Three-Dimensional Transthoracic Echocardiography for Semiautomated Analysis of the Tricuspid Annulus: Validation and Normal Values.

BACKGROUND: The expansion of tricuspid valve (TV) interventions has underscored the need for accurate and reproducible three-dimensional (3D) transthoracic echocardiographic (TTE) tools for evaluating the tricuspid annulus and for 3D normal values of this structure. The aims of this study were to develop new semi-automated software for 3D TTE analysis of the tricuspid annulus, compare its accuracy and reproducibility against those of multiplanar reconstruction (MPR) reference, and determine normative values. METHODS: Three-dimensional TTE images of 113 patients with variable degrees of tricuspid regurgitation were analyzed using the new semiautomated software and conventional MPR methodology (as the reference standard), each by three independent readers. For each measured parameter, intertechnique agreement was assessed using linear regression and Bland-Altman analyses, and interreader variability using intraclass correlation coefficients and coefficients of variation. Additionally, 3D TTE data sets of 789 subjects from the WASE (World Alliance Societies of Echocardiography) study were analyzed using this new software to determine normal values for each tricuspid annular (TA) parameter. RESULTS: Semiautomated measurements showed excellent agreement with MPR reference values for all TA measurements: high correlations (all r values >0.8) and minimal biases. All measurements were more reproducible than with MPR: higher intraclass correlation coefficients (0.94-0.96 vs 0.82-0.90) and lower coefficients of variation (5%-12% vs 8%-18%). Sex- and age-related differences were identified in 3D normal values of most TA parameters. Dynamic analysis showed that TA parameters vary throughout the cardiac cycle, reaching minimal values at end-systole and maximum values in late diastole. CONCLUSIONS: Novel software for semiautomated analysis of TA geometry and dynamics provides accurate and reproducible measurements. Normal values of TA dimensions, parsed by sex and age, are reported.

Evaluating Long-Term Outcomes in STEMI Patients with New Left Bundle Branch Block: The Impact of Modifiable Risk Factors.

Background/Objectives: Coronary artery disease, a leading global cause of death, highlights the essential need for early detection and management of modifiable cardiovascular risk factors to prevent further coronary events. Methods: This study, conducted at a major tertiary academic PCI-capable hospital in Romania from 1 January 2011 to 31 December 2013, prospectively analyzed 387 myocardial infarction with ST-segment elevation (STEMI) patients to assess the long-term management of modifiable risk factors. This study particularly focused on patients with new-onset left bundle branch block (LBBB) and compared them with a matched control group without LBBB. Results: During median follow-up periods of 9.6 years for LBBB patients and 9.2 years for those without LBBB, it was found that smoking, obesity, and dyslipidemia were prevalent in 73.80%, 71.42%, and 71.42% of the LBBB group, respectively, at baseline. Significant reductions in smoking were observed in both groups, with the LBBB group's smoking rates decreasing significantly to 61.90% (p = 0.034). Patients with LBBB more frequently achieved low-density lipoprotein cholesterol (LDLc) target levels during the follow-up period (from 71.42% to 59.52%; p = 0.026) compared to the control group (from 66.67% to 71.42%; p = 0.046). Prescription rates for dual antiplatelet therapy (DAPT), angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs), beta-blockers, and statins were initially high but then decreased by the follow-up. Statin use was reduced from 97.62% to 69.04% (p = 0.036) in the LBBB group and from 100% to 61.90% (p = 0.028) in the non-LBBB group. This study also highlighted moderate correlations between obesity (r = 0.627, p = 0.040) and subsequent coronary reperfusion in the LBBB group, while dyslipidemia and smoking showed very strong positive correlations across both groups (dyslipidemia: r = 0.903, p = 0.019 for LBBB; r = 0.503, p = 0.048 for non-LBBB; smoking: r = 0.888, p = 0.035 for LBBB; r = 0.517, p = 0.010 for non-LBBB). Conclusions: These findings underscore the crucial need for targeted management of modifiable risk factors, particularly focusing on dyslipidemia and smoking cessation, to improve subsequent coronary reperfusion outcomes post-STEMI, especially in patients with complicating factors like LBBB.

Timing and Patient Position During Cuff Blood Pressure Measurement Affect Myocardial Work Parameters Measured by Echocardiography.

