Comparison of the dyssynchrony parameters recorded with gated SPECT in ischemic cardiomyopathy according to their repeatability at rest and to their ability to detect a synchrony reserve under dobutamine infusion.

BACKGROUND: This study aimed to determine whether the repeatability of dyssynchrony assessment using gated myocardial perfusion SPECT (GSPECT) allows the detection of synchrony reserve during low-dose dobutamine infusion. METHODS AND RESULTS: Sixty-one patients with ischemic cardiomyopathy and LV ejection fraction < 50% were prospectively included in 10 centers. Each patient underwent two consecutive rest GSPECT with 99mTc-labeled tracer (either tetrofosmin or sestamibi) to assess the repeatability of LV function and dyssynchrony parameters, followed by a GSECT acquisition during low-dose dobutamine infusion. LV dyssynchrony was assessed using QGS software through histogram bandwidth (BW), standard deviation of the phase (SD), and entropy. Repeatability was assessed with Lin's concordance correlation coefficient (CCC). Entropy showed a higher CCC (0.80) compared to BW (0.68) and SD (0.75). On average, dobutamine infusion yielded to improve both BW (P = .049) and entropy (P = .04) although significant improvements, setting outside the 95% confidence interval of the repeatability analysis, were documented in only 6 and 4 patients for BW and entropy, respectively. CONCLUSIONS: A synchrony reserve may be documented in patients with ischemic cardiomyopathy through the recording of BW and entropy with low-dose dobutamine GSPECT, with the additional advantage of a higher repeatability for entropy.

Evaluation of tetrafunctional block copolymers as synthetic vectors for lung gene transfer.

In the present study, we evaluated, in mice, the efficacy of the tetrafunctional block copolymer 704 as a nonviral gene delivery vector to the lungs. SPECT/CT molecular imaging of gene expression, biochemical assays, and immunohistochemistry were used. Our dataset shows that the formulation 704 resulted in higher levels of reporter gene expression than the GL67A formulation currently being used in a clinical trial in cystic fibrosis patients. The inflammatory response associated with this gene transfer was lower than that induced by the GL67A formulation, and the 704 formulation was amenable to repeated administrations. The cell types transfected by the 704 formulation were type I and type II pneumocytes, and transgene expression could not be detected in macrophages. These results emphasize the relevance of the 704 formulation as a nonviral gene delivery vector for lung gene therapy. Further studies will be required to validate this vector in larger animals, in which the lungs are more similar to human lungs.

99mTcO4--, auger-mediated thyroid stunning: dosimetric requirements and associated molecular events.

Low-energy Auger and conversion electrons deposit their energy in a very small volume (a few nm3) around the site of emission. From a radiotoxicological point of view the effects of low-energy electrons on normal tissues are largely unknown, understudied, and generally assumed to be negligible. In this context, the discovery that the low-energy electron emitter, 99mTc, can induce stunning on primary thyrocytes in vitro, at low absorbed doses, is intriguing. Extrapolated in vivo, this observation suggests that a radioisotope as commonly used in nuclear medicine as 99mTc may significantly influence thyroid physiology. The aims of this study were to determine whether 99mTc pertechnetate (99mTcO4-) is capable of inducing thyroid stunning in vivo, to evaluate the absorbed dose of 99mTcO4- required to induce this stunning, and to analyze the biological events associated/concomitant with this effect. Our results show that 99mTcO4--mediated thyroid stunning can be observed in vivo in mouse thyroid. The threshold of the absorbed dose in the thyroid required to obtain a significant stunning effect is in the range of 20 Gy. This effect is associated with a reduced level of functional Na/I symporter (NIS) protein, with no significant cell death. It is reversible within a few days. At the cellular and molecular levels, a decrease in NIS mRNA, the generation of double-strand DNA breaks, and the activation of the p53 pathway are observed. Low-energy electrons emitted by 99mTc can, therefore, induce thyroid stunning in vivo in mice, if it is exposed to an absorbed dose of at least 20 Gy, a level unlikely to be encountered in clinical practice. Nevertheless this report presents an unexpected effect of low-energy electrons on a normal tissue in vivo, and provides a unique experimental setup to understand the fine molecular mechanisms involved in their biological effects.

