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Background: Direct coronary arterial evaluation via computed tomography (CT) angiography is the most accurate noninvasive test for the diagnosis of coronary artery disease (CAD). However, diagnostic accuracy is limited in the setting of severe coronary calcification or stents. Ultra-high-resolution CT (UHR-CT) may overcome this limitation, but no rigorous study has tested this hypothesis., Methods: The CORE-PRECISION is an international, multicenter, prospective diagnostic accuracy study testing the non-inferiority of UHR-CT compared to invasive coronary angiography (ICA) for identifying patients with hemodynamically significant CAD. The study will enroll 150 patients with history of CAD, defined as prior documentation of lumen obstruction, stenting, or a calcium score ≥400, who will undergo UHR-CT before clinically prompted ICA. Assessment of hemodynamically significant CAD by UHR-CT and ICA will follow clinical standards. The reference standard will be the quantitative flow ratio (QFR) with <0.8 defined as abnormal. All data will be analyzed in independent core laboratories., Results: The primary outcome will be the comparative diagnostic accuracy of UHR-CT vs. ICA for detecting hemodynamically significant CAD on a patient level. Secondary analyses will focus on vessel level diagnostic accuracy, quantitative stenosis analysis, automated contour detection, in-depth plaque analysis, and others., Conclusion: CORE-PRECISION aims to investigate if UHR-CT is non-inferior to ICA for detecting hemodynamically significant CAD in high-risk patients, including those with severe coronary calcification or stents. We anticipate this study to provide valuable insights into the utility of UHR-CT in this challenging population and for its potential to establish a new standard for CAD assessment., (Copyright © 2024 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background Valvular heart disease and intracardiac shunts can disrupt the balance between left ventricular (LV) and right ventricular (RV) stroke volumes. However, the prognostic value of such imbalances has not been established among asymptomatic individuals. Purpose To assess the association between differential ventricular stroke volumes quantified using cardiac MRI and clinical outcomes in individuals without cardiovascular disease. Materials and Methods This secondary analysis of a prospective study included participants without cardiovascular disease at enrollment (July 2000 to July 2002) who underwent cardiac MRI. Differences in stroke volume were calculated as LV stroke volume minus RV stroke volume, and participants were categorized as having balanced (greater than or equal to -30 mL to ≤30 mL), negative (less than -30 mL), or positive (>30 mL) differential stroke volumes. Multivariable Cox proportional hazard regression models were used to test the association between differences in stroke volume and adverse outcomes. Results A cohort of 4058 participants (mean age, 61.4 years ± 10 [SD]; 2120 female) were included and followed up for a median of 18.4 years (IQR, 18.3-18.5 years). During follow-up, 1006 participants died, 235 participants developed heart failure, and 764 participants developed atrial fibrillation. Compared with participants who had a balanced differential stroke volume, those with an increased differential stroke volume showed a higher risk of mortality (hazard ratio [HR], 1.73 [95% CI: 1.12, 2.67]; P = .01), heart failure (HR, 2.40 [95% CI: 1.11, 5.20]; P = .03), and atrial fibrillation (HR, 1.89 [95% CI: 1.16, 3.08]; P = .01) in adjusted models. Participants in the negative group, with a decreased differential stroke volume, showed an increased risk of heart failure compared with those in the balanced group (HR, 2.09 [95% CI: 1.09, 3.99]; P = .03); however, this was no longer observed after adjusting for baseline LV function ( P = .34). Conclusion Participants without cardiovascular disease at the time of study enrollment who had an LV stroke volume exceeding the RV stroke volume by greater than 30 mL had an increased risk of mortality, heart failure, and atrial fibrillation compared with those with balanced stroke volumes. ClinicalTrials.gov Identifier: NCT00005487 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Almeida in this issue.

