Imaging inflammation in atherosclerotic plaques, targeting SST2 with [111In]In-DOTA-JR11.

BACKGROUND: Imaging Somatostatin Subtype Receptor 2 (SST2) expressing macrophages by [DOTA,Tyr3]-octreotate (DOTATATE) has proven successful for plaque detection. DOTA-JR11 is a SST2 targeting ligand with a five times higher tumor uptake than DOTATATE, and holds promise to improve plaque imaging. The aim of this study was to evaluate the potential of DOTA-JR11 for plaque detection. METHODS AND RESULTS: Atherosclerotic ApoE-/- mice (n = 22) fed an atherogenic diet were imaged by SPECT/CT two hours post injection of [111In]In-DOTA-JR11 (~ 200 pmol, ~ 50 MBq). In vivo plaque uptake of [111In]In-DOTA-JR11 was visible in all mice, with a target-to-background-ratio (TBR) of 2.23 ± 0.35. Post-mortem scans after thymectomy and ex vivo scans of the arteries after excision of the arteries confirmed plaque uptake of the radioligand with TBRs of 2.46 ± 0.52 and 3.43 ± 1.45 respectively. Oil red O lipid-staining and ex vivo autoradiography of excised arteries showed [111In]In-DOTA-JR11 uptake at plaque locations. Histological processing showed CD68 (macrophages) and SST2 expressing cells in plaques. SPECT/CT, in vitro autoradiography and immunohistochemistry performed on slices of a human carotid endarterectomy sample showed [111In]In-DOTA-JR11 uptake at plaque locations containing CD68 and SST2 expressing cells. CONCLUSIONS: The results of this study indicate DOTA-JR11 as a promising ligand for visualization of atherosclerotic plaque inflammation.

Imaging of inflammatory cellular protagonists in human atherosclerosis: a dual-isotope SPECT approach.

PURPOSE: Atherosclerotic plaque development and progression signifies a complex inflammatory disease mediated by a multitude of proinflammatory leukocyte subsets. Using single photon emission computed tomography (SPECT) coupled with computed tomography (CT), this study tested a new dual-isotope acquisition protocol to assess each radiotracer's capability to identify plaque phenotype and inflammation levels pertaining to leukocytes expressing leukocyte function-associated antigen-1 (LFA-1) and the leukocyte subset of proinflammatory macrophages expressing somatostatin receptor subtype-2 (SST2). Individual radiotracer uptake was quantified and the presence of corresponding immunohistological cell markers was assessed. METHODS: Human symptomatic carotid plaque segments were obtained from endarterectomy. Segments were incubated in dual-isotope radiotracers [111In]In-DOTA-butylamino-NorBIRT ([111In]In-Danbirt) and [99mTc]Tc-[N0-14,Asp0,Tyr3]-octreotate ([99mTc]Tc-Demotate 2) before scanning with SPECT/CT. Plaque phenotype was classified as pathological intimal thickening, fibrous cap atheroma or fibrocalcific using histology sections based on distinct morphological characteristics. Plaque segments were subsequently immuno-stained with LFA-1 and SST2 and quantified in terms of positive area fraction and compared against the corresponding SPECT images. RESULTS: Focal uptake of co-localising dual-radiotracers identified the heterogeneous distribution of inflamed regions in the plaques which co-localised with positive immuno-stained regions of LFA-1 and SST2. [111In]In-Danbirt and [99mTc]Tc-Demotate 2 uptake demonstrated a significant positive correlation (r = 0.651; p = 0.001). Fibrous cap atheroma plaque phenotype correlated with the highest [111In]In-Danbirt and [99mTc]Tc-Demotate 2 uptake compared with fibrocalcific plaques and pathological intimal thickening phenotypes, in line with the immunohistological analyses. CONCLUSION: A dual-isotope acquisition protocol permits the imaging of multiple leukocyte subsets and the pro-inflammatory macrophages simultaneously in atherosclerotic plaque tissue. [111In]In-Danbirt may have added value for assessing the total inflammation levels in atherosclerotic plaques in addition to classifying plaque phenotype.

Calcium imaging and selective computed tomography angiography in comparison to functional testing for suspected coronary artery disease: the multicentre, randomized CRESCENT trial.