Adrenal gland infection by serotype 5 adenovirus requires coagulation factors.

Recombinant, replication-deficient serotype 5 adenovirus infects the liver upon in vivo, systemic injection in rodents. This infection requires the binding of factor X to the capsid of this adenovirus. Another organ, the adrenal gland is also infected upon systemic administration of Ad, however, whether this infection is dependent on the cocksackie adenovirus receptor (CAR) or depends on the binding of factor X to the viral capsid remained to be determined. In the present work, we have used a pharmacological agent (warfarin) as well as recombinant adenoviruses lacking the binding site of Factor X to elucidate this mechanism in mice. We demonstrate that, as observed in the liver, adenovirus infection of the adrenal glands in vivo requires Factor X. Considering that the level of transduction of the adrenal glands is well-below that of the liver and that capsid-modified adenoviruses are unlikely to selectively infect the adrenal glands, we have used single-photon emission computed tomography (SPECT) imaging of gene expression to determine whether local virus administration (direct injection in the kidney) could increase gene transfer to the adrenal glands. We demonstrate that direct injection of the virus in the kidney increases gene transfer in the adrenal gland but liver transduction remains important. These observations strongly suggest that serotype 5 adenovirus uses a similar mechanism to infect liver and adrenal gland and that selective transgene expression in the latter is more likely to be achieved through transcriptional targeting.

Compared performance of high-sensitivity cameras dedicated to myocardial perfusion SPECT: a comprehensive analysis of phantom and human images.

UNLABELLED: Differences in the performance of cadmium-zinc-telluride (CZT) cameras or collimation systems that have recently been commercialized for myocardial SPECT remain unclear. In the present study, the performance of 3 of these systems was compared by a comprehensive analysis of phantom and human SPECT images. METHODS: We evaluated the Discovery NM 530c and DSPECT CZT cameras, as well as the Symbia Anger camera equipped with an astigmatic (IQ x SPECT) or parallel-hole (conventional SPECT) collimator. Physical performance was compared on reconstructed SPECT images from a phantom and from comparable groups of healthy subjects. RESULTS: Classifications were as follows, in order of performance. For count sensitivity on cardiac phantom images (counts x s(-1) x MBq(-1)), DSPECT had a sensitivity of 850; Discovery NM 530c, 460; IQ x SPECT, 390; and conventional SPECT, 130. This classification was similar to that of myocardial counts normalized to injected activities from human images (respective mean values, in counts x s(-1) x MBq(-1): 11.4 ± 2.6, 5.6 ± 1.4, 2.7 ± 0.7, and 0.6 ± 0.1). For central spatial resolution: Discovery NM 530c was 6.7 mm; DSPECT, 8.6 mm; IQ x SPECT, 15.0 mm; and conventional SPECT, 15.3 mm, also in accordance with the analysis of the sharpness of myocardial contours on human images (in cm(-1): 1.02 ± 0.17, 0.92 ± 0.11, 0.64 ± 0.12, and 0.65 ± 0.06, respectively). For contrast-to-noise ratio on the phantom: Discovery NM 530c had a ratio of 4.6; DSPECT, 4.1; IQ x SPECT, 3.9; and conventional SPECT, 3.5, similar to ratios documented on human images (5.2 ± 1.0, 4.5 ± 0.5, 3.9 ± 0.6, and 3.4 ± 0.3, respectively). CONCLUSION: The performance of CZT cameras is dramatically higher than that of Anger cameras, even for human SPECT images. However, CZT cameras differ in that spatial resolution and contrast-to-noise ratio are better with the Discovery NM 530c, whereas count sensitivity is markedly higher with the DSPECT.

