Nuclear Medicine
CLINICAL DECISION SUPPORT
Tracers suitable for SPECT scan: [99mTc]sestamibi (sestamibi) is a cationic complex that diffuses passively through the capillary and cell membrane. Within the cell it is retained in intact mitochondria and reflects viable myocytes. Elimination of the radiotracer occurs through the hepatobiliary system and to a lesser extent the kidneys. ([99mTc]Tc-Tetrofosmin is also cleared rapidly from the blood, and its myocardial uptake, approximately 1.2% of the administered dose, is similar to that of sestamibi and likely by a similar mechanism. Elimination of ([99mTc]Tc-tetrofosmin occurs mostly through the kidneys and the hepatobiliary system, and clearance is slightly more rapid than in the case of sestamibi. Myocardial uptake of the technetium-99m labelled tracers increases almost proportionately with increase in perfusion. However, technetium-99m labelled tracers reach a plateau in myocardial uptake at a myocardial perfusion around twice the resting levels.
Following intravenous (i.v.) injection of thallium-201, ~88% is cleared from the blood after the first circulation with ~4% of the injected activity localizing in the myocardium in proportion to regional perfusion and viability. Thallium-201 is a potassium analogue, and ~60% of the administered activity enters the myocytes via the sodium-potassium ATPase-dependent exchange mechanism, and the remainder enters passively along an electric potential gradient. The extraction efficiency is generally maintained under conditions of acidosis and hypoxia, and the extraction is reduced only when myocytes are irreversibly damaged and replaced by fibrotic tissue is extraction reduced. Myocardial uptake of thallium-201 increases proportionately with perfusion, and perfusion increases up to 2-2.5 times above resting levels before reaching a plateau in myocardial uptake. After initial uptake, prolonged retention depends on the intactness of cell membrane and hence on viability. Moreover, because thallium-201 is not trapped in myocytes or in other tissues, redistribution of thallium-201 occurs over several hours after administration. This redistribution/re-availability leads to thallium-201 myocardial extraction in regions that had a decreased myocardial perfusion when thallium-201 was injected at peak stress, thus redistribution images can be acquired that are fairly independent of perfusion flow and mainly reflect the extent of residual viable myocardium in the LV wall. Sensitivity of detection of viability in thallium-201 rest imaging can be enhanced by injection of a top up dose of Thallium-201 after stress imaging.
Tracers suitable for PET scan: Rubidium-82 is a positron emitting cationic analogue of potassium. It is a radionuclide generator product with a physical half-life of 76 sec and kinetic properties similar to those of thallium-201.
[13N]ammonia is produced from cyclotron produced nitrogen-13 which has a radioactive half-life of 9.96 min. It readily diffuses across plasma and cell membranes leading to virtually complete extraction from the vascular pool. It then becomes metabolically trapped inside the myocyte. Its retention by the myocardium has a nonlinear and inverse relationship with blood flow.
[15O]water is produced from the cyclotron produced radionuclide oxygen-15 which has a radioactive half-life of 2.04 minutes. This tracer is metabolically inert and freely diffuses across capillaries and cell membranes of the myocardium. Its first-pass extraction is close to unit and it is independent of flow. Shortly after injection equilibrium between 15O concentration in myocardial tissue and in venous blood is achieved. These characteristics of the tracer in association with limits in spatial resolution of PET system and motion of heart make it difficult to separate the blood activity from the myocardial tissue images. In clinical routine the use of this tracer is limited because no true morphological images can be obtained and gated studies are highly demanding.
Compared with myocardial perfusion scintigraphy, Perfusion Positron Emission Tomography (PET) offers high spatial resolution of images, lower radiation exposure, and overall improved diagnostic accuracy for the detection of CAD.
It is not recommended to interrupt breast feeding when using technetium-99m labelled compounds, although to be on the safe side, an interruption of 4 h during which one meal is discarded can be advised. Breast feeding should be interrupted 48h following administration of thallium-201, but no interruption is recommended with the short-lived positron emitters [1–3] Breast milk could be collected and stored beforehand, in order to be provided to the infant during the interruption period.
