Microdosing in early lead discovery.

Microdosing provides a tool to enhance drug development by initiating human studies prior to Phase I studies. The purpose is to assist in the go versus no-go decision-making process and to eliminate early ineffective compounds from the drug pipeline. Selection of multiple potential leads can be performed at the clinical stage instead of in preclinical studies. The microdosing approach can be easily used for a molecularly targeted potential drug compound with a known mechanism of action. It provides useful data regarding accessibility and biodistribution that can be used in many estimations benefiting the development of the molecule. In addition, steady state and genetic investigations are becoming possible. Microdosing has a sparing effect on timelines and costs, however, the real importance is not yet known because, although it is known to be widely performed, only a few original reports have been published.

Nuclear medicine methods for evaluation of skeletal infection among other diagnostic modalities.

Skeletal infection continues to be a common and difficult condition in clinical practice and early accurate diagnosis is very challenging. Clinical and laboratory features of skeletal infections are not always present, may be confusing, and are nonspecific for bone infection in its early stages, therefore, several imaging modalities are used for early detection of osteomyelitis. Plain films should always be the first step in the imaging assessment of osteomyelitis, however, the sensitivity for X-ray radiography has been reported to range from 43% to 75%, and the specificity from 75% to 83%. Over years, scintigraphic procedures have become an essential part of the diagnostic procedure for osteomyelitis. The standard approach for bone scintigraphy with tech 99mTc labeled methylene diphosphonate to assess for osteomyelitis is to perform a three-phase procedure. The positive uptake on all three phases is highly sensitive for osteomyelitis (sensitivity 73% to 100%). 67Ga citrate gained more attention for the more specific diagnosis of osteomyelitis due to its known capacity to localize in cases of active infection and pus. The reported specificity for 67Ga scintigraphy in osteomyelitis is around 67-70% and the specificity is much higher (92%) when 67Ga single photon emission tomography was obtained. Labeled white blood cell (WBC) imaging has become the procedure of choice to diagnose most cases of skeletal infections except for those of the spine. Labeling of leucocytes can be done either by 111In or 99mTc labeled hexamethylpropylene amineoxime. The sensitivity and specificity for labeled WBCs are in the high range of 80% to 90%. [18F]fluorodeoxyglucose positron emission tomography (PET) has been found to accumulate non-specifically at sites of infection and inflammation. Investigational studies showed that PET is particularly valuable in the evaluation of chronic osteomyelitis and infected prostheses. Other imaging modalities include sonography, computed tomography (CT) and magnetic resonance imaging (MRI). The sensitivity and specificity of CT for the diagnosis of osteomyelitis has not been established clearly and are in the range of 65% to 75%. The sensitivity of MRI for osteomyelitis has been generally reported as being between 82% and 100%, and specificity between 75% and 96%. Cases of osteomyelitis commonly referred to diagnostic imaging departments include chronic osteomyelitis, diabetic foot infections, vertebral osteomyelitis, joint prostheses and patients with suspected reinfection. These specific entities need special attention and careful selection of the correct tracer or combination of imaging modalities that is best suited for the proper therapeutic management protocols.

Detection of fungal infections using radiolabeled antifungal agents.