AIMS: To compare the effectiveness and safety of a cardiac computed tomography (CT) algorithm with functional testing in patients with symptoms suggestive of coronary artery disease (CAD). METHODS AND RESULTS: Between April 2011 and July 2013, 350 patients with stable angina, referred to the outpatient clinic of four Dutch hospitals, were prospectively randomized between cardiac CT and functional testing (2 : 1 ratio). The tiered cardiac CT protocol included a calcium scan followed by CT angiography if the Agatston calcium score was between 1 and 400. Patients with test-specific contraindications were not excluded from study participation. By 1 year, fewer patients randomized to cardiac CT reported anginal complaints (P = 0.012). The cumulative radiation dose was slightly higher in the CT group (6.6 ± 8.7 vs. 6.1 ± 9.3 mSv; P < 0.0001). After 1.2 years, event-free survival was 96.7% for patients randomized to CT and 89.8% for patients randomized to functional testing (P = 0.011). After CT, the final diagnosis was established sooner (P < 0.0001), and additional downstream testing was required less frequently (25 vs. 53%, P < 0.0001), resulting in lower cumulative diagnostic costs (€369 vs. €440; P < 0.0001). CONCLUSION: For patients with suspected stable CAD, a tiered cardiac CT protocol offers an effective and safe alternative to functional testing. Incorporating the calcium scan into the diagnostic workup was safe and lowered diagnostic expenses and radiation exposure.

Acute Coronary Syndrome Subphenotypes Based on Repeated Biomarker Measurements in Relation to Long-Term Mortality Risk.

BACKGROUND: We aimed to identify patients with subphenotypes of postacute coronary syndrome (ACS) using repeated measurements of high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and growth differentiation factor 15 in the year after the index admission, and to investigate their association with long-term mortality risk. METHODS AND RESULTS: BIOMArCS (BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome) was an observational study of patients with ACS, who underwent high-frequency blood sampling for 1 year. Biomarkers were measured in a median of 16 repeated samples per individual. Cluster analysis was performed to identify biomarker-based subphenotypes in 723 patients without a repeat ACS in the first year. Patients with a repeat ACS (N=36) were considered a separate cluster. Differences in all-cause death were evaluated using accelerated failure time models (median follow-up, 9.1 years; 141 deaths). Three biomarker-based clusters were identified: cluster 1 showed low and stable biomarker concentrations, cluster 2 had elevated concentrations that subsequently decreased, and cluster 3 showed persistently elevated concentrations. The temporal biomarker patterns of patients in cluster 3 were similar to those with a repeat ACS during the first year. Clusters 1 and 2 had a similar and favorable long-term mortality risk. Cluster 3 had the highest mortality risk. The adjusted survival time ratio was 0.64 (95% CI, 0.44-0.93; P=0.018) compared with cluster 1, and 0.71 (95% CI, 0.39-1.32; P=0.281) compared with patients with a repeat ACS. CONCLUSIONS: Patients with subphenotypes of post-ACS with different all-cause mortality risks during long-term follow-up can be identified on the basis of repeatedly measured cardiovascular biomarkers. Patients with persistently elevated biomarkers have the worst outcomes, regardless of whether they experienced a repeat ACS in the first year.

Serially measured high-sensitivity cardiac troponin T, N-terminal-pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and growth differentiation factor 15 for risk assessment after acute coronary syndrome: the BIOMArCS cohort.

