Non-Invasive Tests and Imaging Modalities: Role in the Management of CCL Patients

Abstract

Before patients enter the cardiac cath lab for a procedure, almost all have undergone one or more diagnostic tests, imaging studies, an electrocardiogram (ECG), or blood work such as serum troponin levels to confirm the likelihood of coronary artery disease. Tests and imaging studies include stress tests, echocardiography, nuclear imaging, positron emission tomography (PET), computed tomography angiography (CTA), and magnetic resonance imaging (MRI). These procedures aid in the detection and diagnosis of cardiovascular disease by isolating areas of cardiac pathology, myocardial viability, and likelihood of significant coronary artery disease. When these tests are positive, or suggestive of coronary artery disease, it is important to confirm the diagnosis with a cardiac catheterization. This article will discuss an overview of these non-invasive imaging modalities, their role in detecting cardiac and coronary artery disease, and how the cath lab staff can use this information in daily practice.

Introduction

According to the American Heart Association, approximately 81 million American adults have one or more forms of cardiovascular disease, and 17 million have had a heart attack, angina pectoris or both.¹ Cardiovascular disease is also the leading killer of adult men and women in the United States. Heart attacks account for over 600,000, or 26%, of the annual deaths in the United States, and every year, around 785,000 Americans have a first heart attack.² In this setting, cardiovascular disease management is national healthcare priority, and it is the reason why more tests are performed on the cardiovascular system than any other part of the body. The direct and indirect impact of heart disease on the American economy, including health care expenditures and lost productivity, is estimated to be over 500 billion dollars per year.³ This makes effective use and interpretation of cardiovascular procedures a vital component in containing healthcare costs and effectively diagnosing cardiovascular disease. Over 1 million Americans have an inpatient cardiac catheterization annually, with significant numbers of patients having elective, outpatient catheterizations.⁴ However, the majority of patients who have non-invasive imaging of the heart do not require cardiac catheterization.

Understanding the diagnostic tools that evaluate cardiovascular and coronary artery disease (CAD) provides important benefits for cath lab staff. These tools can indicate areas causing angina and ischemia. They can determine if an area of interest has myocardial viability and can be an important determinant in providing treatment strategies for patients diagnosed with CAD. A positive stress test or ECG change in the inferior wall, for instance, may lead the cardiologist to perform a percutaneous coronary intervention (PCI) on a right coronary lesion or dominant circumflex lesion. This is important if the patient has disease in more than one vessel. Myocardial viability studies such as a nuclear stress test, dobutamine echocardiography, PET scan, or MRI may determine whether a patient is treated with medical therapy, stents, or surgery. This article will survey the major non-invasive cardiac tests and imaging modalities, and aid the cath lab staff in understanding their applications.

Electrocardiogram

Before a patient enters the cardiac cath lab, they will usually undergo a variety of non- or minimally-invasive procedures to make a diagnosis. Some of the most reliable detection tests for the heart are the easiest to perform. The electrocardiogram (ECG) takes a couple of minutes, and provides important data concerning the electrical and mechanical activity of the heart. It is the most important frontline diagnostic tool used in cardiac medicine. It detects a wide variety of disease processes, and is the entry point for activating acute myocardial infarction (MI) protocols. An ECG detects injury and ischemia by looking for ST segment elevations, depressions and T-wave inversions. New onset of left bundle branch blocks and Q wave changes can also be a predictor of a new onset of CAD. The ECG also identifies old infarcts, hypertrophy, atrial fibrillation, tachycardias, bundle branch blocks, and other arrhythmias that are extremely valuable in managing patient outcomes and treating patients in the cardiac cath lab.

The ECG is also important because it influences the type of procedure that will properly screen a patient to rule out CAD. For example, cardiac computed tomography (CTA) and magnetic resonance imaging (MRI) are most effective at heart rates of 60 beats per minute (BPM). Higher heart rates or arrhythmia may make the test sub-optimal. A patient with left ventricular hypertrophy or a persistent tachycardia may have a contraindication to exercise stress testing. All of the non-invasive imaging modalities and tests discussed in this article are strongly influenced by the ECG. Heart rate and rhythm are procedural endpoints, determine if a procedure can be done, and are manipulated or targeted to obtain procedural results.

Stress Testing

Stress testing is a commonly performed, non-invasive test that can be combined with imaging modalities to diagnose a wide variety of pathologies and predict the likelihood of obstructive CAD. There are two primary methods for stress testing the heart. Perfusion can be increased by exercise or a state of hyperemia can be induced with a pharmaceutical agent. In either case, the objective is to increase blood flow to the heart and cause it to perform under conditions of exertion. The increased heart rate allows critical lesions to be found, and the predictability of the test is also influenced by its use in conjunction with imaging modalities like nuclear imaging, echocardiography, and MRI. In turn, stress testing used in conjunction with one of these techniques increases the specificity and accuracy of the test, and also diagnoses more pathology.

