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Cardiac investigation—nuclear and other imaging techniques 

Cardiac investigation—nuclear and other imaging techniques

Chapter:
Cardiac investigation—nuclear and other imaging techniques
Author(s):

Nikant Sabharwal

, Andrew Kelion

, Theo Karamitsos

, and Stefan Neubauer

DOI:
10.1093/med/9780199204854.003.160303_update_002

Update:

Use of rogadenoson as a vasodilator in myocardial perfusion scanning (MPS). Prognostic value of MPS in patients with reversible ischaemia and its use in decision making in resvascularisation. The use of T1 and T2 imaging in detection of oedema in ischaemia, myocarditis and cardiomyopathies. Guidelines for use of CT calcium scoring and angiography in risk assessment and the assessment of chest pain.

Updated on 29 Oct 2015. The previous version of this content can be found here.
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Essentials

Myocardial perfusion scintigraphy

Myocardial perfusion scintigraphy (MPS) provides physiological information about the coronary circulation, in contrast to the anatomical information provided by angiography.

Three radionuclide-labelled perfusion tracers are routinely used in single photon emission computed tomography (SPECT) imaging: thallium-201 and the technetium-99 m-labelled complexes sestamibi and tetrofosmin. Imaging is performed following tracer injection during stress (exercise or pharmacological) and at rest; comparison allowing determination of whether regional perfusion is normal, or if there is inducible hypoperfusion or infarction/scar.

Myocardial perfusion imaging is minimally invasive, and—in contrast to other methods of investigation—can be performed regardless of overall exercise capacity, abnormalities of the resting electrocardiograph (ECG), pacemakers, obesity, claustrophobia, renal dysfunction, iodine allergy, or acoustic windows.

In the investigation of the patient with possible coronary artery disease, a normal SPECT study is very reassuring, predicting a very low chance of a major cardiac endpoint event in the following few years (<1% per year). High-risk markers on SPECT provide additional prognostic value to clinical, exercise test, and even angiographic variables, and decisions about revascularization can be usefully informed by SPECT imaging.

ECG-gated SPECT allows images to be taken throughout the cardiac cycle, when comparison of end-systolic and end-diastolic images then allows volumetric analysis and calculation of left ventricular ejection fraction.

Positron emission tomography (PET)

Using PET, myocardial perfusion imaging can be performed with nitrogen-13 ammonia or rubidium-82, and metabolic imaging with fluorine-18 fluorodeoxyglucose (FDG). Cardiac PET is expensive, but image quality is superior to SPECT and absolute flow quantification is possible. PET is gaining a significant foothold in the developed world, largely driven by the roll-out of scanners for oncological imaging and the availability of generator-supplied rubidium-82 as a perfusion tracer. Imaging using oxygen-15-water is considered the gold standard for absolute quantification of myocardial perfusion (though static perfusion images cannot be obtained), and metabolic imaging with FDG occupies the same position in the assessment of myocardial viability.

Cardiac MRI

MRI uses the magnetic properties of the hydrogen nucleus, radio waves, and powerful magnets, to provide high-quality still and cine images of the cardiovascular system with and without the use of exogenous contrast (gadolinium). Cardiovascular MRI (CMR) is the gold standard method for the three-dimensional analysis of cardiothoracic anatomy, the assessment of global and regional myocardial function, and viability imaging (late gadolinium enhancement technique). Using first-pass perfusion imaging under vasodilator stress, CMR has high diagnostic accuracy for the identification of myocardial ischaemia. Oedema imaging using T2-weighted techniques is useful for the identification of acute coronary syndromes and myocardial inflammation. Coronary MRI is feasible, and particularly indicated for anomalous coronaries. Its spatial and temporal resolution is inferior to CT or conventional angiography, and the identification and grading of stenoses remains challenging. Molecular imaging may in future allow visualization of unstable plaque. Novel techniques such as T1 and T2 mapping have been recently developed and offer a quantitative measure of tissue characteristics. CMR also provides important prognostic data for many cardiovascular diseases. CMR is now an essential component of an advanced cardiovascular imaging service, and it is anticipated that its role will continue to grow.

Cardiac CT

Multidetector computed tomography (MDCT) is a fast and noninvasive method for the visualization of the coronary arteries. In comparison to CT imaging of other organs, it requires a scanner with at least 64 detectors and ECG gating. CT can be used to assess the overall burden of coronary atheroma in terms of calcification, and angiographic images can be obtained following power injection of iodinated X-ray contrast.

The spatial and temporal resolution of cardiac CT remains inferior to invasive angiography. Its positive predictive value is limited by artefacts, particularly in relation to calcified plaques, though in experienced hands this may be less of a problem than the literature suggests. However, the great strength of the technique lies in its extremely high negative predictive value, which exceeds 99% in most studies. Hence cardiac CT is an excellent test to rule out coronary stenoses in patients with low to intermediate likelihood of disease. With further technical developments it is likely that coronary CT will replace invasive coronary angiography for many diagnostic purposes.

Nuclear imaging

Myocardial perfusion scanning (MPS) can provide the information on (1) viable vs infarcted myocardium on the resting scan; (2) inducible hypoperfusion on the stress scan (in comparison with rest); and (3) regional and global left ventricular function. both at rest and post-stress.

The procedure is versatile and minimally invasive, and is not limited by overall exercise capacity, abnormalities of the resting ECG, pacemakers, obesity, claustrophobia, renal dysfunction, iodine allergy, or acoustic windows. Indeed, it is very difficult to identify any patient who is not suitable for nuclear perfusion imaging, and as a result the technique has matured into a first-line procedure for the assessment of coronary artery disease in many countries. Over 5 million nuclear cardiology procedures were undertaken in the United States of America in 2001.

Basic principles

An intravenous injection of a radiopharmaceutical tracer is administered, which enters intact myocardial cells and is retained within them to allow time for subsequent imaging.

Usually, the comparison of stress and rest images determines whether regional myocardial perfusion is uniform, or if there are inducible or reversible perfusion defects (corresponding to inducible ischaemia) or fixed perfusion defects (corresponding to infarction) (Fig. 16.3.3.1).

