Uptake Of 99mTc-pyrophosphate Research Articles

Cardiac Amyloidosis Imaging, Part 1: Amyloidosis Etiology and Image Acquisition.

Cardiac amyloidosis is a systemic form of amyloidosis in which protein-based infiltrates are deposited in myocardial extracellular space. The accumulation of amyloid fibrils causes the myocardium to thicken and stiffen, leading to diastolic dysfunction and, eventually, heart failure. Until recently, cardiac amyloidosis was considered rare. However, the recent adoption of noninvasive diagnostic testing, including 99mTc-pyrophosphate imaging, has revealed a previously undiagnosed sizable disease prevalence. Light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR), the 2 primary types, account for 95% of cardiac amyloidosis diagnoses. AL results from plasma cell dyscrasia and has a very poor prognosis. The usual treatment for cardiac AL is chemotherapy and immunotherapy. Cardiac ATTR is more chronic, usually resulting from age-related instability and misfolding of the transthyretin protein. ATTR is treated by managing heart failure and using new pharmacotherapeutic drugs. 99mTc-pyrophosphate imaging can efficiently and effectively distinguish between ATTR and cardiac AL. Although the exact mechanism of myocardial 99mTc-pyrophosphate uptake is unknown, it is believed to bind to amyloid plaque microcalcifications. 99mTc-pyrophosphate imaging has a 97% sensitivity and nearly 100% sensitivity for identifying cardiac ATTR when the AL form of the disease is ruled out through serum free light-chain and serum and urine protein electrophoresis with immunofixation testing. Although there are no published 99mTc-pyrophosphate cardiac amyloidosis imaging guidelines, the American Society of Nuclear Cardiology, Society of Nuclear Medicine and Molecular Imaging, and others have published consensus recommendations to standardize test performance and interpretation. This article, part 1 of a 3-part series in this issue of the Journal of Nuclear Medicine Technology, describes amyloidosis etiology and cardiac amyloidosis characteristics, including the types, prevalence, signs and symptoms, and disease course. It further explains the scan acquisition protocol. Part 2 of the series focuses on image/data quantification and technical considerations. Finally, part 3 describes scan interpretation, along with the diagnosis and treatment of cardiac amyloidosis.

Microcalcification and 99mTc-Pyrophosphate Uptake without Increased Bone Metabolism in Cardiac Tissue from Patients with Transthyretin Cardiac Amyloidosis.

Transthyretin cardiac amyloidosis (ATTR-CA) is characterized by high 99mTc-labeled bone tracer uptake in the heart. However, the mechanism of bone tracer uptake into the heart remains controversial. Since bone tracer uptake into metastatic bone tumors is thought to be associated with increased bone metabolism, we examined 99mTc-pyrophosphate (PYP) scintigraphy findings, endomyocardial biopsy (EMB) tissue findings, and the expression of bone metabolism-related genes in the EMB tissues in patients with ATTR-CA, amyloid light-chain cardiac amyloidosis (AL-CA), and noncardiac amyloidosis (non-CA) in this study. The uptake of 99mTc-PYP in the heart was significantly higher in the ATTR-CA patients than in the AL-CA and non-CA patients. A higher percentage of ATTR-CA EMB tissue showed von Kossa-positive microparticles: ATTR-CA, 62%; AL-CA, 33%; and non-CA, 0%. Calcified microparticles were identified using transmission electron microscopy. However, none of the osteogenic marker genes, osteoclastic marker genes, or phosphate/pyrophosphate-related genes were upregulated in the EMB samples from ATTR-CA patients compared to those from AL-CA and non-CA patients. These results suggest that active calcification-promoting mechanisms are not involved in the microcalcification observed in the heart in ATTR-CA. The mechanisms explaining bone tracer uptake in the heart, which is stronger than that in the ribs, require further investigation.

Incidental extra-cardiac uptake of 99mTc-pyrophosphate

Incidental extra-cardiac uptake of 99mTc-pyrophosphate

Difference Uptake of 99mTc-Pyrophosphate vs 99mTc- Methylenediphosphate in Detecting Cardiac Amyloidosis; First Experience in Hasan Sadikin General Hospital

