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Author(s): Shabani, Mahsima; Bakhshi, Hooman; Ostovaneh, Mohammad R; Ma, Xiaoyang; Wu, Colin O; Ambale-Venkatesh, Bharath; Blaha, Michael J; Allison, Matthew A; Budoff, Matthew J; Cushman, Mary; Tracy, Russell P; Herrington, David M; Szklo, Moyses; Cox, Christopher; Bluemke, David A; Lima, Joao AC | Abstract: AimsLittle is known about the association of temporal changes in inflammatory biomarkers and the risk of death and cardiovascular diseases. We aimed to evaluate the association between temporal changes in C-reactive protein (CRP), fibrinogen, and interleukin-6 (IL-6) and risk of heart failure (HF), cardiovascular disease (CVD), and all-cause mortality in individuals without a history of prior CVD.Methods and resultsParticipants from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort with repeated measures of inflammatory biomarkers and no CVD event prior to the second measure were included. Quantitative measures, annual change, and biomarker change categories were used as main predictors in Cox proportional hazard models stratified based on sex and statin use. A total of 2258 subjects (50.6% female, mean age of 62nyears) were studied over an average of 8.1nyears of follow-up. The median annual decrease in CRP levels was 0.08nmg/L. Fibrinogen and IL-6 levels increased by a median of 30nmg/dL and 0.24npg/mL annually. Temporal changes in CRP were positively associated with HF risk among females (HR: 1.18 per each standard deviation increase, Pnln0.001) and other CVD in both female (HR: 1.12, Pn=n0.004) and male participants (HR: 1.24, Pn=n0.003). The association of CRP change with HF and other CVD was consistently observed in statin users (HR: 1.23 per SD increase, Pn=n0.001 for HF and HR: 1.19 per SD increase, Pnln0.001 for other CVD). There were no significant associations between temporal changes of fibrinogen or IL-6 with HF or other CVD. Men with sustained high values of IL-6 had a 2.3-fold higher risk of all-cause mortality (Pnln0.001) compared with those with sustained low values.ConclusionsTemporal change in CRP is associated with HF only in women and statin users, and other CVD in both women and men, and statin users. Annual changes in fibrinogen and IL-6 were not predictive of cardiovascular outcomes in either sex.

AIMS CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. METHODS AND RESULTS Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. CONCLUSIONS This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

Objective To assess the incidence of contrast-associated acute kidney injury (CAAKI) after repeated exposure to contrast material for computed tomography (CT) and conventional coronary angiography within short intervals. Methods We studied 651 patients enrolled in the CorE-64 (November 5, 2005–January 30, 2007) and CORE320 (October 21, 2009–August 17, 2011) multicenter studies. Participants with suspected obstructive coronary heart disease were referred for diagnostic cardiac catheterization and underwent coronary CT angiography for research before invasive angiography. Nonionic, low-osmolality iodinated contrast material was used for all imaging. Results The median age of the patients was 62 years, and 190 (29%) were women. Major risk factors for acute kidney injury were present in 277 of 651 (43%) patients. The median interval between CT imaging and invasive angiography was 3.1 days (interquartile range, 0.9-8.0 days). The median volume of contrast material was 100 mL for each test. In 16 (2.5%) of 651 patients, CAAKI developed. Of these cases, 1 occurred after the CT scan, whereas 6 were documented after invasive angiography (compared with post-CT creatinine concentration assessment). In 9 patients, CAAKI was found in comparing creatinine concentration after completion of both tests with baseline values (but not compared with post-CT imaging). Conclusion Acute kidney injury after repeated exposure to iodinated contrast media within a few days is uncommon even in a population of patients with highly prevalent risk factors. Withholding of clinically indicated contrast-enhanced imaging may therefore not be justified in this setting.

Background Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marr...

Aims Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. Methods and results We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients. Conclusion Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. Trial registration Clinicaltrials.gov identifier: NCT01458405.

Aims Soluble tumour necrosis factor‐α receptor 1 (sTNF‐αR1) and interleukin‐2 receptor α (sIL‐2Rα) predict incident heart failure (HF) in the elderly population. However, the association of these biomarkers with HF in a multi‐ethnic asymptomatic population is unclear. We aimed to investigate the association of sTNF‐αR1 and sIL‐2Rα with incident HF in a multi‐ethnic population of middle age and older participants. Methods and results The multi‐ethnic study of atherosclerosis is a prospective population‐based study of 6814 participants aged 45–84 years who were free of clinical cardiovascular disease at enrolment. We included 2869 participants with available sTNF‐αR1 or sIL‐2Rα level measurement at baseline multi‐ethnic study of atherosclerosis exam (2000–2002). We used Cox proportional‐hazards model to investigate the association between sTNF‐αR1 and sIL‐2Rα with incident HF after adjusting for traditional cardiovascular risk factors and coronary artery calcium score measured by cardiac computed tomography. Among the included participants, the mean (standard deviation) age was 61.6 (10.2) years and 46.7% were men. The median (interquartile range) sTNF‐αR1 and sIL‐2Rα were 1293 (1107–1547) and 901 (727–1154) pg/mL. During a median follow‐up of 14.2 (interquartile range: 11.7–14.8) years, 130 participants developed HF. In multivariable analysis, the hazard ratio (95% confidence interval, P value) of incident HF for each standard deviation increment of log‐transformed sTNF‐αR1 and sIL‐2Rα was 1.43 (1.21–1.7, P ≤ 0.001) and 1.26 (1.04–1.53, P = 0.02), respectively. Excluding participants with interim coronary heart disease, we found a statistically significant association between sTNF‐αR1 and HF with hazard ratio of 1.39 (95% confidence interval: 1.11 to 1.74, P = 0.005) and sIL‐2Rα and HF showing a hazard ratio of 1.39 (95% confidence interval: 1.09 to 1.76, P = 0.007). Conclusions sTNF‐αR1 and sIL‐2Rα are associated with a higher risk of incident HF in a multi‐ethnic cohort without a previous history of cardiovascular disease.

Cross-sectionally measured NT-proBNP (N-terminal pro-B-type natriuretic peptide) is related to incident dementia. However, data linking changes in NT-proBNP to risk of future dementia are lacking. We aimed to examine the association of change in NT-proBNP over 3.2 years with incident dementia. We included 4563 participants in MESA (Multi-Ethnic Study of Atherosclerosis) prospective cohort who were free of cardiovascular disease at enrollment, had NT-proBNP level measured at MESA exams 1 (baseline, 2000–2002) and 3 (2004–2005), and had no diagnosis of dementia before exam 3. The association of change in NT-proBNP level between MESA exams 1 through 3 and all-cause hospitalized dementia (by International Classification of Diseases, Ninth Revision , codes) after MESA exam 3 (2004–2005) through 2015 was assessed using competing-risks Cox proportional hazard regression analysis. During 45 522 person-years of follow-up, 223 dementia cases were documented. Increase in log-NT-proBNP from MESA exams 1 through 3 was positively associated with incidence of dementia (multivariable hazard ratio, 1.28 [95% CI, 1.001–1.64]; P =0.049). An increase of at least 25% in NT-proBNP level from MESA exam 1 through 3 was associated with a 55% ( P =0.02) increase in the risk of dementia in multivariable analysis. Addition of temporal NT-proBNP change to a model including risk factors and baseline NT-proBNP improved the prediction of dementia (Harrell C statistic from 0.85 to 0.87, P =0.049). Increase in NT-proBNP is independently associated with future all-cause hospitalized dementia and offers a moderately better predictive performance for risk of dementia compared with risk factors and baseline NT-proBNP. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00005487.