The outcome of antifungal therapy depends on the progression of the infection at the start of therapy. Unfortunately, most patients are diagnosed once the fungal infection has progressed considerably as a result of the non-specific clinical signs of fungal infections in immunocompromised patients and the poor sensitivity of current mycological diagnostic tests. This review will highlight current fungal diagnostic techniques and will focus on scintigraphic methods for the specific detection of fungal infections in mice. For this purpose, antifungal components (e.g. fluconazole and antifungal peptides) are radiolabeled e.g. with technetium-99m ((99m)Tc) and their in vivo distribution is monitored in infected mice. It has been demonstrated that (99m)Tc-fluconazole is an excellent tracer to detect Candida albicans infections in mice as it distinguishes these infections from bacterial infections and sterile inflammations. However, this radiopharmaceutical only poorly detects infections with Aspergillus fumigatus in mice. (99m)Tc-peptides derived from antifungal peptides/proteins, such as human ubiquicidin and lactoferrin, can distinguish C. albicans and A. fumigatus infections from sterile inflammations, but not from bacterial infections, in mice. Furthermore, the efficacy of fluconazole in C. albicans-infected mice could be successfully monitored using (99m)Tc-ubiquicidin. In conclusion, neither (99m)Tc-fluconazole nor the (99m)Tc-peptides tested are optimal tracers for fungal infections. Nonetheless, since early initiation of antifungal therapy for candidemia reduces its high mortality rate, a positive result with (99m)Tc-fluconazole scintigraphy is of clinical relevance. Finally, the possibility that other (radiolabeled) antifungal agents, e.g. voriconazole, caspofungin, antifungal plant or insect defensins, can be useful for detection of fungal infections should be considered.

Long-term renal function after hemopoietic stem cell transplantation in children.

Glomerular function of all long-term survivors who underwent hemopoietic stem cell transplantation (HSCT) from 1991 to 1998 (study I, n=121) was studied retrospectively. In addition, we prospectively analyzed glomerular and tubular function of all long-term surviving children who received an HSCT between 1998 and 2000 (study II, n=41). We found a lower prevalence of children with chronic renal failure (CRF) post-HSCT in our more recent cohort (study II: 10%) as compared to the older cohort (study I: 24%) 5.0 (0.7 s.d.) and 7.6 (2.4 s.d.) year's post-HSCT, respectively. Furthermore, it seems that renal function may stabilize after 1-year post-HSCT. None of the patients required dialysis or antihypertensive medication at long-term follow-up. The sole predictor of CRF in our study was high serum creatinine pre-HSCT (P=0.007), while acute renal failure within 3 months after HSCT (P=0.08) only showed a trend towards predicting CRF. We could not confirm a relation of conditioning with irradiation with CRF post-HSCT, as was shown in several other pediatric and adult studies. Proximal and distal tubular dysfunction only occurred in a minority of long-time survivors of HSCT (3-12 and 9-13%, respectively) and had no clinical consequences.

99mTc-antimicrobial peptides: promising candidates for infection imaging.

This review presents the state of the art of imaging of bacterial and fungal infections in laboratory animals using antimicrobial peptides labelled with technetium-99m ((99m)Tc). The mechanistic basis of this approach is that these peptides accumulate at sites of infection, but not in sterile inflammatory lesions, because of their preferential binding to bacteria and fungi over mammalian cells. For practical reasons, such as production of large amounts of peptides under good laboratory practice conditions and favourable pharmacokinetics, synthetic peptides representing such binding domains of natural antimicrobial peptides are preferred. On the basis of their preferential in vitro and in vivo binding to microorganisms over human cells, fast and easy penetration into the target area, and rapid clearance from the circulation via the urinary tract, various (99m)Tc-antimicrobial peptides were identified. Next, it was determined whether these radiopharmaceuticals distinguish infectious foci from sites of sterile inflammation. Further experiments with (99m)Tc-ubiquicidin-derived peptides in infected laboratory animals have revealed that the radioactivity at the infectious site correlated well with the number of viable bacteria present, indicating that these (99m)Tc-labelled peptides may enable the monitoring of the efficacy of antimicrobial therapy. Together, (99m)Tc-labelled synthetic peptides derived from human ubiquicidin are promising candidates for imaging of bacterial and fungal infections in nuclear medicine.

A reassessment of bone scintigraphy and commonly tested pretreatment biochemical parameters in newly diagnosed osteosarcoma.

