负荷^201Tl／静息^99Tc^m-MIBI双核素心肌断层显像鉴别活性心肌的应用

目的探讨多巴酚丁胺负荷-再分布^201Tl／静息^99Tc^m-MIBI双核素心肌断层显像法鉴别活性心肌的临床应用。方法102例临床怀疑有冠心病的病人进行了多巴酚丁胺负荷-再分布^201Tl／静息^99Tc^m-MIBI同时心肌断层显像，原始图像经三维重建后由两位以上有经验的核医学医师进行图像分析。断层显像后2周内102例病人全部进行了冠状动脉造影。结果（1）102例病人行冠状动脉造影均发现冠状动脉狭窄，其中单支病变48例，两支病变33例，三支病变21例。（2）20例负荷。^201Tl图像和静息^99Tc^m-MIBI图像放射性缺损，再注射^201Tl图像发现放射性填充，提示冬眠心肌存在；41例负荷^201Tl图像放射性稀疏缺损，静息^99Tc^m-MIBI图像和再分布^201Tl图像发现放射性填充，考虑为缺血心肌；以上两种心肌均为活性心肌。（3）35例负荷^201Tl和静息^99Tc^m-MIBI图像均发现放射性缺损，而再注射^201Tl图像未发现放射性填充考虑为梗死心肌即无活力心肌。（4）6例负荷^201Tl及再分布^201Tl图像和静息^99Tc^m-MIBI图像均未发现放射性稀疏，为假阴性。结论多巴酚丁胺负荷-再分布^201T1／静息^99Tc^m-MIBI双核素心肌断层显像法是一种有效、无创的鉴别活性心肌的方法。     

Toxicity of thallium on isolated rat liver mitochondria: The role of oxidative stress and MPT pore opening

Thallium(I) is a highly toxic heavy metal; however, up to now, its mechanisms are poorly understood. The authors' previous studies showed that this compound could induce reactive oxygen species (ROS) formation, reduced glutathione (GSH) oxidation, membrane lipid peroxidation, and mitochondrial membrane potential (MMP) collapse in isolated rat hepatocyte. Because the liver is the storage site of thallium, it seems that the liver mitochondria are one of the important targets for hepatotoxicity. In this investigation, the effects of thallium on mitochondria were studied to investigate its mechanisms of toxicity. Mitochondria were isolated from rat liver and incubated with different concentrations of thallium (25–200 µM). Thallium(I)‐treated mitochondria showed a marked elevation in oxidative stress parameters accompanied by MMP collapse when compared with the control group. These results showed that different concentrations of thallium (25–200 µM) induced a significant (P < 0.05) increase in mitochondrial ROS formation, ATP depletion, GSH oxidation, mitochondrial outer membrane rupture, mitochondrial swelling, MMP collapse, and cytochrome c release. In general, these data strongly supported that the thallium(I)‐induced liver toxicity is a result of the disruptive effect of this metal on the mitochondrial respiratory complexes (I, II, and IV), which are the obvious causes of metal‐induced ROS formation and ATP depletion. The latter two events, in turn, trigger cell death signaling via opening of mitochondrial permeability transition pore and cytochrome c expulsion. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 232–241, 2015.     

Detection of coronary artery disease by vasodilator thallium imaging of the heart with amyl nitrite inhalation: a pilot study.

Thallium imaging of the heart using dipyridamole-induced coronary arteriolar vasodilation has proven to be an effective means of detecting significant coronary stenosis. However, intravenous dipyridamole has not yet been made available for general use. We therefore examined the feasibility of substituting amyl nitrite inhalation as an arteriolar vasodilator prior to thallium imaging. Seventeen patients, all of whom had catheterization-proven coronary stenosis, inhaled amyl nitrite for 2-5 min. Thallium was injected after 45-60 s of inhalation. Completion of inhalation was followed immediately by planar imaging. Of 6 patients who inhaled amyl nitrite for at least 4 min, 5 had moderate or severe image defects on immediate scans which completely resolved on delayed scans. Only 3 of 11 who inhaled amyl nitrite for 2 min or less prior to scanning had similarly positive tests. Overall sensitivity for significant stenosis was 8 of 17 (47%). Inhalation was well tolerated with only one episode of angina and hypotension. We conclude that amyl nitrite inhalation for at least 4 min may offer an effective and readily available alternative to intravenous dipyridamole for vasodilator imaging of the heart.     

Novel insights into the pathophysiology of different forms of stress testing

Background

The impact of different forms of cardiac stress testing (exercise versus pharmacological stress testing) on cardiac wall stress and myocardial ischemia is incompletely understood.

