Nuclear Cardiology in Clinical Practice in the 21st Century

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During the last few years we have been facing a revolution in the field of cardioimaging for both diagnostic and short- and long-term prognostic purposes. The introduction of multislice computed tomography (CT) in clinical practice has allowed us to carry out non-invasive coronariography or, when performed without contrast agents, the imaging of coronary artery calcification. Arteriosclerosis can now be diagnosed and followed up with the new magnetic resonance imaging (MRI) scans.

In the near future, it will be possible to identify the high-risk ateromatous plaque, providing information about artery wall status and the degree of inflammation. Evaluation of treatment response is another treatment advantage offered by this procedure that has drawn the attention of physicians. These are non-invasive methods that are easy to perform and can be applied in most patients, but their real utility in clinical practice is still to be demonstrated. Their application for evaluating prognosis in asymptomatic patients with cardiovascular risk factors is potentially high, but large, multicentre trials are needed to demonstrate this. Nevertheless, in symptomatic patients utility seems limited. In these patients, prognosis is more related to functional parameters such as ischaemia and left ventricular function than to anatomical plaque measurement. In this group of perfusion single-photon-emission computed tomography (SPECT), myocardial perfusion imaging (MPI), which provides these functional data, is an excellent tool for determining short-term risk, while coronary arteriosclerosis imaging methods are more useful in the evaluation of long-term risk and subsequently helpful for making preventative or more aggressive decisions. There is no information concerning the prognostic value of non-invasive coronary angiography. It seems more promising for diagnostic purposes. Nevertheless, it is frequently equivocal or non-diagnostic, and the significance and repercussion of arterial lesions, when found, must be carefully evaluated. Finally, there are a significant number of patients with known coronary artery disease (CAD) in whom this methodology is not effective.1 However, MPI is fully established as a non-invasive method and is a cornerstone in the management of cardiac patients and for ruling out CAD. The accumulated experience is high and strong. Moreover, it is included in numerous guideline procedures.

Prognostic Applications

MPI is the more frequently used non-invasive imaging method and the best documented by which to stratify cardiac risk. It is the most cost-effective technique in patients with a moderate risk of a subsequent cardiac event.1 The high acceptance of the methodology is based on two facts that are clearly established in the literature. A normal perfusion study defines the group of patients at a low risk (<1%) of suffering a subsequent cardiac event;2,3 and risk increases exponentially with the worsening of perfusion defects.4,5 Based on this evidence, physicians can treat patients showing a normal MPI scan without revascularisation surgery procedures, knowing that coronariography will not help in patient management. On the other hand, there are the high-risk large, severe perfusion defects that usually make revascularisation necessary. The management of mild defects is more controversial. Many patients probably do not need revascularisation, but others do. Other scintigraphic factors that will help in the decision and support the need for revascularisation are: low left ventricular ejection fraction, left ventricular ischaemic transitory dilatation, increased lung uptake, positive haemodynamic adenosine tests, a high pre-test probability of CAD, severely positive electrocardiogram (ECG) stress test or any other clinical information suggesting a high risk, e.g. diabetes or atrial fibrillation.1 This analysis has driven the class 1 indications of MPI in the risk evaluation of patients at an intermediate or high risk of CAD.6 Risk evaluation with MPI improves when functional parameters such as left ventricular ejection fraction and telesystolic volume (obtained from the Gated-SPECT study) and left ventricular dilatation are added to the analysis.

Diagnostic Utility

Stress–rest myocardial scintigraphy has demonstrated high diagnostic accuracy and clinical utility. Nevertheless, it is important to use the test according to the CAD pre-test probability. Regarding diagnostic purposes, the highest utility is achieved when the pre-test probability following an ECG stress test is intermediate, at 10–90%.

In patients who undergo non-cardiac surgery, cardiac events are one of the main causes of morbidity and mortality. These patients show an increased risk of cardiac morbidity due to congestive cardiac failure, angina, arrhythmia and difficult post-surgery recovery. This high cardiac surgical risk is considered to be due to CAD that is apparently stabilised or clinically silent.

It is too expensive and risky to obtain a coronariography for all of these patients. Classic clinical signs and symptoms have been used to evaluate these patients, but they are not accurate enough. Nowadays, non-invasive cardiac tests are the most frequently used methods, in particular the stress–rest myocardial perfusion SPECT test. The latter has shown utility in the evaluation of cardiac risk of patients undergoing non-cardiac surgery. Eagle et al.7 reviewed 23 papers and showed that the absence of reversible perfusion defects has a negative predictive value of 95%. Thus, patients without reversible defects are low-risk. Unfortunately, the positive predictive value varied significantly. Thus, any perfusion defect must be evaluated in the clinical scenario, including the type of surgery the patient is going to undergo. In CAD patients, it is known that thoracic, abdominal, vascular and head and neck surgery are related to a higher risk of cardiac events than urological, orthopaedic, breast and skin surgery.8

Medical Treatment or Revascularisation?