Summary Background A fixed-dose combination therapy (polypill strategy) has been proposed as an approach to reduce the burden of cardiovascular disease, especially in low-income and middle-income countries (LMICs). The PolyIran study aimed to assess the effectiveness and safety of a four-component polypill including aspirin, atorvastatin, hydrochlorothiazide, and either enalapril or valsartan for primary and secondary prevention of cardiovascular disease. Methods The PolyIran study was a two-group, pragmatic, cluster-randomised trial nested within the Golestan Cohort Study (GCS), a cohort study with 50 045 participants aged 40–75 years from the Golestan province in Iran. Clusters (villages) were randomly allocated (1:1) to either a package of non-pharmacological preventive interventions alone (minimal care group) or together with a once-daily polypill tablet (polypill group). Randomisation was stratified by three districts (Gonbad, Aq-Qala, and Kalaleh), with the village as the unit of randomisation. We used a balanced randomisation algorithm, considering block sizes of 20 and balancing for cluster size or natural log of the cluster size (depending on the skewness within strata). Randomisation was done at a fixed point in time (Jan 18, 2011) by statisticians at the University of Birmingham (Birmingham, UK), independent of the local study team. The non-pharmacological preventive interventions (including educational training about healthy lifestyle—eg, healthy diet with low salt, sugar, and fat content, exercise, weight control, and abstinence from smoking and opium) were delivered by the PolyIran field visit team at months 3 and 6, and then every 6 months thereafter. Two formulations of polypill tablet were used in this study. Participants were first prescribed polypill one (hydrochlorothiazide 12·5 mg, aspirin 81 mg, atorvastatin 20 mg, and enalapril 5 mg). Participants who developed cough during follow-up were switched by a trained study physician to polypill two, which included valsartan 40 mg instead of enalapril 5 mg. Participants were followed up for 60 months. The primary outcome—occurrence of major cardiovascular events (including hospitalisation for acute coronary syndrome, fatal myocardial infarction, sudden death, heart failure, coronary artery revascularisation procedures, and non-fatal and fatal stroke)—was centrally assessed by the GCS follow-up team, who were masked to allocation status. We did intention-to-treat analyses by including all participants who met eligibility criteria in the two study groups. The trial was registered with ClinicalTrials.gov , number NCT01271985 . Findings Between Feb 22, 2011, and April 15, 2013, we enrolled 6838 individuals into the study—3417 (in 116 clusters) in the minimal care group and 3421 (in 120 clusters) in the polypill group. 1761 (51·5%) of 3421 participants in the polypill group were women, as were 1679 (49·1%) of 3417 participants in the minimal care group. Median adherence to polypill tablets was 80·5% (IQR 48·5–92·2). During follow-up, 301 (8·8%) of 3417 participants in the minimal care group had major cardiovascular events compared with 202 (5·9%) of 3421 participants in the polypill group (adjusted hazard ratio [HR] 0·66, 95% CI 0·55–0·80). We found no statistically significant interaction with the presence (HR 0·61, 95% CI 0·49–0·75) or absence of pre-existing cardiovascular disease (0·80; 0·51–1·12; pinteraction=0·19). When restricted to participants in the polypill group with high adherence, the reduction in the risk of major cardiovascular events was even greater compared with the minimal care group (adjusted HR 0·43, 95% CI 0·33–0·55). The frequency of adverse events was similar between the two study groups. 21 intracranial haemorrhages were reported during the 5 years of follow-up—ten participants in the polypill group and 11 participants in the minimal care group. There were 13 physician-confirmed diagnoses of upper gastrointestinal bleeding in the polypill group and nine in the minimal care group. Interpretation Use of polypill was effective in preventing major cardiovascular events. Medication adherence was high and adverse event numbers were low. The polypill strategy could be considered as an additional effective component in controlling cardiovascular diseases, especially in LMICs. Funding Tehran University of Medical Sciences, Barakat Foundation, and Alborz Darou.

Background Patient preference is pivotal for widespread adoption of tests in clinical practice. Patient preferences for invasive versus other noninvasive tests for coronary artery disease are not known. Purpose To compare patient acceptance and preferences for noninvasive and invasive cardiac imaging in North and South America, Asia, and Europe. Materials and Methods This was a prospective 16-center trial in 381 study participants undergoing coronary CT angiography with stress perfusion, SPECT, and invasive coronary angiography (ICA). Patient preferences were collected by using a previously validated questionnaire translated into eight languages. Responses were converted to ordinal scales and were modeled with generalized linear mixed models. Results In patients in whom at least one test was associated with pain, CT and SPECT showed reduced median pain levels, reported on 0-100 visual analog scales, from 20 for ICA (interquartile range [IQR], 4-50) to 6 for CT (IQR, 0-27.5) and 5 for SPECT (IQR, 0-25) (P < .001). Patients from Asia reported significantly more pain than patients from other continents for ICA (median, 25; IQR, 10-50; P = .01), CT (median, 10; IQR, 0-30; P = .02), and SPECT (median, 7; IQR, 0-28; P = .03). Satisfaction with preparation differed by continent and test (P = .01), with patients from Asia reporting generally lower ratings. Patients from North America had greater percentages of "very high" or "high" satisfaction than patients from other continents for ICA (96% vs 82%, respectively; P < .001) and SPECT (95% vs 79%, respectively; P = .04) but not for CT (89% vs 86%, respectively; P = .70). Among all patients, CT was preferred by 54% of patients, compared with 18% for SPECT and 28% for ICA (P < .001). Conclusion For cardiac imaging, patients generally favored CT angiography with stress perfusion, while study participants from Asia generally reported lowest satisfaction. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Woodard and Nguyen in this issue.

BackgroundMost cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility.MethodsIn this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF ResultsIn total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3 (10.8) and 108 (87.1%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (−0.5% (4.0)) compared with placebo (0.2% (3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of −0.7% (3.5) in patients receiving CDC vs 0.04% (3.7) in the placebo group, p=0.04).ConclusionsIn patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI.Trial registration numberNCT01458405.

BackgroundAutomatic coronary angiography (CAG) assessment may help in faster screening and diagnosis of patients. Current CNN-based vessel-segmentation suffers from sampling imbalance, candidate frame selection, and overfitting; few have shown adequate performance for CAG stenosis classification. We aimed to provide an end-to-end workflow that may solve these problems.MethodsA deep learning-based end-to-end workflow was employed as follows: 1) Candidate frame selection from CAG videograms with CNN+LSTM network, 2) Stenosis classification with Inception-v3 using 2 or 3 categories (25%, and/or total occlusion) with and without redundancy training, and 3) Stenosis localization with two methods of class activation map (CAM) and anchor-based feature pyramid network (FPN). Overall 13744 frames from 230 studies were used for the stenosis classification training and 4-fold cross-validation for image-, artery-, and per-patient-level. For the stenosis localization training and 4-fold cross-validation, 690 images with >25% stenosis were used.ResultsOur model achieved an accuracy of 0.85, sensitivity of 0.96, and AUC of 0.86 in per-patient level stenosis classification. Redundancy training was effective to improve classification performance. Stenosis position localization was adequate with better quantitative results in anchor-based FPN model, achieving global-sensitivity for LCA and RCA of 0.68 and 0.70 with mean square error (MSE) values of 39.3 and 37.6 pixels respectively, in the 520 × 520 pixel image.ConclusionA fully-automatic end-to-end deep learning-based workflow that eliminates the vessel extraction and segmentation step was feasible in coronary artery stenosis classification and localization on CAG images.Key PointsThe fully-automatic, end-to-end workflow which eliminated the vessel extraction and segmentation step for supervised-learning was feasible in the stenosis classification on CAG images, achieving an accuracy of 0.85, sensitivity of 0.96, and AUC of 0.86 in per-patient level.The redundancy training improved the AUC values, accuracy, F1-score, and kappa score of the stenosis classification.Stenosis position localization was assessed in two methods of CAM-based and anchor-based models, which performance was acceptable with better quantitative results in anchor-based models.Summary StatementA fully-automatic end-to-end deep learning-based workflow which eliminated the vessel extraction and segmentation step was feasible in the stenosis classification and localization on CAG images. The redundancy training improved the stenosis classification performance.

