Search

BackgroundThe 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.MethodsWe 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.ResultsThe 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.ConclusionsHigher levels of aldosterone and PRA are associated with concentric LV remodeling changes. Moreover, aldosterone was related to deleterious LA remodeling changes.

With the availability of massive amounts of data from electronic health records and registry databases, incorporating time-varying patient information to improve risk prediction has attracted great attention. To exploit the growing amount of predictor information over time, we develop a unified framework for landmark prediction using survival tree ensembles, where an updated prediction can be performed when new information becomes available. Compared to conventional landmark prediction with fixed landmark times, our methods allow the landmark times to be subject-specific and triggered by an intermediate clinical event. Moreover, the nonparametric approach circumvents the thorny issue of model incompatibility at different landmark times. In our framework, both the longitudinal predictors and the event time outcome are subject to right censoring, and thus existing tree-based approaches cannot be directly applied. To tackle the analytical challenges, we propose a risk-set-based ensemble procedure by averaging martingale estimating equations from individual trees. Extensive simulation studies are conducted to evaluate the performance of our methods. The methods are applied to the Cystic Fibrosis Foundation Patient Registry (CFFPR) data to perform dynamic prediction of lung disease in cystic fibrosis patients and to identify important prognosis factors.

BackgroundRare pathogenic variants in cardiomyopathy (CM) genes can predispose to cardiac remodeling or fibrosis. We studied the carrier status for such variants in adults without clinical cardiovascular disease (CVD) in whom cardiac MRI (CMR)-derived measures of myocardial fibrosis were obtained in the Multi-Ethnic Study of Atherosclerosis (MESA).ObjectivesTo identify CM-associated pathogenic variants and assess their relative prevalence in participants with extensive myocardial fibrosis by CMR.MethodsMESA whole-genome sequencing data was evaluated to capture variants in CM-associated genes (n = 82). Coding variants with a frequency of

BackgroundSex hormones associated with both the left atrial (LA) and left ventricular (LV) structures in women, but the association of menopause status with left atrioventricular coupling is not established.AimTo assess the prognostic value of a left atrioventricular coupling index (LACI) in peri-menopausal women without a history of cardiovascular disease (CVD).Materials and methodsIn all women participating in MESA study with baseline cardiovascular MRI, the LACI was measured as the ratio of the LA end-diastolic volume to the LV end-diastolic volume. Cox models were used to assess the association between the LACI and the outcomes of atrial fibrillation (AF), heart failure (HF), coronary heart disease (CHD) death, and hard CVD.ResultsAmong the 2,087 women participants (61 ± 10 years), 485 cardiovascular events occurred (mean follow-up: 13.2 ± 3.3 years). A higher LACI was independently associated with AF (HR 1.70; 95%CI [1.51-1.90]), HF (HR 1.62; [1.33-1.97]), CHD death (HR 1.36; [1.10-1.68]), and hard CVD (HR 1.30; [1.13-1.51], all p < 0.001). Adjusted models with the LACI showed significant improvement in model discrimination and reclassification when compared to traditional models to predict: incident AF (C-statistic: 0.82 vs. 0.79; NRI = 0.325; IDI = 0.036), HF (C-statistic: 0.84 vs. 0.81; NRI = 0.571; IDI = 0.023), CHD death (C-statistic: 0.87 vs. 0.85; NRI = 0.506; IDI = 0.012), hard CVD (C-statistic: 0.78 vs. 0.76; NRI = 0.229; IDI = 0.012). The prognostic value of the LACI had a better discrimination and reclassification than individual LA or LV parameters.ConclusionIn a multi-ethnic population of pre- and post-menopausal women, the LACI is an independent predictor of HF, AF, CHD death, and hard CVD.Clinical trial registration[https://clinicaltrials.gov/], identifier [NCT00005487].