Cardiac amyloidosis (CA) is a disorder caused by deposits of insoluble fibrils in the myocardium and an underdiagnosed cause of heart failure. Immunoglobulin Light Chain-Associated Amyloid (AL) and Amyloidosis Transthyretin-related (ATTR) are the two protein precursors that most commonly cause cardiac amyloidosis. It is important to distinguish between these two types of amyloidosis because the treatment and prognosis of each types is different. Recent advances in cardiac radionuclide imaging, in particular using bone-seeking agents such as 99mTc-Pyrophosphate (PYP) and 99mTc-Methylenediphosphate (MDP), can differentiate AL from ATTR. This study aimed was to investigate the uptake characteristic of both tracers in CA. Three patients with suspected of having cardiac amyloidosis underwent two cardiac radionuclide imaging examinations using those two different radiopharmaceuticals. The cardiac images were analyzed quantitatively and semi-quantitatively based on ASNC (American Society of Nuclear Medicine) criteria. Cardiac radioactivity uptake of 99mTc-PYP was better from those of 99mTc-MDP based on quantitative as well as semi-quantitative (visual assessment).
 Keywords: cardiac amyloidosis; cardiac imaging; 99mTc-PYP; 99mTc-MDP

Interatrial septal 99mTc-pyrophosphate uptake and reduced strain in wild-type transthyretin amyloid cardiomyopathy

Interatrial septal 99mTc-pyrophosphate uptake and reduced strain in wild-type transthyretin amyloid cardiomyopathy

Tc-99m pyrophosphate imaging of poloxamer-treated electroporated skeletal muscle in an in vivo rat model

Objective This study investigates whether 99mTc pyrophosphate (PYP) imaging provides a quantitative non-invasive assessment of the extent of electroporation injury, and of the effect of poloxamer in vivo on electroporated skeletal muscle. Methods High-voltage electrical shock was used to produce electroporation injury in an anesthetized rat's hind limb. In each experiment, the injured limb was treated intravenously by either poloxamer-188, dextran, or saline, and subsequently imaged with 99mTc PYP. The radiotracer's temporal behavior among the experimental groups was compared using curve fitting of time–activity curves from the dynamic image data. Results The washout kinetics of 99mTc PYP changed in proportion to the electric current magnitude that produced electroporation. Also, 99mTc PYP washout from electroporated muscle differed between poloxamer-188 treatment and saline treatment. Finally, 10-kDa dextran treatment of electroporated muscle altered 99mTc PYP washout less than poloxamer-188 treatment. Conclusions Behavior of 99mTc PYP in electroporated muscle appears to be an indicator of the amount of electroporation injury. Compared to saline, intravenous polaxamer-188 treatment reduced the amount of 99mTc PYP uptake. Coupled to results showing poloxamer-188 seals ruptured cellular membranes, lessens the extent of electroporation injury and improves cell viability, 99mTc PYP imaging appears to be a useful in vivo monitoring tool for the extent of electroporation injury.

Dose the uptake of 99mTc-pyrophosphate (PYP) mean myocardial infarction?

Dose the uptake of 99mTc-pyrophosphate (PYP) mean myocardial infarction?

Infarcted heart uptake and biodistribution of radiolabelled anti-myosin monoclonal antibody in rat and dog myocardial infarct models

A new mouse monoclonal antibody that recognizes α- and β-heavy chains of human atrial and ventricular myosin and β-heavy chain of human slow skeletal muscle myosin was obtained. The 125I- and 111In-labelled antibody, and its F(ab′) 2 and Fab fragments localize in isoproterenol induced infarcted rat heart, with the F(ab′) 2 fragment showing the highest uptake. Comparison with 99mTc-pyrophosphate uptake in infarcted dog heart, induced by selective obstruction of a coronary artery, suggest that the 111In-labelled F(ab′) 2 localizes specifically in infarcted myocardium only.

Quantitation of postischemic skeletal muscle necrosis: Histochemical and radioisotope techniques

Skeletal muscle necrosis will result from prolonged periods of ischemia. The purpose of this study was to develop a method to estimate the extent of necrosis using nitroblue tetrazolium staining and technetium scanning. The bilateral canine gracilis muscle preparation with total vascular isolation was exposed to 4 hr of complete normothermic ischemia followed by reperfusion. After 45 hr of reperfusion 99mTc pyrophosphate (PYP) was injected and 3 hr later the muscles were harvested, cut into six slices, and stained with nitroblue tetrazolium. Biopsies were taken from tetrazolium-positive and -negative areas for electron microscopy to confirm the ability of the stain to distinguish viable from necrotic muscle. Computerized planimetry of the staining pattern was used to estimate the extent of necrosis as a percentage of the total muscle. Electron microscopy confirmed the validity of nitroblue tetrazolium to discriminate between viable and necrotic skeletal muscle in this experimental model. After 4 hr of ischemia the percentage necrosis was 30.2 ± 6.1% (mean ± SEM, n = 12), there was no difference in the extent of necrosis in left vs right paired muscles, using tetrazolium staining or technetium PYP uptake. There was a statistically significant correlation between the percentage necrosis and the density of 99mTc PYP uptake per muscle ( r = 0.83, P < 0.001) and per slice ( r = 0.94, P < 0.001). This study demonstrates the ability of tetrazolium staining to accurately differentiate between viable and necrotic skeletal muscle and provides a reproducible method for estimating the extent of necrosis in the gracilis muscle model.

