Diagnostic and prognostic value of Technetium-99m pyrophosphate uptake quantitation for transthyretin cardiac amyloidosis.

BACKGROUND: 99mTc-pyrophosphate imaging has emerged as an important non-invasive method to diagnose transthyretin cardiac amyloidosis (ATTR-CM). Quantitation of 99mTc-pyrophosphate activity, on SPECT images, could be a marker of ATTR-CM disease burden. We assessed the diagnostic accuracy and clinical significance of 99mTc-pyrophosphate quantitation. METHODS AND RESULTS: Patients who underwent 99mTc-pyrophosphate imaging for suspected ATTR-CM were included. Using SPECT images, radiotracer activity in the myocardium was calculated using cardiac pyrophosphate activity (CPA) and volume of involvement (VOI), with thresholds for abnormal activity derived from LVBP activity. Diagnostic accuracy was assessed using area under the receiver operating characteristic curve (AUC). In total, 124 patients were identified, mean age 73.9 ± 11.4, with ATTR-CM diagnosed in 43 (34.7%) patients. CPA had the highest diagnostic accuracy (AUC .996, 95% CI .987-1.00), and was significantly higher compared to the Perugini score (AUC .952, P = .016). In patients with ATTR-CM, CPA was associated with reduced left ventricular ejection fraction (adjusted odds ratio 1.28, P = .035) and heart failure hospitalizations (adjusted hazard ratio 1.29, P = .006). CONCLUSION: Quantitative assessment of myocardial radiotracer activity with CPA or VOI have high diagnostic accuracy for ATTR-CM. Both measures are potential non-invasive markers to follow progression of disease or response to therapy.

Cardiac scintigraphy with 99mTc-diphosphonates in cardiac amyloidosis. / Gammagrafía cardíaca con 99mTc-difosfonatos en la amiloidosis cardíaca.

Transthyretin cardiac amyloidosis (ATTR) has traditionally been considered a rare, difficult-to-diagnose and untreatable disease. However, its prevalence is known to be greater than what was previously thought, non-invasive diagnostic methods are available, and that effective treatments are emerging. In this context, cardiac scintigraphy (CS) with 99mTc-labelled diphosphonates has aroused a noticeable surge in interest by demonstrating high sensitivity and specificity for the reliable, non-invasive diagnosis of ATTR. By way of a guide, this article aims to identify the critical components in the performance of CS that are useful in everyday clinical practice and, thus, help specialists use optimal radiopharmaceuticals, obtain the most appropriate images, interpret the results thereof, and acquaint themselves with those clinical scenarios in which it is convenient to perform CS.

Tc-99m-pyrophosphate scintigraphy for the diagnosis of ATTR cardiac amyloidosis: Comparison of quantitative and semi-quantitative approaches.

BACKGROUND: ATTR cardiac amyloidosis (CA) can be diagnosed with Tc-99m-PYP scintigraphy. There are two recommended interpretative approaches: the quantitative heart-to-contralateral lung ratio (H/CL) at 1 hour and the semi-quantitative visual system at 3 hours. This study's aim was to compare both approaches and to apply the semi-quantitative method at 1 hour. METHODS: Tc-99m-PYP scans of 122 consecutive subjects were reviewed using both approaches. On 1 hour planar images, regions of interest were drawn over the heart and contralateral chest to determine H/CL. Myocardial uptake was graded on 1 and 3 hour SPECT images according to the semi-quantitative method. Concordance was examined using kappa statistics. RESULTS: 31, 10, and 81 studies were positive, negative, and equivocal, respectively, for ATTR-CA using the H/CL approach. Using the grading system, 35, 77, and 10 scans were positive, negative, and equivocal, respectively. The quantitative approach led to a significantly higher proportion of equivocal studies compared to the semi-quantitative approach (P < .0001). These approaches yielded discordant results in 2 subjects; biopsy results were concordant with SPECT grade. 1 and 3 hour SPECT grades provided concordant result in 99% of cases. CONCLUSIONS: The H/CL approach resulted in a high proportion of equivocal studies. Using SPECT imaging, the semi-quantitative approach minimized this proportion and showed high concordance at 1 and 3 hours.