PURPOSE: In patients with an osteosarcoma, the prognosis is still poor. The aim of the present study was to investigate whether routinely tested biochemical parameters or additional parameters on bone scintigraphy could be identified which can select prognostic subgroups at the time of diagnosis. METHODS: A retrospective study was performed in 115 consecutive patients (70 male, 45 female) (mean age: 25.6 years; range: 3.50-78.0 years) who were referred for bone scintigraphy prior to treatment from March 1986 to September 2000 because of a newly diagnosed osteosarcoma. All bone scans were reassessed for the intensity and pattern of uptake and a bone-scan index. All pre-treatment general, histological, biochemical, and scintigraphic data were correlated with clinical outcome during follow-up. RESULTS: During follow-up 54 patients died. Tumour volume and GGT showed significance as independent variables for metastases. Patients with metastases demonstrated a significantly lower survival rate (23% 5-year survival) than patients without metastases (98% 5-year survival). Tumours of the humerus and femur had a significantly lower survival rate. With respect to significant biochemical parameters (ALP, GGT, ASAT), it was not possible to determine a cut-off value that could be used to differentiate between high- and low-risk patients. Additional parameters assessed on bone scintigraphy were not important for prognostic stratification. CONCLUSION: The strongest predictor of survival in osteosarcoma is the presence or absence of metastasis. Some biochemical parameters have prognostic value, but they cannot be used for the unequivocal identification of subgroups. Additional scintigraphic parameters are irrelevant for prognostic stratification.

Circulating tumor markers and nuclear medicine imaging modalities: breast, prostate and ovarian cancer.

Clinical oncologists have always shown great interest in circulating tumor markers. There are several markers that in the clinical routine are a signal of particular tumor types; some of them are strictly tissue-specific such as prostatic specific antigen (PSA) for prostatic cancer, AFP and HCG for germ cell tumors of the testis and ovary, others such as CA 15.3, CA125, CEA or cytokeratins are less specific since their elevations can be found in different varieties of cancers even if they are preferentially associated to a certain tumor type, thus are considered markers for breast, ovarian cancer and colon adenocarcinoma. The most useful clinical applications of these parameters is their determination during the follow-up of the treated patients, in order to detect the tumor recurrence early, and also to evaluate the evolution of the disease by monitoring the treatment responses. During follow-up, increasing levels of tumor markers can be observed even several months before the clinical demonstration of cancer recurrence. The association of tumor marker tests with imaging modalities can lead to several advantages: the first is to confirm the diagnosis of relapses, possibly before the appearence of the related clinical symptoms due to tumor growth; the second is to localize the sites of lesions, while tumor markers provide only a general indication of the existence of metastases; the third is to make possible a correct whole body restaging. In the assessment of cancer response tumor markers are often very reliable and their changes are faster than the morphological ones. Among all the imaging modalities, nuclear medicine plays an important role in detecting recurrences and metastatic localizations as it is able to investigate functional rather than morphological aspects of tumors, and provide different information in comparison to morphologic imaging. In addition, the scintigraphic techniques offer the possibility to evaluate treatment responses, confirming or not the information from biochemical changes. This review aims to show some examples (breast, prostate and ovarian cancer) in which the combination of nuclear medicine imaging modalities and tumor marker tests is proposed for clinical practice. The advantages and some critical aspects are discussed on the basis of the clinical findings and the most important clinical indications are described.

Improved radioiodination of biomolecules using exhaustive Chloramine-T oxidation.

To improve standardization in analytical reagents we investigated Chloramine-T radioiodination (125I) of several biomolecules based on the use of a single amount of the oxidizing agent Chloramine-T as the limiting reagent being exhausted during the course of the reaction. Whenever the labeling yield resulted in less than one atom 125I/molecule, a second amount of the oxidizing agent was added. Thereafter, the integrity of the various biomolecules was assessed using radioimmunoassays, radioreceptor binding assays, or radioimmunometric assays. Purification yields were done by gel permeation (56% +/- 19%, n=230) or by precipitation with trichloroacetic acid (59% +/- 19%, n=230). Specific activity (117 +/- 61 MBq/nmol) and the degree of iodine incorporation (1.4 +/- 0.8 atoms of 125I/molecule) were achieved after 300 sec of incubation. A second addition of Chloramine-T resulted in an increased labeling yield of all biomolecules tested by a mean factor of 1.8 +/- 0.9. After the second addition of Chloramine-T, we observed for some biomolecules a significant (p<0.001) decreased effect in biological performance. In conclusion, the use of Chloramine-T as a limiting reagent resulted in molecules with appropriate immunological and biological performance. In general, tracers were minimally damaged and assessment of the shelf life as well as storing conditions showed the usefulness of the standardization of biomolecule labeling.