AimsThe association of subclinical atherosclerotic disease in the coronary arteries and thoracic aorta with incident peripheral arterial disease (PAD) is unknown. We investigated the association between coronary artery calcium score (CACs) and thoracic aortic calcium score (TACs) with incident clinical and subclinical PAD.Methods and resultsThe Multi-Ethnic Study of Atherosclerosis (MESA) recruited 6814 men and women aged 45-84 from four ethnic groups who were free of clinical cardiovascular disease at enrolment. Coronary artery calcium score and thoracic aortic calcium score were measured from computed tomography scans. Participants with a baseline ankle-brachial index (ABI) ≤0.90 or >1.4 were excluded. Abnormal ABI was defined as ABI ≤0.9 or >1.4 at follow-up exam. Multivariable logistic regression and Cox proportional hazards models were used to test the associations between baseline CACs and TACs with incident abnormal ABI and clinical PAD, respectively. A total of 6409 participants (female: 52.8%) with a mean age of 61 years were analysed. Over a median follow-up of 16.7 years, 91 participants developed clinical PAD. In multivariable analysis, each unit increase in log (CACS + 1) and log (TACs + 1) were associated with 23% and 13% (P < 0.01for both) higher risk of incident clinical PAD, respectively. In 5725 (female: 52.6%) participants with an available follow-up ABI over median 9.2 years, each 1-unit increase in log (CACs + 1) and log (TACs + 1) were independently associated with 1.15-fold and 1.07-fold (P < 0.01for both) higher odds of incident abnormal ABI, respectively.ConclusionHigher baseline CACs and TACs predict abnormal ABI and clinical PAD independent of traditional cardiovascular risk factors and baseline ABI.

AimsLittle is known about the association of temporal changes in inflammatory biomarkers and the risk of death and cardiovascular diseases. We aimed to evaluate the association between temporal changes in C-reactive protein (CRP), fibrinogen, and interleukin-6 (IL-6) and risk of heart failure (HF), cardiovascular disease (CVD), and all-cause mortality in individuals without a history of prior CVD.Methods and resultsParticipants from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort with repeated measures of inflammatory biomarkers and no CVD event prior to the second measure were included. Quantitative measures, annual change, and biomarker change categories were used as main predictors in Cox proportional hazard models stratified based on sex and statin use. A total of 2258 subjects (50.6% female, mean age of 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

AimsAnecdotal reports have suggested increased soft tissue calcification in individuals with long-term exposures to high blood glucose. The association of costal cartilage calcification (CCC), a reliably quantifiable marker obtainable from non-contrast cardiac computed tomography (CT) with cumulative fasting blood glucose (FBG) exposure, is unknown. In this study, we aimed to determine the association between quantified CCC and cumulative glucose exposure using non-contrast coronary artery calcium (CAC) scoring computed tomography (CT) images in the Multi-Ethnic Study of Atherosclerosis (MESA).MethodsThe volume of bilateral CCC was quantified in high-density pixels (threshold of Hounsfield Unit>180) using the CAC scoring CT images acquired in the 5th MESA exam. Prior long-term cumulative exposure to FBG was calculated by area under the FBG-time curve over ten years before the time of the CT exam.ResultsA total of 2,305 participants (mean age: 69, female/male: 1.3) were included in this study. The median CCC volume was lower in females than males (1158 mm3 [IQR: 1751] vs. 3054 mm3 [3851], p