Exercise Stress Test

To induce physical stress, the patient is placed running or walking on a treadmill, or cycling on a stationary bicycle. Utilizing variations of the Bruce or Naughton protocols, the testing methods may vary, but are designed to make a patient reach a target heart rate or identify ischemic changes on the ECG. The total time for testing is usually 10-20 minutes, the amount of time for target ECG changes to be seen, or until the patient can no longer endure the exam. The procedural endpoints are not only influenced by target heart rates or ECG changes, but other variables such as beta blocker therapy, anti-hypertensive drugs, arrhythmias, excessive response to exercise, or excessive fatigue.⁵

The maximum heart rate (HR) can be between 160-200 beats per minute and the formula for calculation is HR (max) = 220 – age.⁶ For many patients, this test is sufficient to rule out obstructive CAD. In patients with CAD, the exercise stress test diagnoses obstructive CAD by monitoring the ECG and the patient’s response to the increased oxygen demand while being placed under increased physical exertion. The average sensitivity and specificity of an exercise stress test for CAD is between 70-80%, and the likelihood that an individual patient will have CAD is a product of the test’s sensitivity and specificity, as well as pre-test probability of CAD.⁷ Although there are many risk factors for CAD, the strongest predictors are age, the presence or absence of chest pain, and the quality of the chest pain if present.⁷ Therefore, it is imperative to have highly qualified cardiologists determining the type of test that should be used to detect and diagnose CAD. Positive stress tests often require a cardiac catheterization to confirm the suspicion of CAD.

When selecting candidates for exercise stress tests, it is important to make sure that they can physically meet the demands of the tests. Exercise stress testing is also contraindicated in patients with ECGs that demonstrate active injury or ischemia, unstable angina, symptomatic left ventricular (LV) dysfunction, severe aortic valve stenoses and other medical conditions that make the procedure too dangerous to perform. Acute MI, positive cardiac biomarkers, sustained supraventricular tachycardia (SVT), Wellen’s syndrome, Wolf-Parkinson-White disease, and thromboembolic disease are also contraindication to subjecting a patient to an exercise stress test.⁸ Proper selection of exercise stress test candidates is important, because a positive stress test is an indication for cardiac catheterization, which should only be done when necessary.

Pharmacological Stress Test

Because exercise stress testing is limited or contraindicated in many patient subsets for CAD, more stress tests are being performed with pharmaceutical agents and in conjunction with other imaging modalities. When a patient cannot exercise on a treadmill, several pharmaceutical agents can provoke active hyperemia. This hyperemia is caused by an increased flow of blood to an area by active dilation of both the arterioles and capillaries. It is associated with neurogenic, hormonal, and metabolic function.⁹ The heart is made hyperemic with medications like adenosine, dipyridamole (persantine), or dobutamine. This type of testing provokes cardiac stimulation, and measures its physiological effects, while mimicking physical exercise on the heart and coronary vessels. Any of these medications may be used in addition to a radionuclide isotope during a myocardial perfusion nuclear stress imaging test or in conjunction with standard echocardiography (SE), cardiac magnetic resonance imaging (CMRI), cardiac computed tomography angiography (CCTA), PET scanning, and diagnostic cardiac catheterization. Pharmacological stress testing, rather than exercise stress testing, is necessary when being used with PET, CCTA, CMRI and the cath lab, because patients must be positioned in the scanner pre-procedurally.

Three of the most common pharmaceutical agents used for stress testing are adenosine, dipyridamole and dobutamine. Adenosine is a naturally occurring chemical in the cellular makeup of human DNA (deoxyribonucleic acid). The function of adenosine is to control blood flow in vascular tissue. Adenosine causes vasodilatation of the vascular smooth muscle of the vessel. In patients with CAD, the adenosine is unable to fully dilate the diseased vessel segment, because of the reduced coronary vascular flow, while coronary arterial blood flow in healthy vessels is increased.¹⁰ This effect causes a diminished or attenuated hyperemic response and creates flow deficiencies, which are extremely well identified when the test is performed in conjunction with nuclear imaging.¹¹

During an adenosine stress test, a standard infusion is given intravenously (IV) at a dose of 140mcg/kg/min. For most patients, the timeline for infusion is 6 minutes. The adenosine infusion must continue throughout the entire scan, and once the infusion is terminated, it dissipates quickly. Early termination of adenosine stress testing is indicated by signs and symptoms like moderate to severe angina, significant hypotension, cyanosis, pallor, sustained ventricular tachycardia and significant ST segment changes.¹² Low-impact exercise such as light walking can help increase the accuracy of the test if the patient can tolerate it.

The majority of patients who have adenosine stress tests experience minor side effects from infusion, with the most common side effects being facial flushing, nonspecific chest pain and shortness of breath. The effect on the respiratory system makes it important to triage patients for airway disease such as asthma and chronic obstructive pulmonary disease (COPD) before considering which pharmaceutical agent to use for stress testing. Since adenosine decreases conduction through the atrioventricular (AV) conduction pathway, it can produce 1st, 2nd or 3rd degree heart blocks, as well as bradycardia and tachycardia,¹³ and requires vigilant hemodynamic monitoring.