Normalisation to blood activity is required for the accurate quantification of Na/I symporter ectopic expression by SPECT/CT in individual subjects.

The utilisation of the Na/I symporter (NIS) and associated radiotracers as a reporter system for imaging gene expression is now reaching the clinical setting in cancer gene therapy applications. However, a formal assessment of the methodology in terms of normalisation of the data still remains to be performed, particularly in the context of the assessment of activities in individual subjects in longitudinal studies. In this context, we administered to mice a recombinant, replication-incompetent adenovirus encoding rat NIS, or a human colorectal carcinoma cell line (HT29) encoding mouse NIS. We used (99m)Tc pertechnetate as a radiotracer for SPECT/CT imaging to determine the pattern of ectopic NIS expression in longitudinal kinetic studies. Some animals of the cohort were culled and NIS expression was measured by quantitative RT-PCR and immunohistochemistry. The radioactive content of some liver biopsies was also measured ex vivo. Our results show that in longitudinal studies involving datasets taken from individual mice, the presentation of non-normalised data (activity expressed as %ID/g or %ID/cc) leads to 'noisy', and sometimes incoherent, results. This variability is due to the fact that the blood pertechnetate concentration can vary up to three-fold from day to day. Normalisation of these data with blood activities corrects for these inconsistencies. We advocate that, blood pertechnetate activity should be determined and used to normalise the activity measured in the organ/region of interest that expresses NIS ectopically. Considering that NIS imaging has already reached the clinical setting in the context of cancer gene therapy, this normalisation may be essential in order to obtain accurate and predictive information in future longitudinal clinical studies in biotherapy.

The use of molecular imaging of gene expression by radiotracers in gene therapy.

INTRODUCTION: Progress with gene-based therapies has been hampered by difficulties in monitoring the biodistribution and kinetics of vector-mediated gene expression. Recent developments in non-invasive imaging have allowed researchers and clinicians to assess the location, magnitude and persistence of gene expression in animals and humans. Such advances should eventually lead to improvement in the efficacy and safety of current clinical protocols for future treatments. AREAS COVERED: The molecular imaging techniques for monitoring gene therapy in the living subject, with a specific highlight on the key reporter gene approaches that have been developed and validated in preclinical models using the latest imaging modalities. The applications of molecular imaging to biotherapy, with a particular emphasis on monitoring of gene and vector biodistribution and on image-guided radiotherapy. EXPERT OPINION: Among the reporter gene/probe combinations that have been described so far, one stands out, in our view, as the most versatile and easy to implement: the Na/I symporter. This strategy, exploiting more than 50 years of experience in the treatment of differentiated thyroid carcinomas, has been validated in different types of experimental cancers and with different types of oncolytic viruses and is likely to become a key tool in the implementation of human gene therapy.

Distribution and dynamics of (99m)Tc-pertechnetate uptake in the thyroid and other organs assessed by single-photon emission computed tomography in living mice.

BACKGROUND: (99m)Tc pertechnetate is a well-known anion, used for clinical imaging of thyroid function. This gamma emitter is transported by the sodium iodide symporter but is not incorporated into thyroglobulin. Scintigraphy using (99m)Tc pertechnetate or (123)iodide represents a powerful tool for the study of sodium iodide symporter activity in different organs of living animal models. However, in many studies that have been performed in mice, the thyroid could not be distinguished from the salivary glands. In this work, we have evaluated the use of a clinically dedicated single-photon emission computed tomography (SPECT) camera for thyroid imaging and assessed what improvements are necessary for the development of this technique. METHODS: SPECT of the mouse neck region, with pinhole collimation and geometric calibration, was used for the individual measurement of (99m)Tc pertechnetate uptake in the thyroid and the salivary glands. Uptake in the stomach was studied by planar whole-body imaging. Uptake kinetics and biodistribution studies were performed by sequential imaging. RESULTS: This work has shown that thyroid imaging in living mice can be performed with a SPECT camera originally built for clinical use. Our experiments indicate that (99m)Tc pertechnetate uptake is faster in the thyroid than in the salivary glands and the stomach. The decrease in (99m)Tc pertechnetate uptake after injection of iodide or perchlorate as competitive inhibitors was also studied. The resulting rate decreases were faster in the thyroid than in the salivary glands or the stomach. CONCLUSIONS: We have shown that a clinically dedicated SPECT camera can be used for thyroid imaging. In our experiments, SPECT imaging allowed the analysis of (99m)Tc pertechnetate accumulation in individual organs and revealed differences in uptake kinetics.