BACKGROUND: Although cuff blood pressure measurement is a critical parameter to calculate myocardial work noninvasively, there is no recommendation about when and how to measure it. Accordingly, we sought to evaluate the effects of the timing during the echo study and the patient's position on the scanning bed during the cuff blood pressure measurement on myocardial work parameter calculations. METHODS: One hundred one consecutive patients (44 women, 66 ± 14 years) undergoing clinically indicated echocardiography were prospectively enrolled. During the echocardiographic study, we measured the cuff blood pressure 4 times, using a fully automatic digital blood pressure monitor applied to the right and left arm in the same position throughout the study: BP1, before the start of the echo study, with the patient lying in the supine position; BP2, after positioning the patients on their left side to start the echo study; BP3, at the time of the acquisition of the 3 apical views (4- and 2-chamber and long-axis) used to measured left ventricular global longitudinal strain; and BP4, at the end of the echo study with the patient again in the supine position. RESULTS: Systolic blood pressureat BP1 was 147 ± 21 mm Hg. Between BP1 and BP2, it dropped by 17 ± 9 mm Hg (P < .05). Systolic blood pressure at BP3 was significantly lower than BP2 (130 ± 20 mm Hg vs 122 ± 18 mm Hg, P < .05), and at BP4 was significantly lower than at BP1 (-9 ± 13 mm Hg, P < .05). The average global longitudinal strain was -16% ± 3%. Accordingly, the global work index was 1,929 ± 441 mm Hg% at BP1, dropped to 1,717 ± 421 at BP2, decreased to 1,602 ± 351 mm Hg% at BP3, and increased to 1,815 ± 386 mm Hg% at BP4 (P < .001). CONCLUSIONS: The timing during the echocardiography study and the patient's position on the scanning bed are critical determinants of the measured cuff systolic blood pressure and the resulting values of myocardial work parameters.

Peak atrial longitudinal strain and risk stratification in moderate and severe aortic stenosis.

AIMS: We sought to investigate the association of left atrial strain with the outcome in a large cohort of patients with at least moderate aortic stenosis (AS). METHODS AND RESULTS: We analysed 467 patients (mean age 80.6 ± 8.2 years; 51% men) with at least moderate AS and sinus rhythm. The primary study endpoint was the composite of all-cause mortality and hospitalizations for heart failure. After a median follow-up of 19.2 (inter-quartile range 12.5-24.4) months, 96 events occurred. Using the receiver operator characteristic curve analysis, the cut-off value of peak atrial longitudinal strain (PALS) more strongly associated with outcome was <16% {area under the curve (AUC) 0.70 [95% confidence interval (CI): 0.63-0.78], P < 0.001}. The Kaplan-Meier curves demonstrated a higher rate of events for patients with PALS < 16% (log-rank P < 0.001). On multivariable analysis, PALS [adjusted HR (aHR) 0.95 (95% CI 0.91-0.99), P = 0.017] and age were the only variables independently associated with the combined endpoint. PALS provided incremental prognostic value over left ventricular (LV) global longitudinal strain, LV ejection fraction, and right ventricular function. Subgroup analysis revealed that impaired PALS was also independently associated with outcome in the subgroups of paucisymptomatic patients [aHR 0.98 (95% CI 0.97-0.98), P = 0.048], moderate AS [aHR 0.92, (95% CI 0.86-0.98), P = 0.016], and low-flow AS [aHR 0.90 (95% CI 0.83-0.98), P = 0.020]. CONCLUSION: In our patients with at least moderate AS, PALS was independently associated with outcome. In asymptomatic patients, PALS could be a potential marker of sub-clinical damage, leading to better risk stratification and, potentially, earlier treatment.

Cardiac and Renal Fibrosis, the Silent Killer in the Cardiovascular Continuum: An Up-to-Date.

Cardiovascular disease (CVD) and chronic kidney disease (CKD) often coexist and have a major impact on patient prognosis. Organ fibrosis plays a significant role in the pathogenesis of cardio-renal syndrome (CRS), explaining the high incidence of heart failure and sudden cardiac death in these patients. Various mediators and mechanisms have been proposed as contributors to the alteration of fibroblasts and collagen turnover, varying from hemodynamic changes to the activation of the renin-angiotensin system, involvement of FGF 23, and Klotho protein or collagen deposition. A better understanding of all the mechanisms involved has prompted the search for alternative therapeutic targets, such as novel inhibitors of the renin-angiotensin-aldosterone system (RAAS), serelaxin, and neutralizing interleukin-11 (IL-11) antibodies. This review focuses on the molecular mechanisms of cardiac and renal fibrosis in the CKD and heart failure (HF) population and highlights the therapeutic alternatives designed to target the responsible pathways.