The extent and distribution of skeletal muscle necrosis after graded periods of complete ischemia.

The management of an acutely ischemic extremity requires knowledge of the response of skeletal muscle (the largest component of the lower limb) to prolonged periods of complete normothermic ischemia. We have used the canine gracilis muscle model to evaluate the extent and distribution of ischemic necrosis after 3 and 5 hours of ischemia and 48 hours of reperfusion. Each muscle was cut into six slices, and the extent and distribution of postischemic necrosis identified by means of nitroblue tetrazolium staining and 99mTc pyrophosphate uptake. After 3, 4, and 5 hours of ischemia the extent of necrosis was 2.0% +/- 0.9%, 30.3% +/- 6.0%, and 90.1% +/- 3.5% (mean +/- SEM), respectively. A statistically significant correlation exists between the extent of necrosis and the uptake of 99mTc pyrophosphate uptake per gram of tissue (y = 1574.9x - 8.4, r = 0.84, p less than 0.001). Most necrosis was centrally located and found in the thickest portion of the muscle. We conclude that there is a graded response in the extent of skeletal muscle necrosis related to the length of ischemic stress rather than an "all-or-none" phenomenon. This central distribution of necrosis makes the usual external evaluation of ischemic damage clinically unreliable. In addition, since there was no enveloping fascia in this model, a compartment release alone may not prevent the development of skeletal muscle necrosis. This knowledge of the response of skeletal muscle to ischemia may lead to an improved clinical approach to an extremity suffering a prolonged ischemic insult.

Clinical significance of early myocardial 99mTc-pyrophosphate uptake in patients with acute myocardial infarction

Early 99mTc-pyrophosphate (PYP) scintigrams of 29 patients receiving coronary thrombolysis induced by urokinase, 3.9 ± 1.2 hours after the onset of acute myocardial infarction (AMI), were evaluated. Intravenous 99mTc-PYP scintigraphy was performed 2.8 to 8.0 hours after the onset of AMI. All 19 patients with positive findings on early scintigrams had good recanalization, compared to only 3 of the 10 patients with negative findings. The seven patients with unsuccessful recanalization after coronary thrombolysis had total occlusion or subtotal occlusion with delayed washout of contrast material, and three of them had collaterals. The sensitivity, specificity, and predictive accuracy of positive results of early scintigraphy in predicting the presence of early reperfusion were 73%, 100%, and 90%, respectively. Patients with positive early scintigrams showed increasing regional ejection fraction and decreasing thallium defect scores from the acute stage to the chronic stage. These findings indicate that early 99mTc-PYP scintigraphy is a sensitive noninvasive technique for detecting early recanalization in infarcted vessels. The collateral flow or antegrade flow with delay is not enough to cause 99mTc-PYP uptake in a very early stage of AMI.

EVALUATION OF 99mTc PYROPHOSPHATE TO DIAGNOSE ACUTE CARDIAC REJECTION IN THE RAT WITH STUDIES ON THE EFFECT OF CYCLOSPORINE

Uptake of 99mTc pyrophosphate (PYP) has been shown to be a sensitive and specific indicator of ischemia myocardial injury. We investigated the uptake of 99mTc PYP during acute cardiac rejection in an experimental model of heterotopic transplantation in the rat. The model allowed comparison of uptake of PYP between the transplanted and the recipient's native heart, and the results were corrected for weight and expressed as a ratio: Transplanted/Native. Four groups of ratio were studied: Group 1 (N = 6) was between animals of isogeneic strain and the ratio of uptake was 1.85 ± 0.9 (M ± SD) which was significantly different from the ratio of 3.23 ± 0.96 in Group 2 (N = 11) in which transplants were between non-isogeneic animals (P<0.01). Group 3 (N = 7) were non-isogeneic animals treated with Cyclosporine 10 mg/Kg/day and the ratio 2.14 ± 0.5 was not different from Group 1, but was statistically different from Group 2 (P< 0.01). In contrast the ratio of uptake between non-isogeneic animals treated with subtherapeutic doses of Cyclosporine (1mg/Kg/day) Group 4 (N = 4) was 2.81 ± 0.6 which was not different from Group 2. In groups 1, 2 and 3 there was correlation between the histology of the transplanted hearts graded 1 to 5 blindly according to the severity of rejection and the uptake of 99mTc PYP. 99mTc PYP can therefore be used to diagnose cardiac rejection in a rat model, and the results correlate well with the severity of rejection as assessed histologically.