An intracoronary stress test can be performed in the cath lab using standard adenosine infusion protocols or by injection of a bolus that can vary from 40-60 micrograms. This stress test is target-specific, assesses hemodynamic function, and rules out obstructive CAD after cardiac catheterization and other imaging modalities are indeterminant. An obstructive lesion is defined as one that has a fractional flow reserve (FFR) of 0.80 or lower. The advantages of the intracoronary stress test include the identification of significant lesions in a coronary artery, ruling out obstructive disease and promoting better patient management. Randomized European trials showed that use of the fractional flow technique reduced stenting by one-third and also demonstrated a significant reduction in major adverse cardiac events (MACE).¹⁴ Primary disadvantages are that an intracoronary stress test is invasive and requires anti-coagulation therapy.

Dipyridamole is a pharmacologic agent that causes coronary artery vasodilation in a process of increasing adenosine levels by suppressing the intracellular reuptake and deamination of adenosine.¹⁵ Adenosine achieves slightly more flow through the coronary arteries, and this flow happens sooner than when using dipyridamole. The ability to diagnose CAD, however, is not much different when comparing dipyridamole and adenosine.¹⁶ Therefore, while adenosine may be a better selection for pharmacological stress testing, both drugs deliver similar results and similar complication rates.

Technique. Dipyridamole is administered via an infusion pump or by hand, manually injected into the patient. The standard dipyridamole drip (0.14 mg/kg/min) is typically infused over a five-minute period of time.¹⁷ ECG, heart rate, and blood pressure should be regularly monitored, and ECG monitoring continues until the dipyridamole and its effects are out of the system. Low-impact treadmill exercise can be done by patients who can tolerate it to improve the accuracy of the test.

Side effects are similar with adenosine and dipyridamole, but are reported more frequently with adenosine. In studies conducted on side effects of dipyridamole, 44% complained of some form of adverse reaction to dipyridamole stress testing. Headache was the most frequent complaint (37.1%). Chest pain (12.1%) and nausea (11.1%) were the second and third most common adverse reactions recorded.¹⁸ Patients need vigilant monitoring during this time, as profound symptoms may be a procedural endpoint. Patients may be given aminophylline to reverse the effects of dipyridamole, and a history of asthma, COPD, or other airway disease may be a procedural contraindication.

Dobutamine is a synthetic sympathomimetic alpha-1/beta-1 and beta-2 agonist. Cardiac beta-1 adrenergic stimulation results in increased myocardial contractility and HR (the inotropic effect being greater then chronoscopic effect).¹⁹ Dobutamine increases the HR, blood pressure, and myocardial contractility. However, the ability of dobutamine to augment coronary flow and test the coronary flow reserve is lower than that of adenosine, even when applied to maximal dose.²⁰ Although subjects are carefully selected, around 10% need to be terminated before results can be obtained,²⁰ and some patients never reach the target heart rate. Dobutamine usage is also limited by some of the same constraints placed on exercise stress testing, such as aortic stenosis and uncontrolled hypertension. It has many of the same side effects as adenosine or dipyridamole, including tachycardia, hypotension, and chest pain, which are usually reversed with beta blockers.

Because of these reasons, dobutamine stress tests are performed less frequently than adenosine or dipyridamole stress tests. In some subsets, however, dobutamine may be advantageous. Dobutamine is considered a safer choice than adenosine or dipyridamole for patients who have significant pulmonary or airway disease. It is also the agent of choice when used in conjunction with echocardiography to evaluate CAD and myocardial viability.

Dobutamine is administered via infusion pump. The dobutamine infusion rate is around 5 mcg/kg/min for the first 3 minutes, and is increased at 3-minute intervals up to 40mcg/kg/min or until the target heart rate is reached. Atropine can be injected if the target heart rate is not achieved, and the physician determines the total dosing of dobutamine. Numerous European trials have been conducted using dobutamine in conjunction with imaging modalities, and that the data has supported the use of dobutamine echocardiography, because of its ability to make complex diagnoses inexpensively.

Imaging Procedures

Exercise and pharmacologic stress tests have limitations, and are only about 80% accurate in identifying obstructive CAD in best-case scenarios. Therefore, many stress tests are being performed with imaging modalities to improve the predictability of CAD. As these procedures also cost more and have limitations, it is important to understand their application and value in diagnosing obstructive CAD. Imaging stress tests tend to be more accurate at detecting coronary heart disease than standard (non-imaging) stress tests and when used properly, can predict the risk of a future heart attack or premature death. Available tests all have advantages and drawbacks, and none can be considered suitable for all patients. Clinicians are confronted with a rapidly evolving arsenal of imaging techniques which may be the optimal choice for their clinical question. Each imaging modality has the tendency to put itself forward as the better technique and claim the holy grail of the “one-stop shop.”²¹ Many patient evaluations now include a stress test component in conjunction with an imaging study such as single photon emission computed tomography (SPECT), echo, MRI, CTA, PET, and PET/CT. The supplemental evaluation not only evaluates ischemia, it allows the disease processes to be quantified and provides better predictions of patient outcomes, and advanced treatment strategies.