Technetium pyrophosphate nuclear scintigraphy for cardiac amyloidosis: Imaging at 1 vs 3 hours and planar vs SPECT/CT.

BACKGROUND: Multi-societal consensus recommendations endorse both planar and single photon emission tomographic (SPECT) image acquisitions for the evaluation of cardiac amyloidosis. However, the correlation between planar and SPECT findings and the optimal timing of image acquisitions remain uncertain. METHODS: This is an analysis of 109 consecutive patients who underwent technetium pyrophosphate nuclear scintigraphy for the evaluation of cardiac amyloidosis. Patients were imaged at 1 and 3 hours after radiotracer injection using both planar and SPECT/CT, and the correlations between imaging protocols were compared. RESULTS: In the overall cohort (median age 77 years, 75% male), 33 patients had radiotracer localized to the myocardium on SPECT/CT images. There was strong correlation between 1- and 3-hour planar heart-to-contralateral lung ratios (mean difference 0.07, r = 0.94). However, there was discordance between planar image interpretation (based upon semiquantitative score and H/CL ratio) and myocardial localization of radiotracer on SPECT/CT in 17 patients (16%). The pattern of SPECT/CT uptake was identical at 1 and 3 hours in all cases (32 diffuse, 1 focal). CONCLUSION: These data support the recommendation that SPECT/CT should be obtained in addition to planar images when performing nuclear scintigraphy for the detection of cardiac amyloidosis. A 1-hour planar and SPECT/CT protocol appears optimal.

Diffuse Hepatosplenic 99mTc-Pyrophosphate Activity Caused by Amyloidosis.

A 46-year-old man underwent Tc-pyrophosphate scan to evaluate possible infiltrative myocardiopathy revealed by echocardiography. The images did not show abnormal cardiac activity. However, diffuse abnormal activity in the liver and spleen was noted. Pathological examination from the specimen acquired from hepatic biopsy demonstrated amyloidosis, light chain type.

Evaluation of the effect of mitomycin-C on the bioavailability of technetium-99m-labelled sodium pyrophosphate in mice.

We have reported that drugs alter the biodistribution of radiopharmaceuticals used in diagnostic imaging in nuclear medicine. Knowledge of such altered biodistribution is important in making diagnostic from scintigraphy. Mitomycin-C is used as component of many chemotherapeutic regimens to treat different tumors. The biological activities of mitomycin-C can be explained by its ability to inhibit deoxyribonucleic acid synthesis. Since patients on chemotherapeutic treatment can be submitted to nuclear medicine procedures, we studied the mitomycin-C effect on the bioavailability of the technetium-99m-labelled sodium pyrophosphate (9mTc-PYP) using an animal model. Mitomycin (0.45 mg) was administered by ocular plexus way Balb/c mice. One hour after the last dose, 99mTc-PYP (7.4 MBq) was administered and after 0.5 hr the animals (n = 15) were rapidly sacrificed. The organs were isolated, the radioactivity counted in a well counter and the percentage of radioactivity (%ATI) calculated. The results have shown that in the treated animals the %ATI has been decreased in spleen, thymus, heart and brain and increased in lung, liver and bone. The effect of this chemotherapeutic drug on the 99mTc-PYP biodistribution was statistically significant (Wilcoxon test, p < 0.05) and it could be explained by the metabolization or therapeutic action of mitomycin-C.

Uptake of 99mTc(5+)-complexes in ischemic myocardial slices and their dissociable ability.