Dose dependency and reversibility of serotonin-induced valvular heart disease in rats.

Serotonergic drugs may lead to valvular heart disease in humans and more recently also in rats. Although clinical data suggest that dose dependency and reversibility after drug cessation might occur, proof of this is lacking. For that purpose, a total of 106 rats were prospectively enrolled: 22 control animals and 7 groups of 12 rats that received daily subcutaneous serotonin injections (5, 10, 20, 30, 40, 50 and 60 mg/kg respectively) for 12 weeks. At 12 weeks, half of the animals of each group were killed for histological analysis, whereas the remaining rats were further followed (without serotonin injections) for an additional 8 weeks. After 12 weeks of serotonin treatment, aortic and mitral regurgitation (AR, MR) were more frequently observed in the high dose groups (>30 mg/kg) compared to controls. Moreover, aortic and mitral valves were also thicker in the high dose groups compared to controls. After 8 weeks free of serotonin injections, AR and MR were no longer significantly higher than controls. Moreover, aortic and mitral valve thickness had normalized, returning to control levels. In conclusion, this study provides evidence for a dose-dependent valvular toxicity of serotonergic drugs, which appears to be reversible after drug withdrawal.

Comparison of the prognostic value of dipyridamole and dobutamine myocardial perfusion scintigraphy in hemodialysis patients.

Screening for coronary artery disease (CAD) in hemodialysis patients is hampered by contraindications and/or limitations of the available techniques in this population. Myocardial perfusion scintigraphy (MPS) using dipyridamole has been considered inaccurate due to abnormally high basal levels of adenosine in uremia that could blunt the vasodilatory response. Since dobutamine may be more reliable, we directly compared the two in patients on hemodialysis. We performed MPS at rest and after separate dipyridamole or dobutamine stress in 121 chronic hemodialysis patients. More numerous, larger, and more intense reversible lesions were induced with dobutamine than with dipyridamole, mainly in the anteroseptal segments. Reversibility with dipyridamole but not dobutamine MPS was independently and strongly related with mortality associated with CAD and with fatal and non-fatal CAD. We hypothesize that the chronotropic action of dobutamine induced alterations of wall motion, leading to spurious perfusion defects, not unlike artifacts seen with left bundle branch block. Our study shows that even though dobutamine induced more pronounced myocardial ischemia than dipyridamole in chronic hemodialysis patients, dipyridamole MPS more accurately identifies patients at high risk for subsequent cardiac death or non-fatal CAD than dobutamine.

Cyproheptadine prevents pergolide-induced valvulopathy in rats: an echocardiographic and histopathological study.