Echocardiogram With and Without Stress Testing

The echocardiogram offers extra benefits when performed in conjunction with the exercise or pharmacological stress test. It can evaluate the wall motion of the heart and detect abnormalities associated with CAD. Echocardiography is also very useful in diagnosing valvular heart disease, pulmonary hypertension, septal defects, and other structural disease. When combined with exercise or pharmacologic stress testing, echocardiography is an important diagnostic tool for evaluating balanced ischemia. Balanced ischemia is global ischemia resulting from multi-vessel disease. On nuclear imaging studies, balanced ischemia from triple-vessel disease may not show an area of decreased perfusion. This is because all areas have equally poor perfusion, and none stands out on the nuclear imaging study. When performing stress echo studies, images on the exercise or stress phase can be compared. This allows myocardial wall motion to be studied at exercise and during rest. It also demonstrates the global hypokinesis that is associated with multi-vessel disease.

Myocardial contractility normally increases with exercise, whereas ischemia causes hypokinesis, akinesis, or other wall motion defects. A test is considered positive if wall motion abnormalities develop with exercise in previously normal territories or worsen in an already abnormal segment.²² Pharmacologic stress echocardiography is effective in risk stratification of single-vessel disease and can accurately discriminate patients in whom coronary revascularization can have the maximal beneficial effects.²³ The accuracy of stress echocardiography for detection of significant coronary stenoses ranges from 80-90%, exceeding that of the exercise or pharmacologic stress tests, and comparable to that of stress myocardial perfusion studies.²⁴ Although this may be debated, the fact remains that stress echo studies have a high diagnostic yield, are less expensive than nuclear studies, and don’t expose patients to radiation.

Echocardiography is particularly useful with a dobutamine stress test for management of patients with acute, severe LV dysfunction or cardiogenic shock that may occur as a result of an acute MI. Persistent wall motion abnormalities and myocardial viability can be observed by echocardiography at a time when chest pain, ST-segment deviation, and regional perfusion has recovered.²⁵

Hibernating myocardium, which may show up as non-viable or necrotic myocardium on other tests, can be detected as viable myocardium with stress echocardiography. This is important because various methods are used to determine potential outcomes of revascularization procedures. Several groups have published data regarding predictions of recovery of myocardial dysfunction after revascularization.²⁶ Data suggests that echocardiography is an essential tool in studying myocardial function status post (s/p) MI, and is also useful for evaluating patients who have suffered through a stress-induced cardiomyopathy, such as Tako-Tsubo syndrome.

Stress echocardiography images are obtained at baseline and after pharmacologic infusion or exercise. A new or worsening wall-motion abnormality constitutes a positive test for ischemia. The high diagnostic value of the procedure may be limited by factors such as obesity, body habitus, and the quality of the equipment. Overall, however, it has excellent predictive value. On the basis of the aggregate data available in studies of nearly 1,000 women with suspected CAD, stress echocardiography had a mean sensitivity of 81% (89% in women with multi-vessel disease), a specificity of 86%, and overall accuracy of 84% for detecting or excluding significant CAD.²⁷

In patients with suspected but no history of CAD, fixed perfusion abnormalities were associated with a higher risk of death compared with reversible perfusion abnormalities.²⁸ The sensitivities for the detection of CAD are 85%, 80% and 78% for exercise, dobutamine and dipyridamole stress echocardiography, respectively, with corresponding specificities of 77%, 86% and 91%, respectively.²⁹ With a high specificity and sensitivity, stress echocardiography is an excellent tool for evaluating myocardial function and CAD.

Radiation Considerations for Nuclear Studies, Computed Tomography and Cardiac Catheterization

With over six million cardiac nuclear stress procedures performed annually in the United States, physicians rely heavily on this test to evaluate patients for cardiovascular disease.³⁰ Radionuclide scanning in conjunction with pharmacological or exercise stress testing is a highly specific test that aids the cardiologist in the detection and diagnosis of CAD. It offers the advantages of stress testing in conjunction with a radionuclide agent that can detect disease, locate lesions, and evaluate wall motion of the heart, ejection fractions, myocardial viability, fixed and reversible defects, and other useful information.

