European Nuclear Medicine Guide
The radio-labelled bisphosphonates HMDP/DPD and PYP are usually used for bone imaging and are incorporated into the surface of hydroxyapatite crystals in proportion with local bone vascularization and osteoblastic activity. Three/four hours post injection, approximately 60% of the injected amount will be fixed to the skeleton, the unbound fraction (34%) is excreted in the urine, and only 6% remains in circulation.
Cardiac uptake of these tracers in cardiac amyloidosis is well established in the literature; the positivity of their uptake into the heart seems to be linked to the ability of certain types of amyloid to promote calcium deposition, that appears to be the substrate for tracer uptake, but the certain mechanism of cardiac uptake remains unknown.
Many hypothesis were made to justify the unusual uptake in an extra bone site like in the heart: it could be due by higher calcium content or the type of mutation and the result of the proteolysis of myocardial fibres (full-length only vs full-length plus C-terminal ATTR fragments, that could justify the preferential detection in ATTR form- amyloid transthyretin) that could determine uptake of bone radiotracers by amyloid fibrils [23,24].
Recent studies highlight the value of DPD, HMDP, and PYP in diagnosing cardiac ATTR and differentiating it from AL amyloidosis [25].
Furthermore, DPD and HMDP allow the possibility of detecting extra-cardiac (skeletal muscle and lung) amyloid infiltration [26,27]
Patients with suspicion of cardiac amyloidosis based on the diagnosis or clinical suspicion of systemic amyloidosis or on the echocardiographic test of restrictive or hypertrophic cardiomyopathy and / or aspects suggestive for infiltrative pathology.
Pregnancy is a relative contra-indication. It is not recommended to interrupt breast feeding [3].
Cardiac involvement has major clinical and prognostic implications in amyloidosis. Acquired monoclonal immunoglobulin light-chain (AL) and transthyretin (TTR)-
related (familial and wild-type/senile) disease are the most frequent causes of cardiac amyloidosis [28].
Diagnosis of amyloidosis and differentiation between subtypes is important for prognosis, therapy, and genetic counselling.
Differential diagnosis between TTR-related and AL amyloidosis is often complex and challenging.
In the past, the diagnosis of cardiac amyloidosis required endomyocardial biopsy and typing of the amyloid fibrils. This practice has already changed; it is now rarely used since a non-invasive diagnostic imaging method using bone tracers or 99mTc-pyrophosphate (PYP)] have been shown in several studies to have high sensitivity and specificity for the diagnosis of cardiac amyloidosis, especially in ATTR form [29–31].
740 MBq (15 to 25 mCi) of 99mTc -labelled diphosphonate or PYP intravenously, with a total-body effective dose estimated for the suggested activities at a range of 3.3-4.4 mSv.
Caveat
“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."
The uptake of the bone tracer in the cardiac region must be localized in the myocardial wall and not referable to persistence of intravascular blood pool. Criteria for assessing the intensity of cardiac uptake have been proposed, using as a reference the bone (rib) tracer’s uptake.
Perugini score has been assessed and used as semi-quantitative visual scoring of cardiac retention [29]:
Based on previously published results, visual scores of
greater than or equal to 2 on planar [29,30] or on SPECT images at 3 hours [31] are classified as ATTR positive, and scores of less than 2 as not suggestive of ATTR.
While grade 2 or 3 is strongly suggestive of ATTR amyloidosis, any degree of DPD, HMDP or PYP myocardial uptake can occasionally be seen inAL amyloidosis. Indeed, we have to mention that substantial cardiac uptake has been reported in more than 20% of patients with AL cardiac amyloidosis [25].
Therefore, DPD, HMDP and PYP should always be interpreted in conjunction with serum and urine immunofixation and serum free light chain assay studies to exclude AL amyloidosis.
An overall interpretation of the findings into categories for ATTR cardiac amyloidosis, include:
No specific test preparation is required.
A dual-head camera equipped with low-energy, high-resolution collimators is recommended to be used.
If you use 99mTc -labelled diphosphonate, whole body scans were obtained five minutes (early) and three hours (late) after injection [29]
Some Authors suggest to only perform late images three hours after injection [25].
If you use PYP , a series of planar images of anterior thorax (and optionally lateral and left anterior oblique planar views) with the heart centred in the field of view have to be obtained at 1 hour post injection (over 8 minutes duration) to calculate a semi-quantitative analysis of heart retention by drawing a region of interest (ROI) over the heart and on the contralateral chest. The fraction of mean counts in the heart ROI-to-contralateral chest ROI was calculated as the heart-to-contralateral (H/CL) ratio.
A semi-quantitative visual scoring of cardiac retention has to be assessed in the late images at three hours (late) after injection.
Planar whole-body late imaging is useful for visual interpretation, especially when negative, and when positive for quantification of the degree of myocardial uptake by visual comparison to rib uptake, using both 99mTc-labeled diphosphonate or PYP. It may be helpful to identify uptake of 99mTc-DPD or HMDP in the shoulder and hip girdles (a specific sign of systemic ATTR amyloidosis) and to identify a low bone soft-tissue update in the extremities, which is a sign for systemic ATTR amyloidosis) [31].
The single-photon positive emission computed tomography (SPECT) imaging is performed if there is myocardial uptake of these tracers on planar images. Acquisition parameters for the SPECT imaging were low-energy, high-resolution collimators, matrix 64×64 with 1.46 zoom. The Butterworth filter is used with a cut off of 0.50 and order of 5.00.
SPECT imaging is necessary in all cases with positive planar scintigraphy to:
Recently, quantification of myocardial uptake can be done by using CZT cameras in patients with amyloidosis which can be useful to evaluate therapy in patients with ATTR disease [32]