Clinical Impact of the Volumetric Quantification of Ventricular Secondary Mitral Regurgitation by Three-Dimensional Echocardiography.

BACKGROUND: The assessment of ventricular secondary mitral regurgitation (v-SMR) severity through effective regurgitant orifice area (EROA) and regurgitant volume (RegVol) calculations using the proximal isovelocity surface area (PISA) method and the two-dimensional echocardiography volumetric method (2DEVM) is prone to underestimation. Accordingly, we sought to investigate the accuracy of the three-dimensional echocardiography volumetric method (3DEVM) and its association with outcomes in v-SMR patients. METHODS: We included 229 patients (70 ± 13 years, 74% men) with v-SMR. We compared EROA and RegVol calculated by the 3DEVM, 2DEVM, and PISA methods. The end point was a composite of heart failure hospitalization and death for any cause. RESULTS: After a mean follow-up of 20 ±11 months, 98 patients (43%) reached the end point. Regurgitant volume and EROA calculated by 3DEVM were larger than those calculated by 2DEVM and PISA. Using receiver operating characteristic curve analysis, both EROA (area under the curve, 0.75; 95% CI, 0.68-0.81; P = .008) and RegVol (AUC, 0.75; 95% CI, 0.68-0.82; P = .02) measured by 3DEVM showed the highest association with the outcome at 2 years compared to PISA and 2DEVM (P < .05 for all). Kaplan-Meier analysis demonstrated a significantly higher rate of events in patients with EROA ≥ 0.3 cm2 (cumulative survival at 2 years: 28% ± 7% vs 32% ± 10% vs 30% ± 11%) and RegVol ≥ 45 mL (cumulative survival at 2 years: 21% ± 7% vs 24% ± 13% vs 22% ± 10%) by 3DEVM compared to those by PISA and 2DEVM, respectively. In Cox multivariable analysis, 3DEVM EROA remained independently associated with the end point (hazard ratio, 1.02, 95% CI, 1.00-1.05; P = .02). The model including EROA by 3DEVM provided significant incremental value to predict the combined end point compared to those using 2DEVM (net reclassification index = 0.51, P = .003; integrated discrimination index = 0.04, P = .014) and PISA (net reclassification index = 0.80, P < .001; integrated discrimination index = 0.06, P < .001). CONCLUSIONS: Effective regurgitant orifice area and RegVol calculated by 3DEVM were independently associated with the end point, improving the risk stratification of patients with v-SMR compared to the 2DEVM and PISA methods.

Patient-Related Factors Predicting Stent Thrombosis in Percutaneous Coronary Interventions.

Over the past four decades, percutaneous coronary intervention (PCI) safety and efficacy have significantly improved, particularly with the advent of the drug-eluting stent (DES). First-generation DESs reduced in-stent restenosis rates and targeted lesion revascularization; however, safety issues emerged, due to high incidences of stent thrombosis (ST) linked to death, myocardial infarction, and repeat revascularization. Second-generation DESs were developed to overcome these issues, reducing late-thrombotic-event risk while maintaining anti-restenosis efficacy. Nevertheless, ST still occurs with second-generation DES use. Stent thrombosis etiology is multifaceted, encompassing lesion-, patient-, procedural-, and stent-related factors. Overall, most early-stent-thrombosis cases are linked to procedural and patient-related aspects. Factors like premature discontinuation of dual antiplatelet therapy, resistance to clopidogrel, smoking, diabetes mellitus, malignancy, reduced ejection fraction or undertaking coronary angioplasty for an acute coronary syndrome can increase the risk of stent thrombosis. The aim of this study is to assess patient-related factors that potentially heighten the risk of stent thrombosis, with the objective of pinpointing and addressing modifiable contributors to this risk. By focusing on both patient- and procedure-related factors, a multifaceted approach to coronary revascularization can help minimize complications and maximize long-term benefits in managing ST.

Multi-tracer and multiparametric PET imaging to detect the IDH mutation in glioma: a preclinical translational in vitro, in vivo, and ex vivo study.