Nuclear imaging, PET scan, cardiac CTA and cardiac catheterization all use radiation to diagnose cardiovascular disease. Patients may receive between 4.6 and 57 milli-sieverts (mSv) of exposure during a cath, depending on the complexity of the procedure and if an intervention was performed.³¹ Nuclear stress tests may expose a patient to doses between 5.6 -11.8 mSv.³² PET scans can use as much as 14.0 mSv, and CTA uses between 3.0 and 16 mSv, depending on how involved the scan is and what type of techniques are used.³³ In other words, nuclear studies and cardiac CTA studies have similar exposure rates to cardiac caths, depending on the types of equipment and complexity of the imaging. Most heart imaging studies are done with radionuclides. When researchers looked at cumulative effective dose, myocardial perfusion also stood out as the largest contributor, accounting for 74%, compared with 21.4% for cardiac catheterization and PCI.³⁴ It is important to understand dosing, especially when performing multiple procedures on a patient. There is no consensus on carcinogenic effects from medical imaging, but best practices presume that it does increase cancer risks. The principles of ALARA (as low as reasonably achievable) should always be practiced in medical imaging. It is essential to have qualified personnel administering and regulating radiation exposure. In the cardiac cath lab, the staff members as well as the patients are exposed to these doses, making safety a paramount concern for all patients and staff. Patients need to be properly screened to obtain the best possible diagnosis with the least amount of radiation. Background radiation and other natural sources comprise 50% of the dose people receive, while the amount from medical imaging is increasing. Medical imaging accounts for 36% of all radiation exposure in the U.S. and nuclear medicine is accountable for one-third of all the radiation-based medical procedures.³⁵

Nuclear Stress Imaging

Stress tests with radionuclide scanning combine exercise or pharmacologic stress testing with the injection of a radiopharmaceutical. The nuclear stress test necessitates radiation exposure, but is important because of its advanced diagnostic capabilities. Nuclear stress testing is far more sensitive than a standard stress test to diagnose disease, because isotope studies can demonstrate dead heart muscle and scar tissue versus live tissue. This test helps differentiate between scar (old infarctions), live heart muscle that doesn’t have enough blood supply but has not yet died (muscle at risk for infarction in the future), and healthy heart muscle with adequate blood supply.³⁶

SPECT/myocardial perfusion imaging (MPI) scans can be used in conjunction with cardiac stress testing to evaluate regional myocardial blood flow. Stress testing is accomplished using treadmill exercise or pharmacologic agents such as adenosine, dipyridamole, or dobutamine. A radiopharmaceutical is injected into a peripheral vein and its delivery to the myocardium is dependent on regional blood flow. To detect ischemia or infarction, a radiopharmaceutical distribution is imaged at rest and after stress, demonstrating myocardial regional uptake, which is proportional to regional blood flow.³⁷ The mechanism of uptake of the radiopharmaceutical into the myocytes varies according to the radiopharmaceutical used. If the radiopharmaceutical is injected while the heart is at peak stress, images will show the state of perfusion of the myocardium during stress. A baseline, or resting, study shows the state of myocardial perfusion when the heart is not under stress. Overall test sensitivity of SPECT imaging has been found to approach 90% both for exercise technitium-99m, sestamibi, and thallium-201 SPECT, which gives it an excellent track record as a non-invasive imaging modality.³⁸

Radiopharmaceuticals currently available for MPI SPECT include technetium-99m (Tc-99m), sestamibi, Tc-99m tetrofosmin, and Thallium-201 (Tl-201) thallous chloride. Tl-201, thallous chloride, is the original MPI radiopharmaceutical, and has been used since the 1970’s.³⁹ The Tl-201 thallous ion is handled by the body in a similar way to a potassium ion, and uptake to the myocardium occurs via the sodium-potassium-ATPase pump. This means the distribution of Tl-201 in the myocardium changes over time. Nuclear imaging must be performed at specified times after radiopharmaceutical injection so that images reflect the state of myocardial perfusion at stress and at rest. An advantage of Tl-201 is that its distribution in the myocardium at 24 hours after stress injection demonstrates viability and can be used to evaluate cases of stunned or hibernating myocardium.⁴⁰ Poor spatial resolution of the images is a limitation of Tl-201. The activity of Tl-201 that can be administered to a patient is limited by the radiation dose that is conferred on other organs in the patient’s body, specifically, the kidneys and male genitalia. Body habitus limits procedural results, particularly in obese patients and women with large breasts.

Tc-99m sestamibi and Tc-99m tetrofosmin were developed in the 1990’s. They have similar mechanisms of action. Delivery to the myocardium is blood-flow dependent and following diffusion into the myocytes, these radiopharmaceuticals bind to proteins in the mitochondria and become trapped in place. Neither radiopharmaceutical undergoes redistribution, so separate injections must be given for stress and rest imaging. The imaging characteristics of Tc-99m are more favorable than those of Tl-201.⁴¹ A larger activity can be administered to the patient and, consequently, image quality is improved. Some institutions use a dual-isotope technique, in which Tl-201 thallous chloride is injected for the rest images and Tc-99m sestamibi or tetrofosmin for the stress images.

