Background
Heart disease, specifically coronary artery disease (CAD), is the leading cause of death and disability among both men and women in the US. Reductions in blood supply due to narrowings of the arteries that supply the heart muscle with oxygen and nutrients (coronary arteries) result in chest pain and shortness of breath and may lead to permanent scarring of the heart muscle, as in the setting of a heart attack (myocardial infarction) or cause sudden death, due to irregular heart rhythms. Additionally, CAD is the most frequent cause of heart failure, which is the leading cause of hospitalization in the US. Therefore, ischemic heart disease has important ramifications for the morbidity and mortality, as well as a substantial impact on healthcare expenditures.
Nuclear cardiology studies allow for the detection of abnormal blood flow to the heart muscle, as well as the assessment of the pumping function of the heart. The most common procedure is myocardial perfusion imaging (MPI) or single-photon emission computed tomography (SPECT). Small amounts of radioactive material are injected intravenously and these tracers are taken up and retained in the heart tissue in proportion to regional blood supply. Usually, two scans are obtained after tracer injection, one at rest and one in which the agent is injected during exercise or medication-induced stress, such as with adenosine, dipyridamole, or dobutamine. Areas with reduced blood supply, either under resting conditions or following stress testing, indicates regions of scar or reversible perfusion alterations (ischemia), respectively.
Nuclear Cardiology Procedures
Nuclear cardiology has experienced explosive growth during the past decade, founded on the solid evidence that this discipline provides the clinician with an accurate assessment of patients with suspected ischemic heart disease.
It is estimated that approximately 7.8 million MPI studies were performed in the US during 2002, an almost four-fold increase in procedural volume during the past decade and an 11% increase over the preceding year. The vast majority of in-hospital studies are in small (<400 bed), non-teaching institutions, indicating the penetrance of the procedure into routine clinical care. However, double digit annual growth has occurred primarily in the setting of office-based laboratories, with an increasing percentage of studies being performed by cardiologists.
MPI initially began as a rather crude way to determine relative blood flow. However, tomographic (SPECT) imaging has now been widely used for more than 15 years and provides a true three-dimensional (3-D) depiction of myocardial blood flow, with improved localization of abnormalities, and enhances sensitivity for the detection of disease. The radiopharmaceuticals used for imaging have also undergone change, with the development and extensive utilization of Tc-99m tetrofosmin and Tc-99m sestamibi, which provide superior imaging characteristics to thallium-201, which was the only agent available prior to 1990. These agents have permitted the development of collecting image data synchronized to the cardiac cycle and permitting the assessment of both global and regional information about cardiac function in addition to myocardial perfusion. Gated SPECT is now performed in 92% of all studies performed in the US.
MPI was initially developed to assess blood flow at rest and following either treadmill or bicycle exercise. However, many patients with known or suspected CAD are unable or unwilling to perform maximal exercise. Medication-induced or pharmacologic stress testing has been shown to provide similar diagnostic and prognostic information to that obtained with exercise MPI and extends the population of patients who may gain the benefit of non-invasive radionuclide testing. It is estimated that approximately 48% of all MPI performed in the US in 2003 were done with pharmacologic stress testing methods. Adenosine and dipyridamole, coronary vasodilators that unmask flow abnormalities, are used for about 90% of patients. However, when severe lung disease or other contraindications for the use of these ages is present, dobutamine infusions may be used as alternative stress modality. New agents are currently being developed for stress testing, including selective adenosine A2a receptor agonists, which provide for coronary vasodilation but with likely improved safety and tolerability, as side-effects will be minimized by the lack of effect on other receptors which otherwise might cause chest pain, shortness of breath/wheezing, or electrical conduction disturbances.
Clinical Apllications
MPI provides improved diagnostic information over routine stress testing, as it has an enhanced ability to detect CAD, as well as higher specificity for an abnormal test to be associated with the presence of disease. Important, however, is the ability of MPI to provide information about the severity, extent, and location of disease. This information is useful for planning treatment strategies, such as angioplasty or bypass surgery.
From a diagnostic perspective, MPI may also be used for patients who present to the emergency department with chest pain but lack a clear diagnosis. Additionally, the physiologic information provided by MPI may help even after coronary angiography is performed, as this test serves to define the overall importance of an observed coronary stenosis by determining if blood flow is reduced within a specific coronary artery.