Background: Our understanding of the specific aspects of vascular contributions to dementia remains unclear., Objectives: We aim to identify the correlates of incident dementia in a multi-ethnic cardiovascular cohort., Methods: A total of 6806 participants with follow-up data for incident dementia were included. Probable dementia diagnoses were identified using hospitalization discharge diagnoses according to the International Classification of Diseases Codes (ICD). We used Random Forest analyses to identify the correlates of incident dementia and cognitive function from among 198 variables collected at the baseline MESA exam entailing demographic risk factors, medical history, anthropometry, lab biomarkers, electrocardiograms, cardiovascular magnetic resonance imaging, carotid ultrasonography, coronary artery calcium and liver fat content. Death and stroke were considered competing events., Results: Over 14 years of follow-up, 326 dementia events were identified. Beyond age, the top correlates of dementia included coronary artery calcification, high sensitivity troponin, common carotid artery intima to media thickness, NT-proBNP, physical activity, pulse pressure, tumor necrosis factor-α, history of cancer, and liver to spleen attenuation ratio from computed tomography. Correlates of cognitive function included income and physical activity, body size, serum glucose, glomerular filtration rate, measures of carotid artery stiffness, alcohol use, and inflammation indexed as IL-2 and TNF soluble receptors and plasmin-antiplasmin complex., Conclusion: In a deeply phenotyped cardiovascular cohort we identified the key correlates of dementia beyond age as subclinical atherosclerosis and myocyte damage, vascular function, inflammation, physical activity, hepatic steatosis, and history of cancer., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ostovaneh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Our objective is to use computed tomography angiography (CTA) and computed tomography perfusion (CTP) to identify the ischemic significance of myocardial bridging (MB). We also seek to determine the long-term prognostication of MB in the presence or absence of obstructive coronary artery disease (CAD). The CORE320, a prospective, multicenter study including 381 patients with known or suspected CAD clinically referred for invasive coronary angiography who underwent combined (CTA-CTP) and single-photon emission computed tomography before conventional coronary angiography. The incidence of MB was identified in 135 patients (35.4%) with 93.9% identified in the left anterior descending artery. MB were divided as partially encased versus fully encased. There was no difference in ischemia identified between partially encased MB and fully encased MB (37 [40%] vs 25 [35%], p = 0.54]. Ischemia was identified at similar rates in partially versus fully encased MB by single-photon emission computed tomography at (8 [9%] vs 8 [11%], p = 0.57] and CTP (34 [37%] vs 21 [30%], p = 0.33]. There was no difference in the primary outcome of 5-year outcome of combined incidence of myocardial infarction or death. The restricted mean survival time in patients with CTA with <50% stenosis with or without a MB was 4.906 years (95% confidence interval 4.759 to 5.000) and 4.891 years (95% confidence interval 4.718 to 5.000), respectively (p = 0.824). Cardiac computed tomography perfusion imaging can assess both anatomic and functional significance of myocardial bridging with diagnostic accuracy similar to current standard imaging. Furthermore, 5-year cardiovascular events were not different with the presence of MB in both obstructive and non-obstructive CAD., Competing Interests: Declaration of Competing Interest Dr. George is an employee at AstraZeneca. Dr. Vavere is an employee at AstraZeneca. Dr. Chen is an employee of the Division of Intramural Research, Department of Health and Human Services, National Heart, Lung, and Blood Institute, National Institutes of Health. The remaining authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The coronary atheroma burden drives major adverse cardiovascular events (MACE) in patients with suspected coronary heart disease (CHD). However, a consensus on how to grade disease burden for effective risk stratification is lacking. The purpose of this study was to compare the effectiveness of common CHD grading tools to risk stratify symptomatic patients., Methods: We analyzed the 5-year outcome of 381 prospectively enrolled patients in the CORE320 international, multicenter study using baseline clinical and cardiac computer-tomography (CT) imaging characteristics, including coronary artery calcium score (CACS), percent atheroma volume, "high-risk" plaque, disease severity grading using the CAD-RADS, and two simplified CAD staging systems. We applied Cox proportional hazard models and area under the curve (AUC) analysis to predict MACE or hard MACE, defined as death, myocardial infarction, or stroke. Analyses were stratified by a history of CHD. Additional forward selection analysis was performed to evaluate incremental value of metrics., Results: Clinical characteristics were the strongest predictors of MACE in the overall cohort. In patients without history of CHD, CACS remained the only independent predictor of MACE yielding an AUC of 73 (CI 67-79) vs. 64 (CI 57-70) for clinical characteristics. Noncalcified plaque volume did not add prognostic value. Simple CHD grading schemes yielded similar risk stratification as the CAD-RADS classification. Forward selection analysis confirmed prominent role of CACS and revealed usefulness of functional testing in subgroup with known CHD., Conclusion: In patients referred for invasive angiography, a history of CHD was the strongest predictor of MACE. In patients without history of CHD, a coronary calcium score yielded at least equal risk stratification vs. more complex CHD grading., (Copyright © 2023 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: The effects of the renin-angiotensin-aldosterone system in cardiovascular system have been described based on small studies. The aim of this study was to evaluate the relationship between aldosterone and plasma renin activity (PRA) and cardiovascular structure and function., Methods: We studied a random sample of Multi-Ethnic Study of Atherosclerosis participants who had aldosterone and PRA blood assays at 2003-2005 and underwent cardiac magnetic resonance at 2010. Participants taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were excluded., Results: The aldosterone group was composed by 615 participants, mean age 61.6 ± 8.9 years, while the renin group was 580 participants, mean age 61.5 ± 8.8 years and both groups had roughly 50% females. In multivariable analysis, 1 SD increment of log-transformed aldosterone level was associated with 0.07 g/m2 higher left ventricle (LV) mass index (P = 0.04) and 0.11 ml/m2 higher left atrium (LA) minimal volume index (P < 0.01). Additionally, higher log-transformed aldosterone was associated with lower LA maximum strain and LA emptying fraction (P < 0.01). Aldosterone levels were not significantly associated with aortic measures. Log-transformed PRA was associated with lower LV end diastolic volume index (β standardized = 0.08, P = 0.05). PRA levels were not significantly associated with LA and aortic structural or functional differences., Conclusions: Higher levels of aldosterone and PRA are associated with concentric LV remodeling changes. Moreover, aldosterone was related to deleterious LA remodeling changes., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To determine the prevalence and correlates of left atrial (LA) late gadolinium enhancement (LGE) at cardiac MRI and its association with atrial fibrillation (AF) in a population-based sample from the Multi-Ethnic Study of Atherosclerosis (MESA)., Materials and Methods: In this secondary post hoc analysis of the MESA cohort (ClinicalTrials.gov no. NCT00005487), participants without AF underwent LGE cardiac MRI at the fifth examination (2010-2012). LA LGE burden was quantified using the image intensity ratio technique on biplane long-axis two-dimensional (2D) LGE images without fat saturation. Survival analysis was performed with log-rank testing and Cox regression., Results: Of 1697 participants (mean age, 67 years ± 9 [SD]; 872 men), 1035 (61%) had LA LGE, and 75 (4.4%) developed AF during follow-up (median, 3.95 years). At univariable analysis, LA LGE was associated with age (β = .010 [95% CI: .005, .015], P < .001), diastolic blood pressure (β = .005 [95% CI: .001, .009], P = .02), HbA1c level (β = .06 [95% CI: .02, .11], P = .009), heart failure (β = .60 [95% CI: .11, 1.08], P = .02), LA volume (β = .008 [95% CI: .004, .012], P < .001), and LA function (emptying fraction, LA global longitudinal strain, LA early diastolic peak longitudinal strain rate, and LA late diastolic peak strain rate; all P < .05). After adjusting for the variables in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) AF score, LA LGE independently helped predict incident AF (hazard ratio = 1.46 [95% CI: 1.13, 1.88], P = .003). The highest tertile (LGE > 2%) was twice as likely to develop AF., Conclusion: Although limited by the 2D LGE technique employed, LA LGE was associated with adverse atrial remodeling and helped predict AF in a multiethnic population-based sample.Clinical trial registration no. NCT00005487 Keywords: MR Imaging, Cardiac, Epidemiology Supplemental material is available for this article. © RSNA, 2023., Competing Interests: Disclosures of conflicts of interest: T.Z. No relevant relationships. T.Q.A.C.S. No relevant relationships. B.A.V. No relevant relationships. E.X. No relevant relationships. M.R.O. No relevant relationships. M.H. No relevant relationships. D.A.B. Editor emeritus for Radiology. E.Z.S. No relevant relationships. C.O.W. No relevant relationships. S.R.H. Support for the present article from the National Institutes of Health (NIH), paid to author's institution. S.N. Research funding from Biosense Webster, Imricor, Siemens, ADAS software, and the NIH; consulting fees from CardioSolv and Circle CVI; payment for lectures from Circle CVI. J.A.C.L. NIH grant support., (© 2023 by the Radiological Society of North America, Inc.)

