BACKGROUND:Extracellular volume (ECV) and native T1 time (nT1) are markers of interstitial-myocardial-fibrosis (IMF) by cardiac MRI (CMR) and are associated with CV events, heart failure and death. However, the association between smoking and IMF at the population level has not been explored. OBJECTIVES:This study investigated the relationship between smoking and IMF by CMR, as well as the sex differences of this association in the MESA cohort. METHODS:A total of 2118 participants (53% women) had data on smoking between 2000 and 2012 and ECV(%) and nT1 (ms) at exam-5 (2010-2012). We constructed participant-specific trajectories of average cigarettes per day (ACPD) based on linear interpolation to estimate ACPD between exams 1 through 5 (ACPD1-5). We explored the associations of smoking status at Exam-5, ACPD at Exam-5, ACPD1-5 and temporal change in smoking status, with ECV and nT1 using multivariable analysis. RESULTS:Current smoking status was associated with increased markers of IMF in women but not in men, ECV% (ꞵ=2% p=<0.001 vs. 0.5%; p=0.2) and nT1 (ꞵ=28ms; p=<0.001 vs. 3ms; p=0.5) in women vs. men, respectively. A higher ACPD1-5 was associated with increased ECV% (ꞵ =0.1%; p<0.001) and nT1 (ꞵ=1ms; p=0.003) in women but not in men. Similarly, higher ACPD at Exam-5 was associated with higher ECV% in women vs. men. Sex interaction ascertained prior to stratification was statistically significant. CONCLUSION:In this population study, cigarette smoking was associated with a higher prevalence of IMF in females but not in males, indicating differences in the pathophysiology of CVD by sex.

PURPOSE:Pulse wave velocity (PWV) is a quantitative marker of arterial stiffness which is widely validated in the systemic circulation. Pulmonary artery (PA) stiffness, as measured by PWV, and its associations with disease, risk factors, and outcomes are largely unestablished. We aimed to assess the association of PA PWV with smoking history. METHODS:This prospective cohort study was conducted among participants enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) COPD who received cardiac magnetic resonance (CMR). 2-D phase contrast images were acquired to assess flow. PA PWV was assessed using validated semi-automated software for the main, right, and left PA by a single reader. Non-parametric, skewed data were log-transformed as appropriate and univariable, and multivariable linear regression models were used to analyze association of PA PWV and to demographic factors and cardiopulmonary risk. RESULTS:A total of 166 participants were included in this study after excluding for artifacts or incomplete scans. Participants were 65% male, average age 68 ± 7 years, smoked an average of 34 ± 20 pack-years, and 36% had COPD. A unit increase in pack-year was associated with a higher log average PA PWV of 0.007 (p < 0.01). This association persisted after adjustment for demographics, vascular risk factors, COPD stage and ABI. PA PWV was not associated with COPD status. CONCLUSIONS:We demonstrated that a severe smoking history was independently associated with a greater PA PWV. Our study advances the understanding of the mechanisms of cardiopulmonary risk factors and underscores the potential clinical applicability of PA PWV measurement for early disease detection.

Background Diabetes mellitus is associated with dyslipidemia, elevated blood pressure, and increased risk for incident cardiovascular disease (CVD). Objectives This study examined whether diagnosed diabetes before age 40 years is associated with incident CVD risk independent of other measured risk factors. It also evaluated whether cumulative glucose exposure from young adulthood to age 40 years is associated with subsequent CVD risk and explored the relative contribution of diabetes compared with other CVD risk factors. Methods Using CARDIA (Coronary Artery Risk Development in Young Adults) study data, we created a sequential propensity-score-matched sample at age 40 years: Each participant with diabetes was matched to one prediabetes participant and up to 2 without diabetes. Cox proportional hazards regression models were used to assess associations of diabetes and cumulative glucose exposure with incident CVD and its components: coronary heart disease, stroke, and congestive heart failure. Results Of 4,931 individuals, 766 propensity-score-matched participants experienced 103 incident CVD events during a median 22-year follow-up after age 40 years. Diagnosed diabetes was independently associated with incident CVD after adjustment for other known risk factors (HR: 2.13; 95% CI: 1.33-3.41 for diabetes vs nondiabetes, P = 0.002); CVD risk rose as cumulative glucose exposure increased. Among matched participants, the excess CVD rate associated with diabetes was greater than the rate difference associated with other cardiovascular risk factors commonly elevated in diabetes. Conclusions Diabetes by age 40 years was associated with higher subsequent CVD risk beyond established risk factors, with CVD risk increasing as cumulative glucose exposure rose.