99mTc-labeling experiments on CCK(4) by a direct method.

99mTc-labeling studies have been performed on CCK(4) fragment of cholecystokinin, starting from 99mTc-pertechnetate, by using tin(II)pyrophosphate or tin(II)gluconate as reducing agents, together with NaBH(4) acting as a stabilizing agent of tin(II). Gluconate has been used as exchange ligand in the carrier added experiments and in the syntheses of 99Tc-CCK(4) and Re-CCK(4) complexes to be able to reproduce at macroscopic level the same chemical reactions occurring at non carrier added conditions. 99mTc-labeling yields higher than 95% have been achieved depending on Sn(II) concentration, CCK(4)/gluconate ratio, reaction time and applied temperature. The species produced with 99mTc, 99Tc, and cold rhenium nuclides have been compared by means of HPLC measurements, which showed similar retention times and thus probably the same species in the three situations.

The clinical value of 18F-FDG detection with a dual-head coincidence camera: a review.

Positron emission tomography (PET) has evolved into a technique that can accurately determine the distribution of positron-emitting radionuclides. The addition of a coincidence detection mode to a standard dual-head detector system has resulted in the option of single-photon and annihilation coincidence detection. This new device for imaging fluorine-18 2-fluoro-2-deoxy-D-glucose (18F-FDG) accumulation in neoplasms became commercially available in 1994. Besides conventional low-energy imaging in the collimated single-photon mode, it offers a relatively inexpensive opportunity to perform uncollimated PET by switching to the coincidence acquisition mode. This review summarises the clinical value of 18F-FDG detection with a dual-head coincidence camera in oncology. The results are compared with the overall results obtained using dedicated PET scanners. With respect to head and neck tumours, 18F-FDG coincidence mode gamma camera imaging (CGI) yields results that are in agreement with those obtained with dedicated PET scanners. With regard to other malignancies, such as lung cancer, lymphoma and brain tumours, data in the literature are too scarce to draw any definite conclusions. In general, the results of 18F-FDG CGI in tumours >15 mm seem to be comparable to those obtained with dedicated PET scanners, whereas in tumours <15 mm, the relative sensitivity of 18F-FDG CGI is approximately 80%. Using attenuation correction, the diagnostic yield of 18F-FDG CGI may increase. However, further clinical investigation is required to definitely establish its value in staging primary disease, therapy monitoring and assessment of tumour recurrence in clinical oncology.

Perfusion and functional abnormalities outside the septal region in patients with left bundle branch block assessed with gated SPECT.