Single photon emission computed tomography (SPECT) is performed with the heart at stress and the heart at rest. The two image sets are compared to determine whether areas of absent perfusion (defects) on the stress images are permanent or transient. Permanent defects imply areas of infarct/scarring, while transient or reversible defects suggest ischemia. Viability of persistent areas of myocardial ischemia may be demonstrated by a myocardial viability study.

MPI stress images are usually gated (a technique to reduce artifacts and improve image quality) so that parameters such as LV ejection fraction (LVEF) can be calculated, and features such as LV wall motion, dilatation, and wall thickening can be observed concurrently with myocardial perfusion. Gating enhances the accuracy of MPI image interpretation. Some SPECT scanners include a system for attenuation correction, which enhances sensitivity, but increases the duration of the scan considerably. The advantages of SPECT imaging include widespread availability, and strong research data and literature supporting its use. Some of the limitations include attenuation artifacts due to body habitus that limit sensitivity and specificity, limited utility for showing extent of underlying CAD, and the LVEF not being measured at peak stress. SPECT has 87% sensitivity, and 73% specificity for detecting greater than 50% stenosis.⁴² If the choice of treatment is uncertain after catheterization, nuclear stress testing can be used to determine whether to manage a patient medically or with revascularization.⁴³

SPECT Myocardial Viability Imaging

Tl-201 redistribution (rest) imaging is usually performed 3-4 hours after the Tl-201 injection (given at peak stress). In some patients with Tl-201 defects and LV dysfunction, 4 hours is not sufficient time to allow for complete redistribution of the Tl-201. Viability imaging subsequent to injection of a small dose of Tl-201 thallous chloride is usually performed 24 hours after the original stress injection. With this technique, many defects that appeared irreversible on the 4-hour redistribution scan may now show perfusion and viability. PET scanning using F-18 flurodeoxyglucose (FDG) can also be used to image myocardial viability. FDG image quality is superior to that of thallium scans, and PET represents the future of nuclear imaging studies.

PET Myocardial Perfusion Imaging

Positron emission tomography (PET) can be used in conjunction with cardiac stress testing to evaluate regional myocardial blood flow. All PET stress testing must be pharmacologic, and performed with the patient already lying inside the PET scanner. The radiopharmaceuticals used contain positron-emitting radioisotopes. These tend to possess very short half-lives, which introduce technical challenges and necessitate special imaging considerations such as the use of pharmacological stress agents like adenosine in order to produce a quality study.⁴⁴ It is necessary to begin stress imaging within seconds of the radiopharmaceutical injection, but evolving techniques for producing quality stress images seem to show this technology a bright future.

PET perfusions cans have higher spatial resolution images than SPECT, and produce less scatter and less diagnostic uncertainty. LVEF can be measured at peak stress, and predicts disease extent and severity. Quantification of myocardial blood flow, critical for detecting multi-vessel disease in cases of balanced ischemia, is superior in PET versus SPECT scanning. However, SPECT is well established, and the usefulness of PET is limited by access to the technology, as well as the strong track record of SPECT scanning.

A PET scan can underestimate the extent of CAD, unless absolute coronary vasodilator reserve is measured and this is not often performed. PET shows the extent and severity of CAD, but not presence and extent of anatomic atherosclerosis. The test has a 92% sensitivity and 85% specificity for diagnosing CAD when evaluating 50% or greater stenosis.⁴⁵ The PET scan is not widely used for CAD evaluation at this time, but this may change as the technology advances and proves its diagnostic worth and cost effectiveness. Patients in whom stress imaging with exercise is neither required nor feasible, and patients with a high likelihood of false positive or false negative studies by SPECT are likely to benefit from PET imaging.⁴⁶

PET Myocardial Viability Imaging

The PET radiopharmaceutical commonly used for evaluating myocardial viability is fluorine-18 (F-18) fluorodeoxyglucose (FDG). The FDG molecule is an analog of glucose in which one hydroxyl group has been substituted with a fluorine-18 atom. Up to a point, the body handles FDG in a similar way to unsubstituted glucose. FDG is transported into cells that use glucose as an energy substrate, and enters into the glycolysis pathway. After phosphorylation, further metabolism cannot occur and so the FDG remains trapped within the cell for detection with the PET scanner. Thus, FDG uptake is seen in all cells metabolizing glucose. Under normal aerobic conditions, myocytes preferentially metabolize fatty acids. However, in hypoxic areas, glucose metabolism is the mechanism of choice. Therefore, FDG uptake in the myocardium indicates cellular viability.

Used in conjunction with myocardial perfusion PET or SPECT, FDG PET is invaluable in diagnosing patients with severely ischemic yet viable myocardium who might benefit from a revascularization procedure. FDG PET is the gold standard for myocardial metabolism assessment (assessment of myocardial viability and its accuracy is increased when using PET/CT).⁴⁷ It is important to mention that FDG is not a suitable radiopharmaceutical for evaluating regional myocardial perfusion, since its uptake is related to phosphorylation, not blood flow. Therefore, other isotopes or tests are better suited for this diagnosis.