AIM: To find how some technetium-complexes to deliver the active species, TcO4(3-), to the target tissue from a dissociable polynuclear Tc5+ species in preserved states in vivo. METHODS: Effect of dissociation ability of the polynuclear Tc5+ complexes on their accumulation in ischemic myocardium was tested. Ability of dissociation as having an appropriate conformation to become biologically functional after entering the blood circulation was tested using a simple dilution method by thin layer chromatography (TLC) analysis. Various degree of ischemic myocardium slices of rat were incubated with 1/100 diluted 99mTc(5+)-succimer, 99mTc(5+)-GH and 99mTc(5+)-PPi. RESULTS: The TLC patterns of 99mTc(5+)-GH and 99mTc(5+)-PPi showed the presence of a fast increasing of free Tc-species as dilution degree increased. The relative radioactivity of peak of free pertechnetate (Rf = 0.85-1.0) with 1:500 dilution was: 99mTc(5+)-succimer 0%, 99mTc(5+)-GH 28.1% +/- 1.3%, and 99mTc(5+)-PPi 46.0% +/- 2.9% respectively. The uptake of the myocardium after ischemia for 3 h was 99mTc(5+)-succimer 420% +/- 110% dose/g tissue, 99mTc(5+)-GH 710% +/- 180% dose/g tissue, and 99mTc(5+)-PPi 1295% +/- 390% dose/g tissue respectively. CONCLUSION: The dissociation and myocardial uptake showed: 99mTc(5+)-succimer < 99mTc(5+)-GH < 99mTc(5+)-PPi, the uptake by the ischemic myocardium is positively correlated to their dissociation.

Scintigraphic diagnosis of gastrointestinal bleeding with 99Tcm-dextran.

Intravenously administered dextran is used clinically as a plasma expander. The aim of this study was to assess the use of 99Tcm-dextran in the diagnosis of gastrointestinal (GI) blood leaks. Twenty-one patients with GI blood loss underwent 99Tcm-dextran scintigraphy, 17 of whom were found to be positive. Pathologic or 99Tcm-RBC (red blood cell) blood pool correlation was possible in 15 cases, while 2 were unconfirmed. No case had a positive 99Tcm-RBC blood pool study and a negative 99Tcm-dextran study. Images obtained with 99Tcm-dextran were generally better than those with 99Tcm-RBC. This agent may have several other advantages over 99Tcm-RBC blood pool and 99Tcm-sulphur colloid scintigraphy for detecting GI blood loss.

Limitation of infarct size with preconditioning and calcium antagonist (diltiazem): difference in 99mTc-PYP uptake in the myocardium.

UNLABELLED: Ischemic cell injury and the uptake mechanism of 99mTc-PYP (Pyrophosphate) were studied with preconditioning and calcium antagonist. METHOD: The coronary artery of an adult mongrel dog was clamped for 1 hour, followed by reperfusion and 99mTc-PYP injection. A control group (group C, n = 8), a group in which continuous drip infusion of diltiazem (10 mg/kg) (group D, n = 7), and a group preconditioned by six 5-minute clampings and perfusions before occlusion (group P, n = 6) were compared. RESULTS: Wall motion was fully recovered in group D but not in group P after 2 hours of reperfusion. The 99mTc-PYP uptake ratio showed a significant (p < 0.05) reduction in group D (11.5 : 3.6 compared with group C), but not in group P (11.5 : 9.1, p = 0.25). The infarct area was 1.2 +/- 0.6% of the left ventricle in group D, 1.3 +/- 0.4 in group P, and 6.4 +/- 1.0 in group C (p < 0.01 in groups D and P vs. group C). CONCLUSIONS: These findings suggest that preconditioning does not alleviate stunning, but it improves cell injury in spite of high uptake of 99mTc-PYP. Diltiazem protects from both stunning and cell injury, suggesting a different mechanism of myocardial protection from that of preconditioning.

Hyperbaric oxygen reduces ischemia-induced skeletal muscle injury.