BACKGROUND: The presence of a left bundle branch block (LBBB) pattern on the electrocardiogram may frequently lead to perfusion defects in the septum not necessarily due to ischemic heart disease, but probably due to abnormal septal wall motion. The introduction of gated single photon emission computed tomography (SPECT) allows the evaluation of myocardial perfusion and function in one study. Accordingly, we analysed perfusion and function and the relation between perfusion and regional function in the septal region in patients with a LBBB without evidence of a previously sustained myocardial infarction. METHODS: We selected 37 patients with a LBBB without a history of a previous myocardial infarction, which was confirmed by echocardiography and/or coronary angiography. All patients underwent technetium-99m tetrofosmin gated SPECT myocardial imaging. Twelve control patients with a low likelihood of coronary artery disease and a normal technetium-99m tetrofosmin gated SPECT myocardial perfusion scintigram were selected as a reference population. The left ventricle (LV) was divided into 18 segments, which were scored for perfusion and function (wall motion and wall thickening) on a 4-point scale. RESULTS: The average LV end-diastolic volume was higher and the average LV ejection fraction was lower in patients with LBBB as compared to controls (142+/-90 vs. 81+/-18 ml, and 48+/-19 vs 62+/-7%, p=0.03 and p=0.02, respectively). Not only in the septum, but also in the other segments, reduced myocardial perfusion and abnormal wall motion/wall thickening was observed in the patients with LBBB (p<0.0001 vs controls). Patients with LBBB showed no correlation between perfusion and function in the septum, and between perfusion in septum and global LV function (r=0.21, p=0.2; r=0.10, p=0.6, respectively). Conversely, a good correlation was found between perfusion and function, either regional or global, in the remote segments (both r=0.79, p<0.0001). CONCLUSIONS: We conclude that patients with LBBB without a previous myocardial infarction show cardiomyopathic changes with perfusion and wall motion abnormalities, involving the entire left ventricle. The severity of diminished septal perfusion is not directly associated with the severity of septal wall motion abnormalities or global LV function. However, in the myocardial segments remote from the septum, reduced perfusion is closely associated with functional abnormalities.

Radiopharmaceuticals for bone lesions. Imaging and therapy in clinical practice.

Bone scintigraphy continues to be one of the most commonly performed procedures in nuclear medicine. The radionuclide bone scan remains an excellent modality to detect metastatic disease in patients suffering from primary malignancies. This article reviews a number of aspects of bone scintigraphy such as bone physiology, radiopharmaceuticals and uptake mechanisms. As 99mTc labelled bis(di)phosphonates are the most frequently used this article is centred around these imaging agents. In addition to diagnostic bone scintigraphy the use of various bone seeking agents has been extended to the palliative treatment of bone metastases. In this context the radiobiological characteristics of various radionuclides as 89Sr, 32p, 153Sm, 186Re and 117Sn is elucidated. In addition, the clinical efficacy for pain killing of these radionuclides is elucidated on the basis of the radiation properties of these agents. It is concluded that 89Sr and 186Re are presently the radionuclides of choice. The latter agent has a slight advantage as its imaging photons enable individual dosimetry, resulting in an optimosed application scheme.

Assessment of regional myocardial wall motion and thickening by gated 99Tcm-tetrofosmin SPECT: a comparison with magnetic resonance imaging.

Gated single photon emission computed tomography (SPECT) imaging allows the simultaneous assessment of both perfusion and function by using one single study. The assessment of regional wall motion and thickening pattern with gated SPECT allows viability studies to be performed. Magnetic resonance imaging (MRI) is well validated for the assessment of myocardial wall motion and thickening in patients with normal and impaired ventricular function. The aim of the study was to analyse the concordance between wall motion and thickening scores derived by gated SPECT and MRI imaging. Furthermore, the agreement for myocardial wall motion and thickening according to myocardial perfusion was analysed with both techniques. We studied a group of 21 patients, including 13 with a previous myocardial infarction (all more than 4 months before the study), using both gated SPECT 99Tcm-tetrofosmin myocardial perfusion imaging and MRI. A 13-segment model was used for both gated SPECT and MRI and each segment was visually scored using a scale of 1-3 for wall motion and thickening. There was a high agreement between gated SPECT and MRI for both wall motion (229/273, 84%; k = 0.72, P<0.001) and wall thickening (236/273, 86%; k = 0.77, P<0.001). The agreement for wall motion and thickening was 80% (k = 0.66) and 83% (k = 0.70), respectively, for patients with myocardial infarction; and 90% (k = 0.81) and 92% (k = 0.86), respectively (P = NS), for patients without myocardial infarction. Agreement in segmental wall motion and thickening scores between gated SPECT and MRI was 90% (k = 0.80) and 91% (k = 0.84), respectively, for segments with normal or mild to moderate hypoperfusion; and 71% (k = 0.45) and 77% (k = 0.57), respectively, for segments with severe hypoperfusion or no perfusion. Of the 70 (41%) segments that had severely diminished or no perfusion in post-myocardial infarction patients, 22 (31%) showed preserved wall motion and 17 (24%) showed preserved wall thickening both by gated SPECT and MRI, suggesting residual myocardial viability in malperfused segments. Our results suggest that gated SPECT imaging is a reliable tool for the assessment of regional wall motion and thickening in patients with known or suspected coronary artery disease. In patients with a previous myocardial infarction gated SPECT imaging has the potential to detect preserved wall motion and thickening in regions with fixed perfusion defects indicating the potential presence of residual myocardial viability.