BACKGROUND: This translational study explores multi-tracer PET imaging for the non-invasive detection of the IDH1 mutation which is a positive prognostic factor in glioma. METHODS: U87 human high-grade glioma (HGG) isogenic cell lines with or without the IDH1 mutation (CRISP/Cas9 method) were stereotactically grafted into rat brains, and examined, in vitro, in vivo and ex vivo. PET imaging sessions, with radiotracers specific for glycolytic metabolism ([18F]FDG), amino acid metabolism ([18F]FDopa), and inflammation ([18F]DPA-714), were performed sequentially during 3-4 days. The in vitro radiotracer uptake was expressed as percent per million cells. For each radiotracer examined in vivo, static analyses included the maximal and mean tumor-to-background ratio (TBRmax and TBRmean) and metabolic tumor volume (MTV). Dynamic analyses included the distribution volume ratio (DVR) and the relative residence time (RRT) extracted from a reference Logan model. Ex vivo analyses consisted of immunological analyses. RESULTS: In vitro, IDH1+ cells (i.e. cells expressing the IDH1 mutation) showed lower levels of [18F]DPA-714 uptake compared to IDH1- cells (p < 0.01). These results were confirmed in vivo with lower [18F]DPA-714 uptake in IDH+ tumors (3.90 versus 5.52 for TBRmax, p = 0.03). Different values of [18F]DPA-714 and [18F] FDopa RRT (respectively 11.07 versus 22.33 and 2.69 versus - 1.81 for IDH+ and IDH- tumors, p < 0.02) were also observed between the two types of tumors. RRT [18F]DPA-714 provided the best diagnostic performance to discriminate between the two cell lines (AUC of 100%, p < 0.01). Immuno-histological analyses revealed lower expression of Iba-1 and TSPO antibodies in IDH1+ tumors. CONCLUSIONS: [18F]DPA-714 and [18F] FDopa both correlate with the presence of the IDH1 mutation in HGG. These radiotracers are therefore good candidates for translational studies investigating their clinical applications in patients.

Role of Diphosphonates Bone Scintigraphy in Correlation with Biomarkers for a Personalized Approach to ATTR Cardiac Amyloidosis in North-Eastern Romania.

Transthyretin cardiac amyloidosis (ATTR) is a rare cardiac protein deposition disease characterized by progressive thickening of both ventricles, the inter-atrial-ventricular septum and the atrioventricular valves. The gold standard method for diagnosing this rare pathology is endomyocardial biopsy. If this method cannot be used, the alternative is a mixture of clinical and paraclinical tests. Over the course of five years, we examined 58 patients suspected of cardiac amyloidosis based on electrocardiography and ultrasonography criteria, who had been sent for bone scintigraphy in order to determine the presence of ATTR cardiac amyloidosis. However, the final diagnosis was set by correlating the bone scan with genetic testing, free light chain dosage or soft tissue biopsy. Based on the final diagnosis we analyzed the patients' predominant biomarkers in order to determine a possible correlation between them. This analysis is designed to help the general practitioner set a possible cardiac amyloidosis diagnosis.

Triglyceride-Rich Lipoproteins and Their Remnants as Silent Promoters of Atherosclerotic Cardiovascular Disease and Other Metabolic Disorders: A Review.

While targeting elevated serum levels of low-density lipoprotein cholesterol has been the mainstay of atherosclerosis prevention and treatment for decades, the evidence regarding the atherogenic role of hypertriglyceridemia is still controversial. Various epidemiological population-based studies on statin-treated subjects nominated triglycerides, triglyceride-rich lipoproteins (namely, chylomicrons and very-low-density lipoprotein particles), and their remnants as major determinants of the substantial residual cardiovascular risk. With the triglyceride-glucose index and triglyceride to high-density lipoprotein ratio emerging as surrogate indicators of peripheral artery disease and atherosclerotic cerebrovascular disease, one can conclude that further research addressing the intricate relationship between triglycerides and atherosclerosis is warranted. Therefore, this review aims to provide insight into the current clinical and epidemiological state of knowledge on the relationship between triglycerides and atherosclerotic cardiovascular disease. It also intends to highlight the connection between triglycerides and other metabolic disorders, including diabetes mellitus, and the potential benefits of triglyceride-lowering agents on cardiovascular outcomes and all-cause mortality.