Cardiac Computed Tomography Angiography (CTA)

Cardiac computed tomography is a radiation-based imaging scan of the heart, blood vessels, and surrounding structures. The cardiac CT scan takes various images of the heart and compiles them into three-dimensional images of the entire heart and surrounding structures, including the aorta. Iodinated contrast is injected intravenously to highlight the heart structures for optimal visualization. Cardiac CT is recommended for detection of accumulation of calcium within the coronary arteries, which can indicate early CAD. It is based on a system known as Agatston scoring. Agatston scores of < 10, 11 to 99, 100 to 400, and > 400 have been proposed to categorize individuals into groups having minimal, moderate, increased, or extensive amounts of calcification, respectively.⁴⁸ Scores of > 100 have high predictive value for determining morbidity and mortality. The disadvantage of cardiac CTA is that it has poor resolution for quantifying calcific disease.

Radiopaque contrast highlights the coronary arteries for evaluation of stenosis, evaluation of dysfunction within the heart and valves, detection of aortic or dissecting aneurysms, detection of pulmonary embolisms, visualization of the pulmonary veins for anomalies like atrial fibrillation, and diagnosis of pericardial disease, such as, pericarditis or pericardial effusions.⁴⁸ Mowatt et al found that CTA may have an increasing role in patients that fall into an intermediate category with an uncertain CAD diagnosis after clinical assessment and other non-invasive tests, such as nuclear stress or stress echocardiography.⁴⁹ Therefore, cardiac CTA may be useful in providing physicians with medical management strategies and non-invasive options for patients, especially as cardiac CTA continues to emerge as a high-quality imaging study.

CTA also has > 95% negative predictive value,⁵⁰ which makes it a highly valuable tool for screening patients with indications of CAD on other imaging studies, but who the cardiologist believes will have a normal coronary angiography. It is also excellent for detecting non-calcific atherosclerotic disease, but is not as accurate for calcific disease. The presence and amount of coronary calcification significantly increases the relative risk for future coronary events, independent from traditional risk factors,⁵¹ so cardiac CTA calcium scores provide important clinical information, even though calcific disease is difficult to quantify in the blood vessels with cardiac CTA. Moreover, patients without any coronary plaque seem to have a very low likelihood of future cardiovascular events.⁵²

Issues to Consider With Cardiac CTA
If the cardiac CTA is positive for significant CAD, it will require a cardiac catheterization to confirm and treat the blockages. Cardiac CTA is difficult to perform when patients have rapid heart rates, especially when they are > 90 beats per minute. Even with ultra-fast scanners, the American Heart Association does not recommend ultrafast CT as a replacement for stress testing and/or angiography in patients with conventional risk factors and in patients with typical angina.⁵³ If iodinated contrast is going to be used, the renal health of the patient needs to be considered. Can the patient tolerate numerous procedures with iodinated contrast? If not, then the cardiac cath is a better approach, because it makes a definitive diagnosis. In the cath lab, other diagnostic tools such as intravascular ultrasound and FFR can be performed to further evaluate questionable areas of stenoses. Once diagnosed, stenoses are usually treated in the same setting. Labs that have bi-plane technology can cut the contrast dose in half, and this allows the diagnosis of significant CAD with as little as 30 mLs of contrast. Presently, there are also significant reimbursement constraints on cardiac CTA, making it less likely to be used to diagnose CAD.

CT scans are extremely useful, however, in understanding and managing CAD, and will play an increasingly vital role to screen future patients. It is likely that as the technology improves, cardiac CTA will play a more prominent role in the diagnosis and treatment of CAD. It may even supersede diagnostic cardiac catheterization for diagnostic value, as it has done with non-cardiac angiography.

Cardiac Magnetic Resonance Imaging (MRI)

MRI can diagnose a wide range of cardiac disease pathology. It is particularly useful because the excellent soft tissue contrast of cardiac MRI permits delineation of cardiac structures (e.g., ventricular myocardium) and paracardiac structures related to the heart and great vessels.⁵⁴ It is a technology with great future potential. MRI is an extremely valuable tool in diagnosing and evaluating cardiomyopathies, ventricular function, and valvular heart disease. It also has the diagnostic ability to study pathologies of the aortic root and aortic arch. It is limited by heart rate and, currently, is not optimal for coronary artery imaging. It is, however, becoming increasingly useful in the assessment of CAD and for evaluating myocardial viability, particularly when used with a pharmacological stress agent such as adenosine. It is also a very useful tool to evaluate recovery times and to assess overall health of the ventricle.⁵⁴

There is no radiation dose or use of ionizing radiation involved with cardiac MRI, which provides advantages when compared to nuclear imaging or computed tomography. Cardiac MRI does have several limitations, including patients with medical implants, claustrophobia and tachycardias, because of similar imaging techniques to cardiac CTA. It is not widely used or available at this time, and cardiac MRI is also cost prohibitive, especially when compared to well-defined studies such as SPECT, echocardiography and cardiac cath.