99mTc-labeled antimicrobial peptides for detection of bacterial and Candida albicans infections.

UNLABELLED: This study compared the possibilities and limitations of 99mTc-labeled synthetic peptides derived from two human antimicrobial peptides, namely, ubiquicidin (UBI) and lactoferrin (hLF), for the scintigraphic detection of bacterial and fungal infections in mice and rabbits. The rationale of our approach was that selected peptides accumulate in infected areas but not in sterile inflammatory lesions, because they bind preferentially to microorganisms. 99mTc-labeled human neutrophil peptides (defensins), ciprofloxacin, and human polyclonal IgG were included as control agents. METHODS: 99mTc-labeled peptides and control agents were injected intravenously into animals that had been injected intramuscularly 18 h earlier with multidrug-resistant Staphylococcus aureus, Klebsiella pneumoniae, or fluconazole-resistant Candida albicans. Sterile inflammatory sites were induced by the injection of heat-killed microorganisms or lipopolysaccharide (LPS) into the thigh muscle. Up to 4 h after injection, the accumulation of 99mTc-labeled compounds in the infected/inflamed thigh muscles was determined using scintigraphic techniques and radioactivity counts in dissected tissues. RESULTS: Scintigraphy revealed that 99mTc-labeled peptides UBI 29-41, UBI 18-35, UBI 31-38, hLF 1-11, and defensins, which showed preferential in vitro binding to microorganisms in a former study, accumulated at a significantly higher rate (P < 0.01) in bacterial and C. albicans infections in mice and rabbits than in inflamed tissues induced by heat-killed microorganisms or by LPS. No significant difference in the accumulation of 99mTc-labeled ciprofloxacin was observed between infected and sterile inflamed thigh muscles in mice. CONCLUSION: 99mTc-labeled antimicrobial peptides UBI 29-41, UBI 18-35, UBI 31-38, hLF 1-11, and defensins accumulate significantly in tissues infected with gram-positive and gram-negative bacteria and C. albicans. Significantly lower (P < 0.01) accumulation of these peptides occurs in sterile inflamed tissues. These data indicate that the peptides preferentially tag microorganisms at the site of infection, which is in agreement with their preferential binding to the microorganisms in vitro and in vivo. 99mTc-labeled ciprofloxacin does not distinguish between infections and sterile inflammatory lesions, which implies that its specificity for the detection of bacterial infections is not warranted.

Positron emission tomography with 2-[18F]-fluoro-2-deoxy-D-glucose in oncology. Part IIIa: Therapy response monitoring in breast cancer, lymphoma and gliomas.

Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) is considered to be a very useful adjunct to anatomic imaging techniques and is now primarily used for oncological indications. These indications include diagnosis, staging, and therapy monitoring. In this review, we discuss the articles in which FDG-PET is clinically used for monitoring therapy in breast cancer, lymphomas and gliomas. It is found that the amount of FDG uptake strongly correlates with response to therapy in breast cancer, lymphomas, and gliomas; a decrease in FDG uptake after therapy indicates a positive response to therapy. However, this conclusion is based on small patient numbers, whereas the exact response mechanism is still unknown. Therefore, more studies in comparable patient groups are required to achieve a better understanding of FDG uptake patterns after therapy. Part IIIb deals with lung, and head and neck cancer, hepatocellular and colorectal tumours, and sarcoma.