Background: Automatic coronary angiography (CAG) assessment may help in faster screening and diagnosis of stenosis in patients with atherosclerotic disease. We aimed to provide an end-to-end workflow that separates cases with normal or mild stenoses from those with higher stenosis severities to facilitate safety screening of a large volume of the CAG images., Methods: A deep learning-based end-to-end workflow was employed as follows: (1) Candidate frame selection from CAG videograms with Convolutional Neural Network (CNN) + Long Short Term Memory (LSTM) network, (2) Stenosis classification with Inception-v3 using 2 or 3 categories (<25%, >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 13,744 frames from 230 studies were used for the stenosis classification training and fourfold cross-validation for image-, artery-, and per-patient-level. For the stenosis localization training and fourfold cross-validation, 690 images with > 25% stenosis were used., Results: Our 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 left coronary artery (LCA) and right coronary artery (RCA) of 0.68 and 0.70., Conclusion: We demonstrated a fully automatic end-to-end deep learning-based workflow that eliminates the vessel extraction and segmentation step in coronary artery stenosis classification and localization on CAG images. This tool may be useful to facilitate safety screening in high-volume centers and in clinical trial settings., Competing Interests: JL reported receipt of grant support from Canon Medical Systems. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cong, Kato, Vasconcellos, Ostovaneh, Lima and Ambale-Venkatesh.)

Background: There are multiple predictive factors for cardiovascular (CV) mortality measured at, or after heart failure (HF) diagnosis. However, the predictive role of long-term exposure to these predictors prior to HF diagnosis is unknown., Objectives: We aim to identify predictive factors of CV mortality in participants with HF, using cumulative exposure to risk factors before HF development., Methods: Participants of Multi-Ethnic Study of Atherosclerosis (MESA) with incident HF were included. We used stepwise Akaike Information Criterion to select CV mortality predictors among clinical, biochemical, and imaging markers collected prior to HF. Using the AUC of B-spline-corrected curves, we estimated cumulative exposure to predictive factors from baseline to the last exam before HF. The prognostic performance for CV mortality after HF was evaluated using competing risk regression with non-CV mortality as the competing risk., Results: Overall, 375 participants had new HF events (42.9% female, mean age: 74). Over an average follow-up of 4.7 years, there was no difference in the hazard of CV death for HF with reduced versus preserved ejection fraction (HR = 1.27, p = 0.23). The selected predictors of CV mortality in models with the least prediction error were age, cardiac arrest, myocardial infarction, and diabetes, QRS duration, HDL, cumulative exposure to total cholesterol and glucose, NT-proBNP, left ventricular mass, and statin use. The AUC of the models were 0.72 when including the latest exposure to predictive factors and 0.79 when including cumulative prior exposure to predictive factors ( p = 0.20)., Conclusion: In HF patients, besides age and diagnosed diabetes or CVD, prior lipid profile, NT-proBNP, LV mass, and QRS duration available at the diagnosis time strongly predict CV mortality. Implementing cumulative exposure to cholesterol and glucose, instead of latest measures, improves predictive accuracy for HF mortality, though not reaching statistical significance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shabani, Ostovaneh, Ma, Ambale Venkatesh, Wu, Chahal, Bakhshi, McClelland, Liu, Shea, Burke, Post, Watson, Folsom, Bluemke and Lima.)