Relationship of mitochondrial alterations and 99mTc pyrophosphate uptake during myocardial ischemia.

Relationship of mitochondrial alterations and 99mTc pyrophosphate uptake during myocardial ischemia.

Accuracy of localization of acute myocardial infarctionby 12 lead electrocardiography

Until recently, ECG accuracy in localizing acute myocardial infarction (AMI) could be assessed only by comparing the ECGs with autopsy findings. This approach, however, preselected patients, including only those who died. It is possible that this postmortem group of patients would be different from the whole population of patients with AMI. Myocardial imaging with 99mTc-pyrophosphate offers the advantage of directly localizing the region of injured myocardium in the acute phase of AMI. In 34 patients with confirmed AMI and focal uptake of 99mTc-pyrophosphate, serial ECGs were obtained and interpreted by two independent observers. The sensitivity and specificity of serial ECGs in determining the location of AMI in the five left ventricular (LV) wall segments were determined: (1) in the anterior wall sensitivity was 86.7% and specificity was 89.5%; (2) in the lateral wall sensitivity was 73.7% and specificity was 80.0%; (3) in the high lateral wall sensitivity was 80.0% and specificity was 87.5%; (4) in the inferior wall sensitivity was 87.5% and specificity was 100%; (5) in the "true" posterior wall sensitivity was 83.3% and specificity was 86.4%. Overall, in the 170 LV wall segments (five per patient) examined, scans localized with a sensitivity of 81.9% and a specificity of 88.8%. After four patients with LBBB were excluded, sensitivity increased to 87.1%. Overall, localization of AMI by serial ECG was accurate in 85.9% of the 34 patients included in the study.

Liver uptake of 99mTc-pyrophosphate

A 56-yr-old chronic schizophrenic with a prior history of anterior myocardial infarction was hospitalized with a 2-day history of progressive abdominal pain and shortness of breath. Physical examination revealed an agitated male with regular pulse of 100/min, blood pressure of 112/70, respiratory rate of 30/rain, and slightly elevated temperature of 100~ The jugular veins were distended to the level of the jaw and bibasilar rates were ausculted in the lungs. The liver was enlarged, firm, and mildly tender. The chest roentgenogram showed pulmonary interstitial edema and pulmonary venous congestion. On admission, creatine phosphokinase (CPK) was 2464, lactate dehydrogenase (LDH) 1110, glutamic oxalactic transaminase (SGOT) 1210, bilirubin 0.8, and alkaline phosphatase 177. The prothrombin time and partial thromboplastin time were elevated at 22.5 and 45.4 sec, respectively. Serum urea nitrogen (BUN) was 66 with creatinine level 1.9. The EKG showed right bundle branch block, old Q waves in the precordiaI leads, and new Q waves in leads I1, lI1, and AVF. Diagnosis on admission was recent inferior MI, rightand left-sided congestive heart failure, congestive hepatopathy, and acute renal failure. Subsequent CPK isoenzyme fractionation failed to support the diagnosis of acute myocardial infarction, and a 99mTc-pyrophosphate myocardial scintigram was performed on the third hospital day that showed intense labeling of the liver without demonstrable myocardial activity. (Fig. 1). It was postulated that the patient's myocardial infarction had occurred 3-5 days prior to admission, and that the persistent elevation of CPK was due to rhabdomyolysis. Right heart catheterization performed after correction of coagulation parameters with fresh frozen plasma revealed markedly elevated right-sided pressures, with right atrial pressure 23 mm Hg, RV 47/20, and pulmonary artery wedge 28. The cardiac output was 2.8 liter/min. On nitroprusside and dopamine, the hemodynamic parameters improved somewhat with diuresis and concomitant improvement in hepatic function. On the seventh hospital day, the patient developed supraventricular tachycardia, which progressed to ventricular fibrillation. Resuscitation was performed; however, a downhi|l course ensued and the patient expired 3 days later. Permission for autopsy was not granted. This case demonstrates diffuse hepatic labeling by 99mTc-pyrophosphate in a clinical setting with high likelihood of central hepatic necrosis secondary to severe congestive heart failure. Liver uptake of bone imaging agents is unusual; in a study of 250 consecutive bone scans, liver uptake occurred only in 5 cases, 2 of which were associated with metastases and the remaining 3 due to poor radiopharmaceutical quality. ''~ Diffuse hepatic uptake of 99roTe-phosphate compounds has since been shown to occur in massive liver necrosis, 2 in the presence of high serum AI +§ levels, 3 and in amyloidosis. 4 Animal studies have shown elevated liver uptake with increased phosphate salt concentration: and with combination of tin and 99mTc-reagents prior to the addition of the phosphate-chelating agent during radiopharmaceutical preparation. 6 In liver necrosis and amyloidosis, labeling occurs presumably due to phosphate localization at sites of cellular damage by mechanisms to be discussed, while in the other cases, reticuloendothelial uptake of microcolloidal particles is the postulated mechanism: ~ Focal uptake of 99roTe-phosphate compounds by hepatic metastases from adenocarcinoma of the colon, breast carcinoma, oat cell carcinoma of the lung, malignant melanoma, and esophageal squamous cell carcinoma has been reported. 7-~~ A single case of uptake by cholangiocarcinoma has also been described. 8 Tumor localization of phosphate compounds probably