Serotonergic drugs, such as pergolide, have been associated with the development of cardiac valvular myxoid thickening and regurgitation in humans and more recently in rats. These effects are potentially mediated by the 5-hydroxytryptamine (5-HT)(2B) receptor (5-HT(2B)R). Therefore, we sought to determine whether cyproheptadine, a 5-HT(2B)R antagonist, might prevent toxic valvulopathy in an animal model of pergolide-induced valvular heart disease. For this purpose, 50 male Wistar rats received daily intraperitoneal injections of pergolide (0.5 mg/kg, n = 14), pergolide (0.5 mg/kg) combined with cyproheptadine (10 mg/kg, n = 12), cyproheptadine (10 mg/kg, n = 12), or no injections (control, n = 12) for 20 wk. Echocardiography was performed blindly at baseline and at 10 and 20 wk followed by pathology. At baseline, no differences between groups were found with echocardiography. At 20 wk, aortic regurgitation was present in all pergolide-treated animals, whereas it was less frequently observed in the other groups (P < 0.0001). For the other valves, this difference was less pronounced. On histopathology, not only aortic but also mitral valves were thicker, myxoid, and exhibited more 5-HT(2B)R-positive cells in pergolide-treated animals compared with the other groups. Moreover, regurgitant aortic and mitral valves were thicker than nonregurgitant aortic and mitral valves. In conclusion, we found that cyproheptadine prevented pergolide-induced valvulopathy in rats, which was associated with a reduced number of 5-HT(2B)R-positive valvular cells. This may have important clinical implications for the prevention of serotonergic drug-induced valvular heart disease.

Echocardiographic and histological assessment of age-related valvular changes in normal rats.

Aging is associated with morphologic and functional alterations of the rat's left ventricle. However, the time-course of valvular function and morphology in normal aging rats has not yet been studied. For this purpose, 30 male Wistar rats (318 +/- 5g, 10 weeks old) underwent serial echocardiograms for 58 weeks under sodium pentobarbital 50 mg/kg IP anesthetization followed by necropsy. Histopathology was also performed in two additional groups of 10 rats at 10 and 30 weeks of age. Regurgitations were considered as any retrograde flow on 2-D or M-mode color Doppler echocardiography. Tricuspid regurgitation was already found at 10 weeks of age and became more frequent with age. Pulmonary, mitral and aortic regurgitation was seldom observed at 10 weeks but became more frequent after 30 weeks. For the mitral and aortic valve, this was also associated with an increase in valvular thickness because of nodular or segmental myxoid leaflet changes. The severity of valvular regurgitations did not increase with age. In conclusion, aging leads to morphologic and functional valvular changes in normal rats. This is important when investigating models of valvular heart disease in small animals.

Effect of streptozotocin-induced diabetes on myocardial blood flow reserve assessed by myocardial contrast echocardiography in rats.

UNLABELLED: The role of structural and functional abnormalities of small vessels in diabetes cardiomyopathy remains unclear. Myocardial contrast echocardiography allows the quantification of myocardial blood flow at rest and during dipyridamole infusion. The aim of the study was to determine the myocardial blood flow reserve in normal rats compared with streptozotocin-induced diabetic rats using contrast echocardiography. METHODS: We prospectively studied 40 Wistar rats. Diabetes was induced by intravenous streptozotocin in 20 rats. All rats underwent baseline and stress (dipyridamole: 20 mg/kg) high power intermittent imaging in short axis view under anaesthesia baseline and after six months. Myocardial blood flow was determined and compared at rest and after dipyridamole in both populations. The myocardial blood flow reserve was calculated and compared in the 2 groups. Parameters of left ventricular function were determined from the M-mode tracings and histological examination was performed in all rats at the end of the study. RESULTS: At six months, myocardial blood flow reserve was significantly lower in diabetic rats compared to controls (3.09 +/- 0.98 vs. 1.28 +/- 0.67 ml min-1 g-1; p < 0.05). There were also a significant decrease in left ventricular function and a decreased capillary surface area and diameter at histology in the diabetic group. CONCLUSION: In this animal study, diabetes induced a functional alteration of the coronary microcirculation, as demonstrated by contrast echocardiography, a decrease in capillary density and of the cardiac systolic function. These findings may offer new insights into the underlying mechanisms of diabetes cardiomyopathy.

Doppler myocardial imaging in the diagnosis of early systolic left ventricular dysfunction in diabetic rats.