Methods

In a prospective study, 331 consecutive patients with suspected myocardial ischemia referred for nuclear perfusion imaging were enrolled: 266 underwent exercise (bicycle) stress testing and 65 adenosine stress testing. Levels of B-type natriuretic peptide (BNP) measured before and 1 min after stress testing, ischemic ECG changes, and typical angina symptoms were used to compare the 2 testing modalities.

Results

Cardiac wall stress as quantified by changes in BNP levels significantly increased in the exercise stress group, but not in the adenosine group (increase in BNP levels 22 pg/ml (IQR 6–46) versus − 3 pg/ml (IQR − 3 to 28); p < 0.001). In the bicycle exercise stress group, patients with reversible defects on nuclear perfusion imaging more often had angina symptoms (25% vs. 9%, p = 0.0001) and ischemic ECG changes (33% vs. 12%, p = 0.0001) during the stress test, and a greater increase in BNP levels (28 (IQR 11–58) versus 16 (IQR 3–34) pg/ml, p = 0.001) compared to those without reversible defects. Those differences between patients with and without reversible defects were not observed with the adenosine protocol (p-values all > 0.05).

Conclusion

Exercise stress testing but not adenosine stress results in an increase of cardiac wall stress, angina symptoms and ECG changes. The absence of these surrogates of myocardial ischemia suggests that adenosine stress does not induce acute myocardial ischemia, but rather displays relative perfusion differences.     

Stress myocardial imaging in patients with mitral valve prolapse: Evidence of a perfusion abnormality

Twenty-four patients with mitral valve prolapse underwent cardiac catheterization, exercise testing, and exercise ²⁰¹thallium scintigraphy. Of 10 patients with coronary artery disease, six had abnormal scintigrams. Two of these six had exercise-induced reversible defects, two had defects that persisted during redistribution, and two had both reversible and persistent defects. Of 14 patients with normal coronary arteries, five had negative scintigrams. Of the remaining nine patients, two had exercise-induced defects, and seven (50%) had defects involving the inferior or posterior wall that persisted during redistribution. Possible mechanisms for this latter finding are discussed. In contrast to previous reports, exercise ²⁰¹thallium scintigraphy was not entirely successful in identifying patients with coronary artery disease in our patients with mitral valve prolapse.     

Exercise 201thallium myocardial scans in patients with disease limited to the secondary branches of the left coronary system.

Coronary disease (greater than or equal to 50% narrowing) confined to only the diagonal branch of the left anterior descending artery or to the marginal branch of the left circumflex artery, or both, is uncommon. Only 19 patients with disease as defined above were identified in a group of 1000 consecutive patients with an angiographic diagnosis of coronary heart disease. All 19 patients were studied because of angina pectoris and all underwent stress myocardial perfusion scintigraphy with 201Tl (201thallium) during maximal treadmill exercise testing (exercise electrocardiogram: E/ECG). Ten patients (52%) had positive E/ECG's; seven patients (36%) had positive 201Tl and 13 patients (68%) had one or both tests positive. In 12 patients, the diseased branch was small, i.e. it supplied a comparatively small portion of myocardium, and in seven patients it was determined to be large. The 201Tl test results were positive in four out of seven patients (57%) with large diseased branches, as compared with three out of 12 (25%) with small diseased branches (p: NS). Also, three out of seven patients (42%) with large diseased branches had positive E/ECG's as compared with seven out of 12 patients (58%) with small diseased branches (p: NS). Patients with branch disease may present with typical angina pectoris, however, they are rare and thus not likely to account for the majority of false-negative 201Tl test results among symptomatic patients with CHD. Approximately one-third of the patients with branch disease have positive 201Tl test results, one-half have positive E/ECG's, and in two-thirds, one or both tests are positive.     

Dipyridamole thallium imaging may not be a reliable screening test for coronary artery disease in patients undergoing vascular surgery

Dipyridamole thallium imaging has been proposed for cardiac risk stratification in patients undergoing peripheral vascular surgery. The purpose of this study was to define the benefit of this investigation in routine preoperative evaluation of these patients. The outcome of 86 patients undergoing vascular surgery procedures was examined in light of preoperative clinical assessment and dipyridamole SPECT thallium imaging (DST). Fifty-one patients (59%) were considered at high risk on clinical grounds, and 22 patients (26%) had perfusion defects. Ten patients suffered a perioperative coronary event, including unstable angina, myocardial infarction, or cardiac death. Seven of the patients with such events were among the 51 clinically high-risk subjects (14%). Three perioperative events occurred in the group of 19 patients with positive DST images who underwent surgery (16%), but the DST test failed to identify 7 patients who suffered coronary events. The frequency of abnormal thallium imaging was similar to the prevalence of angiographically significant coronary disease reported previously at this center, but considerably less than the rate of abnormal thallium imaging in past studies of vascular surgery patients. The application of the test to a low to moderate risk population is probably responsible for its lower predictive accuracy for coronary events. DST is not an ideal routine noninvasive technique for risk stratification in patients undergoing vascular surgery.     