Background Cardiovascular disease is associated with higher incidence of frailty. However, the nature of the mechanisms underlying this association remains unclear. The purpose of this study is to identify cardiovascular phenotypes most associated with physical frailty and functional performance in the Multi-Ethnic Study of Atherosclerosis (MESA). Methods As part of the MESA study, 3 045 participants underwent cardiovascular magnetic resonance and computed tomography between 2010 and 2012. Of these, 1 743 completed a Six-Minute Walk test (6MWT) and questionnaires (follow-up exam: 2016–2018) which were used to generate a binary combined frail/prefrail versus robust score according to a modified FRAIL Scale (self-report questionnaire). Multivariable logistic (binary frail outcome) or linear (6MWT) regression assessed the association between frailty and cardiovascular structure and function, aortic stiffness, coronary artery calcium, and myocardial fibrosis (ECV, extracellular volume fraction). Results Participants were 66 ± 8 years, 52% female at the time of imaging, and 29.4% were classified as frail or prefrail. Older age and female gender were associated with greater odds of being in the frail/prefrail group. Concentric left ventricular remodeling (odds ratio [OR] 1.89, p  = .008; Coef. −52.9, p  < .001), increased ECV (OR 1.10, p  = .002; Coef. −4.0, p  = .001), and worsening left atrial strain rate at early diastole (OR 1.56, p ≤.001; Coef. −22.75, p  = .027) were found to be associated with a greater likelihood of being in a frail state and lower 6MWT distance (m). All associations with 6MWT performance were attenuated with adjustments for risk factors whereas ECV and LA strain rate remained independently associated with frailty. Conclusions These findings suggest a significant overlap in pathways associated with subclinical cardiac dysfunction, cardiovascular fibrosis, and physical frailty. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether thoracic aortic volume (TAV) is useful for cardiovascular (CV) disease prognosis and risk assessment. Purpose: This study evaluated cross‐sectional associations of TAV with CV risk factors, and longitudinal association with incident CV events in the multiethnic study of atherosclerosis. Study Type: Retrospective cohort analysis of prospective data. Population: 1182 participants (69 ± 9 years, 54% female, 37% Caucasian, 18% Chinese, 31% African American, 14% Hispanic, 60% hypertensive, and 20% diabetic) without prior CV disease. Field Strength and sequences: Axial black‐blood turbo spin echo or bright blood steady‐state free precession images on 1.5T scanners. Assessment: TAV was calculated using Simpson's method from axial images, and included the ascending arch and descending segments. Traditional CV risk factors were assessed at the time of MRI. CV outcomes over a 9‐year follow‐up period were recorded and represented a composite of stroke, stroke death, coronary heart disease (CHD), CHD death, atherosclerotic death, and CVD death. Statistical Tests: Multivariable linear regression models adjusted for height and weight were used to determine the relationship (β coefficient) between TAV and CV risk factors. Cox regression models assessed the association of TAV and incident CV events. A P‐value of <0.05 was deemed statistically significant. Results: Mean TAV was = 139 ± 41 mL. In multivariable regression, TAV was directly associated with age (β = 1.6), male gender (β = 23.9), systolic blood pressure (β = 0.1), and hypertension medication use (β = 7.9); and inversely associated with lipid medication use (β = −5.3) and treated diabetes (β = −8.9). Compared to Caucasians, Chinese Americans had higher TAV (β = 11.4), while African Americans had lower TAV (β = −7.0). Higher TAV was independently associated with incident CV events (HR: 1.057 per 10 mL). Conclusion: Greater TAV is associated with incident CV events, increased age, and hypertension in a large multiethnic population while treated diabetes and lipid medication use were associated with lower TAV. Level of Evidence: 2 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

BackgroundAlthough 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 resultsThe 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.ConclusionsCAC 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.