Introduction: ALLSTAR, a trial of cardiosphere-derived cells in iCM, phenotyped the subjects by cardiac magnetic resonance (CMR) at baseline, and 6- and 12- months post-randomization. The overall CMR dataset provides an opportunity to study temporal remodeling of the LA in the context of iCM-related LV alterations. Hypothesis: We hypothesize that LA volumetric and functional remodeling in iCM are coupled to LV determinants. Methods: LA volumes (LAV; maximum and minimum) were obtained from 4- and 2-chamber cine CMR images. LA functional parameters included total, passive and active LA emptying fractions and global longitudinal strain (GLS). LV parameters included end-diastolic and end-systolic volumes (indexed to body surface area; LVEDVi and LVESVi), as well as LV ejection fraction (EF), infarct size, GLS and end-diastolic mass. Six- and 12-month differences from the baseline CMR study were calculated for LA and LV parameters. Linear regression models were used to evaluate univariate associations between LA and LV parameters (at baseline, 6-months, 12-months and their differences [Δ]), independent of treatment effect (which is the subject of ongoing analysis). Results: 101 participants had 6-month follow up CMR studies; 57 had 12-month studies. Baseline means(SD): age 53.9(10.9) years; 87(86.1%) male; LVEF 39.7%(7.0%); infarct size 22.7%(5.4%). In univariate analyses at 6 months, ΔLVEDVi and ΔLVESVi were both significantly associated with ΔLAVimax and ΔLAVimin, but not with LA functional parameters (Table). At 12 months, ΔLVEDVi remained significantly associated with ΔLAVimax, and ΔLVESVi with ΔLAVimin. No association with LA functional parameters was seen. LVEF, infarct size, GLS and end-diastolic mass were not associated with any volumetric or functional LA parameters (not shown). Conclusions: In conclusion, in this cohort of iCM, pathologic dilatation of the LV appears coupled to volumetric LA remodeling, but not other functional LA parameters.

Background Noninvasive evaluation of patients with stable angina is preferable over invasive testing if it leads to similar patient outcome. The combination of coronary angiography and vasodilator challenge myocardial perfusion imaging by computed tomography allows fast, comprehensive assessment of patients with suspected coronary heart disease. Purpose To compare the long-term prognostic value of combined computed tomography angiography (CTA) and myocardial CT perfusion imaging (CTP) with invasive coronary angiography (ICA) and single photon emission tomography (SPECT) in patients with suspected hemodynamically significant coronary heart disease. Methods At 16 centres, 381 patients were followed for major adverse cardiac events (MACE) for the CORE320 study. All patients underwent coronary CTA, CTP, and SPECT before ICA. Prognostic performance according binary results (normal/abnormal) was assessed by 5-year major cardiovascular events (MACE) free survival and area under the receiver-operating-characteristic curve (AUC). Results Follow up beyond 2-years was available in 323 patients. MACE-free survival rate was greater among patients with normal combined CTA/CTP findings compared to ICA/SPECT: 85 vs. 80% (95% confidence interval [CI] for difference 0.1, 11.3) though event-free survival time was similar (4.54 vs. 4.37 years, 95% CI for difference: 0.03, 0.36). Abnormal results by combined CTA/CTP was associated with 3.83 years event-free survival vs. 3.66 years after abnormal combined ICA/SPECT (95% CI for difference: 0.05, 0.39, CI −1.0, 11.1) (Figure). Predicting MACE by AUC also was similar: 65 vs. 65 (difference 0.1; 95% CI: −4.6, 4.9). When MACE was restricted to death, myocardial infarction, or stroke, AUC for CTA/CTP was 66 vs. 61 by ICA/SPECT (difference 5.1; 95% CI: −7.1, 12.9). Conclusions Combined CTA/CTP yield similar 5-year prognostic performance as joined ICA/SPECT assessment in patients presenting with suspected coronary heart disease and thus may represent a fast, non-invasive alternative to the traditional diagnostic approach. Figure 1. 5-year event-free survival Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): National Institutes of Health

ObjectiveTo assess the feasibility, safety, and efficacy of intracoronary allogeneic cardiosphere-derived cells (CAP-1002) in patients with Duchenne muscular dystrophy (DMD).MethodsThe Halt Cardiomyopathy Progression (HOPE)-Duchenne trial is a phase I/II, randomized, controlled, open-label trial (NCT02485938). Patients with DMD >12 years old, with substantial myocardial fibrosis, were randomized (1:1) to usual care (control) or global intracoronary infusion of CAP-1002 (75 million cells). Participants were enrolled at 3 US medical centers between January and August 2016 and followed for 12 months. An independent Data and Safety Monitoring Board provided safety oversight. Cardiac function and structure were assessed by MRI, and analyzed by a blinded core laboratory. Skeletal muscle function was assessed by performance of the upper limb (PUL).ResultsTwenty-five eligible patients (mean age 17.8 years; 68% wheelchair-dependent) were randomized to CAP-1002 (n = 13) or control (n = 12). Incidence of treatment-emergent adverse events was similar between groups. Compared to baseline, MRI at 12 months revealed significant scar size reduction and improvement in inferior wall systolic thickening in CAP-1002 but not control patients. Mid-distal PUL improved at 12 months in 8 of 9 lower functioning CAP-1002 patients, and no controls (p = 0.007).ConclusionsIntracoronary CAP-1002 in DMD appears safe and demonstrates signals of efficacy on both cardiac and upper limb function for up to 12 months. Thus, future clinical research on CAP-1002 treatment of DMD cardiac and skeletal myopathies is warranted.Classification of evidenceThis phase I/II study provides Class II evidence that for patients with DMD, intracoronary CAP-1002 is feasible and appears safe and potentially effective.

BACKGROUND: Serum N-terminal pro–B-type natriuretic peptide (NT-proBNP) is considered a marker that is expressed in response to myocardial strain and possibly fibrosis. However, the relationship to myocardial fibrosis in a community-based population is unknown. OBJECTIVES: The authors evaluated the relationship between cardiac magnetic resonance (CMR) measures of fibrosis and NT-proBNP levels in the MESA (Multi-Ethnic Study of Atherosclerosis) study. METHODS: A total of 1,334 participants (52% white, 23% black, 11% Chinese, 14% Hispanic, and 52% men with a mean age of 67.6 years) at 6 sites had both serum NT-proBNP measurements and CMR with T1 mapping of indices of fibrosis at 1.5 T. Univariate and multivariable regression analyses adjusting for demographics, cardiovascular risk factors, and left ventricular (LV) mass were performed to examine the association of log NT-proBNP with CMR T1 mapping indices. RESULTS: In the fully adjusted model, each 1-SD increment (0.44 pg/ml) of log NT-proBNP was associated with a0.62% increment in extracellular volume fraction (p < 0.001), 0.011 increment in partition coefficient (p < 0.001), and 4.7-ms increment in native T1 (p = 0.001). Results remained unchanged after excluding individuals with clinical cardiovascular disease or late gadolinium enhancement (n = 167), and after replacing LV mass by LV end-diastolic volume in the regression models. CONCLUSIONS: Elevated NT-proBNP is related to subclinical fibrosis in a community-based setting. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487) (J Am Coll Cardiol 2017;70:3102–9) Published by Elsevier on behalf of the American College of Cardiology Foundation.