AIMS: Evidence regarding the role of serial measurements of biomarkers for risk assessment in post-acute coronary syndrome (ACS) patients is limited. The aim was to explore the prognostic value of four, serially measured biomarkers in a large, real-world cohort of post-ACS patients. METHODS AND RESULTS: BIOMArCS is a prospective, multi-centre, observational study in 844 post-ACS patients in whom 12 218 blood samples (median 17 per patient) were obtained during 1-year follow-up. The longitudinal patterns of high-sensitivity cardiac troponin T (hs-cTnT), N-terminal-pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), and growth differentiation factor 15 (GDF-15) were analysed in relation to the primary endpoint (PE) of cardiovascular mortality and recurrent ACS using multivariable joint models. Median age was 63 years, 78% were men and the PE was reached by 45 patients. The average biomarker levels were systematically higher in PE compared with PE-free patients. After adjustment for 6-month post-discharge Global Registry of Acute Coronary Events score, 1 standard deviation increase in log[hs-cTnT] was associated with a 61% increased risk of the PE [hazard ratio (HR) 1.61, 95% confidence interval (CI) 1.02-2.44, P = 0.045], while for log[GDF-15] this was 81% (HR 1.81, 95% CI 1.28-2.70, P = 0.001). These associations remained significant after multivariable adjustment, while NT-proBNP and hs-CRP were not. Furthermore, GDF-15 level showed an increasing trend prior to the PE (Structured Graphical Abstract). CONCLUSION: Longitudinally measured hs-cTnT and GDF-15 concentrations provide prognostic value in the risk assessment of clinically stabilized patients post-ACS. CLINICAL TRIAL REGISTRATION: The Netherlands Trial Register. Currently available at URL https://trialsearch.who.int/; Unique Identifiers: NTR1698 and NTR1106.

Nuclear Imaging of Post-infarction Inflammation in Ischemic Cardiac Diseases - New Radiotracers for Potential Clinical Applications.

Acute myocardial infarction is one of the leading causes of death in the western world. Despite major improvements in myocardial reperfusion with sophisticated percutaneous coronary intervention technologies and new antithrombotic agents, there is still no effective therapy for preventing post- infarction myocardial injury and remodeling. Death of cardiomyocytes following ischemia results in "danger signals" that elicit an inflammatory reaction to remove cell debris and form scar tissue. Optimal healing of the damaged myocardial tissue requires a coordinated cellular response for sufficient wound healing and scar formation. However, if this inflammatory reaction is overactive or incompletely resolved, adverse left ventricular remodeling and heart failure may occur. Treatment aimed at the modulation of the post-MI inflammatory response has been widely pursued and investigated. Although improved infarct healing was shown in many experimental preclinical studies, to date, clinical trials using anti-inflammatory treatment strategies have been far less successful. Clearly, a need exists for predicting and selecting patients at risk and selecting the most appropriate therapy for individual patients. To this end, imaging of the post-MI response has been a topic of significant interest. In this review, we first discuss the clinical complications resulting from myocardial inflammation following AMI and the need for non-invasive imaging techniques using radiolabeled tracers. We then discuss the inflammatory reaction cascade following acute myocardial infarction, the inflammatory reaction cascade following acute myocardial infarction focusing on inflammatory cell types involved herein, and potential imaging targets for identifying these cells during the inflammatory process. In addition, we discuss specific characteristics and limitations of various preclinical animal models for ischemic heart disease since they are crucial in the development and evaluation of the imaging techniques. Finally, we discuss the need for non-invasive imaging approaches using radiolabeled tracers.

Autoradiographical assessment of inflammation-targeting radioligands for atherosclerosis imaging: potential for plaque phenotype identification.

PURPOSE: Many radioligands have been developed for the visualization of atherosclerosis by targeting inflammation. However, interpretation of in vivo signals is often limited to plaque identification. We evaluated binding of some promising radioligands in an in vitro approach in atherosclerotic plaques with different phenotypes. METHODS: Tissue sections of carotid endarterectomy tissue were characterized as early plaque, fibro-calcific plaque, or phenotypically vulnerable plaque. In vitro binding assays for the radioligands [111In]In-DOTATATE; [111In]In-DOTA-JR11; [67Ga]Ga-Pentixafor; [111In]In-DANBIRT; and [111In]In-EC0800 were conducted, the expression of the radioligand targets was assessed via immunohistochemistry. Radioligand binding and expression of radioligand targets was investigated and compared. RESULTS: In sections characterized as vulnerable plaque, binding was highest for [111In]In-EC0800; followed by [111In]In-DANBIRT; [67Ga]Ga-Pentixafor; [111In]In-DOTA-JR11; and [111In]In-DOTATATE (0.064 ± 0.036; 0.052 ± 0.029; 0.011 ± 0.003; 0.0066 ± 0.0021; 0.00064 ± 0.00014 %Added activity/mm2, respectively). Binding of [111In]In-DANBIRT and [111In]In-EC0800 was highest across plaque phenotypes, binding of [111In]In-DOTA-JR11 and [67Ga]Ga-Pentixafor differed most between plaque phenotypes. Binding of [111In]In-DOTATATE was the lowest across plaque phenotypes. The areas positive for cells expressing the radioligand's target differed between plaque phenotypes for all targets, with lowest percentage area of expression in early plaque sections and highest in phenotypically vulnerable plaque sections. CONCLUSIONS: Radioligands targeting inflammatory cell markers showed different levels of binding in atherosclerotic plaques and among plaque phenotypes. Different radioligands might be used for plaque detection and discerning early from vulnerable plaque. [111In]In-EC0800 and [111In]In-DANBIRT appear most suitable for plaque detection, while [67Ga]Ga-Pentixafor and [111In]In-DOTA-JR11 might be best suited for differentiation between plaque phenotypes.