AIM: To find out if Doppler myocardial imaging (DMI) can detect early signs of left ventricular (LV) dysfunction in a rat model of diabetic cardiomyopathy. METHODS: Eight control and 12 Streptozotocin (STZ)-induced diabetic rats underwent transthoracic echocardiography with high-resolution technology at baseline and 2, 4, 8, 12, and 16 weeks after STZ injection. Radial function was analysed using conventional M-mode, and velocity, strain and strain rate imaging. Longitudinal function was analysed using pulsed Doppler imaging of the mitral annulus. RESULTS: In the diabetic rats, a significant increase in LV end diastolic and end systolic diameter was measured when compared with controls (P < 0.001). Fractional shortening and LV ejection fraction remained unchanged in both groups. Using DMI, diabetic rats demonstrated a decrease in radial systolic velocity (rate of change: +0.01 vs. -0.003 week(-1); P < 0.01) and radial systolic strain rate (+0.003 vs. -0.205 week(-1); P = 0.08) of the anteroseptal wall. Histologic examination revealed dilated cardiomyopathy with no signs of fibrosis. CONCLUSION: Although LV ejection fraction remained preserved, velocity and strain rate imaging was able to detect radial systolic dysfunction in diabetic rats. The absence of histological signs of fibrosis suggests that other mechanisms play a role in the development of diabetic cardiomyopathy.

Impact of anesthesia on valvular function in normal rats during echocardiography.

Anesthetic agents have different effects on hemodynamic and cardiac functional parameters. The influence of these changes on valvular function has not been studied in small animals. For this purpose, 48 male Wistar rats were divided into three equal groups. An echocardiogram was performed under inhaled isoflurane 2% gas (group I) or under intraperitoneal pentobarbital 50 mg/kg (group II) or ketamine/xylazine (group III) 40/8 mg/kg. Aortic regurgitation was only found in group III (80%, p < 0.0001 vs. groups I and II). Pulmonary and mitral regurgitation (PR, MR) were observed in all groups but were more frequent in group III (PR 67%, MR 100%) compared with group I (PR 13%, p = 0.003; MR 44%, p = 0.001 vs. group III) and group II (PR 19%, p = 0.011; MR 25%, p < 0.0001 vs. group III). Moreover, valvular regurgitations in group III (except tricuspid regurgitation) were more severe compared with groups I and II. The findings in group III were the result of increased blood pressure and afterload, left ventricular (LV) dilation and decreased function. Also in group III, the regurgitations diminished over time as the blood pressure decreased and LV function recovered. Isoflurane and pentobarbital had less pronounced effects on valvular function (5 and 10 min after induction, respectively) compared with ketamine/xylazine and, therefore, might be the anesthetics of choice for valvular evaluation in male Wistar rats. In conclusion, anesthesia causes hemodynamic changes that may result in functional valvular regurgitations in normal rats.

Effect of streptozotocin-induced diabetes on left ventricular function in adult rats: an in vivo Pinhole Gated SPECT study.

BACKGROUND: Recent studies have suggested that diabetes mellitus (DM) may cause left ventricular (LV) dysfunction directly resulting in increased susceptibility to heart failure. Using pinhole collimators and advances in data processing, gated SPECT was recently adapted to image the rat heart. The present study was aimed to assess this new imaging technique for quantifying LV function and remodeling from the Streptozotocin (STZ) rat model compared to controls. METHODS: Twenty one rats were randomly assigned to control or diabetic group. Six months after the induction of diabetes by STZ, Pinhole 99 m Tc-sestamibi gated SPECT was performed for determining rat LV volumes and function. Post-mortem histopathologic analysis was performed to evaluate the determinant of LV remodeling in this model. RESULTS: After six months, the normalized to body weight LV End-systolic volume was significantly different in diabetic rats compared to controls (0.46 +/- 0.02 vs 0.33 +/- 0.03 microL/g; p = 0.01). The normalized LV End-diastolic volume was also different in both groups (1.51 +/- 0.03 vs 0.88 +/- 0.05 microL/g; p = 0.001) and the normalized stroke volume was significantly higher in STZ-rats (1.05 +/- 0.02 vs 0.54 +/- 0.06 microL/g; p = 0.001). The muscular fibers were thinner at histology in the diabetic rats (0.44 +/- 0.07 vs 0.32 +/- 0.06 AU; p = 0.01). CONCLUSION: Pinhole 99 m Tc-sestamibi gated SPECT can successfully be applied for the evaluation of cardiac function and remodeling in STZ-induced diabetic rats. In this model, LV volumes were significantly changed compared to a control population, leading to a LV dysfunction. These findings were consistent with the histopathological abnormalities. Finally, these data further suggest the presence of diabetes cardiomyopathy.