Hybrid Imaging (SPECT/CT and PET/CT)

The term “image fusion” refers to the direct comparison of images representing the same structures that have been acquired by different imaging modalities. For the whole body, functional information from PET or SPECT is fused with anatomic information from CT or MRI to diagnose patient pathology, and is very useful in cancer management strategies. The technique has now been expanded to include cardiac and neurologic applications. Two-dimensional transfer functions are used to combine into a single image functionally relevant regions of myocardium seen on myocardial perfusion SPECT or PET, with anatomically relevant details seen on cardiac CTA.⁵⁵ Fusion imaging offers the ability to assess the anatomy of the heart and coronary arteries, and the perfusion status of the myocardium either at stress (for assessment of induced ischemia) or at rest (for viability). LV systolic function⁵⁶ and Agatston calcium score can also be assessed, all within a single imaging session.

PET/CT and SPECT/CT scanner designs incorporate detectors for both modalities into one gantry. Both scans are acquired in one imaging session, without necessitating movement and repositioning of the patient. Additionally, the CT scan can be used for attenuation correction of the PET or SPECT data. Both PET/CT and SPECT/CT have been abundantly reported as improving the diagnostic accuracy of either imaging modality on its own. Hybrid scans have many advantages over single-modality imaging. They can show anatomic extent and physiologic severity of obstructive disease in a single setting. Calcium scoring can be used to detect and quantify plaque, and identify flow-limiting coronary stenoses and their physiological significance. At the same sitting, myocardial perfusion imaging can be used to show the hemodynamic significance of the stenoses. Hybrid scans also improve non-invasive detection of CAD and prediction of cardiac risk, as well as permit the assessment of subclinical disease. Finally, they help compensate for shortcomings of a single imaging modality, like motion artifacts that may occur with CTA scanning with a tachycardic patient. Limitations to hybrid scanning include radiation doses to the patient, cost effectiveness and availability. Because of limited access, few medical centers perform these procedures, also reducing its usefulness as a diagnostic tool. Compared to cardiac CTA alone, the combination of SPECT and cardiac CTA has demonstrated a significant increase in specificity (from 80 to 92%) and positive predictive value (from 69 to 85%) without any change in sensitivity (95%) and negative predictive value (97%).⁵⁷ Cardiac CTA also offers advantages with its ability to identify calcific disease and its high negative predictive value.

Hybrid Scan Radiation Doses to Patients
The patient-absorbed dose from hybrid imaging can be quite large, and needs to be balanced against the need for the information that is obtained from these studies. This type of imaging combines the dosing effects of ionizing radiation from the cardiac CTA with the injection of a radiopharmaceutical for nuclear imaging. Techniques are being developed to minimize these doses, which can vary widely, depending on the combination of imaging techniques that are used, body habitus of the patient, and the type of scanners that are used for imaging.

Conclusion

Cardiovascular disease is a paramount health issue in the United States. The large numbers of patients affected by cardiovascular and cardiac disease means that cardiac imaging modalities will play a primary role in patient care. Understanding the various tests that are used to diagnose and treat cardiovascular disease is critical for cath lab staff, because virtually all of the patients entering the cath lab will have had one or more of these tests pre-procedurally. In many cases, cath lab staff may assist in performing these procedures, so understanding their results is essential for providing quality patient care.

In modern medicine, the cardiac cath lab makes the definitive diagnosis of CAD. Advanced diagnostic tools such as intravascular ultrasound (IVUS), optical coherence tomography (OCT) and fractional flow reserve (FFR) allow questionable area to be quantified by structure or physiology. However, echocardiography, SPECT, PET, cardiac CTA and cardiac MRI imaging play an increasingly important role in the detection and diagnosis of coronary artery and cardiovascular disease. These tests assist the cath lab by identifying candidates for cath by using non-invasive or minimally invasive technologies. They also help evaluate the viability of myocardium pre and post intervention, and in other cases where medical management or surgery may be recommended. Myocardial viability is an important predicator of patient outcomes, and may determine whether a patient has a stent placed, goes for bypass surgery, or is managed by medication.

As these technologies continue to emerge, improve, and become practically assimilated into cardiac practice, they will become more important in the frontline care and treatment of patients. Cath lab staff should understand the capabilities of these technologies, what their findings mean, how to interpret the results, and how assimilate them into cath lab practice. Cardiac catheterization is invasive, uses iodinated contrast and requires the patient and staff to be exposed to ionizing radiation. Quality patient care, safety, outcomes and cost containment are the ultimate goals for patients with cardiovascular disease. The judicious use of cardiac tests and imaging modalities should guide the medical community as we seek to diagnose and treat cardiovascular disease patients.

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The authors can be contacted at richardmerschen@verizon.net.