Side-by-side viewing of anatomically aligned left ventricular segments in three-dimensional stress echocardiography.

BACKGROUND: Dobutamine stress echocardiography (DSE) suffers from high interobserver and inter-institution variability in the diagnosis of myocardial ischemia. Therefore, we developed a three-dimensional (3D) analysis tool that makes it possible to anatomically align 3D rest and stress data systematically, to generate optimal, nonforeshortened standard anatomical cross sections and to analyse the images synchronized and side-by-side. AIM OF THE STUDY: To investigate whether this 3D analysis tool could improve interobserver agreement on myocardial ischemia during 3D DSE. METHODS: The study comprised 34 consecutive patients with stable chest pain who underwent both noncontrast and contrast 3D DSE. Two observers scored segmental wall motion using a conventional analysis and the novel analysis with the new 3D tool. RESULTS: The two observers agreed on the presence or absence of myocardial ischemia in 81 of 102 coronary territories (agreement 79%, kappa (kappa) 0.28) during noncontrast 3D imaging and 92 of 102 coronary territories (agreement 90%, kappa 0.65) during contrast-enhanced 3D imaging. With the new 3D analysis software these numbers improved to 98 of 102 coronary territories (agreement 96%, kappa 0.69) during noncontrast 3D imaging and 98 of 102 coronary territories (agreement 96%, kappa 0.82) during contrast-enhanced 3D imaging. CONCLUSION: The use of a 3D DSE analysis tool improves interobserver agreement for myocardial ischemia both for noncontrast and contrast images.

Contrast-enhanced three-dimensional dobutamine stress echocardiography: between Scylla and Charybdis?

AIMS: Real-time three-dimensional echocardiography (RT3DE) allows quick volumetric scanning of the left ventricle (LV). We evaluated the diagnostic accuracy of contrast-enhanced stress RT3DE for the detection of coronary artery disease (CAD) in comparison with coronary arteriography as the reference technique. METHODS AND RESULTS: Forty-five consecutive patients (age 59 +/- 10, 31 males) referred for coronary angiography were examined by contrast-enhanced RT3DE. Wall motion analysis was performed off-line by dedicated software. New or worsening wall motion abnormalities were detected in 17 of 28 patients with significant CAD (sensitivity 61%), and in two of 17 patients without significant CAD (specificity 88%). The sensitivity for detection of single-vessel CAD was 8/15 patients (53%), for two-vessel CAD 4/6 (67%), and for three-vessel CAD 5/7 (71%). In 35 patients, comparison with conventional RT3DE was available. The image quality index at rest improved from 2.5 +/- 1.2 to 3.2 +/- 1.0 (P < 0.001) with contrast and at peak stress from 2.3 +/- 1.2 to 3.1 +/- 1.0 (P < 0.001). Interobserver agreement on the diagnosis of myocardial ischaemia improved from 26 of 35 studies (74%, kappa = 0.44) with conventional stress RT3DE to 30 of 35 studies (86%, kappa = 0.69) with contrast-enhanced stress RT3DE. Sensitivity increased from 50 to 55% and specificity from 69 to 85% with contrast-enhanced stress RT3DE in this subset of patients. CONCLUSION: Despite some important practical and theoretical benefits, contrast-enhanced stress RT3DE currently has only moderate diagnostic sensitivity due to several technical limitations as temporal and spatial resolution.

Dobutamine stress echocardiography for the detection of coronary artery disease in women.