Summary: Diamond–Blackfan anaemia (DBA) is a rare, inherited bone marrow failure syndrome with a ribosomal defect causing slowed globin chain production with normal haem synthesis, causing an overabundance of reactive iron/haem and erythroid‐specific cellular toxicity. Eltrombopag, a non‐peptide thrombopoietin receptor agonist, is a potent intracellular iron chelator and induced a robust durable response in an RPS19‐mutated DBA patient on another trial. We hypothesized eltrombopag would improve RBC production in DBA patients. We conducted a single‐centre, single‐arm pilot study (NCT04269889) assessing safety and erythroid response of 6 months of daily, fixed‐dose eltrombopag for DBA patients. Fifteen transfusion‐dependent (every 3–5 weeks) patients (median age 18 [range 2–56]) were treated. One responder had sustained haemoglobin improvement and >50% reduction in RBC transfusion frequency. Of note, 7/15 (41%) patients required dose reductions or sustained discontinuation of eltrombopag due to asymptomatic thrombocytosis. Despite the low response rate, eltrombopag has now improved erythropoiesis in several patients with DBA with a favourable safety profile. Dosing restrictions due to thrombocytosis may cause insufficient iron chelation to decrease haem production and improve anaemia in most patients. Future work will focus on erythropoiesis dynamics in patients and use of haem synthesis inhibitors without an impact on other haematopoietic lineages. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Analysis of hematopoietic stem cell function in nonhuman primates provides insights that are relevant for human biology and therapeutic strategies. In this study, we applied quantitative genetic barcoding to track the clonal output of transplanted autologous rhesus macaque hematopoietic stem and progenitor cells over a time period of up to 9.5 months. We found that unilineage short-term progenitors reconstituted myeloid and lymphoid lineages at 1 month but were supplanted over time by multilineage clones, initially myeloid restricted, then myeloid-B clones, and then stable myeloid-B-T multilineage, long-term repopulating clones. Surprisingly, reconstitution of the natural killer (NK) cell lineage, and particularly the major CD16(+)/CD56(-) peripheral blood NK compartment, showed limited clonal overlap with T, B, or myeloid lineages, and therefore appears to be ontologically distinct. Thus, in addition to providing insights into clonal behavior over time, our analysis suggests an unexpected paradigm for the relationship between NK cells and other hematopoietic lineages in primates.

The occurrence of clonal perturbations and leukemia in patients transplanted with gamma-retroviral (RV) vector-transduced autologous hematopoietic stem and progenitor cells (HSPCs) has stimulated extensive investigation, demonstrating that proviral insertions may perturb adjacent proto-oncogene expression. Although enhancer-deleted lentiviruses are less likely to result in insertional oncogenesis, there is evidence that they may perturb transcript splicing, and one patient with a benign clonal expansion of lentivirally transduced HPSC has been reported. The rhesus macaque model provides an opportunity for informative long-term analysis to ask whether transduction impacts on long-term HSPC properties. We used two techniques to examine whether lentivirally transduced HSPCs from eight rhesus macaques transplanted 1-13.5 years previously are perturbed at a population level, comparing telomere length as a measure of replicative history and gene expression profile of vector positive versus vector negative cells. There were no differences in telomere lengths between sorted GFP+ and GFP- blood cells, suggesting that lentiviral (LV) transduction did not globally disrupt replicative patterns. Bone marrow GFP+ and GF- CD34+ cells showed no differences in gene expression using unsupervised and principal component analysis. These studies did not uncover any global long-term perturbation of proliferation, differentiation, or other important functional parameters of transduced HSPCs in the rhesus macaque model.

Introduction:The objective of this study was to understand whether use of audio-only telemedicine visits differed by individual- and neighborhood-level patient characteristics during the COVID-19 pandemic. Methods:We conducted a retrospective cross-sectional study of telemedicine encounter data from a large academic health system. The primary outcome was rate of audio-only versus video visits. The exposures of interest were individual- (age, race, insurance, preferred language) and neighborhood-level (Social Deprivation Index [SDI]) patient characteristics. Results:Our study included 1,054,465 patient encounters from January 1, 2020 to December 31, 2021, of which 18.33% were completed via audio-only. Encounters among adults 75 years or older, Black patients, Spanish-speakers, and those with public insurance were more frequently conducted by audio-only (p < 0.001). Overall, populations showed decreasing rates of audio-only visits over time. We also observed an increase in the rate of audio-only encounters as SDI scores increased. Discussion:We found that audio-only disparities exist in telemedicine utilization by individual and zip code level characteristics. Though these disparities have improved over time as seen by our temporal analysis, marginalized and minority groups still showed the lowest rates of video utilization. In conclusion, access to audio-only care is a critical component to ensure that telemedicine is accessible to all populations. State and federal policy should support continued reimbursement of audio-only care to ensure equitable access to care while the implications of different care modalities are further studied. [ABSTRACT FROM AUTHOR]