Evidence that intracoronary-injected CD133+ peripheral blood progenitor cells home to the myocardium in chronic postinfarction heart failure.

OBJECTIVE: To study the biodistribution of purified CD133(+) cells after intracoronary injection in patients with stable chronic postinfarction heart failure. PATIENTS AND METHODS: Patients with longstanding myocardial infarction (>12 months prior to inclusion) and with an accessible left coronary artery were eligible. CD133(+) cells were mobilized with granulocyte colony-stimulating factor and purified with a CliniMACS device. Cells were labeled with (111)Indium and injected through a balloon catheter in a coronary artery feeding the necrotic or viable infarct-related region of the left ventricle during a standard coronary catheterization procedure. The total body biodistribution of (111)Indium was studied with a dual-head gamma camera in combination with (99m)Technetium-sestaMIBI cardiac distribution analysis. RESULTS: The number of CD133(+) cells injected ranged between 5 and 10 x 10(6) cells (low dose, three patients) or between 18.5 and 50 x 10(6) cells (high dose, five patients). In the five patients receiving the higher cell doses, a clear residual radioactivity was observed at the level of the chronic injury at 2, 12, and up to 36 hours after injection. A detailed analysis in two patients showed 6.9% to 8.0% (after 2 hours) and 2.3% to 3.2% (after 12 hours) residual radioactivity at the heart. No adverse events were observed during the procedure and up to 3 months follow-up. CONCLUSIONS: We demonstrate that CD133(+) progenitor cells are capable of homing to the postinfarction remodeling myocardium after intracoronary injections in patients with chronic postinfarction heart failure.

Possible association between 3,4-methylenedioxymethamphetamine abuse and valvular heart disease.

Valvular heart disease, inducing valvular regurgitation, has been described in users of drugs such as anorectic agents and ergot derivates. 3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") also leads in vitro to the proliferation of cardiac valvular interstitial cells by activation of the 5-hydroxytryptamine 2B receptor. The aim of this study was to determine the occurrence of valvulopathy in young adults taking MDMA. Twenty-nine subjects using or having used MDMA and 29 gender- and age-matched controls were blindly evaluated with echocardiography. Eight subjects (28%) who took MDMA had abnormal echocardiographic results using the United States Food and Drug Administration's criteria for appetite suppressant-induced valvular heart disease, compared with none in the control group (p = 0.0045). Six (21%) subjects had mitral regurgitation of 1/4 and 4 (14%) of > or =2/4, compared with none in the control group (p = 0.002). The mean mitral regurgitant area ratios (jet/atrium) were 12 +/- 9.8% and 5 +/- 1.3%, respectively (p = 0.007). Tricuspid regurgitation > or =2/4 was present in 13 MDMA users (45%) and absent in controls (p <0.001). The mean tricuspid regurgitant area ratios were 19 +/- 9.5% and 9 +/- 4.5%, respectively (p <0.001). Four MDMA users (14%) had mild aortic regurgitation (p = 0.11). Valvular "strands" were present in 6 MDMA users (21%) and in none of the controls (p = 0.02). In conclusion, MDMA may lead to mild to moderate valvular heart disease and valvular strands.