Background CT allows evaluation of atherosclerosis, coronary stenosis, and myocardial ischemia. Data on the characterization of ischemia and no obstructive stenosis (INOCA) at CT remain limited. Purpose This was an observational study to describe the prevalence of INOCA defined at coronary CT angiography with CT perfusion imaging and associated clinical and atherosclerotic characteristics. The analysis was also performed for the combination of invasive coronary angiography (ICA) and SPECT as a secondary aim. Materials and Methods The prospective CORE320 study (ClinicalTrials.gov: NCT00934037) enrolled participants between November 2009 and July 2011 who were symptomatic and referred for clinically indicated ICA. Participants underwent CT angiography, rest-adenosine stress CT perfusion, and rest-stress SPECT prior to ICA. For this ancillary study, the following three phenotypes were considered, using either CT angiography/CT perfusion or ICA/SPECT data: (a) participants with obstructive (≥50%) stenosis, (b) participants with no obstructive stenosis but ischemia (ie, INOCA) on the basis of abnormal perfusion imaging results, and (c) participants with no obstructive stenosis and normal perfusion imaging results. Clinical characteristics and CT angiography atherosclerotic plaque measures were compared by using the Pearson χ2 or Wilcoxon rank-sum test. Results A total of 381 participants (mean age, 62 years [interquartile range, 56-68 years]; 129 [34%] women) were evaluated. A total of 31 (27%) of 115 participants without obstructive (≥50%) stenosis at CT angiography had abnormal CT perfusion findings. The corresponding value for ICA/SPECT was 45 (30%) of 151. The prevalence of INOCA was 31 (8%) of 381 (95% confidence interval [CI]: 5%, 11%) with CT angiography/CT perfusion and 45 (12%) of 381 (95% CI: 9%, 15%) with ICA/SPECT. Participants with CT-defined INOCA had greater total atheroma volume (118 vs 60 mm3, P = .008), more positive remodeling (13% vs 1%, P = .006), and greater low-attenuation atheroma volume (20 vs 10 mm3, P = .007) than participants with no obstructive stenosis and no ischemia. Comparisons for ICA/SPECT showed similar trends. Conclusion In CORE320, ischemia and no obstructive stenosis (INOCA) prevalence was 8% and 12% at CT angiography/CT perfusion and invasive coronary angiography/SPECT, respectively. Participants with INOCA had greater atherosclerotic burden and more adverse plaque features at CT compared with those with no obstructive stenosis and no ischemia. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Francois in this issue.

Background Longitudinal change in left atrial (LA) structure and function could be helpful in predicting risk for incident AF. We used cardiac magnetic resonance (CMR) imaging to explore the relationship between change in LA structure and function and incident AF in a multi-ethnic population free of clinical cardiovascular disease at baseline. Methods and results In the Multi-Ethnic Study of Atherosclerosis (MESA), 2338 participants, free at baseline of clinically recognized AF and cardiovascular disease, had LA volume and function assessed with CMR imaging, at baseline (2000–02), and at Exam 4 (2005–07) or 5 (2010–12). Free of AF, 124 participants developed AF over 3.8±0.9 years (to 2015) following the second imaging. In adjusted Cox regression models, an average annualized change in all LA parameters were significantly associated with an increased risk of AF. An annual decrease of 1–SD unit in total LA emptying fractions (LAEF) was most strongly associated with risk of AF after adjusting for AF clinical risk factors, baseline LA parameters and left ventricular mass-to-volume ratio (hazard ratio per SD=1.91,95% confidence interval=1.53–2.38, P Model discrimination, NRI and IDI Model: CHARGE-AF risk factors# + Baseline LA variable + ΔLA variable CHARGE-AF ΔLAVImin (mL/m2/y) ΔTotal LAEF (%/y) ΔPeak LA Strain (%/y) C-statistic (95% CI) 0.757 (0.721–0.794) 0.787 (0.749–0.824) 0.779 (0.737–0.820) 0.770 (0.732–0.808) NRI† (p-value) – 0.000 (0.991) 0.107 (0.017) 0.017 (0.634) IDI (p-value) – 0.049 (5%. *Model calibration: Grønnesby and Borgan's modified Hosmer-Lemeshow chi-square statistic for survival analysis. Kaplan-Meier curves of ΔTotal LAEF Conclusion In this multi-ethnic study population free of clinical cardiovascular disease at baseline, a greater increase in LA volumes and decrease in LA function were associated with incident AF. The addition of change in total LAEF to risk prediction models for AF improved model discrimination and reclassification of AF risk. Acknowledgement/Funding This research was supported by contracts HHSN2682015ehz745.01623I,N01-HC-95159-69 from the NHLBI and UL1-TR-ehz745.016240,UL1-TR-001079,R01-HL-127659 from NIH

Aims Longitudinal change in left atrial (LA) structure and function could be helpful in predicting risk for incident atrial fibrillation (AF). We used cardiac magnetic resonance (CMR) imaging to explore the relationship between change in LA structure and function and incident AF in a multi-ethnic population free of clinical cardiovascular disease at baseline. Methods and results In the Multi-Ethnic Study of Atherosclerosis (MESA), 2338 participants, free at baseline of clinically recognized AF and cardiovascular disease, had LA volume and function assessed with CMR imaging, at baseline (2000–02), and at Exam 4 (2005–07) or 5 (2010–12). Free of AF, 124 participants developed AF over 3.8 ± 0.9 years (2015) following the second imaging. In adjusted Cox regression models, an average annualized change in all LA parameters were significantly associated with an increased risk of AF. An annual decrease of 1-SD unit in total LA emptying fractions (LAEF) was most strongly associated with risk of AF after adjusting for clinical risk factors for AF, baseline LA parameters, and left ventricular mass-to-volume ratio (hazard ratio per SD = 1.91, 95% confidence interval = 1.53–2.38, P Conclusion In this multi-ethnic study population free of clinical cardiovascular disease at baseline, a greater increase in LA volumes and decrease in LA function were associated with incident AF. The addition of change in total LAEF to risk prediction models for AF improved model discrimination and reclassification of AF risk.

Background Ongoing advancements of coronary computed tomographic angiography (CTA) continue to challenge the role of invasive coronary angiography (ICA) as the gold standard for the evaluation of coronary artery disease (CAD). We sought to investigate the diagnostic accuracy of 320-slice CTA for detecting obstructive CAD in reference to ICA and nuclear myocardial perfusion imaging using single-photon emission computed tomography. Methods For the CORE320 study (Coronary Artery Evaluation Using 320-Row Multidetector Computed Tomography Angiography and Myocardial Perfusion), 381 patients at 16 centers underwent CTA, nuclear myocardial perfusion imaging by single-photon emission computed tomography, and ICA for the evaluation of CAD. Imaging studies were analyzed in blinded core laboratories, and a stenosis of ≥50% by quantitative coronary angiography was considered obstructive, whereas a stress difference score of ≥1 indicated inducible myocardial ischemia. The area under the receiver operating characteristic curve was used to evaluate diagnostic accuracy. Results Of 381 patients, 229 (60%) had obstructive CAD by quantitative coronary angiography. Diagnostic accuracy of CTA on a per-patient analysis revealed an area under the receiver operating characteristic curve of 0.90 (95% CI, 0.87–0.93). Per-vessel and per-segment analysis revealed lower area under the receiver operating characteristic curve of 0.87 (0.84–0.90) and 0.81 (0.78–0.83), respectively. Median radiation dose was lower for CTA versus ICA: 3.16 (interquartile range, 2.82–3.59) versus 11.97 (interquartile range, 7.60–17.8) mSv ( P P >0.05). Furthermore, accuracy for identifying patients who subsequently underwent clinically driven coronary revascularization also was similar for CTA (0.76 [0.71–0.81]) and ICA (0.78 [0.74–0.83]; P =0.20). Conclusions Contemporary CTA accurately identifies patients with obstructive CAD by ICA at lower radiation exposure; however, agreement is lower in vessel- and segment-level analyses. Both CTA and ICA perform similarly for predicting clinically driven revascularization and for detecting myocardial ischemia by myocardial perfusion imaging using single-photon emission computed tomography, suggesting that limitations by both CTA and ICA contribute to variability of stenosis quantification. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00934037.