Background: Inflammation surrounding the coronary arteries can be non-invasively assessed using pericoronary adipose tissue attenuation (PCAT). While PCAT holds promise for further risk stratification of patients with low coronary artery disease (CAD) prevalence, its value in higher risk populations remains unknown., Methods: CORE320 enrolled patients referred for invasive coronary angiography with known or suspected CAD. Coronary computed tomography angiography (CCTA) images were collected for 381 patients for whom clinical outcomes were assessed 5 years after enrollment. Using semi-automated image analysis software, PCAT was obtained and normalized for the right coronary (RCA), left anterior descending (LAD), and left circumflex arteries (LCx). The association between PCAT and major adverse cardiovascular events (MACE) during follow up was assessed using Cox regression models., Results: Thirty-seven patients were excluded due to technical failure. For the remaining 344 patients, median age was 62 (interquartile range, 55-68) with 59% having ≥1 coronary artery stenosis of ≥50% by quantitative coronary angiography. Mean attenuation values for PCAT in RCA, LAD, and LCx were -74.9, -74.2, and -71.2, respectively. Hazard ratios and 95% confidence intervals (CI) for normalized PCAT in the RCA, LAD, and LCx for MACE were 0.96 (CI: 0.75-1.22, p ​= ​0.71), 1.31 (95% CI: 0.96-1.78, p ​= ​0.09), and 0.98 (95% CI: 0.78-1.22, p ​= ​0.84), respectively. For death, stroke, or myocardial infarction only, hazard ratios were 0.68 (0.44-1.07), 0.85 (0.56-1.29), and 0.57 (0.41-0.80), respectively., Conclusions: In patients referred for invasive coronary angiography with suspected CAD, PCAT did not predict MACE during long term follow up. Further studies are needed to understand the relationship of PCAT with CAD risk., (Copyright © 2022 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Aims: To evaluate whether myocardial fibrosis predicts cardiovascular events (CVEs) and mortality in the Multi-Ethnic Study of Atherosclerosis., Methods and Results: Cardiac magnetic resonance (CMR) T1 mapping with gadolinium administration for assessment of extracellular volume fraction (ECV) was performed in 1326 participants, in whom myocardial scar was assessed by late gadolinium enhancement (LGE). The clinical outcomes were defined as all-cause mortality, atherosclerotic CVEs, and incident heart failure (HF) during an average of 8 years of follow-up after the scan. Participants' mean native T1 time was 971 ms [standard deviation (SD) 45.5], ECV was 27 (SD 2.9), and 117 (8.8%) of them had LGE. At the time of the CMR exam, participant age was 68 years (SD 9) and 48% of them were women. Ideal cut-offs were identified using classification and regression trees accounting for time-to-event outcomes for ECV (30%) and native T1 time (954 ms). Over the follow-up period, 106 participants died, 78 developed CVE, and 23 developed HF. After adjustment for risk factors, ECV >30% was associated with death [hazard ratio (HR): 1.67, P < 0.05], incident CVE (HR: 2.02, P < 0.05), and incident HF (HR: 2.85, P < 0.05). After adjustments, native T1 >954 ms was associated with incident CVE (HR: 2.09, P < 0.05). Myocardial scar by LGE was not predictive of clinical outcomes after adjustments., Conclusion: ECV is an independent prognostic marker of incident HF, atherosclerotic CVEs, and all-cause mortality. ECV, with its ability to characterize both diffuse and focal fibrosis processes, better predicted incident events than regional myocardial abnormalities as visualized by LGE imaging in a large multi-ethnic population., Competing Interests: Conflict of interest: none declared., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Background: Few data exist on long-term outcome in patients undergoing combined coronary CT angiography (CTA) and myocardial CT perfusion imaging (CTP) as well as invasive coronary angiography (ICA) and single photon emission tomography (SPECT)., Methods: At 16 centers, 381 patients were followed for major adverse cardiac events (MACE) for the CORE320 study. All patients underwent coronary CTA, CTP, and SPECT before ICA within 60 days. 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). Predicting MACE by AUC also was similar: 65 vs. 65 (difference 0.1; 95% CI -4.6, 4.9). When MACE was restricted to cardiovascular death, myocardial infarction, or stroke, AUC for CTA-CTP was 71 vs. 60 by ICA-SPECT (difference 11.2; 95% CI -1.0, 19.7)., Conclusions: Combined CTA-CTP evaluation yields at least equal 5-year prognostic information as combined ICA-SPECT assessment in patients presenting with suspected coronary artery disease. Noninvasive cardiac CT assessment may eliminate the need for diagnostic cardiac catheterization in many patients., Clinical Trial Registration: NCT00934037., (Copyright © 2021 Society of Cardiovascular Computed Tomography. All rights reserved.)