Prior to elective invasive coronary angiography (ICA), a test for ischemia is strongly recommended by cardiological guidelines (ESC). However, a recent retrospective analysis of 23,887 patients with stable CAD undergoing elective coronary angioplasty revealed that stress testing prior to the examination (either exercise treadmill, stress echocardiography, or nuclear MPI) was performed in only 44% of patients MPI with Single-photon emission computed tomography (SPECT) is widely available and is by far the best validated non-invasive method for this purpose [4].MPI with SPECT is robust, not only in detecting haemdynamic obstructive CAD (with sensitivity and specificity >85%), but also in quantifying the magnitude of jeopardized myocardium and assessing the extent of myocardial viability.
Ischemic evaluation has shown superior prognostic value compared with visually analysed ICA which adds no incremental prognostic value over the combination of gender, risk factors, exercise, and SPECT MPI data. Although a normal or mildly abnormal SPECT MPI does not exclude the presence of subclinical non-obstructive CAD (rendering the patient prone to more aggressive cardiovascular risk modification), in a large cohort of patients it was associated with an annual major adverse cardiac event (MACE) rate of about 1%. This risk varies from a low of 0.3% for women to a high of nearly 2% for patients undergoing pharmacologic stress imaging.
MPI is cost-effective as a gatekeeper to ICA in patients with stable chest pain. It has also been shown that patients with less reversible ischemia on SPECT MPI have a survival advantage with medical therapy rather than revascularization, while those with more severe ischemia are more likely to benefit from invasive procedures. In addition, in patients with apparently “false-positive” results in MPI, endothelial dysfunction can often be demonstrated, and this is linked to adverse cardiovascular outcomes regardless of ICA visual anatomical findings. The fourfold increase in cardiac risk associated with abnormal findings by SPECT MPI in patients with normal ICA further emphasizes the prognostic power of the technique.
However, SPECT MPI may fail to identify some of the lesions in multivessel CAD, since the technique depicts only the territory supplied by the most severe stenosis. Balanced reduction of hyperaemic flow in patients with multivessel disease is rare, but it may explain paradoxical underestimation of clinical risk in a normal or near normal SPECT in high-risk cohorts.Recently, new CZT gamma cameras allow high sensitivity and better spatial resolution which can lead to provide dynamic acquisitions and therefore to quantify myocardial blood flow and flow reserve during
PET MPI has higher spatial and temporal resolution than SPECT and inherently uses accurate depth-independent attenuation correction which allows quantification of basal and hyperaemic regional myocardial perfusion [5,6]. Quantification of regional perfusion appears to be useful in patients with diffuse CAD or balanced disease, where the relative assessment of myocardial perfusion by SPECT may fail to detect true perfusion changes. PET, therefore, presumably has a higher accuracy than SPECT in the diagnosis of CAD, and has shown values of sensitivity and specificity of 90% in two recent reviews, although larger direct comparative studies between the two technologies are lacking [7,8].Several series with Rubidium-82 PET MPI reported an incremental contribution to prognostication by adding measurement of changes in the ejection fraction which improved the identification of multivessel CAD [9,10]. Moreover, due to the possibility to perform an absolute quantitative evaluation of myocardial blood flow at rest, during stress and to calculate the myocardial blood flow reserve, perfusional myocardial PET has a crucial role in Patients with three coronary arteries disease and in subjects with microvascular dysfunction [11].
The suggested activities to administer for adults (for a normal weight adult patient (e.g. BMI<25) are:
In paediatric nuclear medicine, the activities should be modified according to the EANM paediatric dosage card (https://www.eanm.org/publications/dosage-calculator/).
The effective doses per administered activity are [3,12]:
The organs with the highest absorbed dose per unit activity administered (mGy/MBq) are the gallbladder and kidneys for [99mTc]Tc-sestamibi , the gallbladder and colon for [99mTc]Tc-tetrofosmin, and the bone surface and kidney for [201Tl]Tl-chloride.
Caveat (This statement applies to all dosimetry entries):
“Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."