Fig. 16.3.3.1 Myocardial perfusion imaging—an example of inducible hypoperfusion in the anterior wall and apex. Panels from left to right show representative vertical long axis (VLA), horizontal long axis (HLA), and mid short-axis (SAX) slices, with stress above rest. The white arrows show a perfusion defect on the stress slices which resolves at rest.

Fig. 16.3.3.1
Myocardial perfusion imaging—an example of inducible hypoperfusion in the anterior wall and apex. Panels from left to right show representative vertical long axis (VLA), horizontal long axis (HLA), and mid short-axis (SAX) slices, with stress above rest. The white arrows show a perfusion defect on the stress slices which resolves at rest.

There are currently three radiopharmaceutical perfusion tracers used in single photon emission computed tomography (SPECT) imaging: thallium-201, and two technetium-99 m-labelled agents, sestamibi and tetrofosmin. All are monovalent cations, roughly the same size as a hydrated potassium ion. Following injection, they are delivered to the myocardium in proportion to blood supply, and enter the cells down the electrochemical gradient.

Thallous-201 chloride has been in use since the mid-1970s. It is produced in a commercial cyclotron, and has a half-life of 73 h. It emits photons of varying energies (predominantly 68–80 keV). Following myocardial uptake, thallium-201 gradually re-equilibrates with the extracellular space (redistribution). Therefore, following injection of 80 MBq during stress (exercise or pharmacological), imaging must be performed immediately (within 10 min). A redistribution scan 3–4 h later reflects resting viability/perfusion without the need for a second injection. Nevertheless, a second injection of thallium (40 MBq) may be administered at rest to optimize the assessment of myocardial viability.

Sestamibi and tetrofosmin are organic complexes with technetium-99 m. Technetium-99 m is widely available in nuclear medicine departments from a generator, and is used to label a freeze-dried product in a vial. Technetium-99 m emits γ‎-rays at 140 keV and has a half-life of 6 h. Sestamibi and tetrofosmin bind to intracellular components, and hence their distribution at the time of imaging (typically 30–60 min after injection) reflects myocardial perfusion at the time of imaging. Separate injections are required for stress and rest imaging, either on separate days (typically 400 MBq on each day) or on the same day (with a larger second dose—750 MBq after 250 MBq—to swamp residual activity). Sublingual glyceryl trinitrate (GTN) can be given before the resting injection of sestamibi or tetrofosmin to maximize the detection of myocardial viability.

Photons emitted from the patient are imaged by a gamma camera, the head of which is essentially a large crystal of sodium iodide. Absorption of a gamma photon produces a burst of photons within the visible range (scintillation), which is detected by underlying photomultiplier tubes. The gamma camera rotates around the patient over a 180° arc from right anterior oblique (RAO) to left posterior oblique (LPO). A planar image is acquired at each of a series of 32–64 steps, and these can be gated to the patient’s ECG to provide functional information on the processed scan. Acquisition usually takes 15–20 min. The planar projections are reconstructed to give sets of vertical long-axis, horizontal long-axis, and short-axis slices. Stress and rest slices are viewed side by side to facilitate comparison.

A new generation of gamma cameras is becoming available, which use cadmium zinc telluride (CZT) as solid-state detectors, rather than sodium iodide. These cameras have far higher sensitivity and spatial resolution, offering the potential for substantially reduced acquisition times (2–5 min) and/or tracer dose reductions.

Principles of stress testing

The wide range of stress modalities available to nuclear cardiology is one of its major advantages. Exercise (or physiological) stress can be achieved with a treadmill or bicycle following a specified protocol, such as the Bruce protocol. This is the preferred method, mimicking ‘real world’ stress and providing valuable physiological data. The increase in myocardial oxygen demand provokes secondary coronary arteriolar dilatation. The radiopharmaceutical is injected at peak stress, and the patient maintains exercise for a further 1–2 min while it is being taken up by the myocardium.

Patients unable to exercise can undergo pharmacological stress. Vasodilators such as adenosine or dipyridamole can be injected or infused intravenously to induce maximal coronary arteriolar dilatation, provoking flow heterogeneity between coronary vascular beds. These two vasodilators are contraindicated in patients with significant airways disease and unpaced second- or third-degree atrioventricular block. Cardiac investigation—nuclear and other imaging techniquesRegadenoson is an recently introduced selective adenosine A2A receptor agonist which can safely be used in asthmatics. For patients unable to exercise where there is a contraindication to a vasodilator drug, inotropic stress with escalating doses of dobutamine (± atropine) can be used.

Some practical considerations

The overall radiation exposure of a patient undergoing a stress-rest technetium study is 8–10 mSv, which is greater than for a diagnostic coronary angiogram, but without the invasive and vascular complications.

Cost-effectiveness studies have been performed with SPECT in both Europe and the United States of America. In general, diagnostic strategies that utilize MPS are more cost-effective than those that do not. This has helped to drive a significant increase in the number of SPECT procedures performed worldwide.

Clinical uses of nuclear imaging

Investigation of coronary artery disease

In a large meta-analysis of 33 studies the sensitivity and specificity of myocardial perfusion imaging were 87% and 73% respectively. The normalcy rate, which removes the referral bias of false-positive patients being referred on for coronary angiography, was 91%. Similar results are available for vasodilator and dobutamine stress. More importantly, a wealth of prognostic data is available. The value of a normal SPECT study is beyond doubt, with a meta-analysis including just under 21 000 patients followed up for 2.3 years demonstrating a major cardiac endpoint event rate of 0.7% per year. Follow-up studies extending up to 7 years have demonstrated similar low event rates.

High-risk markers on SPECT have incremental prognostic value over electrocardiographic and clinical variables. They include multivessel disease patterns, a large burden of ischaemia (>10% of myocardium), transient ischaemic left ventricular dilatation, left ventricular ejection fraction (LVEF) <0.4 (see0.4 (see ‘Assessment of left ventricular volume and function’), and lung uptake (only with thallium-201).

SPECT is also able to further risk stratify when risk scores such as the Duke treadmill score are applied to exercise ECG variables (Fig. 16.3.3.2), and can provides additional prognostic value in specific populations such as patients after myocardial infarction or with diabetes mellitus, women, and patients with an abnormal ECG (e.g. left bundle branch block).