Pancreatic tuberculosis is extremely rare and its clinical and radiological findings are similar to those of pancreatic malignancy. The diagnosis of pancreatic tuberculosis is not usually made prior to surgery. Here, we report a case of pancreatic tuberculosis, presented with abdominal pain and weight loss. Abdominal computed tomography (CT) showed a 62 mm × 32 mm septate solid-cystic mass in the pancreatic head area with extension into the hilum of the liver. There was no evidence of inflammation or pancreatitis. Endoscopic ultrasound-fine needle aspiration (EUSFNA) could not yield the diagnosis. Exploratory laparotomy and further pathological evaluation suggested pancreatic tuberculosis. Response to antituberculosis treatment confirmed the diagnosis. Finally, previous case reports and case studies of pancreatic tuberculosis in the literature are fully investigated.

Background—The association of cardiovascular diseases (CVD) with liver fibrosis is poorly understood. We aim to assess the association of liver fibrosis by T1-mapping magnetic resonance imaging and CVD in MESA (Multi-Ethnic Study of Atherosclerosis).Methods and Results—MESA enrolled 6814 participants free of clinical CVD at baseline (2000–2002). A subsample of participants underwent T1-mapping magnetic resonance imaging 10 years after the baseline (Y10 MESA exam, 2010–2012). Liver T1 maps were generated avoiding vessels and biliary ducts from which native T1 (n=2087) and extracellular volume fraction (ECV, n=1234) were determined. Higher ECV and native T1 were indicators of liver fibrosis. Linear regression analysis evaluated the cross-sectional relationship between liver native T1 and ECV at Y10 MESA exam with a history of CVD events (atrial fibrillation, heart failure, and coronary heart disease [CHD]). Of the 2087 participants (68.7±9.1 years; 46% females), 153 had prior CVD events (78 atrial fibrillation, 25 heart failure, and 78 CHD). History of CVD events was associated with 18.5 ms higher liver native T1 (PP=0.06). Prior atrial fibrillation was related to higher liver native T1 (β=21.1;P=0.001) and greater ECV (β=2.2;P=0.02), whereas previous heart failure was associated with greater liver ECV (β=4.1;P=0.02). There was also a relationship of prior CHD with liver native T1 (β=13;P=0.05) and ECV (β=1.9;P=0.05), which was attenuated by adjustment for coronary artery calcium score (β=7.1 and 1.6;P=0.37 and 0.13, respectively).Conclusions—Liver fibrosis by T1-mapping magnetic resonance imaging is associated with history of heart failure, atrial fibrillation, and CHD in a multiethnic cohort. The association of liver fibrosis and CHD is at least in part mediated by atherosclerosis.

Cell therapy is increasingly seen as a viable technique to recover myocardial function by reverse remodeling. The goal of cell therapy is the functional recovery of the heart and consequently prognostic improvement, but the results of prior research has been inconsistent and controversial. Basic science experiments have also shown that cell therapy may improve myocardial function by reducing myocardial fibrosis and promoting the growth of active myocytes. From the aspect of imaging, late gadolinium enhancement imaging alone may not be sufficient to identify the effects of cell therapy. T1 mapping with its’ increased sensitivity to detect diffuse interstitial fibrosis may be seen as a viable and attractive endpoint, particularly, as it pertains to subtle changes in the structure of the underlying extracellular matrix. T1 mapping has also shown prognostic value in studies in participants with non-ischemic cardiomyopathy. The rationale to use T1 mapping in stem cell therapy exists on its utility to assess current disease status, as well as the assessment of future prognosis.

Aims To determine the diagnostic accuracy of semi-automatic quantitative metrics compared to expert reading for interpretation of computed tomography perfusion (CTP) imaging. Methods The CORE320 multicenter diagnostic accuracy clinical study enrolled patients between 45 and 85 years of age who were clinically referred for invasive coronary angiography (ICA). Computed tomography angiography (CTA), CTP, single photon emission computed tomography (SPECT), and ICA images were interpreted manually in blinded core laboratories by two experienced readers. Additionally, eight quantitative CTP metrics as continuous values were computed semi-automatically from myocardial and blood attenuation and were combined using logistic regression to derive a final quantitative CTP metric score. For the reference standard, hemodynamically significant coronary artery disease (CAD) was defined as a quantitative ICA stenosis of 50% or greater and a corresponding perfusion defect by SPECT. Diagnostic accuracy was determined by area under the receiver operating characteristic curve (AUC). Results Of the total 377 included patients, 66% were male, median age was 62 (IQR: 56, 68) years, and 27% had prior myocardial infarction. In patient based analysis, the AUC (95% CI) for combined CTA-CTP expert reading and combined CTA-CTP semi-automatic quantitative metrics was 0.87(0.84–0.91) and 0.86 (0.83–0.9), respectively. In vessel based analyses the AUC's were 0.85 (0.82–0.88) and 0.84 (0.81–0.87), respectively. No significant difference in AUC was found between combined CTA-CTP expert reading and CTA-CTP semi-automatic quantitative metrics in patient based or vessel based analyses(p > 0.05 for all). Conclusion Combined CTA-CTP semi-automatic quantitative metrics is as accurate as CTA-CTP expert reading to detect hemodynamically significant CAD.

Limited information exists on the longitudinal association between the left ventricular (LV) structure and function and future cognitive impairment and dementia in a large population without clinically recognized cardiovascular disease at baseline. The aim of the present study was to investigate the association between cardiac structure and function and risk of dementia and cognitive impairment in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort. Measures of LV structure and function were determined using magnetic resonance imaging at baseline in 4999 participants free of clinically diagnosed cardiovascular disease and dementia. Probable incident clinical dementia was ascertained from hospitalization discharge records. Cognitive function was evaluated using tests addressing global cognitive function, processing speed, and memory. Associations of measures of LV structure and function with the incidence of clinically diagnosed dementia and cognitive performance were evaluated using Cox proportional hazard regression models adjusted for demographics, cardiovascular risk factors, and cardiovascular events. During a median follow-up of 12 years, 130 probable incident dementia cases were documented. Higher LV mass index (hazard ratio, 1.01; 95% confidence interval, 1.00–1.02) and LV mass-to-volume ratio (hazard ratio, 2.37; 95% confidence interval, 1.25–4.43) were independently associated with incident dementia and impaired cognitive function. Measures of LV function were not associated with risk of dementia or cognitive impairment. In conclusion, in a multiethnic cohort of participants without clinically detected cardiovascular disease and dementia at baseline, LV hypertrophy and concentric remodeling were independently associated with incident dementia and cognitive impairment.

Background Although the association between coronary artery calcium ( CAC ) and future heart failure ( HF ) has been shown previously, the value of CAC progression in the prediction of HF has not been investigated. In this study, we investigated the association of CAC progression with subclinical left ventricular ( LV ) dysfunction and incident HF in the Multi‐Ethnic Study of Atherosclerosis. Methods and Results The Multi‐Ethnic Study of Atherosclerosis is a population‐based study consisting of 6814 men and women aged 45 to 84, free of overt cardiovascular disease at enrollment, who were recruited from 4 ethnicities. We included 5644 Multi‐Ethnic Study of Atherosclerosis participants who had baseline and follow‐up cardiac computed tomography and were free of HF and coronary heart disease before the second cardiac computed tomography. Mean (± SD ) age was 61.7±10.2 years and 47.2% were male. The Cox proportional hazard models and multivariable linear regression models were deployed to determine the association of CAC progression with incident HF and subclinical LV dysfunction, respectively. Over a median follow‐up of 9.6 (interquartile range: 8.8–10.6) years, 182 participants developed incident HF . CAC progression of 10 units per year was associated with 3% of increased risk of HF independent of overt coronary heart disease ( P =0.008). In 2818 participants with available cardiac magnetic resonance images, CAC progression was associated with increased LV end diastolic volume (β=0.16; P =0.03) and LV end systolic volume (β=0.12; P =0.006) after excluding participants with any coronary heart disease. Conclusions CAC progression was associated with incident HF and modestly increased LV end diastolic volume and LV end systolic volume at follow‐up exam independent of overt coronary heart disease.