Perfusion
Visual interpretation is the most reliable means to interpret perfusion images. There are several software programs available for interpreting myocardial perfusion images, however, assessment of myocardial perfusion with software programs should be considered supplemental; visual interpretation should be retained.
The visual rating of perfusion can be described as followed: normal, mildly reduced, moderately reduced, severely reduced, and absent perfusion.
If a perfusion abnormality is seen in the stress study but not in the rest study, this can be judged as ischemia. If a perfusion abnormality is seen in stress and rest, this can be due to an attenuation artefact or a myocardial infarction. The use of gated SPECT is mandatory in this context.
Quantitative analysis
Quantitative analysis of myocardial SPECT data is another way to verify perfusion abnormalities. However, quantitative analysis should never be used without visual review of the images. There are several quantitative software programs available.
The myocardium is displayed in a polar map with the apex in the centre and the base on the periphery. This is the so-called Bull’s-eye. This Bull’s-eye is made for the rest and stress study. The difference in counts between stress and rest circle is displayed in a third polar map. It is important that the rest and stress polar maps are based on identical delineation and orientation of the left ventricle (LV).
In addition, this circle represents the LV in segments, preferably using the American Heart Association 17 segment model. These segments are scored using a 5-point model of a reference population ranging from 0 (normal) to 4 (uptake absent). The total score of the LV is referred to as the summed stress score (SSS), summed rest score (SRS) and summed difference score (SDS). If these scores are reliable, taking into account possible artefacts, they may be reported. The reference database consists of men and women with a low probability of coronary artery disease or proven normal coronary arteries. It should be highlighted, that the reference database may not be a good reference population for your patients. Many parameters influence how the counts are distributed throughout the myocardium, e.g. sex, body habitus, tracer, acquisition and processing protocols, patient position, etc.
Left ventricular volume and function: Gated SPECT and routine SPECT acquisitions can occur simultaneously for any myocardial perfusion study. However, as Thallium-201 has lower count statistics as compared to Technetium-99m labelled tracers, the interobserver variability for wall motion and wall thickening is higher in thallium-201 studies.
If available, functional information should always be reported, as these are known to be independent prognostic markers for cardiac events and cardiac death.
Several software programs are available to quantify LV volumes and ejection fraction and to display the wall motion and wall thickening.
Although good correlations are found between different software programs and imaging modalities normal values for EDV (end diastolic volume), ESV (end systolic volume) and EF (ejection fraction) depend on acquisition and processing protocols and vary between different software programs and imaging modalities. In addition, normal values for LV volumes and ejection fraction differ between men and women.
Taking all these variables into account, one should rely on the department’s own experience of whether LV volumes and EF values are normal or pathological. Routinely review the end diastolic and end systolic edges in which errors may occur. Large perfusion defects, small LVs, extra cardiac activity and LV hypertrophy cause less reliable functional parameters. Regional wall motion and thickening should be assessed visually and reported as normal, mildly affected, severely affected, absent, or dyskinetic. Wall motion and wall thickening can be different therefore both parameters should be assessed, e.g. patients with an LBBB may have normal wall thickening but paradoxical septal wall motion.
Most gated SPECT software programs divide the LV in 17 segments, and these segments are scored for wall motion and wall thickening on a 5-point scale. (0 = normal wall motion/thickening to 4 = dyskinesia). These scores may be reported if they seem reliable at visual inspection.
It should be emphasized that the gated SPECT results of the stress study using Technetium-99m labelled agents is acquired in LV resting conditions approximately 30-60 min after stress. However, in patients with CAD, a worsened LV EF and/or LV dilatation in stress may persist for >60 min after stress. This post stress myocardial stunning or dilatation is an additional sign of stress induced ischemia. Post stress LV dysfunction has an independent prognostic value.