Stress–rest MPI helps to identify patients who will benefit from revascularisation. Among patients who show very mild or no ischaemia, those who are medically treated show a higher survival rate than those who undergo revascularisation procedures. On the other hand, among the patients who show moderate or severe ischaemia, in the perfusion study the highest survival rate was for those who underwent a revascularisation procedure.1 The conclusion can be drawn that stress–rest MPI is a basic, necessary tool not only for staging risk, but also for selecting patients who may benefit from revascularisation.

Therapy Evaluation

In long-term follow-up, myocardial perfusion scintigraphy has been highly effective in monitoring the treatment of CAD patients after both medical and surgical treatment. In acute CAD the rest myocardial perfusion SPECT is useful for evaluating the effectiveness of therapeutic procedures to minimise infarction size. Similarly, in subacute cases serial follow-up scintigraphies can also help to evaluate the effectiveness of therapy. These serial studies have shown significant improvement in perfusion following only medical therapy. This defines a subgroup of low-risk patients following a myocardial infarction in whom angioplasty may not improve the results of medical therapy.1 In patients who undergo revascularisation, myocardial scintigraphy helps to show the effectiveness of treatment, especially if the patient also undergoes a pre-surgery study.

This does not mean that MPI must be carried out in all patients following surgery, but it is especially interesting and useful in cases of diabetic patients with silent angina or when the patient continues to experience increasing pain following revascularisation.

Ischaemic Memory

Following an acute ischaemia, fatty acid metabolism can remain abnormal long after perfusion has become normal again; this phenomenon is known as ‘ischaemic memory’. During the ischaemic memory phase, most of the cell energy is obtained through glucose metabolism. In these cases, labelled fatty acid scintigraphy could help to stratify risk. In fact, 123I-beta-methyl iodopentadecanoic acid (BMIPP) scintigraphy is a line of research into ischaemic memory phenomena. Another method for studying metabolism is the 18F-FDG positron emission tomography (PET) scan, which has shown high sensitivity in the detection of stress-induced myocardial ischaemia.9 The objective of these studies is to analyse myocardial metabolic adaptation to ischaemia, which is probably the first-line response of the myocardium to ischaemia.

Endothelial Dysfunction

Long before haemodynamically significant stenosis appears, endothelial dysfunction may produce a worsening of the coronary vasodilatation induced by stress, leading to a decrease in myocardial blood flow reserve.10 Endothelial dysfunction also causes coronary spasm. Spasm produces ischaemia and clinical symptoms, especially pain. PET studies have shown their utility in the context of endothelial disfunction. Tracers used for PET studies are totally extracted by the myocardium in the first passage, and show low retrograde redistribution; thus, the time necessary to achieve the maximum myocardial uptake depends on the myocardial blood flow speed, which means quantification of myocardial blood flow. Myocardial blood flow measurement with PET allows the quantification of coronary blood flow reserve and endothelial dysfunction. In the near future, these measurements may help to identify early asymptomatic CAD. Low myocardial blood flow or decreased blood flow reserve is observed in asymptomatic patients with high cholesterol levels, smokers, those with hypertension and diabetic insulino-resistants. An abnormal myocardial fractional flow reserve has been shown in more than 50% of the presumed normal vessels of patients with one-vessel disease.

In fact, endothelial dysfunction is now considered to be a prognostic factor of future cardiac events.11 Despite the fact that these flow measurements have shown an improvement of endothelial function and myocardial ischaemia in CAD patients following medical treatment, there are too few studies identifying endothelial dysfunction as a relevant myocardial therapeutic target.

Molecular Applications

Molecular imaging is ushering in a new era in cardiac imaging. Today, it is possible to transfer the continuous developing knowledge of physiopatholgy to the cellular and molecular level of arteriosclerosis and to identify the vulnerable plaque from a clinical point of view. Different cellular and molecular components associated with the instability and progression of the ateromatous plaque has been identified. PET studies offer the possibility of molecular binding: a particular radionuclide can be bound to a molecule that is a component of unstable ateromatous plaque. 18F-FDG uptake is increased in inflamed vascular tissue and can also be a marker of arteriosclerosis. 125I-labelling of low-density lipoproteins has been used to obtain images of arteriosclerotic disease in the carotid arteries. Another possibility for identifying the unstable plaque is the use of 99mTc-annexine V, which localises the apoptotic cells.12

The Capability of Nuclear Medicine in Myocardial Molecular Imaging

The labelling of myocardial intracellular metabolites, or cell surface molecules, would enable the diagnosis and treatment of left ventricular subclinical dysfunction. In the same vein, the same labelling would permit left ventricular remodelling after the fibrosis, apoptosis and other molecular and cellular events that follow cardiac failure.

123I-metaiodobenzylguanidine (MIBG) provides information concerning heart innervation, and is considered a risk marker. A decreased 123I-MIBG uptake accompanying left ventricular dysfunction and cardiac failure is associated with a worse prognosis. Another significant finding using 125I-angiotensine I has been the demonstration that more than 90% of angiotensine I and 75% of angiotensine II found in cardiac tissue are locally synthesised in situ. It is believed that the knowledge of tissular expression of the renin–angiotensin system may have an impact on the management of cardiac failure. Finally, the future applications of SPECT and PET in clinical cardiology practice must include studies that characterise, visualise and quantify cell myocardial survival as well as gene-based therapy monitoring.


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