Dobutamine stress echocardiography (DSE) has good diagnostic accuracy for the diagnosis of coronary artery disease (CAD). However, in most published diagnostic studies, patients are predominantly men. In women, diagnostic accuracy may be lower because of a lower prevalence and extent of CAD, a higher incidence of dobutamine stress-induced hypotension (resulting in less stress or even nondiagnostic test results), smaller left ventricular chamber size, and the beneficial effects of estrogens on the induction of myocardial ischemia. To determine the diagnostic accuracy of DSE in women, 14 diagnostic studies published through 2006 were identified through a Medline search. For a total of 901 patients, the weighted mean sensitivity and specificity were 72% and 88%, respectively. In 7 studies directly comparing results in women and men, conflicting results were reported. However, pooled data showed nearly identical values for sensitivity and specificity in women and men. Additionally, in 6 studies directly comparing DSE results in women with those of stress nuclear scintigraphy, DSE was as sensitive and more specific to detect CAD (90% vs 70%, p <0.0001). The excellent specificity of DSE in women was also confirmed by excellent normalcy rates, ranging from 92% to 100% in women, with a <5% pretest probability of CAD. In conclusion, despite some theoretical limitations, DSE has reasonable sensitivity and excellent specificity for the detection of CAD in women. Considering the diagnostic problems of exercise electrocardiography and nuclear scintigraphy in women, stress echocardiography may be the stress modality of choice in women because of its superior diagnostic specificity.

Usefulness of ultrasound contrast agent to improve image quality during real-time three-dimensional stress echocardiography.

Dobutamine stress echocardiography is an accepted tool for the diagnosis of coronary artery disease. Some investigators have claimed that 3-dimensional imaging improves the diagnostic accuracy of dobutamine stress echocardiography. The purpose of the present investigation was to examine the role of contrast echocardiography in the improvement of segmental quality and interobserver agreement during stress real-time 3-dimensional echocardiography (RT3DE). The study comprised 36 consecutive patients with stable chest pain referred for routine stress testing. Three-dimensional images were acquired with an RT3DE system with an X4 matrix-array transducer. All available reconstructed 2-dimensional segments were graded as optimal, good, moderate, or poor. Wall motion was scored as normal, mild hypokinesia, severe hypokinesia, akinesia, or dyskinesia. At peak stress, 466 of the 612 segments (76%) could be analyzed during conventional RT3DE. With contrast-enhanced RT3DE, the number of available segments increased to 553 (90%). The image quality index during conventional RT3DE was 2.2, whereas with contrast-enhanced RT3DE, it was 3.1. With conventional RT3DE, 2 independent observers agreed on the diagnosis of myocardial ischemia in 85 of 108 coronary territories (79%, kappa = 0.26). With contrast-enhanced RT3DE, agreement increased to 95 of 108 coronary territories (88%, kappa = 0.59). Study agreement on myocardial ischemia was present in 26 of 36 studies (72%, kappa = 0.43) with conventional RT3DE and in 32 of 36 studies (89%, kappa = 0.77) with contrast-enhanced RT3DE. In conclusion, during stress RT3DE, contrast-enhanced imaging significantly decreases the number of poorly visualized myocardial segments and improves interobserver agreement for the diagnosis of myocardial ischemia.

Comparison of contrast agent-enhanced versus non-contrast agent-enhanced real-time three-dimensional echocardiography for analysis of left ventricular systolic function.

Ultrasound contrast has shown to improve endocardial border definition. The purpose of this study was to evaluate the value of contrast agent-enhanced versus non-contrast agent-enhanced real-time 3-dimensional echocardiography (RT3DE) for the assessment of left ventricular (LV) volumes and ejection fraction. Thirty-nine unselected patients underwent RT3DE with and without SonoVue contrast agent enhancement and magnetic resonance imaging (MRI) on the same day. An image quality index was calculated by grading all 16 individual LV segments on a scale of 0 to 4: 0, not visible; 1, poor; 2, moderate; 3, good; and 4, excellent. The 3-dimensional data sets were analyzed offline using dedicated TomTec analysis software. By manual tracing, LV end-systolic volume, LV end-diastolic volume, and LV ejection fraction were calculated. After contrast agent enhancement, mean image quality index improved from 2.4 +/- 1.0 to 3.0 +/- 0.9 (p <0.001). Contrast agent-enhanced RT3DE measurements showed better correlation with MRI (LV end-diastolic volume, r = 0.97 vs 0.86; LV end-systolic volume, r = 0.96 vs 0.94; LV ejection fraction, r = 0.94 vs 0.81). The limits of agreement (Bland-Altman analysis) showed a similar bias for RT3DE images with and without contrast agent but with smaller limits of agreement for contrast agent-enhanced RT3DE. Also, inter- and intraobserver variabilities decreased. In a subgroup, patients with poor to moderate image quality showed an improvement in agreement after administration of contrast agent (+/-24.4% to +/-12.7%) to the same level as patients with moderate to good image quality without contrast agent (+/-10.4%). In conclusion, contrast agent-enhanced RT3DE is more accurate in assessment of LV function as evidenced by better correlation and narrower limits of agreement compared with MRI, as well as lower intra- and interobserver variabilities.