Electrocardiography (ECG) is a practical and cost-effective clinical tool. Machine learning may enable identification of novel ECG variables for predicting incident atrial fibrillation (AF). We included 3151 participants from MESA with 568 baseline ECG variables each in addition to demographic

Although liver biopsy is an invasive procedure, it remains the gold standard technique for the evaluation of hepatic fibrosis in different patients, including those with major thalassemia (MT). Recently, noninvasive imaging techniques, such as transient elastography, have emerged. We investigated the effectiveness of TE, in comparison to liver biopsy, for the evaluation of liver fibrosis in pediatric patients with MT who were candidates for hematopoietic stem cell transplantation (HSCT). Eighty-three pediatric MT patients (48 boys and 35 girls), who were candidates for HSCT, were included in this study. The median age was 8 years. Liver stiffness was assessed for all patients, before transplantation, using both TE, measured in kilopascals (kPa) and liver biopsy, based on the Metavir score. The diagnostic accuracy of TE and liver biopsy were estimated using linear discriminated analysis (the area under the receiver operating characteristic curves [AUROCs]). The median TE score was 4.3 kPa (range, 3.5 to 5.2). The TE value did not differ among patients with different ferritin levels (P = .53). TE increased proportionally to Metavir fibrosis stages (P < .001) and the necro-inflammatory grade (P

There is no consensus regarding the benefit of eradicating Helicobacter pylori (H. pylori) infection in patients with functional dyspepsia (FD). We intended to compare the symptom response to H. pylori eradication in FD patients in presence or absence of microscopic duodenitis (MD).Patients with dyspepsia, normal upper gastrointestinal endoscopy and no psychological comorbidity according to the 12-item General Health Questionnaire underwent duodenal biopsy sampling. Of those, subjects with positive rapid urease test and H. pylori colonization in Wright-Giemsa staining were included in the study and evaluated histologically for presence of MD. All patients received sequential H. pylori eradication therapy and underwent urea breath test 4 weeks after the completion of the treatment to confirm the H. pylori eradication. The severity of dyspepsia was assessed using the Leeds Dyspepsia Questionnaire (LDQ) at baseline, 3rd and 6th months after the H. pylori infection was eradicated.Thirty seven patients were included in the study [mean age: 34.9 (8.1), 54.05 % female]. MD was observed in 16 (43.2 %) of the subjects. The mean LDQ score in patients with MD decreased from 12.5 (4.1) at baseline to 4.3 (2.1) at 3rd month and 2.6 (1.9) at 6th month. In patients without microscopic duodenitis, the mean LDQ score decreased from 10.6 (5.2) at baseline to 6.8 (4.1) and 6.2 (3.8) at 3rd and 6th months, respectively. The improvement in severity of symptoms in presence of MD was significantly greater than when it was absent (P0.001).FD patients with MD achieved greater symptomatic response with H. pylori eradication than those without microscopic duodenitis.

Results: TE values increased proportional to fibrosis stage (r = 0.404, P < 0.001), but was independent of T2-weighted MRI-LIC (r = 0.064, P = 0.581). In multivariate analysis, fibrosis stage was still associated with the log-transformed TE score(standardized b= 0.42 for F4 stage of METAVIR, P = 0.001). No correlation was noted between LIC and TE score (standardized b= 0.064, P = 0.512). The area under the receiver operating characteristic curve for prediction of cirrhosis was 80% (95% confidence interval, 59–100%). A cut-off TE score of 11 had a sensitivity of 78% and specificity of 88.1% for diagnosing cirrhosis. The best cut-off values for “TE-FIB-4 cirrhosis score” comprising TE and FIB-4 and “TE-APRI cirrhosis score” combining TE with aspartate aminotransferase-to-platelet ratio index (APRI) both had 87.5% sensitivity and 91.04% specificity for the diagnosis of cirrhosis. Conclusion: Regardless of LIC, TE alone or when combined with FIB-4 or APRI, is a diagnostic tool with moderate to high accuracy to evaluate liver fibrosis in CHC patients with betathalassemia. However, because splenectomy in a proportion of our subjects might have affected the platelet count, the scores utilizing APRI and FIB-4 should be interpreted cautiously.

Supplemental Digital Content is available in the text, Background and Aims: Although several studies have suggested opium as a risk factor for cancers of the esophagus, stomach, larynx, lung, and bladder, no previous study has examined the association of opium with pancreatic cancer. We aimed to study the association between opium use and risk of pancreatic cancer in Iran, using a case-control design. We also studied the association of cigarette smoking and alcohol consumption with pancreatic cancer, for which little information was available from this population. Methods: Cases and controls were selected from patients who were referred to 4 endoscopic ultrasound centers in Tehran, Iran. We recruited 316 histopathologically (all adenocarcinoma) and 41 clinically diagnosed incident cases of pancreatic cancer, as well as 328 controls from those with a normal pancreas in enodosonography from January 2011 to January 2015. We used logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: After adjustment for potential confounders, opium use (OR 1.91; 95% CI 1.06–3.43) and alcohol consumption (OR 4.16; 95% CI 1.86–9.31) were significantly associated with an increased risk of pancreatic cancer. We did not find an association between ever tobacco smoking and pancreatic cancer risk (OR 0.93; 95% CI 0.62–1.39). Conclusion: In our study, opium use and alcohol consumption were associated with an increased risk of pancreatic cancer, whereas cigarette smoking was not.

Objective To identify independent predictors of mental and physical health in patients with viral hepatitis. Methods Hepatitis C (HCV) and hepatitis B (HBV) infected patients, and community control subjects with equal age and sex distribution were recruited. All subjects filled in personal characteristics questionnaire, Hospital Anxiety and Depression Scale (HADS), Iowa Fatigue Scale (IFS), and Medical Outcomes Survey Short Form-12 (SF-12). All patients had measurement of routine laboratory values, and some had recent liver biopsy. Regression analyses were used to identify predictors of physical and mental health. Results One hundred eighty nine subjects (162 males, 27 females, for each group N = 63) with mean (± SD) age of 39 ± 11 years were included. Anxiety and depression were important predictors of SF-12 (and its subscales MCS and PCS) and IFS scores, whereas IFS scores independently predicted HADS, PCS, MCS, and SF-12 scores. After controlling for confounders, HCV infection was independently associated with impairment of physical health. Moreover, creatinine showed an inverse strong relation with fatigue. Genotype 3a of HCV was independently associated with depressed and anxious states, whereas higher inflammation grade was significantly related to depression. Marital status, non-psychiatric comorbidities, and history of alcohol abuse also predicted health scores in the patients. Adjusted R 2 s for linear models were 0.571 to 0.709, whereas areas under the receiver operating characteristic (ROC) curve for logistic models were 0.90 to 0.93. Conclusion In viral hepatitis patients, besides mental and medical comorbidities, marital status, and alcohol abuse, HCV infection itself is associated with impaired physical and possibly mental health.