Aims: Little 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 Results: Participants 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 62 years) were studied over an average of 8.1 years of follow-up. The median annual decrease in CRP levels was 0.08 mg/L. Fibrinogen and IL-6 levels increased by a median of 30 mg/dL and 0.24 pg/mL annually. Temporal changes in CRP were positively associated with HF risk among females (HR: 1.18 per each standard deviation increase, P < 0.001) and other CVD in both female (HR: 1.12, P = 0.004) and male participants (HR: 1.24, P = 0.003). The association of CRP change with HF and other CVD was consistently observed in statin users (HR: 1.23 per SD increase, P = 0.001 for HF and HR: 1.19 per SD increase, P < 0.001 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 (P < 0.001) compared with those with sustained low values., Conclusions: Temporal 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., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Quantification of non-ischemic myocardial scar remains a challenge due to the patchy diffuse nature of fibrosis. Extracellular volume (ECV) to guide late gadolinium enhancement (LGE) analysis may achieve a robust scar assessment., Methods: Three cohorts of 80 non-ischemic-training, 20 non-ischemic-validation, and 10 ischemic-validation were prospectively enrolled and underwent 3.0 Tesla cardiac MRI. An ECV cutoff to differentiate LGE scar from non-scar was identified in the training cohort from the receiver-operating characteristic curve analysis, by comparing the ECV value against the visually-determined presence/absence of the LGE scar at the highest signal intensity (SI) area of the mid-left ventricle (LV) LGE. Based on the ECV cutoff, an LGE semi-automatic threshold of n-times of standard-deviation (n-SD) above the remote-myocardium SI was optimized in the individual cases ensuring correspondence between LGE and ECV images. The inter-method agreement of scar amount in comparison with manual (for non-ischemic) or full-width half-maximum (FWHM, for ischemic) was assessed. Intra- and inter-observer reproducibility were investigated in a randomly chosen subset of 40 non-ischemic and 10 ischemic cases., Results: The non-ischemic groups were all female with the HIV positive rate of 73.8% (training) and 80% (validation). The ischemic group was all male with reduced LV function. An ECV cutoff of 31.5% achieved optimum performance (sensitivity: 90%, specificity: 86.7% in training; sensitivity: 100%, specificity: 81.8% in validation dataset). The identified n-SD threshold varied widely (range 3 SD-18 SD), and was independent of scar amount (β = -0.01, p = 0.92). In the non-ischemic cohorts, results suggested that the manual LGE assessment overestimated scar (%) in comparison to ECV-guided analysis [training: 4.5 (3.2-6.4) vs. 0.92 (0.1-2.1); validation: 2.5 (1.2-3.7) vs. 0.2 (0-1.6); P < 0.01 for both]. Intra- and inter-observer analyses of global scar (%) showed higher reproducibility in ECV-guided than manual analysis with CCC = 0.94 and 0.78 versus CCC = 0.86 and 0.73, respectively (P < 0.01 for all). In ischemic validation, the ECV-guided LGE analysis showed a comparable scar amount and reproducibility with the FWHM., Conclusions: ECV-guided LGE analysis is a robust scar quantification method for a non-ischemic cohort. Trial registration ClinicalTrials.gov; NCT00000797, retrospectively-registered 2 November 1999; NCT02501811, registered 15 July 2015., (© 2021. The Author(s).)

Background: Most 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., Methods: In this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF <45% and 15% or greater LV scar size were randomised in 2:1 ratio to receive intracoronary infusion of allogenic CDCs or placebo, respectively. Change in segmental myocardial circumferential strain (Ecc) by MRI from baseline to 6 months was compared between CDCs and placebo groups., Results: In 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)., Conclusions: In 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 Number: NCT01458405., Competing Interests: Competing interests: DA, RDS and LM are employed at Capricor therapeutics. RDS, LM and EM hold stocks at Capricor therapeutics. EM is the founder of Capricor therapeutics. TDH is advisory board member at Capricor therapeutics. The remaining authors have no disclosures., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2021 European Society of Cardiology.)

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., (© 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

Background: Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment., Objectives: SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC., Methods: Cancer survivors with chronic AIC (mean age 56.6 years; 68% women; NT-proBNP 1,426 pg/ml; 6 enrolled in an open-label, lead-in phase and 31 subjects randomized 1:1) received 1 × 10 8 allo-MSCs or vehicle transendocardially. Primary objectives were safety and feasibility. Secondary efficacy measures included cardiac function and structure measured by cardiac magnetic resonance imaging (CMR), functional capacity, quality of life (Minnesota Living with Heart Failure Questionnaire), and biomarkers., Results: A total of 97% of subjects underwent successful study product injections; all allo-MSC-assigned subjects received the target dose of cells. Follow-up visits were well-attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-CMR compatible devices, CMR endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes. Secondary measures included 6-min walk test (p = 0.056) and Minnesota Living with Heart Failure Questionnaire score (p = 0.048), which tended to favor the allo-MSC group., Conclusions: In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible, and CMR was successfully performed in the majority of the HF patients with devices. This study lays the groundwork for phase 2 trials aimed at assessing efficacy of cell therapy in patients with AIC.