Fig. 16.3.3.2 Incremental value of myocardial perfusion imaging over exercise ECG: Hard event rates per year as a function of exercise SPECT in patients initially stratified by low, intermediate, and high Duke treadmill scores.

Fig. 16.3.3.2
Incremental value of myocardial perfusion imaging over exercise ECG: Hard event rates per year as a function of exercise SPECT in patients initially stratified by low, intermediate, and high Duke treadmill scores.

Cardiac investigation—nuclear and other imaging techniquesMore recent data have emphasized the value of MPS even in patients with proven coronary artery disease. In a large retrospective study from Cedars-Sinai Hospital (Los Angeles, California), patients managed conservatively had higher event rates than those managed with revascularization if they had inducible hypoperfusion that was more extensive than 10% of the left ventricular myocardium (see Fig. 16.3.3.3). The COURAGE trial failed to show any prognostic benefit of percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) over OMT alone. However, a nuclear substudy suggested that PCI was better at reducing inducible hypoperfusion than OMT alone, and that event rates were lower for patients with greater decreases in inducible hypoperfusion. The implication, which requires further research, is that MPS could be used to identify a subgroup of patients in whom, despite OMT, the prognosis could be improved by PCI.

Fig. 16.3.3.3 Annualized cardiac death rate according to ischaemic burden and treatment strategy. Increasing ischaemia appears to be better treated with revascularization in this retrospective study.

Fig. 16.3.3.3
Annualized cardiac death rate according to ischaemic burden and treatment strategy. Increasing ischaemia appears to be better treated with revascularization in this retrospective study.

From Hachamovitch, R. et al, ‘Comparison of the Short-Term Survival Benefit Associated With Revascularization Compared With Medical Therapy in Patients With No Prior Coronary Artery Disease Undergoing Stress Myocardial Perfusion Single Photon Emission Computed Tomography’, Circulation. 2003; 107: 2900–2907.

Nuclear techniques are well suited to the identification of myocardial viability and predict functional recovery (identified by echocardiography) in approximately 80% of segments after revascularization. This means that decisions about revascularization can be usefully informed by SPECT: retrospective studies have clearly demonstrated that patients with low ischaemic burdens on SPECT have the same cardiac event rate if treated with either medical therapy or revascularization, and that those with significantly abnormal scans have lower event rates with revascularization compared to medical therapy. Comparative studies with low-dose dobutamine echocardiography (see Chapter 16.3.2), positron emission tomography (PET), and cardiovascular magnetic resonance (CMR) have been performed. Each test is broadly similar in its ability to predict functional recovery. SPECT has also been used to assess success of revascularization procedures.

In the acute setting, resting SPECT injections have been performed in patients attending the Emergency Department with chest pain and a nondiagnostic initial ECG. A normal perfusion scan was associated with a lower risk of future events, lower likelihood of requiring cardiac catheterization, and lower costs owing to the shorter hospital stay and fewer subsequent investigations.

Assessment of left ventricular volume and function

Nuclear cardiology techniques have been used for the noninvasive assessment of left ventricular function since the early 1970s. Three radionuclide techniques are available for assessing left ventricular function: first-pass radionuclide ventriculography, equilibrium radionuclide ventriculography, and gated myocardial perfusion SPECT.

The first is rarely performed nowadays and will not be considered further.

Equilibrium radionuclide ventriculography (ERNV)

This investigation, also affectionately (but inaccurately) known as multigated acquisition (MUGA), is performed following labelling of red blood cells with technetium-99 m-pertechnetate. This is usually performed in vivo following a preceding injection of stannous pyrophosphate. For a simple assessment of LVEF, gated planar imaging of the blood pool is performed in a LAO 45° projection to optimize separation of the left and right ventricular cavities. This method is independent of left ventricular geometry, and hence very accurate and reproducible.

The wide availability of echo (with its lack of radiation exposure) has led to a substantial decrease in the number of ERNV studies performed. However the radionuclide method can still be valuable when a quick and reproducible assessment of LVEF is required, for example in the monitoring of patients undergoing chemotherapy with anthracyclines or herceptin.

ECG-gated myocardial perfusion SPECT

SPECT acquisition during MPS can be gated at no extra inconvenience, cost, or risk to the patient. Tomographic slices are reconstructed for each of 8 or 16 frames, and can be played as a cine for visual assessment. Left ventricular volumes and LVEF can be derived following endomyocardial border definition. Gated SPECT (Fig. 16.3.3.4) can be very useful in distinguishing attenuation artefacts (which appear as fixed perfusion defects but demonstrate normal wall motion). Indices of left ventricular function (ejection fraction and end-systolic volume) provide independent prognostic information, and in particular are powerful predictors of cardiac death. Importantly, changes in regional and global function from post-stress to rest imaging can help unmask multivessel ischaemia which has been underestimated by the visible regional perfusion defects.

Fig. 16.3.3.4 Gated SPECT to assess left ventricular systolic function at rest in a patient with an extensive anteroapical and septal infarct and poor left ventricular systolic function. Left column: end-diastolic frame showing (from top to bottom) apical, mid, and basal short-axis slices, horizontal and vertical long-axis slices. Right column: end-systolic frame showing corresponding slices. Right column: calculated volumes and ejection fraction (middle panel), with time-volume curve (bottom panel).

Fig. 16.3.3.4
Gated SPECT to assess left ventricular systolic function at rest in a patient with an extensive anteroapical and septal infarct and poor left ventricular systolic function. Left column: end-diastolic frame showing (from top to bottom) apical, mid, and basal short-axis slices, horizontal and vertical long-axis slices. Right column: end-systolic frame showing corresponding slices. Right column: calculated volumes and ejection fraction (middle panel), with time-volume curve (bottom panel).

Positron emission tomography (PET)

Basic principles

PET relies on coincidence detection of 511-keV photons travelling 180° apart following annihilation of a positron with an electron. Perfusion can be assessed with nitrogen-13-ammonia (requiring an on-site cyclotron) or rubidium-82 (from a generator). Metabolism is assessed with fluorine-18 fluorodeoxyglucose (FDG), which has become widely commercially available with the growth of oncological PET. Absolute myocardial perfusion can be derived using both nitrogen-13-ammonia and rubidium-82, but is best done with oxygen-15-water (though this tracer requires a cyclotron and does not permit myocardial imaging). Cardiac PET studies are no longer confined to research centres, mainly due to the rapid increase in oncological studies requiring combined PET/CT scanners.