To evaluate the microscopic histopathological changes in duodenal tissue and its relationship to the severity of symptoms in patients with functional dyspepsia while taking the effect of Helicobacter pylori (H. pylori) infection into account. Several gastric and duodenal biopsy specimens were obtained in 217 patients with functional dyspepsia and were evaluated for H. pylori infection and histopathological changes. Severity of symptoms was assessed by Leeds Dyspepsia Questionnaire (LDQ) and its relationship to histopathological changes and H. pylori infection status was assessed. Helicobacter pylori infection was associated with presence and severity of microscopic duodenitis (p

Data on the association of adipokines and atrial fibrillation (AF) is not consistent in the literature. This study aimed at exploring the association of adiponectin with incident AF as well as left atrial (LA) structure and function in the Multi-Ethnic Study of Atherosclerosis (MESA). MESA enrolled

Objective: Our objective was to develop an approach for selecting combinatorial markers of pathology from diverse clinical data types. We demonstrate this approach on the problem of pancreatic cyst classification. Materials and Methods: We analyzed 1026 patients with surgically resected pancreatic cysts, comprising 584 intraductal papillary mucinous neoplasms, 332 serous cystadenomas, 78 mucinous cystic neoplasms, and 42 solid-pseudopapillary neoplasms. To derive optimal markers for cyst classification from the preoperative clinical and radiological data, we developed a statistical approach for combining any number of categorical, dichotomous, or continuous-valued clinical parameters into individual predictors of pathology. The approach is unbiased and statistically rigorous. Millions of feature combinations were tested using 10-fold cross-validation, and the most informative features were validated in an independent cohort of 130 patients with surgically resected pancreatic cysts. Results: We identified combinatorial clinical markers that classified serous cystadenomas with 95% sensitivity and 83% specificity; solid-pseudopapillary neoplasms with 89% sensitivity and 86% specificity; mucinous cystic neoplasms with 91% sensitivity and 83% specificity; and intraductal papillary mucinous neoplasms with 94% sensitivity and 90% specificity. No individual features were as accurate as the combination markers. We further validated these combinatorial markers on an independent cohort of 130 pancreatic cysts, and achieved high and well-balanced accuracies. Overall sensitivity and specificity for identifying patients requiring surgical resection was 84% and 81%, respectively. Conclusions: Our approach identified combinatorial markers for pancreatic cyst classification that had improved performance relative to the individual features they comprise. In principle, this approach can be applied to any clinical dataset comprising dichotomous, categorical, and continuous-valued parameters.

Background: Inflammatory biomarkers have been used for cardiovascular disease (CVD) risk stratification. However, the relevance of longitudinal changes in levels of these biomarkers in relation to CVD is unclear. Methods: MESA is a population-based cohort consisting of 6814 participants free of symptomatic cardiovascular disease at baseline. We included all participants who had blood assayed for measurement of inflammatory biomarkers - C-reactive protein (CRP), Interleukin-6 (IL-6), and fibrinogen measured at baseline and follow-up 2-4 years later (n=1,362). Coronary heart disease (CHD) was assessed as any of myocardial infarction, resuscitated cardiac arrest, definite angina, probable angina (if followed by revascularization) and CHD death. CVD was considered a composite of CHD, stroke, stroke death, atherosclerotic death and CVD death. Cox proportional hazard regression analysis was used to assess the association of annual longitudinal changes in inflammatory biomarker level and time to first CHD and CVD event after adjustment for traditional risk factors and demographics. Results: The mean (SD) age was 61.6 (9.8) years and 55% were male. Over 8.6 median (IQR, 8.4-9.3) years of follow-up, there were 87 CHD and 121 CVD events. The median (IQR) CRP (mg/L), IL-6 (pg/ml) and fibrinogen (mg/dl) levels at baseline were 1.74(0.82-3.95) 1.11(0.71-1.72) and 332(292-382); and at follow-up were 1.4(0.69-3.03), 1.76(1.16-2.72) and 421(371-476). An increase in IL6 of 1 pg/mL/year was associated with a 26% increased risk of total CVD events independent of risk factors, while an increase of 1 mg/L/year of CRP was independently associated with a 7% and 6% increased risk of both CHD and CVD events respectively. There were no significant associations with changes in fibrinogen. Conclusion: Longitudinal increases in the inflammatory biomarkers CRP and IL6 are associated with higher risk of future cardiovascular events in a multi-ethnic population.

Intraductal papillary mucinous neoplasms (IPMNs) have malignant potential and can progress from low- to high-grade dysplasia to invasive adenocarcinoma. The management of patients with IPMNs is dependent on their risk of malignant progression, with surgical resection recommended for patients with branch-duct IPMN (BD-IPMN) who develop high-risk features. There is increasing evidence that liver transplant (LT) patients are at increased risk of extrahepatic malignancy. However, there are few data regarding the risk of progression of BD-IPMNs in LT recipients. The aim of this study was to determine whether LT recipients with BD-IPMNs are at higher risk of developing high-risk features than patients with BD-IPMNs who did not receive a transplant. Consecutive patients who underwent an LT with BD-IPMNs were included. Patients with BD-IPMNs with no history of immunosuppression were used as controls. Progression of the BD-IPMNs was defined as development of a high-risk feature (jaundice, dilated main pancreatic duct, mural nodule, cytology suspicious or diagnostic for malignancy, cyst diameter ≥3 cm). Twenty-three LT patients with BD-IPMN were compared with 274 control patients. The median length of follow-up was 53.7 and 24.0 months in LT and control groups, respectively. Four (17.4%) LT patients and 45 (16.4%) controls developed high-risk features (P = 0.99). In multivariate analysis, progression of BD-IPMNs was associated with age at diagnosis but not with LT. There was no statistically significant difference in the risk of developing high-risk features between the LT and the control groups. Liver Transpl 20:1462-1467, 2014. © 2014 AASLD.

Necrosis of distal portion of skin flaps due to ischemia still remains a problem in plastic surgery. Following ischemia, a cascade of deleterious events including over-activity of Na þ –H þ Exchanger (NHE) takes place. In present study we evaluated the effect of the potent NHE inhibitor, 5-(N-ethyl-Nisopropyl) amiloride (EIPA) on ischemic tissue injury in a skin flap model, and investigated the role of mitochondrial ATP-sensitive K þ channels (KATP) in this phenomenon. Seventy-eight rats were randomly divided into thirteen treatment groups (6 rats each). Four groups received different doses of EIPA in the flap. EIPA/GLY group received an effective dose of a KATP channel blocker, glibenclamide (GLY, 0.3 mg/ kg) intraperitoneally (i.p.) 30 min before raising the flap, and a local effective dose of EIPA (0.1 mM) immediately after raising the flap. EIPA/diazoxide group (EIPA/DIA) received a sub-effective dose of diazoxide (7.5 mg/kg i.p.) 30 min before raising the flap and a local sub-effective dose of EIPA (0.075 mM). EIPA 0.1 and 0.2 mM significantly increased flap survival area compared to control group (56.017 6.1%, Po 0.001). The protective effect of EIPA (0.1 mM) was abolished by administration of glibenclamide (0.3 mg/kg i.p.). Co-administration of a sub-effective dose of EIPA (0.075 mM), with a sub-effective dose of diazoxide (7.5 mg/kg i.p.) significantly improved flap survival (Po0.05). We demonstrated that the NHE inhibitor, EIPA can increase random pattern skin flap survival. Administration of diazoxide potentiates this effect, while glibenclamide abolishes that, implicating that the protective effect of EIPA is mediated through mitochondrial-K ATP channels.

We present the long-term results of simultaneous "teapot" ureterocystoplasty and ureteral Mitrofanoff in patients with bilateral megaureters due to neurogenic bladder, and compare urodynamic results before and after the procedure.We treated 13 children (mean age 7.3 years) with end stage neurogenic bladder and refluxing megaureters (mean diameter 5.5 cm) with simultaneous teapot ureterocystoplasty and Mitrofanoff appendicovesicostomy between April 1995 and May 2001. The larger ureter was used for teapot bladder augmentation while keeping its distal 2 cm tubularized. The Mitrofanoff channel was then created using the opposite ureter.Followup ranged from 109 to 169 months (median 121). At the end of the followup period all patients were dry with clean intermittent catheterization and/or voiding. No repeat augmentation was needed and there were no bladder calculi during followup. Median postoperative bladder capacity was 430 ml (IQR 380 to 477), which was increased significantly compared to preoperative evaluations (210 ml, IQR 181 to 230, p = 0.001). During followup bladder compliance also improved significantly (p = 0.001) and serum creatinine level decreased (p = 0.021).Although neurogenic bladder and high grade reflux are poor prognostic factors for ureterocystoplasty, the present modification resulted in enduring bladder augmentation with no calculus formation. Bladders remained compliant with good capacity, presumably because sufficient tissue and blood supply were provided for the augmented flap.