In vivo model of drug-induced valvular heart disease in rats: pergolide-induced valvular heart disease demonstrated with echocardiography and correlation with pathology.

AIMS: Valvular heart disease (VHD), inducing valvular regurgitation, has been described in carcinoid heart disease and recently in Parkinson's patients treated with pergolide. The aim of this study was to develop an in vivo model of drug-induced valvulopathy with pergolide in rats. METHODS AND RESULTS: Thirty male Wistar rats were given daily injections of either pergolide (0.5 mg/kg intraperitoneally) (n = 8), serotonin (20 mg/kg subcutaneously) (n = 8), or the vehicle only (n = 14) for 5 months. At 20 weeks, echocardiography demonstrated the presence of aortic regurgitation (AR) and/or mitral regurgitation (MR) in serotonin (86% AR, P = 0.0001; 57% MR, P = 0.006) and in pergolide animals (67% AR, P = 0.003; 67% MR, P = 0.003) compared with none in placebo. Pulmonary regurgitation (PR) and tricuspid regurgitation (TR) were found in the serotonin (71% PR, P = 0.19; 100% TR, P = 0.06 vs. placebo), pergolide (100% PR, P = 0.014; 83% TR, P = 0.35 vs. placebo), and placebo groups (36% PR; 57% TR). Tricuspid regurgitant area ratio (jet/atrium), however, was more severe in the serotonin [median 26.5 (range 17-42)%; P = 0.02] and pergolide animals [32 (17-39) %; P = 0.03] compared with placebo [12.5 (5-33)%]. We found a good correlation between valvular regurgitation and histologically assessed valvular thickness. Histological examination revealed the presence of diffusely thickened and myxoid aortic, mitral, and tricuspid valves in serotonin and pergolide animals as seen in VHD. CONCLUSION: We demonstrated, for the first time, that long-term pergolide administration led to VHD in rats. This small animal model will permit further in vivo investigation of drug-induced valvulopathies.

Intramyocardial Implantation of bone marrow-derived stem cells enhances perfusion in chronic myocardial infarction: dependency on initial perfusion depth and follow-up assessed by gated pinhole SPECT.

UNLABELLED: Cell therapy-induced changes in the perfusion of areas of myocardial infarction (MI) remain unclear. This study investigated whether an original pinhole SPECT technique could be applied to a rat MI model to analyze local improvement in myocardial perfusion relating to engraftment sites of bone marrow-derived stem cells (BMSCs). METHODS: Four-month-old MI rats were either untreated (n = 8) or treated (n = 10) by intramyocardial injection of (111)In-labeled BMSCs. Early distribution of (111)In-BMSCs within the MI target was evidenced by dual (111)In/(99m)Tc pinhole SPECT 48 h later. Myocardial perfusion was serially monitored by (99m)Tc-sestamibi pinhole gated SPECT up to 3 mo after transplantation. RESULTS: Forty-eight hours after transplantation, (111)In-BMSCs were observed in all treated rats and in 18 of their 32 underperfused MI segments (<70% sestamibi uptake before transplantation). During the subsequent 3-mo follow-up, the perfusion of MI segments worsened in untreated rats (absolute change in sestamibi uptake, -3% +/- 3%; P < 0.05) but improved in treated rats (+4% +/- 7%; P < 0.05). This perfusion improvement was unrelated to the initial detection of (111)In-BMSCs (+2% +/- 6% in segments with (111)In-BMSCs vs. +5% +/- 7% in those without; not statistically significant) but was strongly associated with less severe perfusion defects before transplantation (+6% +/- 6% in segments with 60%-70% sestamibi uptake [n = 19] vs. -1% +/- 6% in those with <60% uptake [n = 13]; P = 0.003). CONCLUSION: When BMSCs are injected within chronic MI, perfusion enhancement predominates in the MI areas showing a high enough residual perfusion before treatment but not in those of the initial cell engraftment, giving evidence of dependency on the perfusion and metabolic environment at implantation sites.