The effect of hyperbaric oxygen treatment on skeletal muscle submitted to 3 or 4 hours of ischemia was studied in a rat hindlimb model after 48 hours of reperfusion. Forty-eight male Sprague-Dawley rats were allocated to four groups. In the two treatment groups, hyperbaric oxygen was given for 45 minutes at 2.2 atm immediately and 4,8,16,24,32, and 40 hours after release of the ischemia-inducing tourniquet. The injury to skeletal muscle was quantified from the uptake of 99mtechnetium-pyrophosphate (injected intravenously after 45 hours of reperfusion) in anterior tibial muscle harvested 3 hours later. The uptake was significantly lower in hyperbaric oxygen-treated rats than in untreated rats with 3 or 4 hours of ischemia (p < 0.01 and P < 0.05). After 4 hours of ischemia, the changes in levels of the intracellular muscle compounds adenosine triphosphate, phosphocreatine, and lactate were less in the hyperbaric oxygen-treated rats than in the untreated animals.

Relative biological effectiveness of 99mTc radiopharmaceuticals.

The radiotoxicity of three 99mTc-labeled compounds is investigated using spermatogenesis in mouse testis as the experimental model, and spermatogonial cell survival as the biological end point. The radiopharmaceuticals studied are pertechnetate (99mTcO4-), pyrophosphate (99mTc-PYP), and hydroxyethylene diphosphate (99mTc-HDP). The mean lethal doses at 37% survival (D37) are 0.70 +/- 0.06, 0.84 +/- 0.13, and 0.59 +/- 0.08 Gy for 99mTcO4-, 99mTc-PYP, and 99mTc-HDP, respectively. When these results are compared with the D37 value obtained with external x rays or internal gamma rays, the relative biological effectiveness (RBE) of these compounds are 0.94 +/- 0.09, 0.79 +/- 0.13, and 1.1 +/- 0.16, respectively. These results show that the radiotoxicity of 99mTc in mouse testis is essentially similar to that of low-LET radiations (i.e., RBE approximately 1). To understand these results, the distribution of these radiocompounds in the testis is determined and correlated with the observed RBE values. The expected range of RBE values for 99mTc radiopharmaceuticals in organs is 0.95 to 1.5, depending on the fraction of organ activity that is bound to DNA. This suggests that the Auger electrons emitted in the decay of 99mTc are not capable of causing extreme toxicity in vivo. These results provide further support for 99mTc as the radionuclide of choice for imaging in nuclear medicine.

Increased technetium uptake is not equivalent to muscle necrosis: scintigraphic, morphological and intramuscular pressure analyses of sore muscles after exercise.

A scintigraphic technique employing technetium pyrophosphate uptake was used to identify the area of skeletal muscle damage in the lower leg of four runners 24 h after an ultramarathon footrace (160 km). Most of the race had been run downhill which incorporated an extensive amount of eccentric work. Soreness was diffuse throughout the posterior region of the lower leg. In order to interpret what increased technetium uptake reflects and to express extreme endurance related damages, a biopsy was taken from the 3-D position of abnormal uptake. In addition, intramuscular pressures were determined in the deep posterior compartment. Scintigraphs revealed increased technetium pyrophosphate uptake in the medial portion of the gastrocnemius muscle. For 3698 fibres analysed, 33 fibres (1%) were necrotic, while a few other fibres were either atrophic or irregular shaped. A cluster of necrotic fibres occurred at the fascicular periphery for one subject and fibre type grouping occurred for another. Ultrastructural analysis revealed Z-line streaming near many capillaries and variously altered subsarcolemmal mitochondria including some with paracrystalline inclusions. The majority of the capillaries included thickened and irregular shaped endothelial cells. Intramuscular pressures of the deep posterior compartment were slightly elevated (12-15 mmHg) for three of the four subjects. Increased technetium uptake following extreme endurance running does not just reflect muscle necrosis but also subtle fibre abnormalities. Collectively, these pathological findings are attributed to relative ischaemia occurring during the race and during pre-race training, whereas, intramuscular pressure elevations associated with muscle soreness are attributed to mechanical stress caused by extensive eccentric work during the race.

[A case of stunned myocardium with marked 99mTc-PYP accumulation].