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

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., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Objective: To evaluate the association of cigarette smoking and right ventricular (RV) systolic and diastolic functions in a population-based cohort of individuals at middle age., Methods: This cross-sectional study included participants who answered the smoking questionnaire and underwent echocardiography at the Coronary Artery Risk Development in Young Adulthood year 25 examination. RV systolic function was assessed by echocardiographic-derived tricuspid annular plane systolic excursion (TAPSE) and by right ventricular peak systolic velocity (RVS'), while RV diastolic function was evaluated by early right ventricular tissue velocity (RVE'). Multivariable linear regression models assessed the relationship of smoking with RV function, adjusting for age, sex, race, body mass index, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, diabetes mellitus, alcohol consumption, pulmonary function, left ventricular systolic and diastolic function and coronary artery calcium score., Results: A total of 3424 participants were included. The mean age was 50±4 years; 57% were female; and 53% were black. There were 2106 (61%) never smokers, 750 (22%) former smokers and 589 (17%) current smokers. In the multivariable analysis, current smokers had significantly lower TAPSE (β=-0.082, SE=0.031, p=0.008), RVS' (β=-0.343, SE=0.156, p=0.028) and RVE' (β=-0.715, SE=0.195, p<0.001) compared with never smokers. Former smokers had a significantly lower RVE' compared with never smokers (β=-0.414, SE=0.162, p=0.011), whereas no significant difference in RV systolic function was found between former smokers and never smokers., Conclusions: In a large multicenter community-based biracial cohort of middle-aged individuals, smoking was independently related to both worse RV systolic and diastolic functions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

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.

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 χ 2 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 mm 3 , P = .008), more positive remodeling (13% vs 1%, P = .006), and greater low-attenuation atheroma volume (20 vs 10 mm 3 , 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 François in this issue.

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 < 0.001). The addition of change in total LAEF to an AF risk score improved model discrimination and reclassification (net reclassification improvement = 0.107, P = 0.017; integrative discrimination index = 0.049, P < 0.001)., 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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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; p interaction =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., (Copyright © 2019 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd.. All rights reserved.)

Background The relationship of coronary artery calcium (CAC) with adverse cardiac remodeling is not well established. We aimed to study the association of CAC in middle age and change in CAC from early adulthood to middle age with left ventricular (LV) function. Methods CAC score was measured by computed tomography at CARDIA study (Coronary Artery Risk Development in Young Adults) year-15 examination and at year-25 examination (Y25) in 3043 and 3189 participants, respectively. CAC score was assessed as a continuous variable and log-transformed to account for nonlinearity. Change in CAC from year-15 examination to Y25 was evaluated as the absolute difference of log-transformed CAC from year-15 examination to Y25. LV structure and function were evaluated by echocardiography at Y25. Results At Y25, mean age was 50.1±3.6 years, 56.6% women, 52.4% black. In the multivariable analysis at Y25, higher CAC was related to higher LV mass (β=1.218; adjusted P=0.007), higher LV end-diastolic volume (β=0.811; adjusted P=0.007), higher LV end-systolic volume (β=0.350; adjusted P=0.048), higher left atrial volume (β=0.214; adjusted P=0.009), and higher E/e' ratio (β=0.059; adjusted P=0.014). CAC was measured at both year-15 examination and Y25 in 2449 individuals. Higher change in CAC score during follow-up was independently related to higher LV mass index in blacks (β=4.789; adjusted P<0.001), but not in whites (β=1.051; adjusted P=0.283). Conclusions Higher CAC in middle age is associated with higher LV mass and volumes and worse LV diastolic function. Being free of CAC from young adulthood to middle age correlates to better LV function at middle age. Higher change in CAC score during follow-up is independently related to higher LV mass index in blacks.

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.

Objective: To assess the feasibility, safety, and efficacy of intracoronary allogeneic cardiosphere-derived cells (CAP-1002) in patients with Duchenne muscular dystrophy (DMD)., Methods: The 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)., Results: Twenty-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)., Conclusions: Intracoronary 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 Evidence: This phase I/II study provides Class II evidence that for patients with DMD, intracoronary CAP-1002 is feasible and appears safe and potentially effective., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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<0.001). Accuracy for identifying patients with inducible myocardial ischemia by SPECT-MPI was similar for CTA and ICA (area under the receiver operating characteristic curve, 0.68 versus 0.71 by quantitative coronary angiography and 0.68 by visual angiographic assessment; 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.

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., (Copyright © 2018 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

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., (© 2018 American Heart Association, Inc.)

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 ( P <0.001) and 1.4% greater ECV ( P =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., (© 2018 American Heart Association, Inc.)

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 a 0.62% 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)., (Published by Elsevier Inc.)