Comparison with other techniques

For physiological assessment of known or suspected coronary artery disease, the alternatives to SPECT and PET are exercise electrocardiography, stress (exercise or dobutamine) echocardiography, and stress CMR (with vasodilator stress for perfusion or dobutamine for wall motion). The exercise ECG is inferior, mainly due to its dependence on exercise ability and the poor sensitivity and specificity of ECG changes.

Stress echocardiography is a good alternative technique, with a slightly lower sensitivity but higher specificity in comparative studies. It is physician-intensive and operator-dependent, but harmonic imaging and microbubble contrast agents have greatly improved image quality. An important advantage over the radionuclide techniques is the avoidance of ionizing radiation, which makes it particularly attractive for younger patients.

Cardiac MRI can assess regional and global left ventricular systolic function during a dobutamine infusion, similar to stress echocardiography. Alternatively, gadolinium can be used as a first-pass myocardial perfusion tracer during vasodilator stress, with late-enhancement used to identify infarction. Two recent comparative studies have suggested that CMR is a good alternative to SPECT, though whether it is better remains a matter of controversy.

In practice, the different modalities should be regarded as largely interchangeable, with local clinical expertise being more important than any marginal differences in technical performance between them. Functional imaging, however performed, is recommended in the latest National Institute for Clinical Excellence (NICE) guidelines for the assessment of patients with chest pain of recent onset.

Cardiac MRI

Introduction

Cardiovascular MRI (CMR) has undergone significant advancement in terms of imaging capabilities, ease of use, and speed of acquisition over the past 15 years. A study of cardiovascular anatomy, left and right ventricular function, and viability/fibrosis (late gadolinium enhancement) with a modern CMR scanner can be performed in less than 30 min by an experienced operator. These improvements have led to the widespread adoption of CMR in clinical practice.

How CMR works

MRI is typically based on the magnetic properties of the hydrogen nucleus, though other nuclei can also be used. Hydrogen nuclei (protons), which are abundant in the human body, behave like small spinning magnets that have an alignment (magnetic moment) parallel to the direction of the external magnetic field and a rotation (precession) frequency proportional to the strength of the field. Radio waves in the form of a radiofrequency pulse transmitted into the patient cause the alignment of the protons to change (i.e. the magnetic moments in that region are flipped out at an angle (flip angle) to the magnetic field (excitation). When this radiofrequency pulse is turned off, the protons in the patient’s body return to their neutral position (relaxation), emitting their own weak radio-wave signals, which are detected by receiver coils and used to produce an image. The contrast between tissues (e.g. heart muscle and fat) depends on the tissue density of hydrogen atoms (proton density), and on two distinct MR relaxation processes that affect the net magnetization: the longitudinal relaxation time (T1), and transverse relaxation time (T2). The differences in these parameters in distinct tissues are used to generate contrast in MR images. Image contrast can also be modified by modulating the way the radiofrequency pulses are played out (the MR sequence): For example, in so-called T1-weighted images, myocardial tissue is dark whereas fat is bright. On the other hand, T2-weighted images highlight unbound water in the myocardium and are used to demonstrate myocardial oedema due to inflammation or acute ischaemia.

CMR requires advanced technology, including a high-field superconducting magnet which produces a homogeneous and stable magnetic field (typically 1.5 Tesla, although 3.0-T systems are increasingly being used), gradient coils within the bore of the magnet which generate the gradient fields, a radiofrequency amplifier to excite the spins with radiofrequency pulses, and a radiofrequency antenna (coil), which receives the radio signals coming from the patient. A computer and specific software are also needed to control the scanner and generate (reconstruct) the images. To prevent artefacts from cardiac motion, most CMR images are generated with ultrafast sequences gated to the R wave of the ECG. Respiratory motion, which is another factor that can produce artefacts, is eliminated by acquiring most CMR images in end-expiratory breath-hold. When acquisition is long and cannot be completed within one breath-hold, special free-breathing sequences that track the diaphragm’s position (navigators) are used.

CMR safety

MRI scan subjects and operators are not exposed to ionizing radiation and there are no known detrimental biological side effects of MRI, if safety guidelines are followed. Ferromagnetic objects can be attracted by the scanner becoming projectiles that could lead to significant patient or operator injury and also damage the scanner. The presence of certain medical implants and devices (e.g. most pacemakers and defibrillators, cochlear implants, cerebrovascular clips) is a contraindication for routine MR scanning, but nearly all prosthetic cardiac valves, coronary and vascular stents, and orthopaedic implants are safe in a 3-T (or less) MR environment. There are now MRI conditional pacemakers (generator and leads) available. Whenever there is uncertainty regarding a particular device or implant, the CMR operator should consult a more detailed source of information, such as reference manuals, dedicated web sites (e.g. <http://www.mrisafety.com>), or the manufacturer’s product information when available. Claustrophobia may be a problem in a small minority of patients, and mild sedation usually helps to overcome this. In the vast majority of patients, gadolinium contrast agents are safe—safer than iodine-based contrast. Recently, gadolinium-containing contrast agents have been linked with the development of a rare systemic disorder called nephrogenic systemic fibrosis. The patients at risk for developing this disease are those with acute or chronic severe renal insufficiency (glomerular filtration rate <30 mL/min/1.73 m2); or acute renal dysfunction of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period. To date, there is no evidence that other patient groups are at risk. Many MR centres use gadolinium agents that are tightly bound to a cyclic chelate, for which the incidence of nephrogenic systemic fibrosis is near zero. Moreover, it is unknown whether immediate haemodialysis protects against nephrogenic systemic fibrosis. Therefore, gadolinium-based contrast media should be avoided in high-risk patients unless the diagnostic information is essential and not available with noncontrast enhanced CMR or other imaging modalities.

Applications of CMR

Normal and pathological anatomy

Historically, the first widespread application of CMR was the three-dimensional analysis of cardiovascular anatomy. By providing excellent soft tissue contrast, cardiovascular anatomy can be assessed in virtually any imaging plane (coronal, transverse, sagittal), or individualized double-angulated planes. The latter is particularly valuable in complex congenital heart disease.