MPI provides the ability to risk stratify patients and has served to define nuclear cardiology, as a tool beyond the establishment of a clinical diagnosis. A basic goal of any test aimed at providing prognostic information is to permit the separation of a low-risk group of patients from those who are at a high risk of sustaining subsequent cardiac events, such as cardiac death or myocardial infarction. It is to the latter group that we direct our resources, avoiding the expense and risk of subsequent tests and procedures, in those subjects deemed to be at low risk for cardiac events.
Effective risk stratification has been shown with exercise or pharmacologic (medication-induced) stress testing simply by determining whether or not the perfusion study is normal or abnormal. A normal myocardial perfusion study is associated with a 0.3% to 1.0% annual risk of myocardial infarction or cardiac-related death, in contradistinction to an abnormal study where the risk is five- to 10-fold increased (see Figure 1). A number of studies have demonstrated not only the independent value of MPI in the prediction of subsequent cardiac events, but that this information is incremental to data that may already be available. Thus, perfusion imaging adds to the clinical and exercise data that is already known and strengthens the model for prediction of myocardial infarction or cardiac death. This incremental value extends for up to six years with regards to the prediction of subsequent cardiac events. It appears that computerized, quantitative analysis provides similar prognostic data to that obtained from expert interpretation, thereby providing potential value especially in laboratories with less experienced visual interpreters. The use of gated SPECT to determine both LV volumes and ejection fraction also has incremental prognostic value.
In addition to the prognostic applications of perfusion imaging in a general population with known or suspected CAD, this technique has shown specific predictive value with regards to events in female patients and in the elderly. Furthermore, diabetics are at a markedly increased risk of heart disease and, recently, MPI has been shown to successfully identify diabetic patients with CAD and may help in planning treatment strategies for such individuals. The application of scintigraphic techniques early after a myocardial infarction permits selection of patients who should be considered for additional cardiac testing, such as cardiac catheterization prior to hospital discharge. Recent trials continue to demonstrate the value of post-MI risk stratification, even when contemporary therapeutics are employed. Patients with vascular disease have been extensively studied with vasodilator scintigraphy, as this group has a high incidence of perioperative cardiac complications. Dipyridamole and adenosine perfusion imaging have demonstrated predictive value regarding cardiac event-free survival both in the perioperative period, and following hospital discharge. The presence of a transient perfusion abnormality associated with vasodilator imaging increases the risk of a perioperative myocardial infarction or cardiac death about four-fold.
One of the most vexing areas in modern cardiology is the evaluation and treatment of heart failure and determination of myocardial viability. Heart failure is the most common reason for hospitalization in the US and more than two-thirds of patients with a diagnosis of heart failure have, as an underlying cause, the presence of CAD. In addition to the usual therapies for heart failure, renewed emphasis is now placed on examining the underlying cause and attempting to determine if the left ventricular dysfunction is potentially reversible. Contemporary MPI techniques and an awareness of previous limitation has led to markedly improved ability to detect heart muscle that may improve function as well as be associated with improved patient outcome after revascularization. The presence of myocardial viability is especially important in patients with severe ventricular dysfunction, where the benefits of coronary revascularization may be questioned due to the increased risk of the procedure. Patients with viable areas clearly demonstrate survival benefit and improved quality of life after revascularization, as compared with those who do not. The latter group may therefore be exposed to substantial operative risk without clear benefit (see Figure 2). Thus, detection of ischemia and viability in patients with heart failure enables the clinician to determine which patients are likely to benefit from coronary revascularization with a reduction in mortality and improved quality of life.
Additional applications are present, such as after coronary artery bypass surgery (CABG) or percutaneous coronary intervention. Perfusion imaging has substantial predictive value regarding the prediction of late cardiac events. The impact of the predictive value of perfusion imaging is most apparent when examining the cost-effectiveness of the technique. In fact, the ability to regulate downstream testing and therapeutics may demonstrate a key value of this method. These factors are especially important in the modern era of healthcare reform. In the evaluation of patients with chest pain, a strategy that employs MPI with the selective use of coronary angiography has been shown to result in similar rates of cardiac events compared with an approach in which all patients undergo cardiac catheterization. Obviously, the group of patients who proceeded directly to coronary angiography had more angiograms performed, as well as a substantially higher number of revascularization procedures (bypass surgery and angioplasty). However, the group that had more invasive procedures did not fair better than those who went for angiography and revascularization only after an abnormal MPI. These data and others demonstrate that perfusion imaging may be used to regulate invasive techniques and provide maximal benefit to patients who most require further intervention while doing so in a financially sound manner (see Figure 3).
