information for determining the intensity of medical therapy or need for revascularization.

Myocardial Viability Imaging to Guide Revascularization

In patients with ischemic heart failure, assessing myocardial viability is critical for determining whether revascularization would improve outcomes. Viable myocardium may be either stunned (temporarily dysfunctional due to ischemia) or hibernating (chronically underperfused but viable). Studies using PET have shown that the extent of viable myocardium correlates with improvements in left ventricular ejection fraction (LVEF) after revascularization.

• 18F-FDG PET: A mismatch pattern, where there is preserved metabolic activity (18F-FDG uptake) despite reduced perfusion, indicates viable myocardium that may recover function after revascularization. Conversely, a matched reduction in both perfusion and metabolism suggests scar tissue without potential for recovery.
• Observational Studies: Studies have demonstrated that patients with significant areas of viable myocardium have better outcomes after revascularization compared to those with predominantly non-viable tissue. However, the STICH trial showed mixed results, suggesting that viability testing should be one part of a comprehensive decision-making process.

Transient Ischemic Dilatation and Increased Lung Uptake

Transient Ischemic Dilatation (TID)

TID of the left ventricle occurs when the LV cavity appears larger on stress images compared to rest images. This phenomenon is thought to be due to diffuse subendocardial ischemia leading to transient LV dysfunction and dilation during stress. TID is considered a marker of severe, often multivessel CAD, and is associated with a high risk of adverse cardiac events.

TID can also occur as an artifact in patients with significant attenuation, such as those with obesity. However, true TID often indicates extensive coronary involvement, including left main or three-vessel disease. This makes it a crucial finding in the interpretation of MPI studies, highlighting the need for aggressive management of the patient’s CAD.

Increased Lung Uptake

Increased lung uptake of radiotracer during stress is another high-risk marker indicative of elevated left ventricular filling pressures and severe ischemia. It reflects impaired LV function and correlates with extensive CAD, including left main or multivessel disease. Increased lung uptake is often associated with transient ischemic dilation and other markers of poor prognosis.

Conclusion

Myocardial perfusion imaging is an indispensable tool for the diagnosis, risk stratification, and management of coronary artery disease. It provides comprehensive insights into myocardial perfusion, ischemia, and viability, which are crucial for making informed decisions about revascularization and other therapeutic interventions. The choice of radiotracer, imaging modality, and stress agent must be tailored to the individual patient to maximize diagnostic accuracy and minimize risks. By understanding and utilizing the high-risk features identified in MPI, clinicians can better predict patient outcomes and optimize treatment strategies, ultimately improving patient care in those with ischemic heart disease.