Positron emission tomography with 2-[18F]-fluoro-2-deoxy-D-glucose in oncology. Part IIIb: Therapy response monitoring in colorectal and lung tumours, head and neck cancer, hepatocellular carcinoma and sarcoma.

Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) is considered to be a very useful adjunct to anatomic imaging techniques and is now primarily used for oncological indications. These indications include diagnosis, staging, and therapy monitoring. In this review, we discuss the articles in which FDG-PET is clinically used for monitoring therapy in lung and colorectal tumours, head and neck cancer, sarcoma, and hepatocellular carcinoma. It is found that the amount of FDG uptake strongly correlates with response to therapy: a decrease in FDG uptake after therapy indicates a positive response to therapy. However, this conclusion is based on small numbers of patients, whereas the exact response mechanism is still unknown. Moreover, in these case series, the interval between tumour therapy and FDG-PET, as well as the method of quantification, SUV or tumour-to-non-tumour ratios, differ per study. Finally, dynamic imaging is a recommended technique by some authors, but it is not a standard technique in clinical practice to evaluate tumour therapy. Therefore, further study is required which has to deal with these major issues before it is possible to draw definite conclusions.

Detection of residual wall motion after myocardial infarction by gated technetium-99m tetrofosmin SPET: a comparison with contrast ventriculography.

The differentiation of residual viability from necrotic myocardium in patients with a prior myocardial infarction is important when deciding whether revascularization is indicated. Myocardial viability can be assessed by studying perfusion and regional wall motion. Gated single-photon emission tomography (SPET) imaging allows the simultaneous assessment of perfusion and function through a single study. The aim of this study was to analyse the concordance between wall motion score derived by gated SPET and by contrast ventriculography. Furthermore, the agreement between myocardial perfusion and regional myocardial wall motion was analysed for both techniques. We studied a homogeneous group of 26 consecutive patients with a prior myocardial infarction, using both gated technetium-99m tetrofosmin SPET and contrast ventriculography. A seven-segment model of the left ventricle was employed to score regional myocardial wall motion on images obtained with gated SPET and contrast ventriculography using a four-point scale. Contrast ventriculography was performed within 2 weeks of the gated SPET study. Prevalence of abnormal wall motion (akinetic or dyskinetic) was 24/182 (13%) for gated SPET and 25/182 (14%) for contrast ventriculography (P = NS). There was a high agreement (80%) in wall motion score between gated SPET and contrast ventriculography (kappa = 0.67, P < 0.001). The agreement was better in segments with normal or mild to moderate hypoperfusion (82%, kappa = 0.69) than in those with severe hypoperfusion (67%, kappa = 0.56). The agreement between myocardial perfusion and myocardial wall motion was 89% (162/182), kappa = 0.57, for gated SPET and 80% (145/182), kappa = 0.21, for contrast ventriculography. The relation between the summed wall motion scores per patient on gated SPET and contrast ventriculography was excellent (y = 0.81x + 2.9, r = 0.82, P < 0.01). Thirteen (43%) out of 30 segments with severely diminished or no myocardial perfusion showed normal or hypokinetic wall motion on gated SPET, suggesting residual myocardial viability in malperfused regions. Our results suggest that gated SPET imaging is a reliable tool for the assessment of regional wall motion in post-myocardial infarction patients. Furthermore, in patients with a previous myocardial infarction, gated SPET imaging has the potential to detect preserved wall motion in regions with fixed perfusion defects, which might be indicative of residual myocardial viability.

Detection of residual wall motion after sustained myocardial infarction by gated 99Tcm-tetrofosmin SPECT: a comparison with echocardiography.