Consensus and Controversy in the Debate over the Biphasic Impact of Alcohol Consumption on the Cardiovascular System.

In the past few decades, research has focused on the importance of addressing modifiable risk factors as a means of lowering the risk of cardiovascular disease (CVD), which represents the worldwide leading cause of death. For quite a long time, it has been considered that ethanol intake has a biphasic impact on the cardiovascular system, mainly depending on the drinking pattern, amount of consumption, and type of alcoholic beverage. Multiple case-control studies and meta-analyses reported the existence of a "U-type" or "J-shaped" relationship between alcohol and CVD, as well as mortality, indicating that low to moderate alcohol consumption decreases the number of adverse cardiovascular events and deaths compared to abstinence, while excessive alcohol use has unquestionably deleterious effects on the circulatory system. However, beginning in the early 2000s, the cardioprotective effects of low doses of alcohol were abnegated by the results of large epidemiological studies. Therefore, this narrative review aims to reiterate the association of alcohol use with cardiac arrhythmias, dilated cardiomyopathy, arterial hypertension, atherosclerotic vascular disease, and type 2 diabetes mellitus, highlighting literature disagreements over the risk and benefits of low to moderate drinking on the cardiovascular system.

In vivo characterization of physiological and metabolic changes related to isocitrate dehydrogenase 1 mutation expcression by multiparametric MRI and MRS in a rat model with orthotopically grafted human-derived glioblastoma cell lines.

The physiological mechanism induced by the isocitrate dehydrogenase 1 (IDH1) mutation, associated with better treatment response in gliomas, remains unknown. The aim of this preclinical study was to characterize the IDH1 mutation through in vivo multiparametric MRI and MRS. Multiparametric MRI, including the measurement of blood flow, vascularity, oxygenation, permeability, and in vivo MRS, was performed on a 4.7 T animal MRI system in rat brains grafted with human-derived glioblastoma U87 cell lines expressing or not the IDH1 mutation by the CRISPR/Cas9 method, and secondarily characterized with additional ex vivo HR-MAS and histological analyses. In univariate analyses, compared with IDH1-, IDH1+ tumors exhibited higher vascular density (p < 0.01) and better perfusion (p = 0.02 for cerebral blood flow), but lower vessel permeability (p < 0.01 for time to peak (TTP), p = 0.04 for contrast enhancement) and decreased T1 map values (p = 0.02). Using linear discriminant analysis, vascular density and TTP values were found to be independent MRI parameters for characterizing the IDH1 mutation (p < 0.01). In vivo MRS and ex vivo HR-MAS analysis showed lower metabolites of tumor aggressiveness for IDH1+ tumors (p < 0.01). Overall, the IDH1 mutation exhibited a higher vascularity on MRI, a lower permeability, and a less aggressive metabolic profile. These MRI features may prove helpful to better pinpoint the physiological mechanisms induced by this mutation.

The Importance of Multimodality Imaging in the Diagnosis and Management of Patients with Infiltrative Cardiomyopathies: An Update.

Infiltrative cardiomyopathies (ICMs) comprise a broad spectrum of inherited and acquired conditions (mainly amyloidosis, sarcoidosis, and hemochromatosis), where the progressive buildup of abnormal substances within the myocardium results in left ventricular hypertrophy and manifests as restrictive physiology. Noninvasive multimodality imaging has gradually eliminated endomyocardial biopsy from the diagnostic workup of infiltrative cardiac deposition diseases. However, even with modern imaging techniques' widespread availability, these pathologies persist in being largely under- or misdiagnosed. Considering the advent of novel, revolutionary pharmacotherapies for cardiac amyloidosis, the archetypal example of ICM, a standardized diagnostic approach is warranted. Therefore, this review aims to emphasize the importance of contemporary cardiac imaging in identifying specific ICM and improving outcomes via the prompt initiation of a targeted treatment.

The Advantages of New Multimodality Imaging in Choosing the Optimal Management Strategy for Patients with Hypertrophic Cardiomyopathy.