BACKGROUND:Lp(a) (lipoprotein[a]) is a known cardiovascular risk factor; however, its role in cardiac remodeling and functional changes over time across diverse racial and ethnic groups remains underexplored. METHODS:MESA is a prospective multi-ethnic cohort study of individuals without a history of cardiovascular disease on enrollment (2000-2002), conducted across 6 sites in the United States. Participants with baseline Lp(a) measurements and cardiac magnetic resonance imaging at both baseline and 10-year follow-up exam were included. Lp(a) was treated as both a log-transformed continuous variable (per SD log) and a categorical variable based on data-driven Lp(a) terciles. Multivariable regression models adjusted for sociodemographic, and cardiovascular risk factors, including coronary artery calcium and interim myocardial infarction, were used to assess associations between Lp(a) and longitudinal changes in left ventricular and atrial structure and function over a decade across different racial/ethnic groups. RESULTS:A total of 2366 participants were included. The average age at baseline was 60±9 with 53% women, 43% White, 24% Black, 21% Hispanic, and 12% Chinese. Each 1-SD increase in log-transformed Lp(a) was associated with an increase in left ventricular end-systolic volume index (β, 0.60 [95% CI, 0.02-1.18]), and left atrial minimum volume index (β, 0.81 [95% CI, 0.09-1.52]), and a decline in left ventricular ejection fraction (β, -0.75 [95% CI, -1.34 to -0.17]), and total left atrial emptying fraction (β, -1.17 [95% CI, -2.09 to -0.24]) in Hispanic subjects over a decade. No significant associations were seen in White, Black, or Chinese participants. The observed findings persisted after adjusting for coronary artery calcium, interim myocardial infarction, and atrioventricular decoupling, and when Lp(a) was treated as a categorical variable with race-specific terciles. CONCLUSIONS:Elevated Lp(a) levels were independently associated with maladaptive left ventricular and left atrial remodeling in Hispanic adults over a decade, while no statistically significant relationships were observed in White, Black, and Chinese participants. This suggests a unique susceptibility of Hispanic individuals to Lp(a)-mediated cardiovascular remodeling, independent of ischemic pathways.