213Bi-[DOTA0, Tyr3]octreotide peptide receptor radionuclide therapy of pancreatic tumors in a preclinical animal model.

PURPOSE: The somatostatin analogue [DOTA0, Tyr3]octreotide (DOTATOC) has previously been labeled with low linear energy transfer (LET) beta-emitters, such as 177Lu or 90Y, for tumor therapy. In this study, DOTATOC labeled with the high-LET alpha-emitter, 213Bi, was evaluated. EXPERIMENTAL DESIGN: The radiolabeling, stability, biodistribution, toxicity, safety, and therapeutic efficacy of 213Bi-DOTATOC (specific activity 7.4 MBq/microg) were investigated. Biodistribution studies to determine somatostatin receptor specificity were done in Lewis rats at 1 and 3 hours postinjection. Histopathology of various organs was used to evaluated toxicity and safety. Therapeutic efficacy of 4 to 22 MBq 213Bi-DOTATOC was determined in a rat pancreatic carcinoma model. RESULTS: Radiolabeling of the 213Bi-DOTATOC was achieved with radiochemical purity >95% and an incorporation yield > or = 99.9%. Biodistribution data showed specific binding to somatostatin receptor-expressing tissues. Administration of free 213Bi, compared with 213Bi-DOTATOC, resulted in higher radioactivity accumulation at 3 hours postinjection in the kidneys [34.47 +/- 1.40% injected dose/g (ID/g) tissue versus 11.15 +/- 0.46%, P < 0.0001] and bone marrow (0.31 +/- 0.01% ID/g versus 0.06 +/- 0.02%, P < 0.0324). A significant decrease in tumor growth rate was observed in rats treated with >11 MBq of 213Bi-DOTATOC 10 days postinjection compared with controls (P < 0.025). Treatment with >20 MBq of 213Bi-DOTATOC showed significantly greater tumor reduction when compared with animals receiving <11 MBq (P < 0.02). CONCLUSIONS: 213Bi-DOTATOC showed dose-related antitumor effects with minimal treatment-related organ toxicity. No acute or chronic hematologic toxicities were observed. Mild, acute nephrotoxicity was observed without evidence of chronic toxicity. 213Bi-DOTATOC is a promising therapeutic radiopharmaceutical for further evaluation.

Three-dimensional echocardiographic analysis of left ventricular function during hemodialysis.

BACKGROUND: The effects of hemodialysis (HD) on left ventricular (LV) function have been studied by various echocardiographic techniques (M-mode, 2D echocardiography). These studies are hampered by a low accuracy of measurements because of geometric assumptions regarding LV shape. Three-dimensional echocardiography (3DE) overcomes this limitation. METHODS: We tested the feasibility of 3DE assessment of LV function during HD. Conventional biplane Simpson rule (BSR) and single plane area length method (SPM) for LV function analysis were used as a reference. RESULTS: 12 HD patients were studied and in 10 (83%) a total of 80 3D datasets were acquired. In 3 patients, one dataset (4%) was of insufficient quality and excluded from analysis. Correlation between SPM, BSR and 3DE for calculation of end-diastolic (EDV, r = 0.89 and r = 0.92, respectively), end-systolic volume (ESV, r = 0.92 and r = 0.93, respectively) and for ejection fraction (EF, r = 0.90 and r = 0.88, respectively) was moderate. Limits-of-agreement results for EDV and ESV were poor with confidence intervals larger than 30 ml. Both 2DE methods underestimated end-diastolic and end-systolic volume, while overestimating ejection fraction. CONCLUSION: 3DE is feasible for image acquisition during HD, which opens the possibility for accurate and reproducible measurement of LV function during HD. This may improve the assessment of the acute effect of HD on LV performance, and guide therapeutic strategies aimed at preventing intradialytic hypotension.