In recent years, significant advances have been made in the diagnosis and therapeutic management of hypertrophic cardiomyopathy (HCM) patients, which has led to an important improvement in their longevity and quality of life. The use of multimodality imaging has an essential role in the diagnosis, assessing the regional distribution and severity of the disease, with important prognostic implications. At the same time, imaging contributes to the identification of optimal treatment for patients with hypertrophic cardiomyopathy, whether it is pharmaceutical, interventional or surgical treatment. Novel pharmacotherapies (like myosin inhibitors), minimally invasive procedures (such as transcatheter mitral valve repair, high-intensity focused ultrasound or radiofrequency ablation) and gene-directed approaches, may soon become alternatives for HCM patients. However, there are only few data on the early diagnosis of patients with HCM, in order to initiate treatment as soon as possible, to reduce the risk of sudden cardiac death (SCD). The aim of our review is to highlight the advantages of contemporary imaging in choosing the optimal management strategies for HCM patients, considering the novel therapies which are currently applied or studied for these patients.

A 1-week extension of a ketogenic diet provides a further decrease in myocardial 18F-FDG uptake and a high detectability of myocarditis with FDG-PET.

BACKGROUND: Short periods of fasting and/or low-carbohydrate diet have been proven beneficial for decreasing the myocardial uptake of 18F-fluorodeoxyglucose (18F-FDG) and enhancing the detection of inflammatory heart diseases by 18F-FDG positron emission tomography (PET). This study aimed at determining whether this benefit is increased when a low-carbohydrate ketogenic diet is prolonged up to 7 days. METHODS: Wistar rats underwent serial 18F-FDG-PET imaging after an 18-hour fasting period and after 2, 4 and 7 days of a ketogenic diet (3% carbohydrate) and they were compared to rats submitted to the same protocol but with normal diet (44% carbohydrate). The 18F-FDG-PET/ketogenic protocol was also applied in rats with immune myocarditis (injection of porcine cardiac myosin). RESULTS: The 7-day ketogenic diet was associated with (1) a sustained increase in circulating ketone bodies at an equivalent level to that reached after 18-hour fasting, (2) a gradual decrease in 18F-FDG uptake within normal myocardium reaching a lower level compared to fasting at the 7th day (myocardium-to-blood ratios: 1.68 ± 1.02 vs 3.25 ± 1.40, P < .05) and (3) a high 18F-FDG-PET detectability of myocarditis areas. CONCLUSION: One-week extension of a ketogenic diet provides a further decrease in the 18F-FDG uptake of normal myocardium and a high detectability of inflammatory areas.

What can hide behind an "idiopathic" dilated cardiomyopathy?

Myocarditis is an infectious-inflammatory disease with viral infections being one of the most common infectious cause. When it is superimposed to an individual genetic background, myocarditis may progress into a chronic heart muscle disorder, most often dilated cardiomyopathy (DCM), with a natural history similar to classic forms of genetic or idiopathic dilated cardiomyopathies. We present the case of a 30-year-old patient, with a persistent infectious episode in the last 8 weeks, pain and swelling in the large joints. At admission the patient had fever, tachycardia and a grade 2/6 systolic mitral murmur. Laboratory findings revealed inflammatory syndrome, hepatocytolysis syndrome and microalbuminuria. The electrocardiogram (ECG) showed possible right atrial tachycardia. The echocardiography revealed a globally enlarged heart with reduced ejection fraction and diffuse hypokinesia. When discussing the etiology of the DCM, the following were taken into consideration: a tachycardiomyopathy, ischemic etiology, genetic component, autoimmune etiology (elevated anti-Ro titer), and myocarditis. The diagnosis of myocarditis was confirmed by the cardiac magnetic resonance imaging which showed diffuse fibrosis of the interstitial space and an important increase of the extracellular volume. This case is distinguished by a particular immunological panel requiring dynamic monitoring in order to diagnose a possible associated autoimmune pathology.

PET imaging of 68Ga-NODAGA-RGD, as compared with 18F-fluorodeoxyglucose, in experimental rodent models of engrafted glioblastoma.