Introduction: Telomere biology disorders (TBDs) are characterized by abnormal telomere maintenance and a clinically heterogenous phenotype, including marrow failure, pulmonary fibrosis, cirrhosis, and malignancy predisposition. Treatment options are limited, including supportive care, androgens, and/or hematopoietic cell transplant (HCT). We have reported the results from a prospective phase I/II study for danazol therapy in a cohort of TBD patients (NCT01441037; Townsley et al, 2016). Here we present long-term follow-up. Methods: Patients were treated with 800mg danazol, daily, for two years, with a primary biologic endpoint of telomere attrition (determined by qPCR). Inclusion criteria required age-adjusted telomere length (TL) ≤ 1st percentile and/or identified mutations in telomere maintenance plus one cytopenia and/or pulmonary fibrosis. Hematologic relapse, overall survival, and event free survival (requiring HCT, lung transplant, liver transplant, or death) were determined using Kaplan-Meier curves. In a subset of patients, error-corrected sequencing (ECS) with a customized panel was retrospectively performed to evaluate clonal hematopoiesis (CH at minimum VAF of 0.5%) in myeloid cancer and telomere related genes. Flow-FISH (RepeatDx) was performed in serial samples post-trial to measure TL during follow-up. Results: Of 26 evaluable patients, most had identifiable mutations in known TBD genes, including TERT (n=10), TERC (n=7), DKC1 (n=3), or RTEL1 (n=1); 6 had no germline variants identified. Pulmonary fibrosis was present in 13 cases, liver fibrosis in 6, and previously diagnosed solid cancers in 2 (not active at time of enrollment). Median follow-up time to last clinical evaluation was 3.3 years, with a range from 0.3 to 12.6 years. Half the cohort (n=13) had at least one post-trial follow-up visit after stopping danazol. After drug discontinuation, either per protocol at two years or when the study was halted for efficacy, the median time to hematologic relapse for responders (n=12) from time of danazol cessation was 1.6 years. Nine patients restarted danazol post-trial at a median dose of 200mg (range: 75-600mg) with hematologic response in 86% (n=7). Median EFS was 5.7 years. Median overall survival was 7.7 years with 62% of participants (n=16) known to have died at last follow-up; the most common known cause of death (n=10) was infection in 60% (n=6). No new solid malignancies developed on trial. One patient developed MDS with multilineage dysplasia (MLD) with monosomy 7 at 24 months, and one TERT-mutated patient, with baseline MDS-MLD, progressed to AML 3 years after drug discontinuation. The patient who developed monosomy 7 on trial had no identified germline variant, a small PNH clone, and later underwent ECS detecting BCOR and PIGA mutations, suggestive of immune AA. Two patients who developed isolated cytogenetic abnormalities on trial, trisomy 21 and +1q, remained without morphologic MDS at last follow-up. A major concern with danazol treatment is the selection/expansion of pre-malignant clones in the marrow. At baseline, 15/24 (63%) patients had CH, most commonly in TERT promoter (n=7, 5 patients), PPM1D (n=6/5), and U2AF1 (n=4/4), and other MDS-related genes (n=8). However, longitudinal analysis of CH in 10 patients (median follow up [range] = 4.5 [2-6.5]) showed that mutations associated with myeloid malignancy (splicing factors, ASXL1, RUNX1, ETV6, SEPBP, and TP53) were largely stable during danazol treatment and follow-up. Serial TL by flow-FISH was available for 9 patients. TL was stable in 5/9 patients, four of whom re-initiated danazol, with median follow up of 4 years (average loss of 7bp per year [SD ± 28 bp/year]); a telomere attrition rate of 51bp/yr is typically seen in heathy individuals. Three individuals, 2 of whom re-initiated danazol, had an average telomere attrition rate of 110bp/yr (median follow-up of 3 years), similar to what is reported in TBD patients. A single patient had telomere elongation over 8 years of follow-up (from 4.5 to 5.5kb). Conclusion: Most patients required continuous administration of danazol to improve hematologic parameters, which worked at lower doses than mandated by protocol. Clonal dynamics were stable on danazol treatment over time. Telomere length, assessed by flow-FISH, was stable over time in a subset patients.

Left ventricular (LV) mass and left atrial (LA) strain are physiologically coupled and individually predict adverse cardiovascular outcomes. Their imbalance may reflect early atrioventricular uncoupling and atrial myopathy before overt structural disease. We evaluated whether a cardiac magnetic resonance (CMR)-derived LV mass-to-LA strain ratio identifies early atrioventricular mechanical uncoupling and predicts cardiovascular events. Participants from the Multi-Ethnic Study of Atherosclerosis underwent CMR at exams 1 (2000-2002) and 5 (2010-2012). The LV mass-to-LA strain ratio was calculated as indexed end-diastolic LV mass divided by peak LA strain. Classification and regression tree analysis identified cut points for baseline ratio and longitudinal change, defining low (<1.04), reference (1.04-3.26), and high (>3.26) groups, and lesser-(≤130%) versus greater-change (>130%) groups. Multivariable Cox models assessed associations with heart failure (HF), atrial fibrillation (AF), myocardial infarction (MI), and all-cause mortality. Among 4,232 participants (mean age 61.5 ± 10.1 yr; 52.8% female), the mean ratio was 1.95 ± 0.72. Over a median 18-yr follow-up, 6.0% developed HF, 5.2% MI, 18.7% AF, and 25.6% died. A high LV mass-to-LA strain ratio independently predicted HF [hazard ratio (HR) 2.85], AF (HR 2.00), MI (HR 1.96), and death (HR 1.70; all P ≤ 0.003). With repeat CMR, an increasing ratio also predicted cardiovascular events, including among individuals with normal LV mass and LA strain. Higher baseline ratios were associated with progression toward abnormal volumetric atrioventricular coupling over time. A higher LV mass-to-LA strain ratio and its increase independently predict cardiovascular events before overt chamber abnormalities, supporting impaired atrial adaptation as an early stage of atrial myopathy.NEW & NOTEWORTHY Left atrial failure underlies two of the most consequential conditions in cardiovascular medicine: atrial fibrillation, with predisposition to stroke and dementia, and heart failure with preserved ejection fraction, a leading cause of hospitalization and mortality. By examining the relationship between left ventricular hypertrophy and left atrial deformation at the population level, we demonstrate that the LV mass-to-LA strain ratio identifies a threshold beyond which adverse atrial remodeling independently predicts incident cardiovascular events-even within normal ranges.