Prediction of single versus multivessel disease following myocardial infarction using 201thallium scintigraphy and electrocardiographic stress testing

We evaluated 50 patients who suffered a single myocardial infarction with graded electrocardiographic stress testing, 201thallium myocardial perfusion imaging and coronary angiography to assess the role of noninvasive indices as predictors of single versus multivessel coronary artery disease. Multivessel involvement was defined angiographically as the presence of two or more major coronary arteries with at least a 70% intraluminal diameter narrowing. Multivessel disease was defined scintigraphically as the presence of stress and/or redistribution perfusion defects in the distribution of more than one coronary artery. The results of stress electrocardiography were not useful in differentiating patients with single (9/16 positive) versus multivessel (22/34 positive) disease. The degree of exercise-induced ST-segment depression was also not helpful. Stress 201thallium imaging did offer limited additional information with correct predictions of multivessel disease in 21 of 26 patients. Predictions of single-vessel disease were accurate in 11 of 24 patients. Eleven of these 13 incorrect predictions of single-vessel disease were due to the relative insensitivity of the thallium stress image to perceive defect in the anterior wall when the left anterior descending artery had significant obstruction at catheterization. Further refinements of stress perfusion imaging are needed before this method can be used to reliably separate patients with single and multivessel disease after myocardial infarction.     

Genetic toxicology of thallium: a review

This review summarizes the current knowledge about the general toxicity of thallium (Tl) and its environmental sources, with special emphasis placed on its potential mutagenic, genotoxic, and cytotoxic effects on both eukaryotic and prokaryotic cells. Tl is a nonessential heavy metal that poses environmental and occupational threats as well as therapeutic hazards because of its use in medicine. It is found in two oxidation states, thallous (Tl⁺) and thallic (Tl³⁺), both of which are considered highly toxic to human beings and domestic and wild organisms. Many Tl compounds are colorless, odorless and tasteless, and these characteristics, combined with the high toxicity of TI compounds, have led to their use as poisons. Because of its similarity to potassium ions (K⁺), plants and mammals readily absorb Tl⁺ through the skin and digestive and respiratory systems. In mammals, it can cross the placental, hematoencephalic, and gonadal barriers. Inside cells, Tl can accumulate and interfere with the metabolism of potassium and other metal cations, mimicking or inhibiting their action. The effects of Tl on genetic material have not yet been thoroughly explored, and few existing studies have focused exclusively on Tl⁺. Both in vivo and in vitro studies indicate that Tl compounds can have a weak mutagenic effect, but no definitive effect on the induction of primary DNA damage or chromosomal damage has been shown. These studies have demonstrated that Tl compounds are highly toxic and lead to changes in cell-cycle progression.     

Novel KCNQ2 channel activators discovered using fluorescence-based and automated patch-clamp-based high-throughput screening techniques

Aim:

To establish an improved, high-throughput screening techniques for identifying novel KCNQ2 channel activators.

Methods:

KCNQ2 channels were stably expressed in CHO cells (KCNQ2 cells). Thallium flux assay was used for primary screening, and 384-well automated patch-clamp IonWorks Barracuda was used for hit validation. Two validated activators were characterized using a conventional patch-clamp recording technique.

Results:

From a collection of 80 000 compounds, the primary screening revealed a total of 565 compounds that potentiated the fluorescence signals in thallium flux assay by more than 150%. When the 565 hits were examined in IonWorks Barracuda, 38 compounds significantly enhanced the outward currents recorded in KCNQ2 cells, and were confirmed as KCNQ2 activators. In the conventional patch-clamp recordings, two validated activators ZG1732 and ZG2083 enhanced KCNQ2 currents with EC50 values of 1.04±0.18 μmol/L and 1.37±0.06 μmol/L, respectively.

Conclusion:

The combination of thallium flux assay and IonWorks Barracuda assay is an efficient high-throughput screening (HTS) route for discovering KCNQ2 activators.