[Real-time 3-dimensional echocardiography: can there be one more dimension?]. / Real-time 3-dimenziós echokardiográfia--lehet egy dimenzióval több?

There is an essential importance of non-invasive imaging methods for evaluation of cardiac patients. Theoretically, the heart can be examined exactly, if due to its nature assessed in three dimensions (3D) concerning the heart cycle. In recent studies it has been confirmed that the second-generation real-time three-dimensional echocardiography offers optimal opportunity for three-dimensional evaluation of cardiac structures. Real-time three-dimensional echocardiography is a valuable tool for exact evaluation of ventricular and atrial volumes and ventricular masses. Valves and congenital abnormalities can be analysed 'en-face' with this new methodology. The usefulness of this method with stress protocols has been confirmed. The aim of the present review is to demonstrate advantages of this new promising method showing recent technological limitations as well.

Sex Differences in the Performance of Cardiac Computed Tomography Compared With Functional Testing in Evaluating Stable Chest Pain: Subanalysis of the Multicenter, Randomized CRESCENT Trial (Calcium Imaging and Selective CT Angiography in Comparison to Functional Testing for Suspected Coronary Artery Disease).

BACKGROUND: Cardiac computed tomography (CT) represents an alternative diagnostic strategy for women with suspected coronary artery disease, with potential benefits in terms of effectiveness and cost-efficiency. METHODS AND RESULTS: The CRESCENT trial (Calcium Imaging and Selective CT Angiography in Comparison to Functional Testing for Suspected Coronary Artery Disease) prospectively randomized 350 patients with stable angina (55% women; aged 55±10 years), mostly with an intermediate coronary artery disease probability, between cardiac CT and functional testing. The tiered cardiac CT protocol included a calcium scan followed by CT angiography if the Agatston calcium score was between 1 and 400. Patients with test-specific contraindications were not excluded from study participation. Sex differences were studied as a prespecified subanalysis. Enrolled women presented more frequently with atypical chest pain and had a lower pretest probability of coronary artery disease compared with men. Independently of these differences, cardiac CT led in both sexes to a fast final diagnosis when compared with functional testing, although the effect was larger in women (P interaction=0.01). The reduced need for further testing after CT, compared with functional testing, was most evident in women (P interaction=0.009). However, no sex interaction was observed with respect to changes in angina and quality of life, cumulative diagnostic costs, and applied radiation dose (all P interactions≥0.097). CONCLUSIONS: Cardiac CT is more efficient in women than in men in terms of time to reach the final diagnosis and downstream testing. However, overall clinical outcome showed no significant difference between women and men after 1 year. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01393028.

Seven-year follow-up after dobutamine stress echocardiography: impact of gender on prognosis.

OBJECTIVES: The aim of this study was to investigate the effects of gender on long-term prognosis of patients undergoing dobutamine stress echocardiography (DSE). BACKGROUND: Gender differences in the predictors of outcome among patients with known or suspected coronary artery disease undergoing DSE have not been adequately studied. METHODS: We studied 2,276 men and 1,105 women with known or suspected coronary artery disease who underwent DSE. Follow-up events were cardiac death and nonfatal myocardial infarction (MI). RESULTS: Dobutamine stress echocardiography was normal in 687 men (30%) and 483 women (44%) (p <0.0001). Ischemia on DSE was present in 1,194 men (52%) and 416 women (38%) (p <0.001). During a mean follow-up of 7 +/- 3.4 years, there were 894 (26%) deaths (442 attributed to cardiac causes) and 145 (4%) nonfatal MIs. The annual cardiac event rate was 2.5% in men and 1.2% in women with normal DSE. Independent predictors of cardiac events in patients with normal DSE using a Cox proportional hazards regression analysis were male gender (hazard ratio [HR]: 1.7 [range 1.1 to 2.8]), age (HR: 1.02 [range 1.01 to 1.04]), history of heart failure (HR: 3.4 [range 1.5 to 7.9]), previous MI (HR: 1.7 [range 1.1 to 2.8]), and diabetes (HR: 2.4 [range 1.3 to 4.5]). Independent predictors of cardiac events in patients with an abnormal DSE were age (HR: 1.03 [range 1.02 to 1.04]), history of heart failure (HR: 1.7 [range 1.3 to 2.1]), diabetes (HR: 1.4 [range 1.1 to 1.8]), heart rate at rest (HR: 2.8 [range 1.4 to 5.8]), wall motion abnormalities at rest (HR: 1.06 [range 1.04 to 1.09]), and ischemia on DSE (HR: 1.04 [range 1.02 to 1.07]). Myocardial ischemia was an independent predictor of cardiac events in both men and women. CONCLUSIONS: Dobutamine stress echocardiography provides independent prognostic information in both men and women. In patients with normal DSE, gender is independently associated with cardiac events. The outcome of patients with abnormal DSE is not related to gender, after adjusting for stress echocardiographic abnormalities.