Abstract: The amyloidogenic V122I variant of the transthyretin (TTR) gene is found in ∼3% of African American individuals and increases cardiovascular mortality risk after the age of 65 years. Sickle cell disease (SCD) primarily affects individuals of African descent, leading to multiorgan damage and premature mortality, with cardiopulmonary issues being a major cause of death. We assessed the impact of TTR V122I on cardiac phenotype and survival in a study of 584 patients with SCD (mean age, 35.9 years; 50.7% women). The prevalence was 3.1% (18/584), mainly female (72.2%). Age, blood pressure, body mass index, and liver/renal markers were similar between carriers and noncarriers, except for higher blood urea nitrogen levels in carriers. Echocardiography showed that carriers had increased septal thickness and left ventricular mass index and lower diastolic function indices. Over a median follow-up of 6.5 years, 219 patients died. The coinheritance of TTR V122I with SCD was associated with increased mortality (hazard ratio, 2.82; 95% confidence interval, 1.57-5.06). At 5 years, the cumulative incidence of death was 52.9% among carriers compared with 14.5% among noncarriers, corresponding to an approximate relative risk of 3.6. TTR protein levels were significantly lower in carriers. In conclusion, TTR V122I prevalence in patients with SCD mirrors that of the general African American population but affects cardiovascular function much earlier, and a contributing factor may be the underlying oxidative stress and chronic anemia. Genetic screening for TTR V122I is important and should be considered for patients with SCD. This trial was registered at www.clinicaltrials.gov as NCT00011648.

Diamond-Blackfan anemia (DBA) is an inherited anemia characterized by ribosome defects that reduce globin chain production, producing an excess of toxic heme. Bitopertin selectively reduces heme synthesis, rebalances globin-heme production, and improves anemia in model systems. We report the first clinical trial of bitopertin for the treatment of steroid-relapsed/refractory DBA. This was an open-label, intrapatient dose-escalation study in 15 heavily pretreated, transfusion-dependent adult DBA patients (ClinicalTrials.gov NCT05828108). Bitopertin dosing increased monthly (5 mg escalating to 60 mg, daily), followed by 3-months maintenance. Primary endpoint was response (hemoglobin level, erythrocyte transfusions). Secondary endpoints were safety (adverse events, AE) and tolerability. Twelve patients completed the full 8-month course (2 discontinued early for non-bitopertin-related serious AE (SAE), 1 lost-to-follow-up). All 12 patients reached the planned 60-mg maximum dose. Two de-escalated to 40 mg (1 grade-2 dizziness, 1 concern for loss of early effect). Seven SAEs were reported, all unlikely/unrelated to bitopertin. Plasma drug levels were consistent with prior studies. At 10 mg daily and greater, all patients reached levels consistent with EC50. There was a time-dependent/dose-dependent reduction of reticulocyte hemoglobin content. There were no clinical responses. Bitopertin is safe, bioavailable, and well-tolerated in steroid-refractory DBA. Although bitopertin did not result in transfusion-independence, iron overload, marrow hypocellularity and prior steroid failure reflect a cohort with long-standing disease and minimal hematopoietic marrow reserve. Additionally, based on model systems, dosing may have escalated too rapidly, missing a potential lower effective dose. Future studies will test slower dose escalation of bitopertin as a steroid-sparing agent for steroid-responsive DBA patients.