A 71-year-old woman with unstable angina was admitted to our department. Upon admission, electrocardiography revealed a QS pattern in Leads V1-V3. Left ventriculography disclosed akinesis of the anterior wall and the septum. Myocardial scintigraphy with 99mTc-pyrophosphate (PYP) revealed marked accumulation (Parkey's grade III) in the anterior wall, septum and apical region. Coronary arteriography revealed stenosis (99% with delay) in the LAD #6. Based on these findings, we performed percutaneous transluminal coronary angioplasty (PTCA) on this patient. About 3 months later, the patient underwent PTCA again because stenosis had recurred. The resting 201Tl myocardial scintigram, taken immediately after the first PTCA, demonstrated complete defects in the anterior wall, septum and apical region. After the second PTCA, no stenosis was observed. About 1 year later, the wall motion returned to normal (except in part of the apical region), suggesting that this was a case of stunned myocardium. On the same occasion, the 201Tl uptake was normal except in the apical region. The present case was regarded as stunned myocardium which demonstrated marked radioactivity accumulation when examined by 99mTc-PYP myocardial scintigraphy. In the past, 99mTc-PYP has been thought to be incorporated into irreversibly impaired myocardium (e.g., in cases of acute myocardial infarction). The uptake of 99mTc-PYP into stunned myocardium has not been reported before. Thus, this case is rare and noteworthy.

Acute subendocardial infarction with diffuse intense Tc-99m PYP uptake and minimal Tl-201 abnormality.

Tc-99m PYP scintigraphy performed on a patient with severe anterior chest pain showed diffuse intense uptake with central decreased activity corresponding to the left ventricular cavity. Tl-201 myocardial perfusion scintigraphy at rest revealed a minimal perfusion abnormality with decreased apical uptake in the lateral view. Because of these findings, diffuse subendocardial infarction was suggested.

Effect of diltiazem on stunned myocardium evaluated with 99mTc-pyrophosphate imaging in canine heart.

The effect of diltiazem on stunned myocardium was evaluated by measuring the myocardial uptake of 99mTc-PYP (pyrophosphate) in open chest experiments with dogs. Myocardial stunning was induced by a 30 min ischemic occlusion of the anterior descending coronary artery. Regional wall motion was monitored by echocardiography of the epicardium for 2 h during reperfusion. After a 30 min occlusion of the coronary artery, it was reperfused and 99mTc-PYP was injected, followed by 201Tl 2 h later. The ischemic area was defined by Evans blue dye, and the infarct area by TTC staining. No dogs showed infarcts or 201Tl defects in this study group. Five dogs of the control-1 group (C1, ischemic area = 19.1 +/- 3.2%) showed decreased regional wall motion during occlusion (15.5 +/- 3.5% of control), and a slow recovery from depressed motion after 2 h of reperfusion (20.3 +/- 9.3%) with uptake ratio (compared to the non-ischemic area uptake) of 99mTc-PYP (4.96 +/- 2.28). In contrast, both groups with diltiazem infusion (20 micrograms/kg/min), started either 30 min before ischemia (D1 = 5 dogs) or just after reperfusion (D2 = 5 dogs), showed significantly better recovery after 2 h of reperfusion (D1:115.4 +/- 36.0%, D2:109.2 +/- 44.2%) than C1 (p less than 0.05), D1 and D2 groups also showed suppressed 99mTc-PYP uptake ratio (D1:1.06 +/- 0.33, D2:2.34 +/- 2.05, p less than 0.05 vs C1) in spite of comparable ischemic area. Four dogs with small ischemic area (C2:5.3 +/- 5.0%) did not show increased 99mTc-PYP uptake (1.15 +/- 0.35), and regional wall motion after 2 h of reperfusion was 96.1 +/- 24.1% of the control value (p less than 0.05 vs C1). Thus, diltiazem was effective in enhancing the suppression of 99mTc-PYP uptake in the stunned myocardium, and similar results were obtained for small ischemic areas. The protective effect of diltiazem appears to be strongly related to the mechanism of 99mTc-PYP uptake.

Clinical study of the stunned myocardium.