Comparison of real-time three-dimensional echocardiography to magnetic resonance imaging for assessment of left ventricular mass.

This is the first study to assess the feasibility and accuracy of real-time 3-dimensional echocardiography (RT-3DE) for the measurements of left ventricular (LV) mass in patients with congenital heart disease (CHD) compared with magnetic resonance imaging (MRI). Twenty patients (60% men) with CHD were evaluated by MRI and RT-3DE on the same day. Their mean age was 29 +/- 8 years (range 19 to 49). RT-3DE was performed with a Philips Sonos 7500 echocardiographic system and LV mass analyses with the assistance of TomTec software. The results for LV mass obtained by manual tracing were compared with Signa 1.5-T MRI data. The acquisition of RT-3DE data sets was feasible in all 20 patients. Nine patients (45%) had good, 5 patients (25%) moderate, and 6 patients (30%) poor image quality of the 3-dimensional data set. The time of 3-dimensional data acquisition was 4 +/- 2 minutes. Off-line image processing and tracing required approximately 11 +/- 3 minutes. A very good correlation was observed between RT-3DE data with sufficient image quality and MRI (r = 0.98, y = 0.96x + 4.1, SEE 9.8 g), with a mean difference of 2.0 +/- 20 g. Interobserver agreement was excellent (r = 0.99, y = 0.97x + 3.81), with a mean difference of -1 +/- 11 g. In conclusion, the assessment of LV mass from RT-3DE data is feasible in patients with CHD. The mass of an abnormally shaped left ventricle can be determined with high accuracy and low interobserver variability in patients with good or moderate echocardiographic image quality.

Hemodynamic responses and long-term follow-up results in patients using chronic beta 1-selective and nonselective beta-blockers during dobutamine stress echocardiography.

OBJECTIVE: This study was undertaken to determine to what extent hemodynamic responses to dobutamine infusion between patients using concomitant beta1-selective or nonselective beta-blockers differ and whether this difference affects the long-term prognostic value of dobutamine stress echocardiography with respect to cardiac events. DESIGN: Single center, observational study. METHODS: A total of 1234 patients using chronic beta-blockers underwent dobutamine stress echocardiography and were prospectively included in the study. Heart rate and blood pressure responses were measured during the dobutamine stress echocardiography protocol. During a median follow-up time of 4 years (range: 0.5-14 years), overall and cardiac mortality and nonfatal myocardial infarction were noted. RESULTS: A total of 954 and 280 patients were using beta1-selective and nonselective beta-blockers, respectively. During dobutamine stress echocardiography, the heart rate response was significantly higher, systolic and diastolic blood pressure responses were significantly lower and the double product of heart rate and systolic blood pressure was similar in patients using beta1-selective than in patients using nonselective beta-blockers. In patients with and without new wall motion abnormalities during dobutamine stress echocardiography, a similar cardiac event-free survival was observed irrespective of the selectivity of beta-blockers (P=0.9 and 0.3, respectively). CONCLUSION: During dobutamine stress echocardiography, heart rate and blood pressure response was different, but the double product was similar in patients using beta1-selective or nonselective beta-blockers, which may explain why the long-term prognostic value of dobutamine stress echocardiography is similar in these two groups.