INTRODUCTION:Albuminuria is a significant marker for cardiovascular disease(CVD) in both diabetics and non-diabetics. However, its relationship with myocardial fibrosis in the general population remains unclear. METHODS:The study included 2,112 participants (52%female, mean age69±9years) from the MESA cohort who had urine albumin and creatinine measurements and underwent CMR with T1-mapping for myocardial fibrosis evaluation in 2010. Analyses were stratified by sex and diabetes stage. Multivariable linear and logistic regression models assessed associations of albuminuria/albumin-creatinine ratio(ACR) with extracellular volume (ECV), native T1-time, and myocardial scar. RESULTS:In fully adjusted models, a one-SD increase in log-transformed albumin and ACR was associated with 0.15% and 0.2% higher ECV and 2.7% and 2.6% higher native T1 time, respectively. In men, a one-SD increase in log-transformed albumin and ACR was associated with greater ECV (0.3% each) and higher native T1 time (3.3% and 2.6%, respectively). Among women, no significant associations with albuminuria or ACR were found. In participants with prediabetes, log-transformed urine albumin and ACR were positively associated with ECV (p < 0.05) but not with native T1. In diabetics, ACR showed a modest association with ECV and native T1, while log-transformed albumin was significantly associated with 0.3% greater ECV and 3% higher native T1 (p<0.05). The odds of myocardial scar were not associated with higher albumin/ACR after adjusting for CV risk factors. CONCLUSIONS:Elevated albuminuria levels are related to subclinical fibrosis in a community-based setting, independent of traditional CV risk factors. This association was more prominent among prediabetics, diabetics and among males.

BACKGROUND:Understanding the influence of cardiovascular risk factors on longitudinal cardiac remodeling requires three-dimensional analysis of longitudinal shape changes beyond scalar indicators such as mass and volumes. The aim of this study is to determine trajectories of cardiovascular risk factor-related remodeling in a large cohort imaging study. METHODS:We examined 2521 participants (54% female, aged 60±9 years) of the multi-ethnic study of atherosclerosis (MESA) at baseline and after 10years. Myocardial remodeling was assessed by longitudinal left ventricular shape trajectories derived from cardiac magnetic resonance imaging using a statistical shape atlas. Penalized logistic regression was used to examine the associations between trajectory scores and cardiovascular risk factors, after adjustment for sex and age at baseline. Multivariate regression was used to determine independent shape changes associated with each risk factor. RESULTS:Between baseline and follow-up, there was a higher prevalence of hypertension (18.4%), antihypertensive medication usage (21.6%), statin usage, and treated diabetes mellitus (8.9%); all p<0.05. Longitudinal shape trajectory scores had stronger associations with obesity, high blood pressure, hypertension medication, and diabetes mellitus, than mass and volume changes (p<0.05). Multivariate regression showed independent longitudinal changes in wall thickening with obesity (13% increase), smoking (11% decrease), and high systolic blood pressure (5.6% increase), with distinct regional variations. CONCLUSION:Trajectories of cardiovascular risk factor-related longitudinal remodeling can be examined using shape atlases. In addition to global changes, each risk factor is associated with a distinct regional remodeling of the myocardium.