Clinical features of 37 cases of stunned myocardium were studied. Mean duration of asynergy was 22.6 +/- 15.7 days. In all 11 cases of unstable angina without any significant serum creatine kinase leakage, the duration of asynergy was within 14 days. Related coronary lesions were reperfused (spontaneously or by interventional therapy) to TIMI grade II or higher. Transient Q waves were observed in 39% of all cases. Negative T waves tended to be prolonged, and persisted after disappearance of asynergy in 74% of all cases. 201Tl uptake in the stunned area varied widely between individual cases (ranging from "absent" to "normal"), although it became normal in all cases in the chronic stage. Mal-distribution of 99mTc-pyrophosphate (PYP) to the endocardial side of the stunned area was observed in 33%. In 186 cases of acute coronary syndrome, we studied whether or not reversibility of ischemia-disturbed myocardium could be predicted by simultaneous dual isotope SPECT, and found that 201Tl-uptake in the chronic stage significantly improved in the region showing absence of 99mTc-PYP accumulation or maldistribution of 99mTc-PYP to the endocardial side, while reversibility of the region showing transmural 99mTc-PYP accumulation and a dought pattern was poor. Ischemia-associated myocardial damage recovered to various degrees, and dual isotope SPECT was useful in evaluating the reversibility of such damage already at the acute stage.

Scintigraphic evaluation of myocardial uptake of thallium 201 and technetium 99m pyrophosphate utilizing a rat model of chronic doxorubicin cardiotoxicity.

To evaluate the usefulness of myocardial scintigraphy as a monitoring tool for chronic doxorubicin (DXR) cardiotoxicity, a rat model was used to investigate the relationship between the myocardial uptake of thallium 201 (Tl) or rechnetium 99m pyrophosphate (99mTc-PPi) and histological changes of the heart. Although there was no significant difference in myocardial Tl uptake between control and DXR-treated rats at an early phase after Tl injection, late-phase Tl uptake was significantly higher in the DXR-treated rats than in the control rats, indicating a slow wash-out of Tl from the myocardium. The wash-out rate calculated from scintigraphic examination of DXR-treated rats was significantly decreased with increasing degree of cardiomyopathy. Since the Tl wash-out rate was sharply decreased even in animals with minimal histological changes, it may be a possible monitoring tool for the early detection of chronic DXR cardiotoxicity. On the other hand, myocardial 99mTc-PPi images could be obtained only in rats with severe myocardial changes and hence would not useful for early detection.

Lactate extraction and myocardial damage after countershock at different energy levels.

The relationship between myocardial lactate metabolism and the energy dose of direct countershock was studied in 15 dogs anesthetized with halothane. Five dogs received two shocks of 5 joules delivered energy each, five animals received two shocks of 10 joules delivered energy each, and five dogs received two shocks of 20 joules delivered energy each. All animals had positive myocardial lactate extraction in the baseline state (5 joules, 38% +/- 23.7 (SD); 10 joules, 59.6% +/- 11.4; 20 joules, 38% +/- 11.1). Lactate extraction after countershock progressively decreased with increasing energy dose and then returned to baseline. The maximal reduction in percent lactate extraction increased with increasing energy dose (5 joules, 13.9% +/- 16.1; 10 joules, 33% +/- 37; 20 joules, 30.5% +/- 37.5) and seemed to reach a threshold below which no further decrease occurred. Myocardial damage, as measured by a damage index derived from myocardial uptake of technetium-99 pyrophosphate, increased steadily with increasing energy dose (2.0 +/- 2.5 with 5-joule shocks; 38 +/- 32 with 10 joules; and 99 +/- 70 with 20 joules). These results show a consistent reduction in aerobic metabolism immediately following electric countershock. Even at low-energy doses, myocardial lactate extraction showed a detectable decrease and at higher energies approached net lactate production. Reductions of global lactate extraction did not completely predict the amount of myocardial damage. Localized measures of anaerobic metabolism or mitochondrial function might provide a better correlation with localized damage.