Myocardial cell damage during attacks of vasospastic angina in the absence of persistent electrocardiographic changes.

We have investigated whether vasospastic anginal attacks might be associated with myocardial cell damage even when permanent ORS or ST-T changes are absent. We obtained serum time-activity curves of creatine kinase MB, of myoglobin, and of alpha hydroxybutyrate dehydrogenase in 15 patients with vasospastic angina admitted to our Coronary Care Unit (CCU). A slight but consistent rise and fall of both myoglobin and creatine kinase MB was observed in 7 patients (4 presented a definitive myocardial uptake of 99mTc pyrophosphate, and I had a faint deposition). A similar pattern was observed for myoglobin alone in 3 patients (1 presented a negative myocardial scan), while no consistent changes were found in the remaining 5 patients (2 presented a faint deposition of 99mTc pyrophosphate). No significant change of alpha hydroxybutyrate dehydrogenase was observed in any of the patients. The coherent rise and fall of the levels of myocardial cytosolic components after prolonged episodes of vasospastic angina suggests that cell damage may occur even in the absence of persistent QRS and ST-T changes.

Abdominal and hepatic uptake of 99mTc-pyrophosphate in neonatal necrotizing enterocolitis.

Abdominal 99mTc-pyrophosphate (99mTc-PYP) scans were obtained in 15 neonates: 12 with neonatal necrotizing enterocolitis (NEC), two with osteomyelitis, and one with myocarditis. Ten of the babies with NEC had at least one positive scan; of these 10 studies, seven (Group A) showed both diffuse abdominal uptake and localized hepatic activity, two (Group B) showed abdominal uptake and questionable hepatic uptake, and one (Group C) demonstrated diffuse abdominal uptake only. The other two babies with NEC had normal scans (Group D). Pneumatosis intestinalis was unquestionably present in two patients from Group A and one from Group B. Upon resolution of the clinical findings, all NEC patients had normal scans. A patient with myocarditis had hepatic uptake of 99mTC-PYP while the abdominal scan in the two infants with osteomyelitis was normal. These preliminary observations suggest that further study of a relationship between abdominal scan findings and the course of NEC is warranted.

Increased 99mTc-Pyrophosphate Uptake with Radiation Pneumonitis

A case of radiation pneumonitis confirmed by tissue biopsy is presented with demonstration of increased uptake of 99mTc-pyrophosphate.

Poorly Differentiated Lymphocytic Lymphoma with Ectopic Parathormone Production: Visualization of Metastatic Calcification by Bone Scan

Metastatic soft tissue calcification is known to occur in hypercalcemia and is usually present in the kidneys, stomach and lungs. 1--3 This case presents two unusual features: 1) ectopic parathormone production in association with poorly differentiated lymphocytic lymphoma; and and 2) uptake of 99mTc-pyrophosphate in the liver in the absence of demonstrable abnormality at autopsy. The more usual sites of metastatic calcification also showed uptake of the radionuclide. We will discuss metastatic soft tissue calcification, ectopic parathyroid hormone production, hypercalcemia in malignancy and bone scan agent localization in soft tissues.

Computed Transaxial Imaging Using Single Gamma Emitters

Emission computed tomography (ECT) studies were performed on test objects and dogs. Conjugate views were obtained for 60 to 120 projections equispaced around 360 degrees by rotation of the subjects in front of a gamma camera. A convolution reconstruction algorithm in which gamma ray attenuation corrections are included in the backprojection step were used to reconstruct the emission images. Reconstructions of x-ray transmission data provided data for gamma ray attenuation corrections of the emission images of 99mTc-pyrophosphate uptake in dogs. Reconstructed images of test objects show spatial resolution uniformity, and attenuation corrections enable estimation of relative activity densities to within 10--15% rms errors, thus demonstrating quantitative imaging capabilities of emission CT.