Background The clinical significance of relative left-to-right chamber volume imbalances, even when individual chamber volumes are within "normal" ranges, remains inadequately established. Purpose To assess whether volumetric imbalance between the left and right ventricles and atria assessed with cardiac MRI is associated with cardiac events in individuals without cardiovascular disease (CVD) history. Materials and Methods This secondary analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) included participants free of CVD at baseline (July 2000-July 2002) who underwent cardiac MRI. The left-to-right ventricular volume ratio (LRVR) was defined at end diastole, whereas the left-to-right atrial volume ratio (LARA) was defined at end systole. LRVR was categorized into balanced (0.8-1.3), low (<0.8), and high (>1.3), whereas LARA was classified into low (≤2) and high (>2). Cox regression models were used to examine the associations of LRVR and LARA with heart failure (HF), atrial fibrillation (AF), and death, adjusting for traditional risk factors. Abnormal chamber volume was defined as indexed volume of more than 95% or less than 5% sex-specific percentile. Results A total of 4073 MESA participants were included (mean age, 61.3 years ± 10 [SD], 2133 females); in the follow-up, 239 (5.9%) developed HF, 772 (19.0%) developed AF, and 906 (22.2%) died. A high LRVR was associated with increased risk of HF (hazard ratio [HR], 2.54; P < .001), AF (HR, 1.57; P = .001), and death (HR, 1.62; P < .001) compared with a balanced LRVR. A low LRVR was not significantly associated with events. In those with normal right ventricle and left ventricle volumes, high LRVR still predicted HF (HR, 1.99; P = .04), AF (HR, 1.55; P = .04), and death (HR, 1.57; P = .02). High LARA was predictive of HF (HR, 1.99; P < .001) and AF (HR, 1.41; P < .001) after full adjustment, particularly influencing outcomes in participants with an LRVR of less than 1.3. Conclusion In participants without a history of CVD, elevated left-to-right ventricular and atrial volumes predicted HF, AF, and death, compared with balanced left-to-right chamber volumes. ClinicalTrials.gov: NCT00005487 © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Cadour and Dacher in this issue.

BACKGROUND:Urbanization has increased impervious cover - surfaces that cannot absorb or filter water - which may raise cardiovascular disease (CVD) risks through reduced walkability, increased heat, and pollution. However, the relationship between imperviousness and subclinical CVD indicators, specifically carotid intima-media thickness (CIMT), remains unexplored, especially across diverse populations. This study aims to investigate whether impervious cover in residential communities is associated with CIMT, and whether these associations differ by race and sex. METHOD:Linking urban impervious cover data from the National Land Cover Database (NLCD 2006) to individual carotid intima-media thickness (CIMT) information from the Coronary Artery Risk Development in Young Adults (CARDIA) study, this research employed linear regression models and examined whether the prevalence of impervious surface in immediate neighborhood and surrounding areas is associated with CIMT among middle-aged adults and whether the association varies across sex and race groups. RESULTS:Overall, there's no significant association between impervious coverage and CIMT, but differences exist among subpopulations. For women, the proportions of impervious surfaces within varying buffers (distance range 50 m to 5000 m) are positively associated with CIMT (β range 0.599 to 1.072 mm/m, with p range < 0.001 to 0.044), which can fully be annulled by a set of social determinants of health. Black adults' CIMT is still positively associated with impervious coverage beyond a buffer of 1 km regardless of the adjustment (β range 0.999 to 1.119 mm/m, with p range 0.024 to 0.043), while no significant association exists for buffers of 750 m or less. By comparison, there are no significant associations for men or White adults. CONCLUSION:Our findings suggest that impervious cover in urban areas may contribute to early CVD development among Black adults. The absence of associations within smaller buffers and among other demographic groups highlights the complexity of environmental pathways and cardiovascular health.

OBJECTIVE:The menopause transition is a period of accelerated cardiovascular disease (CVD) development in women, and sex differences in CVD incidence are reduced after menopause. Higher plasma cyclic guanosine monophosphate (cGMP) levels are also associated with greater CVD risk. Thus, we examined the changes in cGMP levels associated with the menopause transition. METHODS:We measured plasma cGMP levels in 511 women and 283 men in the Coronary Artery Risk Development in Young Adults (CARDIA) study. RESULTS:Over a 20-year follow-up period, women who completed the menopause transition had smaller reductions in cGMP relative to women who remained premenopausal (P < 0.05) but had similar changes compared to men (P = 0.3) after adjusting for demographic variables. CONCLUSIONS:Plasma cGMP changes through the menopause transition may reflect the underlying mechanisms associated with greater cardiovascular disease risk.