The differentiation of residual viability from necrotic myocardium in patients with a previously sustained myocardial infarction is important in deciding indications for revascularization. Myocardial viability can be assessed by studying perfusion and regional wall motion. With gated single photon emission computed tomography (SPECT), it is possible to augment SPECT perfusion data with ventricular functional data both at a global and regional level. The aim of the study was to analyse the concordance between wall motion score derived by gated SPECT and echocardiography. Furthermore, the agreement between myocardial perfusion and left ventricular wall motion was analysed with both techniques. We studied a homogenous group of 25 consecutive patients with a previous myocardial infarction (MI) using both gated SPECT 99Tcm-tetrofosmin myocardial perfusion imaging and two-dimensional echocardiography. Echocardiography was performed within 2 weeks of the gated SPECT study. Both for gated SPECT and for echocardiography the left ventricle was divided into seven regions per patient. For comparison, the gated SPECT regions were matched to the echocardiographic regions, resulting in a total of 175 regions. Prevalence of abnormal wall motion (akinetic or dyskinetic) was 23% (39/171) for echocardiography and 21% (36/175) for gated SPECT (P = NS). There was a high agreement in wall motion score between echocardiography and gated SPECT of 80% (136/171). The agreement between myocardial perfusion and myocardial wall motion was 82% (143/175) for gated SPECT and 76% (130/171) for echocardiography (P = NS). Nineteen (34%) of the 56 regions with severely diminished or absent myocardial perfusion showed normal or hypokinetic wall motion both by gated SPECT and echocardiography suggesting residual myocardial viability in malperfused regions. Our results suggest that, gated SPECT imaging is a reliable tool for the assessment of regional wall motion in post myocardial infarction patients. Furthermore, in patients with a previous myocardial infarction gated SPECT imaging has the potential to detect preserved wall motion in regions with fixed perfusion defects, which might be indicative of residual myocardial viability.

The additive value of gated SPET myocardial perfusion imaging in patients with known and suspected coronary artery disease.

In myocardial perfusion scintigraphy, the clinical significance of fixed defects presents some difficulty. In this study, we evaluated whether additional information on left ventricular function assessed by quantitative gated single-photon emission computed tomography (gated SPET) would increase the diagnostic yield of the study in such patients. We studied 55 patients with a previous myocardial infarction and 20 patients without a previous myocardial infarction using gated SPET 99Tc(m)-tetrofosmin myocardial perfusion imaging. Each patient had to have a persistent perfusion defect consisting of at least three contiguous segments in the same vascular territory. The left ventricle was divided into 20 segments which were analysed for perfusion and wall thickening on a 4-point severity scale. Of the 55 patients with myocardial infarction, 19 (35%) patients showed preserved wall thickening in the region of the previous infarction with fixed perfusion abnormalities, which suggested residual myocardial viability. In the 20 patients without myocardial infarction, preserved wall thickening was seen in 10 (50%) patients with fixed perfusion defects, suggesting an attenuation artefact. Conversely, in 16 (29%) patients in the myocardial infarction group and two (10%) patients in the non-myocardial infarction group normal perfusion was associated with severely diminished wall thickening possibly due to stunning. We found an excellent correlation between wall thickening and left ventricular ejection fraction both for the patients with myocardial infarction and the patients without myocardial infarction (r = 0.86 and r = 0.82, respectively, both P<0.0001). A reasonable correlation between perfusion and left ventricular ejection fraction was found for the patients with myocardial infarction (r = 0.41, P = 0.002), and a non-significant correlation for the patients without myocardial infarction (r = 0.37, P = 0.1). Quantitative gated SPET myocardial imaging allows the detection of residual wall thickening in patients with a previous myocardial infarction who show severe fixed perfusion defects. In patients without myocardial infarction, gated SPET imaging allows differentiation between an attenuation artefact and a fixed perfusion defect due to coronary artery disease. In addition, gated SPET may show diminished ventricular function in normally perfused segments possibly due to myocardial stunning. The addition of gated SPET myocardial perfusion imaging increases diagnostic confidence and may have direct clinical implications for optimal patient management.