Future Directions
Recent technological advances have further improved the diagnostic accuracy of MPI. Gated SPECT imaging assists in the recognition of artifacts caused by soft tissue (obesity, breast) and significantly improved the specificity of the test. Gated SPECT imaging should be routinely performed in all laboratories. More recently, methods for attenuation correction have become available and not only enhance specificity through the identification of artifacts but also may detect more extensive areas of ischemia. Attenuation correction is now recommend by nuclear cardiology leaders, but has not been universally accepted due to the high cost of equipment and the lack of reimbursement for this supplemental method.
New applications are also apparent for MPI. Much emphasis has been placed recently on the potential value of MPI for specific patient groups such as women, the elderly, and diabetics. In addition to diagnostic and prognostic applications, MPI may be used not only to decide on treatment, but to evaluate the efficacy of these therapies. SPECT imaging has been used as an end-point for studies examining novel methods of revascularization, such as with the use of laser techniques or angiogenic substances, including gene therapy. The goal is to demonstrate improved perfusion as a 'hardÔÇÖ end-point in these difficult and expensive clinical trials, thereby demonstrating 'proof of conceptÔÇÖ and also potentially obviating the need for a mortality end-point, which is time-consuming and requires large numbers of subjection.
The ideal perfusion agent has yet to be determined. A number of factors still limit the clinical value of available perfusion agents, including Tc-99m sestamibi, Tc-99m tetrofosmin, and thallium-201. An agent that would provide high quality images, along with an accurate reflection of myocardial perfusion at all levels of stress would be clinically advantageous. New methods for stress testing are currently in development, including medications this selectively stimulate the receptor for coronary artery dilation, without activating other receptors this cause undesirable side-effects. The A2a agents presently in Phase 2 and 3 clinical trials, binodenoson, regadenoson, and BMS068645, offer the promise of improved safety tolerability and convenience.
The use of nonperfusion nuclear imaging will also play a substantial role in the evaluation of patients with heart disease, especially those with severe left ventricular dysfunction. Imaging with I-123 MIBG allows for assessment of the sympathetic nervous system within the heart. Such imaging has been shown to accurately predict response in heart failure patients to certain therapies, such as beta-blockers, and may allow for refining triage decisions regarding ICD implantation. This agent is scheduled to undergo large-scale clinical trials in the US later this year. Metabolic agents such as I-123 BMIPP have also been studied outside of the US and may be of value in the determination of myocardial viability, as well as assessing 'ischemic memoryÔÇÖ in patients with spontaneous or provoked ischemia and then imaged at a later time.
Much of the future for nuclear cardiology may lie in its ability to examine molecular processes within the myocytes to gain in the understanding of heart disease and the evaluation of therapeutics. Molecular cardiovascular imaging will likely help to define processes such as ischemia, necrosis, and apoptosis (programmed cell death). Annexin-V may be radio-labeled and can image apoptic processes occurring after myocardial infarction or in heart failure. It is also possible to image cell receptors, such as those that regulate response to catecholamines (sympathetic and parasympathetic receptors). New agents have recently been developed to image cells that are undergoing or may be receptive to angiogenesis, or the 'growingÔÇÖ of new blood vessels. Finally, an exciting new horizon for nuclear cardiology is the ability to detect and define processes within the atherosclerotic plaque. Using a metabolic agent such as F-18 fluorodeoxyglucose (FDG) or specific agents directed at contents within the plaque, nuclear cardiology methods allow for the distinction between stable plaques from vulnerable (unstable) plaques. The latter are associated with a marked increase in risk for myocardial infarction and cardiac death.
Conclusion
MPI has greatly evolved for its initial role as a method for the detection of CAD. Nuclear cardiology techniques have clearly become a mainstay in the evaluation of patients with known or suspected ischemic heart disease, perhaps primarily due to the ability to effectively risk stratify patients for a variety of clinical situations. The method is well established for this purpose and has demonstrated the cost-effectiveness of this approach. Additional clinical applications are under development. Furthermore, nuclear cardiology is now expanding on its biologic basis to examine molecular processes and will likely provide new information about disease processes and treatment options.