MPI PET: So-called compartment models can describe the kinetics of PET tracers for myocardial blood flow. A single-tissue compartment model, with rate constants K1, describing the transport rate in mL per g tissue per min from blood to tissue, and k2, which is the clearance rate from tissue per minute. This simple compartment model can describe the kinetics of both 15O-water and 82Rb during the first minutes after injection. To accurately describe the kinetics of 13NH3, a second, irreversible, compartment needs to be added, with a rate constant k3 describing diffusion into the glutamine pool. For 15O-water, K1 is identical to MBF, and k2 is also proportional to MBF since water is freely diffusible and water that enters the tissue must be compensated by a similar amount clearing from the tissue to ensure mass balance. Several commercial software programs are available to quantify MBF [13].
Integration of perfusion and function:
On images with mild-moderate perfusion defects in the rest study, one can differentiate between an infarction and attenuation artefact by analysing images after attenuation correction and/or assessing the regional wall thickening. In patients with an artefact, the regional wall thickening should be normal, whereas patients with an infarction will show pathological regional wall thickening. If there is normal perfusion but diminished LV EF and/or a LV dilatation, the patient may have a non-ischemic cardiomyopathy.
Medication
Patients should avoid heavy food and beverages 6 h before the rest and stress study. A light meal is permitted up to 4 h before the stress and rest test. A fasting state is recommended for a minimum of 4 h prior to the injection of the radiopharmaceutical. Diabetics may consume a light meal within 4 h before the test and should lower their insulin dose.
Stress modalities
Physical stress: Dynamic exercise is preferred wherever possible. Physical exercise capacity gives extra information regarding heart performance. Different dynamic exercise modalities are available, e.g. bicycle ergometry and treadmill exercise. Exercise may be stopped if typical symptoms occur with patients achieving >85% of their predicted target heart rate for optimal diagnostic accuracy. The rate pressure product (heart rate x systolic blood pressure) can be applied as another surrogate parameter of myocardial hyperaemia. Values >25,000 mmHg/min indicate adequate hyperaemia and values > 30,000 mmHg/min excellent hyperaemia.
Contra-indications (absolute) to maximal dynamic exercise:
Contra-indications (relative) to maximal dynamic exercise:
Pharmacological stress: Patients who are unable to exercise or who are in a poor physical condition and therefore unlikely to achieve >85% of heart rate may undergo a pharmacological stress test. In addition, patients with a contraindication for physical exercise stress test should also be stressed pharmacologically.
There are 2 groups of pharmacological stress modalities:
Adenosine
Adenosine is a naturally occurring purine which causes direct vasodilatation by binding to the A2 receptor and increases intracellular cyclic AMP. It has a short half-life of 2-10 sec. It leads to a modest increase in heart rate and a modest decrease in blood pressure.
Contra-indications:
Dipyridamole
Dipyridamole is an indirect coronary vasodilator; it increases the tissue levels of adenosine. It has a half-life of 30 min. It leads to a modest increase in heart rate and a modest decrease of blood pressure. Contra indications are similar to those of Adenosine.
Regadenoson
Regadenoson is a low affinity A2a adenosine receptor agonist which leads to coronary artery dilatation and an increase in blood flow with at least a 10-fold lower affinity for the A1 adenosine receptor and a weak affinity for the A2b and A3 receptors. The selectivity of regadenoson towards the A2a receptor reduces side effects such as AV block and bronchospasm which are mediated by the other 3 known adenosine receptors. Patients with asthma or COPD tend to show less dyspnoea with regadenoson as compared to adenosine or dipyridamole. Maximum plasma concentration is achieved within 1-4 min after injection. The half-life of the initial phase is 2-4 min. An intermediate phase follows with a half-life of 30 min. The terminal phase half-life is 2 h.
Contra indications:
Dobutamine
Dobutamine is a synthetic catecholamine. It increases oxygen demand in a dose-related manner due to an increase in heart rate, blood pressure, and myocardial contractility. These effects lead to vasodilatation. The half-life is 2 min. This stressor is used in patients who cannot undergo physical exercise and have contra indications to vasodilators. If the heart rate response is suboptimal, then Atropine may be used.
Contra indications are similar to the contraindications for physical exercise.
Contra indication for Atropine:
The detailed recommendations regarding the imaging and reconstruction parameters are available in the EANM Cardiology Guidelines.