Myocardial function and mass

CMR is now the accepted gold standard for quantification of left and right ventricular function. Using steady-state free precession techniques that provide excellent delineation of the blood-myocardium interface, long-axis and short-axis cine views (Fig. 16.3.3.5) can be obtained during all phases of the cardiac cycle (cine-CMR). Planimetry of each short-axis slice and summation of slice volumes allow precise determination of systolic and diastolic left and right ventricular volumes, stroke volumes, and ejection fraction with high reproducibility. Ventricular mass can also be determined by multiplication of the myocardial volume by its specific weight of 1.05 g/cm3. The excellent inter-study reproducibility of volume and mass measurements by CMR has allowed reductions of sample sizes of 80–97% to achieve the same statistical power for demonstrating a given change in left ventricular volumes, ejection fraction, or cardiac mass.

Fig. 16.3.3.5 End-diastolic still images from multiple contiguous short-axis SSFP cines that encompass the left ventricle, from base to apex. Note the position of the short-axis (SA) slices marked on the still frames of end-diastolic horizontal long axis (HLA) cine image and the excellent delineation of the myocardium from the blood and the surrounding tissue.

Fig. 16.3.3.5
End-diastolic still images from multiple contiguous short-axis SSFP cines that encompass the left ventricle, from base to apex. Note the position of the short-axis (SA) slices marked on the still frames of end-diastolic horizontal long axis (HLA) cine image and the excellent delineation of the myocardium from the blood and the surrounding tissue.

Analysis of regional myocardial function is feasible both at rest and during pharmacological stress, typically using dobutamine. Dobutamine stress CMR has high sensitivity and specificity for detecting ischaemic heart disease and is particularly useful in patients with difficult acoustic windows.

Blood flow

Phase contrast mapping of velocities through planes transecting blood flow in the main pulmonary artery and the ascending aorta can provide accurate measurements of cardiac output, shunt flow, aortic or pulmonary regurgitation and, indirectly, of mitral and tricuspid regurgitation. For stenotic jets, the peak velocity can be measured on through-plane velocity-encoded images. Peak pressure gradients can be estimated according to the modified Bernoulli equation. Valve morphology can be assessed with the use of SSFP cine images and valve area can be assessed with accuracy by direct planimetry using cross-sectional cine images, although valve structure is generally better assessed by echocardiography. Bicuspid aortic valves or fused valve leaflets can be readily identified. CMR is an excellent technique for the quantitative assessment of regurgitation. If a single valve is affected, the regurgitant volume can be measured from the difference in left and right ventricular stroke volumes. If both the mitral and tricuspid valves are affected, the regurgitant volumes can be calculated by subtracting the flow in main pulmonary artery and the ascending aorta, measured by CMR velocity mapping, from the left and right stroke volumes (measured by the volumetric method), respectively. This technique compares favourably with measurements from catheterization and Doppler echocardiography techniques. For pulmonary and aortic regurgitation, direct measurement of regurgitant volume is also possible using CMR velocity mapping. These CMR techniques have high inter-study reproducibility and can be used for the longitudinal follow-up of patients with valve disease over time.

Apart from the evaluation of patients with valve pathologies, flow imaging by CMR is regularly used in assessing patients with congenital heart disease. By measuring flow in the ascending aorta and main pulmonary artery with velocity encoding CMR, the pulmonary-to-systemic flow ratio (Qp/Qs) can be determined. These CMR measurements show excellent correlation with calculations obtained from oximetry during haemodynamic catheterization.

Myocardial viability

The assessment of myocardial viability using gadolinium-based contrast agents (late gadonium enhancement—LGE technique) has revolutionized the use of CMR in cardiology. Gadolinium chelates are extracellular tracers that cannot cross cell membranes. In normal myocardium the myocytes are densely packed and the extracellular space and vascular volume represents less than 15% of the myocardial volume, hence after injection of gadolinium there are only few gadolinium molecules in a myocardial sample volume. By contrast, when the membranes of myocytes rupture, gadolinium molecules can penetrate into the myocytes and stay there, even late after gadolinium injection, such that in scar tissue the interstitial space is expanded and increased gadolinium concentration is found (Fig. 16.3.3.6). In practice, on inversion-recovery T1-weighted sequences obtained 5–10 min after gadolinium administration, nonviable myocardium (scarred or irreversibly injured) shows high signal intensity, whereas normal and viable (stunned, hibernating) myocardium shows low signal intensity.

Fig. 16.3.3.6 Mechanism for late gadolinium enhancement (LGE) in acute and chronic myocardial damage: (a) Densely packed myocytes with intact cell membrane—gadolinium chelates only in the vessels and extracellular space. (b) Acute myocardial damage with ruptured cell membranes of myocytes—intracellular accumulation of gadolinium chelates. (c) Chronic myocardial damage with loss of myoctes and replacement by scar tissue—mostly collagen fibres that are filled with gadolinium chelates.

Fig. 16.3.3.6
Mechanism for late gadolinium enhancement (LGE) in acute and chronic myocardial damage: (a) Densely packed myocytes with intact cell membrane—gadolinium chelates only in the vessels and extracellular space. (b) Acute myocardial damage with ruptured cell membranes of myocytes—intracellular accumulation of gadolinium chelates. (c) Chronic myocardial damage with loss of myoctes and replacement by scar tissue—mostly collagen fibres that are filled with gadolinium chelates.

Myocardial infarction (acute or chronic) has a characteristic LGE pattern due to the wavefront of myocardial necrosis that always involves the subendocardium at the core of the infarct (Fig. 16.3.3.7). The LGE technique has undergone extensive histopathological validation. The superb spatial resolution of LGE-CMR allows the detection of even small subendocardial infarcts that might otherwise be missed by lower spatial resolution techniques such as SPECT. Several studies have demonstrated an inverse relationship between the transmural extent of myocardial infarction and segmental functional recovery after revascularization. In practice, segments which show more than 50% scarring are considered nonviable, whereas segments with only subendocardial enhancement (<50%) have a high likelihood of functional recovery. CMR can also assess myocardial viability using a low-dose dobutamine protocol in a way analogous to echocardiography, but in practice, this is rarely required. Several CMR techniques, including LGE, can also identify areas of microvascular obstruction (no-reflow phenomenon) after revascularization in patients with acute myocardial infarction.