Back ground and Aim: Pancreatic exocrine cancer (PC) is a deadly disease with a 5-year survival of less than 5%, and its etiology is largely unknown. We aimed to study risk factors, epidemiologic features, and survival of PC patients in Iran, using a case-control design. Methods: Cases and controls were selected from patients who were referred to four endoscopic ultrasound centers in Tehran, Iran. We recruited 307 histopathologically (n= 266, all adenocarcinoma) or clinically (n=41) diagnosed incident cases of PC, as well as 322 controls from those who had normal pancreas in enodosonography from January 2011 to March 2014. Results: Mean (±SD) age of cases and controls were 64.8 (±11.4) and 64.6 (±11.8) years and 180 (58.6%) cases and 144 (44.7%) of controls were male, respectively. Opium use was associated with an increased risk (OR 2.06; 95% CI 1.15-3.68) of pancreatic cancer. We did not find a significant association between ever tobacco smoking and PC risk. The median overall survival was 6.3 months and PC cases with pancreatic mass ≤ 3 cm, surgically respectable tumor, and ≥13 years of education had longer survival. Cases who were current opium user had a worse prognosis. Curative surgery was possible in only 16 cases (5.2%). Conclusion: PC presents at a very advanced stage, generally with an unsatisfactory outcome. This study suggests that opium use may be as an important risk factor of PC in Iran.

Purpose: To evaluate the feasibility of screening for retinopathy of prematurity (ROP) by assessing the pupillary response to mydriatics. Methods: This observational case series included 134 eyes of 67 premature infants with birth weight less than 2,000 grams and gestational age less than 33 weeks. A composite eye drop composed of phenylephrine 1%, tetracaine and tropicamide 0.5% was applied 3 times within 5?minute intervals and pupil diameters were measured. The eyes were examined by experienced ROP specialists using an indirect ophthalmoscope. Zone and stage of ROP, presence of plus disease and need for treatment were recorded. The relationship between the pupillary response to mydriatics, and presence and severity of ROP was evaluated. Logistic regression was used for statistical analysis. Results: According to receiver operating characteristic (ROC) curve analysis, final pupil diameter after mydriatic administration was found the most accurate factor among other factors to recognize ROP zone I from zones II and III (Area under ROC: 0.92 [95%CI: 0.85?0.98]). The best cutoff value for final pupil diameter was 5.6 mm, because it could differentiate involvement of zone I from zones II and III with sensitivity of 80% and specificity of 100%. Conclusion: Response of the pupil to mydriatic eye drops may be useful as a less invasive method for rough estimation of ROP in high risk babies who need emergent attention; however, it cannot be considered as a screening test due to its low sensitivity.

Department of Surgery, University of Minnesota, Minneapolis, USAMany studies have focused on the role of irregularmucosal immune response, but there are noteworthyevidences regarding the role of ischemia in pathogen-esis of ulcerative colitis (UC). Hypoxia-induciblefactor-1 alpha (HIF1a) is an intranuclear proteinwhich is produced by decreased level of intracellularoxygen level. Increased levels of HIF1a in tissuespecimens and high levels of vascular endothelialgrowth factor (VEGF) in serum samples of UCpatients are novel findings, strongly congruent withthe role of ischemia in UC pathogenesis. The aim ofthis study is to evaluate the value of tissue hypoxia incellular level in pathogenesis of UC [1–3].Forty subjects in four groups were enrolled inour case control study as follows: 1) ten patientswithleftUC(toobtainbiopsyspecimensfromsparingpartsofthecolon);2)tenhealthyindividuals(referreddue to screening purposes); 3) ten formalin-fixedparaffin-embedded (FFPE) tissue samples frompatients with mesenteric ischemia; and 4) ten FFPEsamples from patients with infectious colitis. Subjectsin group 1 and 2 underwent colonoscopy. In group 1,two biopsy samples were taken, one from ulcerativetissue, and the other from spared intestinal tissue.In group 2, biopsy specimens were obtained from theleft colon. All subjects were evaluated for tissue hyp-oxia by a single expert pathologist utilizing HIF1aimmunohistochemical staining (Novus BiologicalsCompany, Clone ESEE122). Systemic and perirectalarteriolar oxygen saturation was then evaluated ingroups 1 and 2. Systemic oxygen saturation was mea-sured by radial artery blood sampling. Endoscopicultrasound was used for arteriolar blood sampling inperirectal level. The venules and arterioles were dis-tinguished according to wall thickness (Figure 1).Oxygen saturation was quantified within one minuteof blood sampling.Nine (90%) of the biopsy specimens of patientswith ulcerative colitis (ulcerative parts) as well as8 (80%) of the specimens of the subjects with mesen-teric ischemia showedtissue hypoxia in HIF-1a stain-ing. By contrast, only 1 (10%) of the biopsy samplesfrom subjects with infectious colitis and none of thesamples from healthy individuals and samples fromsparing parts of the colon of patients with UChad tissue hypoxia. There were no significant differ-ences between systemic saturation in groups 1 and2 (94.4 vs. 94.3%, p = 0.8), but pericapillary satura-tion was significantly higher in ulcerative colitispatients (96.4 vs. 94.3%, p = 0.001).Our data suggest that ischemia is the main pathol-ogy in a majority of UC patients. In support of ourconclusion, previous studies have shown that HIF1ais involved in triggering cell immune response [4] and

Tu1515 Endoscopic Ultrasound (EUS) for Measurement of Aortic IntimaMedia Thickness: A Marker for Presence of Coronary Artery Disease Seyed Amir Mirbagheri*, Mohammad R. Ostovaneh, Elham Mortazavi Department of Internal Medicine, Gastroenterology, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran Background: Previous studies highlighted the superior independent and incremental value of measures of vascular function like aortic distensibility for predicting atherosclerosis and identification of high risk individuals. Despite the controversies, some consensus statements suggest the use of carotid intimamedia thickness for further clarification of coronary artery disease (CAD) risk assessment. There are studies that evaluated the relationship between Aortic intima-media thickness measured by transesophageal echocardiography and CAD. Endoscopic Ultra-Sound (EUS) technique can serve as a highly accurate technique for measuring the Aortic Intima-Media Thickness (AIMT). To our best knowledge, there is no study to measure the AIMT with EUS and evaluate its relationship with CAD .Aim: to evaluate the relationship between EUS-measured AIMT and presence of coronary artery disease in patients who underwent coronary angiography (CAG). Methods: Two hundred and fifty eight patients who previously underwent CAG and needed to perform EUS for a gastrointestinal reason involved in the study. After obtaining demographic data, AIMT was measured at the aortic arch level with a radial EUS (frequency 10 MHz) for all patients. The endosonologist was blind in regard of CAG result. The patients were then subgrouped into normal individuals without CAD and those with CAD, based on cardiologist-reported CAG and the AIMT was compared between two groups. Results: In patients with normal CAG, the AIMT was 1.49 0.53 mm (CI 0.84-1.14), while it was 1.89 0.53 (CI 1.23-2.55) in presence of CAD(p 0.001). The AIMT increased with age (correlation coefficient 0.557, P 0.001). When compared to normal 20 to 30 years old individuals without CAD risk factors, patients with CAD in CAG had significantly higher AIMT (1.89 0.53 compared to 1.47 .47, P 0.01). On the other hand, AIMT did not differ in normal 20 to 30 years old patients without CAD risk factors compared to the remaining individuals with normal CAG (1.47 0.53 vs 1.63 0.55, P 0.151). When adjusting for age and presence of diabetes mellitus and hyperlipidemia in a logistic regression model, the regression coefficient for AIMT for predicting the presence of CAD in CAG as outcome variable was 0.581 (P 0.001) and subsequently odds ratio was 1.79. Conclusion: AIMT is significantly different in presence or absence of CAD. Even though, it increases with age but adjustment for age revealed its pure effect to predict presence of CAD. AIMT could be used as an independent predictor for presence of CAD. EUS is one of the most accurate techniques to measure AIMT. Evaluation of AIMT in patients who are candidates for EUS for any reason may be useful for detecting the subclinical CAD and optimizing patient management.