Background: The human aorta dilates with advancing age. However, the association between progressive aortic dilation with aging and cardiac remodeling has not been established in studies of community-dwelling adults. The aim of this study was to test the hypothesis that there would be a relationship between aortic size increase over the early adult life span with left ventricular (LV) structural remodeling and subclinical LV dysfunction in middle age, even in the absence of overt cardiovascular and valvular disease., Methods: Included were Coronary Artery Risk Development in Young Adults study participants (N = 2,933) aged 23 to 35 years with available transthoracic echocardiographic measurements during 20 years of follow-up. Multivariate linear regression models assessed sex-specific associations between 20-year change in aortic root diameter with LV structure and function., Results: Larger aortic root diameter at 20-year follow-up was associated with greater LV mass (2.77 vs 2.18 g/mm in men and women, respectively, P < .001). In longitudinal analyses, increase in aortic root diameter over 20-year follow-up was associated with a greater 20-year increase in LV mass and ratio of LV mass to LV end-diastolic volume ratio in both sexes. In women but not in men, increased aortic root diameter over 20 years was associated with increased left atrial dimension, impaired E/E', and impaired early diastolic longitudinal and circumferential strain rates assessed by speckle-tracking echocardiography., Conclusions: Progressive increase in aortic root diameter from early adulthood to middle age was associated with increased LV mass and LV concentric remodeling in both sexes and impaired diastolic function predominantly in women., (Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

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., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

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., (© The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We evaluated the immune response to neonatal HBV immunization in children of infected parents 10-18 years after primary vaccination. Healthy individuals immunized with an infantile course of three doses of HBV vaccine were tested for persistence of anti-HB surface antibody (HBsAb). Those with an HBsAb level of <10 IU/mL received a booster dose of the vaccine with subsequent doses to those without protective titres. HBsAb concentrations were determined 4 weeks after each dose of the booster vaccine. The data were analysed separately for three age groups: 10-11, 12-14 and 15-18 years old. A total of 541 healthy individuals were studied. The highest seroprotection rate of 48% was observed in the youngest vaccinees (10-11 years old). This declined to 26.5% in the oldest (15-18 years old) group (P = 0.008). The youngest vaccinees showed the highest rate of anamnestic immune responses (96%). However, 25% of oldest individuals failed to mount an anamnestic immune response in challenge with a booster dose of the vaccine (P = 0.005), suggesting waning immunity with increasing age. Age (OR: 0.80; P = 0.01) and prebooster HBsAb levels (OR: 0.37; P = 0.01) identified responders to first booster doses of the vaccine by logistic regression analysis. The majority of high-risk vaccinees showed anamnestic immune response 10-11 years after primary immunization. However, we found a significant proportion (25%) of older individuals with no anamnetic response, which suggests a waning of immune memory. Detailed long-term follow-up studies are necessary to determine the risk of natural infection among these individuals before a booster schedule can be recommended., (© 2016 John Wiley & Sons Ltd.)

Background: The PolyIran study is a large-scale pragmatic cluster randomized controlled trial of fixed-dose combination therapy (Polypill) for prevention of cardiovascular diseases (CVD) in Iran. The PolyIran Quality Control Program (PIQCP) including a new questionnaire was developed to assess the quality of data collection during follow-up visits. The aim of this study was to assess the inter-rater reliability of PIQCP questionnaire., Methods: The study was conducted in 26 (11%) randomly selected clusters (from a total of 236 PolyIran clusters). All participants within these 26 clusters were enrolled. The quality scores were measured according to the PIQCP guidelines by two independent raters. The intraclass correlation coefficients (ICC) were measured. In addition, the quality scores were categorized into good (70%) and poor (<70%). The kappa coefficient was used to assess inter-rater agreement for this categorical quality scores., Results: A total number of 945 PolyIran participants were enrolled of which, 501 (53%) were from intervention arm. In 934 participants (98.8%), the quality score could be successfully identified by both raters. The ICC (95%CI) of the overall quality scores was 0.985 (0.983-0.987). It was 0.976 (0.972-0.980) and 0.988 (0.986-0.990) in intervention and control arms, respectively. We found excellent agreement between the two raters in identifying participants with good and poor quality scores (kappa = 0.988, P < 0.001). The kappa values were 0.972 (P < 0.001) and 1.000 (P < 0.001) in intervention and control arms, respectively., Discussion: Our results suggested that the PIQCP questionnaire is a reliable tool for assessing quality of data collection in PolyIran follow-up visits. Using this measure will help us in efficient monitoring of the PolyIran follow-ups and may ensure high quality data.

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.

Background: The complexity of treatment regimens, costs and pill burden decrease the medication adherence and contribute to shortfall in cardiovascular preventive drug coverage. The polypill, a fixed dose combination pill of established drugs, is expected to increase adherence and reduce the costs whilst preventing major cardiovascular events (MCVE)., Design and Methods: The PolyIran trial is a pragmatic cluster randomized trial nested within the Golestan Cohort Study (GCS). Subjects were randomized to either non-pharmacological preventive interventions alone (minimal care arm) or together with a polypill (polypill arm) comprising hydrochlorothiazide, aspirin, atorvastatin and either enalapril or valsartan. This study benefits from the infrastructure of the primary health care system in Iran and the interventions are delivered by the local auxiliary health workers (Behvarz) to the participants. The primary outcome of the study is the occurrence of first MCVE within five years defined as non-fatal and fatal myocardial infarction, unstable angina, sudden death, heart failure, coronary artery revascularization procedures, and non-fatal and fatal stroke., Trial Status: From February 2011 to April 2013, 8410 individuals (236 clusters) attended the eligibility assessment. Of those, 3421 in the polypill arm and 3417 in the minimal care arm were eligible. The study is ongoing., Conclusion: The infrastructure of GCS and the primary health care system in Iran enabled the conduct of this pragmatic large-scale trial. If the polypill strategy proves effective, it may be implemented to prevent cardiovascular disease in developing countries., (© The European Society of Cardiology 2014.)