BACKGROUND: Tracers triggering αvß3 integrins, such as certain RGD-containing peptides, were found promising in previous pilot studies characterizing high-grade gliomas. However, only limited comparisons have been performed with current PET tracers. This study aimed at comparing the biodistribution of 18F-fluorodeoxyglucose (18F-FDG) with that of 68Ga-NODAGA-RGD, an easily synthesized monomeric RGD compound with rapid kinetics, in two different rodent models of engrafted human glioblastoma. METHODS: Nude rodents bearing human U87-MG glioblastoma tumor xenografts in the flank (34 tumors in mice) or in the brain (5 tumors in rats) were analyzed. Kinetics of 68Ga-NODAGA-RGD and of 18F-FDG were compared with PET imaging in the same animals, along with additional autohistoradiographic analyses and blocking tests for 68Ga-NODAGA-RGD. RESULTS: Both tracers showed a primary renal route of clearance, although with faster clearance for 68Ga-NODAGA-RGD resulting in higher activities in the kidneys and bladder. The tumor activity from 68Ga-NODAGA-RGD, likely corresponding to true integrin binding (i.e., suppressed by co-injection of a saturating excess of unlabeled RGD), was found relatively high, but only at the 2nd hour following injection, corresponding on average to 53% of total tumor activity. Tumor uptake of 68Ga-NODAGA-RGD decreased progressively with time, contrary to that of 18F-FDG, although 68Ga-NODAGA-RGD exhibited 3.4 and 3.7-fold higher tumor-to-normal brain ratios on average compared to 18F-FDG in mice and rat models, respectively. Finally, ex-vivo analyses revealed that the tumor areas with high 68Ga-NODAGA-RGD uptake also exhibited the highest rates of cell proliferation and αv integrin expression, irrespective of cell density. CONCLUSIONS: 68Ga-NODAGA-RGD has a high potential for PET imaging of glioblastomas, especially for areas with high integrin expression and cell proliferation, although PET recording needs to be delayed until the 2nd hour following injection in order to provide sufficiently high integrin specificity.

Synthesis and preliminary in vivo evaluation of new [18F]fluoro-inositols as Positron Emission Tomography radiotracers.

This study describes the synthesis and radiosynthesis of eight new [18F]fluoro-inositol-based radiotracers in myo- and scyllo-inositol configuration. These radiotracers are equipped with a propyl linker bearing fluorine-18. This fluorinated arm is either on a hydroxyl group, i.e. O-alkylated inositols, or on the cyclohexyl backbone, i.e. C-branched derivatives. To modulate lipophilicity, inositols were synthesized in acetylated or hydroxylated form. Automated radiosynthesis was performed on the AllInOne module and the radiotracers were produced in good radiochemical yields (15-31.5% dc). Preliminary in vivo preclinical evaluation of these eight [18F]fluoro-inositols as Positron Emission Tomography (PET) imaging agents in a breast tumour-bearing mouse model was performed and compared with [18F]-2-fluoro-2-deoxy-d-glucose ([18F]FDG). Amongst the different inositols, [18F]myo-2 showed the highest tumour uptake 2.34±0.39%ID/g, revealing the potential of this tracer for monitoring breast cancer.

Cognitive consequences of sleep deprivation, shiftwork, and heat exposure for underground miners.

Sleep deprivation, abnormal sleep patterns arising from working rotating shifts, and exposure to high ambient temperatures contribute to physical and cognitive dysfunction. We examined the effects of these on 19 (41.5 ± 5.1 years) male underground miners. Data were collected for 28 to 30 consecutive days such that the participants experienced their full rotating shift schedule, including days off. Objective measures of sleep quality (actigraphy), attentional capacity (psychomotor vigilance task), core body temperature (visceral pill), executive function (BRIEF-A) and subjective measures of fatigue (Karolinska and Epworth Sleepiness scales) were obtained over the 28-30 day period. Non-parametric analyses (χ(2), Wilcoxen Signed ranks) were used to determine differences between shift types and days off. Z-tests were used to compare sample data to population norms. These revealed that the participants experienced poor quality of sleep relative to age-matched norms irrespective of the shift being worked or if the participant was on a scheduled day off [30-39 year olds: z = -14.62, p < 0.001; 40-49 year olds: z = -4.44, p < 0.001]. Participants when working day shift experienced less sleep prior to beginning work compared to their days off or night shift; however, no differences in total sleep time between when participants worked day or night shifts were observed [χ(2) (2, n = 18) = 13.44, p < 0.01]. When measured subjectively, the only time participants reported excessive sleepiness was after a night shift. Objective measures of attentional capacity showed best performance at the beginning of night shifts in contrast to any other time that the task was completed; however, performance degraded dramatically over the course of the night shift [χ(2) (2, n = 12) = 6.50, p < 0.05]. We show that underground miners reported for work sleep deprived. The cognitive consequences of this poor sleep were most pronounced during night shift when their attentional capacity declined rapidly over the course of the night shift.