BackgroundStatistical shape atlases have been used in large-cohort studies to investigate relationships between heart shape and risk factors. The generalisability of these relationships between cohorts is unknown. The aims of this study were to compare left ventricular (LV) shapes in patients with differing cardiovascular risk factor profiles from two cohorts and to investigate whether LV shape scores generated with respect to a reference cohort can be directly used to study shape differences in another cohort.MethodsTwo cardiac MRI cohorts were included: 2106 participants (median age: 65 years, 54% women) from the Multi-Ethnic Study of Atherosclerosis (MESA) and 2960 participants (median age: 64 years, 52% women) from the UK Biobank (UKB) study. LV shape atlases were constructed from 3D LV models derived from expert-drawn contours from separate core labs. Atlases were considered generalisable for a risk factor if the area under the receiver operating characteristic curves (AUC) were not significantly different (p>0.05) between internal (within-cohort) and external (cross-cohort) cases.ResultsLV mass and volume indices were differed significantly between cohorts, even in age-matched and sex-matched cases without risk factors, partly reflecting different core lab analysis protocols. For the UKB atlas, internal and external discriminative performance were not significantly different for hypertension (AUC: 0.77 vs 0.76, p=0.37), diabetes (AUC: 0.79 vs 0.77, p=0.48), hypercholesterolaemia (AUC: 0.76 vs 0.79, p=0.38) and smoking (AUC: 0.69 vs 0.67, p=0.18). For the MESA atlas, diabetes (AUC: 0.79 vs 0.74, p=0.09) and hypercholesterolaemia (AUC: 0.75 vs 0.70, p=0.10) were not significantly different. Both atlases showed significant differences for obesity.ConclusionsThe MESA and UKB atlases demonstrated good generalisability for diabetes and hypercholesterolaemia, without requiring corrections for differences in mass and volume. Significant differences in obesity may be due to different relationships between obesity and heart shapes between cohorts.

OBJECTIVES:Heart failure (HF) and atrial fibrillation (AF) frequently coexist, exacerbate each other and are associated with increased morbidity and mortality rates. However, no previous study has specifically calculated the risk of experiencing either event following the occurrence of the other and also considered competing risks. The aim of this study was to examine the bidirectional relationship of AF and HF in a multiethnic population, taking competing risks into account. METHODS:Two Fine and Gray regression models of the subdistribution functions were implemented to evaluate the bidirectional association between AF and HF and were adjusted for a common set of covariates. Competing events were defined as HF/AF and/or cardiac death vs noncardiac death. For each model, common covariates for AF and HF were pre-identified in the literature, and either HF or AF was used as a time-dependent covariate. RESULTS:In the Multi-Ethnic Study of Atherosclerosis (MESA), 4016 study participants (mean age 67.2 ± 7.6 years and 48.8% male participants), free of clinically recognized cardiovascular disease at baseline, were assessed for AF and HF. After a median (IQR) follow-up of 6034 (3994-6313) days, 1044 incident AFs, 302 incident HFs and 1298 events of death occurred. Deaths were distributed as 313 cardiac deaths and 985 noncardiac deaths, and the incidence of AF was about 3.5 higher than that of HF. We found that HF was associated with a composite outcome of AF and/or cardiac death (HR 2.91, 95%CI [2.49-3.40]; P < 0.001) and that AF was associated with a composite outcome of HF and/or cardiac death (HR 2.05, 95%CI [1.79-2.35]; P < 0.001). CONCLUSION:AF and HF exacerbate the incidence of each other and are strongly and independently associated, suggesting that their joint association should be taken into consideration in future studies. From a clinical perspective, the occurrence of either of these events greatly increases the risk for the other (ClinicalTrials.gov Identifier: NCT00005487).

We propose a procedure to estimate the "time-specific average treatment effect" and "global average treatment effect" for observational studies with outcomes and covariates repeatedly measured over time. This research is motivated by the National Heart, Lung and Blood Institute Growth and Health Study (NGHS), a longitudinal cohort study that aims to evaluate the influences of race and other risk factors on the levels of blood pressure for children and adolescents. As with most longitudinal cohort studies, we do not have a known propensity score model to further discuss the average treatment effects in the NGHS. To solve this problem, a nonparametric machine learning method, the generalized boosted models (GBMs), is used to estimate the propensity score. Based on the estimated propensity score, the "time-specific average treatment effect" can be obtained through the inverse probability weighting methods, then the "global average treatment effect" is also obtained. We apply the proposed GBM-based estimation method to the NGHS blood pressure data and demonstrate through a simulation study that the GBM-based estimation method is superior to the commonly used logistic regression-based method.