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.

Background: To assess the prevalence of nonalcoholic fatty liver (NAFL) in Iran and to evaluate correlates of NAFL in categories of body mass index (BMI)., Methods: Using a cluster random sampling approach, 7723 subjects over 18 years of age underwent abdominal ultrasonography, laboratory evaluations, blood pressure, and anthropometric measurements and were interviewed to obtain baseline characteristics. Prevalence of NAFL according to BMI and waist to hip ratio and its association with metabolic abnormalities in categories of BMI were assessed in multivariate analysis., Results: The overall prevalence of NAFL was 35.2% [95% confidence interval (CI) 34.1-36.3]. A significant number of subjects with BMI < 30 had NAFL [22.1% (CI 21.0-23.2)]. Waist to hip ratio for 38.2% (CI 35.6-40.8) of the subjects with NAFL, and BMI < 30 was higher than normal values. The odds ratio for association of NAFL and dyslipidemias were higher in subjects with BMI < 30 versus those with BMI ≥ 30: (1) hypertriglyceridemia: 2.21 vs. 1.57, P = 0.006; (2) lower high-density lipoprotein: 1.29 versus 0.98, P = 0.046. Higher low-density lipoprotein also revealed greater association with NAFL in subjects with BMI < 25 than those with BMI ≥ 25 (odds ratio 1.84 vs. 1.1, P = 0.015)., Conclusions: NAFL shows stronger association with central obesity compared to high BMI. NAFL has stronger association with dyslipidemias in subjects with low compared with high BMI.

Background and Aim: 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)., Methods: 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., Results: 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 (P < 0.001)., Conclusion: FD patients with MD achieved greater symptomatic response with H. pylori eradication than those without microscopic duodenitis.

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., (© 2014 American Association for the Study of Liver Diseases.)

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 < .001). The TE score also correlated to liver iron content (P < .001), liver size (P < .003), and Lucarelli risk classification (LRC) (P < .001). ROC curve analysis revealed moderate accuracy of the TE score for the diagnosis of fibrosis (AUROC = 73%) and for distinguishing individuals with a LRC III from those classified as I and II (AUROC = 82%). The TE score was also superior to Fibrosis-4 (AUROC = 61%) for the assessment of liver fibrosis and LRC differentiation. The results of this study demonstrated that TE can be a valuable method for assessing liver fibrosis and differentiating LRC III from the other 2 classes in pediatric patients with MT who have been selected for HSCT., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Hepatitis B virus (HBV) infection is the most common cause of end stage liver disease in Iran and in Golestan province. Large-scale population-based prospective cohort studies with long term follow-up are the method of choice to accurately understand the natural course of HBV infection. To date, several studies of HBV epidemiology, natural history, progression to cirrhosis and association with HCC have been reported from other countries. However, few of these are prospective and fewer still are population-based. Moreover, the underlying molecular mechanisms and immunogenetic determinants of the outcome of HBV infection especially in low and middle income countries remains largely unknown. Therefore, the hepatitis B cohort study (HBCS), nested as part of the Golestan Cohort Study (GCS), Golestan, Iran was established in 2008 with the objective to prospectively investigate the natural course of chronic hepatitis B with reference to its epidemiology, viral/host genetic interactions, clinical features and outcome in the Middle East where genotype D HBV accounts for >90% of infections. In 2008, a baseline measurement of HBV surface antigen (HBsAg) was performed on stored serum samples of all GCS participants. A sub-cohort of 3,505 individuals were found to be HBsAg positive and were enrolled in the Golestan HBCS. In 2011, all first degree relatives of HBsAg positive subjects including their children and spouses were invited for HBV serology screening and those who were positive for HBsAg were also included in the Golestan HBCS.

Purpose: So far, a variety of prevalence rates have been reported for the metabolic syndrome (MetS) according to several definitions. The aim of this study was to assess the prevalence of MetS in Iran according to two definitions and compare the characteristics of the subjects who met the MetS criteria according to the different definitions., Methods: Participants were recruited from family registries of public health centers. After obtaining demographic and clinical data, the subjects underwent anthropometric measurements and laboratory evaluations. MetS was defined according to the NCEP-ATPIII and IDF criteria. The subjects were then categorized into 3 groups: 1) Healthy non-MetS subjects based on either definition, 2) Individuals with MetS according to only one of the definitions, and 3) Individuals who met both NCEP-ATPIII and IDF criteria for MetS., Results: Totally, 5826 subjects in Amol and 2243 subjects in Zahedan were enrolled in the study. The weighted prevalence of MetS according to the NCEP-ATPIII and IDF criteria was 27.8% and 26.9% in Amol and 12% and 11.8% in Zahedan, respectively. Overall, 18.9% of the subjects fulfilled both criteria for MetS. However, a considerable proportion (8.5%) met the MetS criteria according to only one definition but not both., Conclusions: MetS is increasingly prevalent in Iran as well as other parts of the world. Due to non-uniform definitions of MetS, some of the subjects who meet MetS according to one set of criteria might be considered healthy according to another definition and consequently would not receive the preventive health services.