Fig. 16.3.3.7 Short-axis late gadolinium enhancement (LGE) image at the midventricular level in a patient with near transmural antero-septal myocardial infarction (white arrows).

Fig. 16.3.3.7
Short-axis late gadolinium enhancement (LGE) image at the midventricular level in a patient with near transmural antero-septal myocardial infarction (white arrows).

LGE-CMR in nonischaemic cardiomyopathies

Specific patterns of regional fibrosis and scarring have also been described for many nonischaemic cardiomyopathic processes (Fig. 16.3.3.8). For example, the majority of patients with hypertrophic cardiomyopathy show patchy fibrosis in the hypertrophied septum involving left/right ventricular junctions, whereas about a third of patients with dilated cardiomyopathy show a midwall band of septal fibrosis. Furthermore, most patients with myocarditis have subepicardial LGE in the lateral left ventricular wall. Several other patterns of LGE exist for other rarer cardiomyopathies such as cardiac amyloidosis or sarcoidosis. The LGE technique is a major part of nearly every scanning protocol and provides valuable diagnostic and pathophysiological insights in both ischaemic and nonischaemic cardiomyopathies.

Fig. 16.3.3.8 Short-axis late gadolinium enhancement (LGE) image at the midventricular level in a patient with hypertrophic cardiomyopathy. Note the patchy LGE due to fibrosis in the hypertrophied septum (white arrows), including both left-right ventricular junctions.

Fig. 16.3.3.8
Short-axis late gadolinium enhancement (LGE) image at the midventricular level in a patient with hypertrophic cardiomyopathy. Note the patchy LGE due to fibrosis in the hypertrophied septum (white arrows), including both left-right ventricular junctions.

Myocardial perfusion

Regional myocardial perfusion can be measured during the first pass of a gadolinium-based contrast agent. Using sequential multislice fast gradient-echo CMR, passage of the contrast agent through the heart chambers and the myocardial tissue can be followed. From a series of such images, regional time–signal intensity curves can be derived. Pharmacological vasodilatation (with adenosine, dipyridamole, or reganedoson) induces a three- to fivefold increase of blood flow in myocardial areas subtended by normal coronary arteries, whereas no (or only minimal) change is found in areas subtended by stenotic coronary arteries. Thus, contrast arrival in these areas is delayed, and they therefore appear hypointense (dark) compared to adjacent normal myocardium (Fig. 16.3.3.9). A large number of clinical trials have assessed the feasibility, safety and diagnostic accuracy of stress perfusion CMR. A recent meta-analysis (2,125 patients) showed that first-pass perfusion CMR under vasodilator stress has excellent sensitivity (89%) and very good specificity (80%) to diagnose coronary artery disease with quantitative coronary angiography as the gold standard. The CE-MARC study compared the diagnostic accuracy of stress perfusion CMR with single photon emission computed tomography (SPECT) and showed that both techniques have similar specificity but CMR is more sensitive to detect ischaemia compared to scintigraphy. It should be noted that CMR perfusion techniques have higher spatial resolution than nuclear techniques (by at least an order of magnitude) and can be used to study the transmural aspect of myocardial perfusion. The clinical implications of this higher resolution (that allows, for example, demonstrating very small perfusion defects not seen on nuclear imaging) remain to be established.

Fig. 16.3.3.9 Example of a stress perfusion scan. Short-axis stress perfusion at the midventricular level showing an extensive perfusion defect (black arrows) in the anterior wall, septum and the inferior wall. The lateral wall (white arrow) has relatively normal perfusion.

Fig. 16.3.3.9
Example of a stress perfusion scan. Short-axis stress perfusion at the midventricular level showing an extensive perfusion defect (black arrows) in the anterior wall, septum and the inferior wall. The lateral wall (white arrow) has relatively normal perfusion.

Myocardial oedema

Various technical improvements have enabled the wide clinical use of T2-weighted CMR for the qualitative or semi-quantitative detection of myocardial oedema and inflammation, primarily in acute coronary syndromes and myocarditis. Despite these improvements, a few well-recognized limitations of conventional T2-weighted techniques remain including the need for a ‘normal’ reference region of interest, in either remote myocardium or skeletal muscle. This can lead to false-negative results when these reference areas are also affected in systemic processes. Novel quantitative T2 and T1 mapping techniques have been developed to overcome these limitations. Myocardial haemorrhage in patients with acute myocardial infarction can also be assessed using T2-weighted CMR.

Coronary arteries

CMR of the coronary arteries remains a technical challenge because of their small size (up to 4 mm) and continuous, complex movement. Fast, flow-sensitive gradient-echo sequences allow imaging of proximal coronary arteries using breath-hold or navigator techniques, with a maximum in-plane resolution of about 700 µm2. However, the sensitivity for coronary stenosis is only 60–90% because of the inferior spatial resolution compared to CT or invasive coronary angiography. Further developments (parallel acquisition, gradient performance, intravascular contrast agents, higher-field magnets) might in the future allow the development of high-resolution MR coronary angiography with CT-like quality. At present, MR coronary angiography can be used for diagnosis of anomalous coronary arteries or coronary aneurysms.

Iron overload

The most common cause of iron overload cardiomyopathy is repeated blood transfusions in patients with transfusion-dependent anaemias (e.g. β‎-thalassaemia major) and in primary hemochromatosis. The cardiomyopathy is reversible if chelation is commenced early, but diagnosis is often delayed because of the late onset of symptoms and patients often die from heart failure. T2* MRI allows the accurate quantification of cardiac and liver iron levels. This allows identification of patients who are at risk of developing heart failure (i.e. those with myocardial T2* <10 ms), allowing more aggressive iron chelation therapy to be administered.

Cardiac investigation—nuclear and other imaging techniquesNovel CMR techniques: T1 and T2 mapping

T1 and T2 mapping refers to parametric maps that are generated from a series of images acquired with different T1 or T2 weighting so that each pixel can be assigned a T1 or T2 value. These maps are usually displayed using colour or thresholded scales to enable quantitative visual interpretation. Each tissue type exhibits a characteristic range of normal T1 and T2 relaxation times at a particular field strength, deviation from which may be indicative of disease. Myocardial T1-mapping methods are used for native (i.e. without the use of gadolinium-based contrast agents) and also for post-contrast T1 measurements. In combination with haematocrit, these T1 measurements enable the quantification of extracellular volume fraction (ECV).

Elevated native T1 times and ECV in the myocardium have been reported in several commonly encountered cardiac conditions including myocardial infarction, myocarditis, hypertrophic and dilated cardiomyopathy, cardiac amyloidosis (Fig. 16.3.3.10), cardiac involvement in systemic diseases and diffuse fibrosis in patients with aortic stenosis. Native myocardial T1 values may be lowered by water–protein interactions, fat, or iron content and thus can also serve as a diagnostic tool in characterizing Anderson—Fabry disease, fat in cardiac masses, and myocardial siderosis.

Fig. 16.3.3.10 Cardiac magnetic resonance (CMR) end-diastolic frame from cine (left panel), ShMOLLI noncontrast T1 map (middle panel), and late gadolinium enhancement (LGE) images (right panel) in normal volunteer, aortic stenosis patient, and cardiac amyloid patient. Note the markedly elevated myocardial T1 time in the cardiac amyloid patient (1170 ms, into the red range of the colour scale) compared to the normal control (955 ms) and the patient with aortic stenosis and left ventricular hypertrophy (998 ms). ED, end-diastolic.

Fig. 16.3.3.10
Cardiac magnetic resonance (CMR) end-diastolic frame from cine (left panel), ShMOLLI noncontrast T1 map (middle panel), and late gadolinium enhancement (LGE) images (right panel) in normal volunteer, aortic stenosis patient, and cardiac amyloid patient. Note the markedly elevated myocardial T1 time in the cardiac amyloid patient (1170 ms, into the red range of the colour scale) compared to the normal control (955 ms) and the patient with aortic stenosis and left ventricular hypertrophy (998 ms). ED, end-diastolic.

Reprinted from the Journal of the American College of Cardiology, Vol 6, Issue 4, Karamitsos, Theodoros D., et al, Noncontrast T1 Mapping for the Diagnosis of Cardiac Amyloidosis, 488-497, Copyright (2013) with permission from Elsevier.

T2 mapping can detect oedematous myocardial territories in a variety of cardiac pathologies, including acute myocardial infarction, myocarditis, takotsubo cardiomyopathy, and heart transplant rejection.

CMR and prognosis

The evolving prognostic evidence base of is rapidly expanding for both ischaemic and nonischaemic cardiomyopathies. The completion of ongoing multicentre trials and registries is expected to provide more outcome and cost-effectiveness data which will further strengthen the clinical role of CMR.

Cardiac CT

Multidetector computed tomography (MDCT) can be used to produce high-quality anatomical images in a variety of cardiac pathologies (e.g. complex congenital heart disease). However, its most widespread use is in the noninvasive anatomical assessment of the coronary arteries. The entire coronary tree is imaged during a single breath-hold over a few cardiac cycles (or even a single cycle if the scanner has sufficient detectors).

A stack of transaxial slices is acquired, covering the thorax between the carina and the diaphragmatic border of the heart. This is achieved over a few cardiac cycles, depending on the number of detectors. Coronary calcification is assessed from a noncontrasted scan. For angiographic imaging (to assess for luminal stenoses), an intravenous infusion of an iodinated X-ray contrast agent is given, typically 60–80 ml at 5–6 ml/s, followed by a saline flush. Following a breath-hold, the scan is triggered once the left side of the circulation is sufficiently opacified. The timing can be judged either by using an initial test bolus, or by a bolus tracking method where a test slice is monitored until the Hounsfield value in the ascending or descending aorta exceeds a certain threshold.

In order to image the coronary arteries free of motion, ECG gating is required. Prospective gating is the most common method, with the patient being imaged (and irradiated) for only a brief period of the cardiac cycle, typically at 75% of the R-R interval. This usually represents end-diastole, when the coronary arteries (particularly the right coronary) are at their stillest. Retrospective gating offers imaging throughout the cardiac cycle, which can be valuable when heart-rate control is poor or information about cardiac function is required. However, radiation exposure is relatively high, and the prospective method is routinely preferred.

High-quality angiographic images also depend on the patient having a relatively slow heart rate (<65 and preferably <60 bpm), which is achieved by giving a β‎-blocker, either orally or intravenously. Many centres also give sublingual GTN prior to the study to achieve coronary vasodilatation.

Once the scan has been acquired and reconstructed, it must be carefully examined. The thin transaxial slices must be reviewed, and a number of tools are available to help reorientate the images to display the coronary arteries and other cardiac structures.

Some of the technical limitations of cardiac CT are shown in Box 16.3.3.1.

Clinical uses of cardiac CT

CT coronary calcium scoring

The ability of CT to detect and quantify calcified structures is unrivalled by other imaging techniques. Pathological studies indicate that coronary calcification is an integral part of the atherosclerotic process, and unique to it (with the possible exception of patients with renal failure). Specifically, the square root of the extent of calcification is directly proportional to the square root of the overall extent of atheromatous plaque. On a non-contrast-enhanced CT scan, the Agatston score is used to quantify the total amount of coronary calcium, and assesses the area and density of plaques in all arteries.

The coronary calcium score is a good measure of the overall coronary atheroma burden, and predicts the likelihood of luminal coronary stenoses, as well as the risk of cardiac events over at least 10 years of follow-up. In particular, a score of zero predicts an extremely low risk.

Stand-alone coronary calcium scoring may be valuable in the risk stratification of asymptomatic patients or those with atypical chest pain. However, its value in patients with possible angina is less straightforward: up to 10% of patients with no coronary calcification will nevertheless have a significant coronary stenosis due to soft plaque. Moreover, the location of calcification is a poor guide to the exact location of luminal stenoses, which are typically caused by noncalcified soft plaques. Therefore, in patients with possible angina, most authorities would regard coronary calcium scoring as complementary to angiography rather than an alternative, though this is at variance with the NICE guidance (see Table 16.3.3.1).

Cardiac investigation—nuclear and other imaging techniquesTable 16.3.3.1 Assessment of patients with stable chest pain (according to NICE Clinical Guideline 95)

Estimated likelihood of CADa

<10 %

Consider noncardiac causes of chest pain

10–29%

Offer CT calcium score:

1–400 offer CT angiography

> 400 follow pathway for >60% probability of CAD

30–60%

Offer noninvasive functional imaging (MPS with SPECT or stress echocardiography or first-pass contrast-enhanced magnetic resonance perfusion or magnetic resonance imaging for stress-induced wall motion abnormalities)

If positive offer invasive coronary angiography

>60%

Invasive coronary angiography

a According type of chest pain, age, and sex (see NICE Clinical Guideline 95)

CAD, coronary artery disease; MPS, myocardial perfusion scintigraphy

CT coronary angiography

Multidetector CT is unique among the noninvasive imaging modalities in providing anatomical (rather than physiological) information about the coronary arteries. Invasive coronary angiography remains the gold standard, as CT does not yet approach its spatial or temporal resolution. However, for the exclusion of coronary stenoses CT appears extremely reliable, with a negative predictive value that approaches 99% in the literature. Positive predictive values are less robust, largely due to artefacts, particularly in relation to calcified plaques (Fig. 16.3.3.11). These observations make CT coronary angiography particularly suitable for the diagnostic investigation of patients with low to intermediate probability of obstructive coronary disease (Fig. 16.3.3.12).

Fig. 16.3.3.11 CT coronary angiography of the left anterior descending coronary artery. Note how the heavy calcification makes it impossible to exclude or confirm significant luminal stenosis at several locations.

Fig. 16.3.3.11
CT coronary angiography of the left anterior descending coronary artery. Note how the heavy calcification makes it impossible to exclude or confirm significant luminal stenosis at several locations.

Fig. 16.3.3.12 CT coronary angiography showing a critical soft plaque stenosis in the left mainstem.

Fig. 16.3.3.12
CT coronary angiography showing a critical soft plaque stenosis in the left mainstem.

As well as its role in patients with stable chest pain, cardiac CT is increasingly used in low-risk patients admitted with acute chest pain, where it is cost-effective compared with alternative strategies.

CT can also be useful in certain groups of patients with established coronary disease. It offers a very straightforward way of assessing graft patency after coronary artery bypass surgery, and can also be valuable in the exclusion of stent obstruction (though artefact can make this difficult for smaller stents).

Acknowledgements

The authors of the CMR section acknowledge support from the National Institute for Health Research Oxford Biomedical Research Centre Programme. Professor Stefan Neubauer also acknowledges support from the Oxford British Heart Foundation Centre of Research Excellence.

Further reading

Nuclear imaging

Anagnostopoulos D, et al. (2012). Myocardial perfusion scintigraphy: technical innovations and evolving clinical applications. Heart, 98, 353–9.Find this resource:

    Berman DS, et al. (2006). Roles of nuclear cardiology, cardiac computed tomography, and cardiac magnetic resonance: noninvasive risk stratification and a conceptual framework for the selection of noninvasive imaging tests in patients with known or suspected coronary artery disease. J Nuclear Med, 47, 1107–18.Find this resource:

    Cardiac Radionuclide Imaging Writing Group (2009). ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine. Circulation, 119, e561–87.Find this resource:

      Dilsizian V, Narula J (2013). Atlas of nuclear cardiology, 4th edition. Springer, New York.Find this resource:

        NICE (2010). Assessment and diagnosis of recent onset chest pain or discomfort of suspected cardiac origin. Clinical guideline 95. www.nice.org.uk/guidance/CG95

        Sabharwal NK, Loong C, Kelion A (2008). Oxford handbook of nuclear cardiology. Oxford University Press, Oxford.Find this resource:

          Zaret B, Beller GA (2010). Clinical nuclear cardiology: state of the art and future directions, 4th edition. Mosby, London.Find this resource:

            Computed tomography

            Taylor AJ, et al. (2010). ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate use criteria for cardiac computed tomography. J Cardiovasc Comput Tomogr, 4, 407.e1–407Find this resource:

            Williams MC, et al. (2011). Cardiac and coronary CT comprehensive imaging approach in the assessment of coronary heart disease. Heart, 97, 1198–205.Find this resource:

              MRI

              American College of Cardiology Foundation Task Force on Expert Consensus D, Hundley WG, Bluemke DA et al. (2010). ACCF/ACR/AHA/NASCI/SCMR 2010 expert consensus document on cardiovascular magnetic resonance: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. J Am Coll Cardiol, 55, 2614–62.Find this resource:

                Bluemke DA, et al. (2008). Noninvasive coronary artery imaging: magnetic resonance angiography and multidetector computed tomography angiography: a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention of the Council on Cardiovascular Radiology and Intervention, and the Councils on Clinical Cardiology and Cardiovascular Disease in the Young. Circulation, 118, 586–606.Find this resource:

                  Eitel I, Friedrich MG. (2011). T2-weighted cardiovascular magnetic resonance in acute cardiac disease. J Cardiovasc Magn Reson, 13, 13.Find this resource:

                    Greenwood JP, et al. (2012). Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial. Lancet, 379, 453–60.Find this resource:

                      Hamon M, et al. Meta-analysis of the diagnostic performance of stress perfusion cardiovascular magnetic resonance for detection of coronary artery disease. J Cardiovasc Magn Reson, 12, 29.Find this resource:

                        Karamitsos TD, et al. (2009). The role of cardiovascular magnetic resonance imaging in heart failure. J Am Coll Cardiol, 54, 1407–24.Find this resource:

                          Kim RJ, et al. (2000). The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med, 343, 1445–53.Find this resource:

                            Moon JC, et al. (2013). Myocardial T1 mapping and extracellular volume quantification: a Society for Cardiovascular Magnetic Resonance (SCMR) and CMR Working Group of the European Society of Cardiology consensus statement. J Cardiovasc Magn Reson, 15, 92.Find this resource:

                              Salerno M, Kramer CM. (2013). Advances in parametric mapping with CMR imaging. JACC Cardiovasc Imaging, 6, 806–22.Find this resource: