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Importance: High-dose trivalent compared with standard-dose quadrivalent influenza vaccine did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations in patients with high-risk cardiovascular disease in the INVESTED trial. Whether humoral immune response to influenza vaccine is associated with clinical outcomes is unknown., Objective: To examine the antibody response to high-dose trivalent compared with standard-dose quadrivalent inactivated influenza vaccine and its associations with clinical outcomes., Design, Setting, and Participants: This secondary analysis is a prespecified analysis of the immune response substudy of the randomized, double-blind, active-controlled INVESTED trial, which was conducted at 157 sites in the United States and Canada over 3 influenza seasons between September 2016 and January 2019. Antibody titers were determined by hemagglutination inhibition assays at randomization and 4 weeks during the 2017-2018 and 2018-2019 seasons. Eligibility criteria included recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor. Data were analyzed from February 2023 to June 2023., Main Outcomes and Measures: Mean antibody titer change, seroprotection (antibody titer level ≥1:40) and seroconversion (≥4-fold increase in titer) at 4 weeks, and the association between seroconversion status and the risk for adverse clinical outcomes., Interventions: High-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine, with revaccination up to 3 seasons., Results: Antibody data were available for 658 of 5260 randomized participants (12.5%; mean [SD] age, 66.2 [11.4] years; 507 male [77.1%], 151 female [22.9%]; 348 with heart failure [52.9%]). High-dose vaccine was associated with an increased magnitude in antibody titers for A/H1N1, A/H3N2, and B-type antigens compared with standard dose. More than 92% of all participants achieved seroprotection for each of the contained antigens, while seroconversion rates were higher in participants who received high-dose vaccine. Seroconversion for any antigen was not associated with the risk for cardiopulmonary hospitalizations or all-cause mortality (hazard ratio, 1.09; 95% CI, 0.79-1.53; P = .59), irrespective of randomized treatment (P = .38 for interaction)., Conclusions and Relevance: High-dose vaccine elicited a more robust humoral response in patients with heart failure or prior myocardial infarction enrolled in the INVESTED trial, with no association between seroconversion status and the risk for cardiopulmonary hospitalizations or all-cause mortality. Vaccination to prevent influenza remains critical in high-risk populations., Trial Registration: ClinicalTrials.gov Identifier: NCT02787044.

Airway inflammation in asthma has been well recognized for several decades, with general agreement on its role in asthma pathogenesis, symptoms, propensity toward exacerbation, and decline in lung function. This has led to universal recommendation in asthma management guidelines to incorporate the use of inhaled corticosteroid as an anti-inflammatory therapy for all patients with persistent asthma symptoms. However, there has been limited attention paid to the presence and potential impact of systemic inflammation in asthma. Accumulating evidence from epidemiological observations and cohort studies points to a host of downstream organ dysfunction in asthma especially among patients with longstanding or more severe disease, frequent exacerbations, and underlying risk factors for organ dysfunction. Most studies to date have focused on cognitive impairment, depression/anxiety, metabolic syndrome, and cardiovascular abnormalities. In this review, we summarize some of the evidence demonstrating these abnormalities and highlight the proposed mechanisms and potential benefits of treatment in limiting these extrapulmonary abnormalities in patients with asthma. The goal of this commentary is to raise awareness of the importance of recognizing potential extrapulmonary conditions associated with systemic inflammation of asthma. This area of treatment of patients with asthma is a large unmet need., (Copyright © 2024. Published by Elsevier Inc.)

Importance: Influenza-like illness (ILI) activity has been associated with increased risk of cardiopulmonary (CP) events during the influenza season. High-dose trivalent influenza vaccine was not superior to standard-dose quadrivalent vaccine for reducing these events in patients with high-risk cardiovascular (CV) disease in the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial., Objective: To evaluate whether high-dose trivalent influenza vaccination is associated with benefit over standard-dose quadrivalent vaccination in reducing CP events during periods of high, local influenza activity., Design, Setting, and Participants: This study was a prespecified secondary analysis of INVESTED, a multicenter, double-blind, active comparator randomized clinical trial conducted over 3 consecutive influenza seasons from September 2016 to July 2019. Follow-up was completed in July 2019, and data were analyzed from September 21, 2016, to July 31, 2019. Weekly Centers for Disease Control and Prevention (CDC)-reported, state-level ILI activity was ascertained to assess the weekly odds of the primary outcome. The study population included 3094 patients with high-risk CV disease from participating centers in the US., Intervention: Participants were randomized to high-dose trivalent or standard-dose quadrivalent influenza vaccine and revaccinated for up to 3 seasons., Main Outcomes and Measures: The primary outcome was the time to composite of all-cause death or CP hospitalization within each season. Additional measures included weekly CDC-reported ILI activity data by state., Results: Among 3094 participants (mean [SD] age, 65 [12] years; 2309 male [75%]), we analyzed 129 285 person-weeks of enrollment, including 1396 composite primary outcome events (1278 CP hospitalization, 118 deaths). A 1% ILI increase in the prior week was associated with an increased risk in the primary outcome (odds ratio [OR], 1.14; 95% CI, 1.07-1.21; P < .001), CP hospitalization (OR, 1.13; 95% CI, 1.06-1.21; P < .001), and CV hospitalization (OR, 1.12; 95% CI, 1.04-1.19; P = .001), after adjusting for state, demographic characteristics, enrollment strata, and CV risk factors. Increased ILI activity was not associated with all-cause death (OR, 1.00; 95% CI, 0.88-1.13; P > .99). High-dose compared with standard-dose vaccine did not significantly reduce the primary outcome, even when the analysis was restricted to weeks of high ILI activity (OR, 0.88; 95% CI, 0.65-1.20; P = .43). Traditionally warmer months in the US were associated with lower CV risk independent of local ILI activity., Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, ILI activity was temporally associated with increased CP events in patients with high-risk CV disease, and a higher influenza vaccine dose did not significantly reduce temporal CV risk. Other seasonal factors may play a role in the coincident high rates of ILI and CV events., Trial Registration: ClinicalTrials.gov Identifier: NCT02787044.

Objectives: Non-invasive methods for monitoring arterial health and identifying early injury to optimize treatment for patients are desirable. The objective of this study was to demonstrate the use of an adaptive Bayesian regularized Lagrangian carotid strain imaging (ABR-LCSI) algorithm for monitoring of atherogenesis in a murine model and examine associations between the ultrasound strain measures and histology., Methods: Ultrasound radiofrequency (RF) data were acquired from both the right and left common carotid artery (CCA) of 10 (5 male and 5 female) ApoE tm1Unc/J mice at 6, 16 and 24 wk. Lagrangian accumulated axial, lateral and shear strain images and three strain indices-maximum accumulated strain index (MASI), peak mean strain of full region of interest (ROI) index (PMSRI) and strain at peak axial displacement index (SPADI)-were estimated using the ABR-LCSI algorithm. Mice were euthanized (n = 2 at 6 and 16 wk, n = 6 at 24 wk) for histology examination., Results: Sex-specific differences in strain indices of mice at 6, 16 and 24 wk were observed. For male mice, axial PMSRI and SPADI changed significantly from 6 to 24 wk (mean axial PMSRI at 6 wk = 14.10 ± 5.33% and that at 24 wk = -3.03 ± 5.61%, p < 0.001). For female mice, lateral MASI increased significantly from 6 to 24 wk (mean lateral MASI at 6 wk = 10.26 ± 3.13% and that at 24 wk = 16.42 ± 7.15%, p = 0.048). Both cohorts exhibited strong associations with ex vivo histological findings (male mice: correlation between number of elastin fibers and axial PMSRI: r s  = 0.83, p = 0.01; female mice: correlation between shear MASI and plaque score: r s  = 0.77, p = 0.009)., Conclusion: The results indicate that ABR-LCSI can be used to measure arterial wall strain in a murine model and that changes in strain are associated with changes in arterial wall structure and plaque formation., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: The acute cardiovascular and pulmonary effects of contemporary electronic nicotine delivery systems (ENDS) in long-term users are not known., Research Question: What are the cardiovascular and pulmonary responses to an acute 15-min product use challenge with ENDS and combustible cigarettes in regular nicotine-containing product users compared with control participants who do not use tobacco or vape?, Study Design and Methods: Observational challenge study before and after nicotine-containing product use of 395 individuals who used ENDS exclusively (n = 164; exhaled carbon monoxide level, < 5 parts per million [ppm]; positive urine NicCheck I [Mossman Associates] results, 82%; fourth-generation ENDS), participants who smoked cigarettes exclusively (n = 117; carbon monoxide level, > 5 ppm; positive urine NicCheck I results), and control participants (n = 114; carbon monoxide level, < 5 ppm; negative urine NicCheck I results)., Results: During the 15-min product challenge, cigarette users took a median of 14.0 puffs (interquartile range [IQR], 9.3 puffs); ENDS users took 9.0 puffs (IQR, 7.5 puffs; P < .001). After product challenge, compared with control participants, ENDS users showed greater increases in adjusted mean differences in systolic BP (5.6 mm Hg [95% CI, 4.4-6.8 mm Hg] vs 2.3 mm Hg [95% CI, 0.8-3.8 mm Hg]; P = .001), diastolic BP (4.2 mm Hg [95% CI, 3.3-5.0 mm Hg] vs 2.0 mm Hg [95% CI, 1.1-3.0 mm Hg; P = .003), and heart rate (4.8 beats/min [95% CI, 4.0-5.6 beats/min] vs -1.3 beats/min [95% CI, -2.2 to -0.3 beats/min]; P < .001) and greater reductions in brachial artery diameter (-0.011 cm [95% CI, -0.013 to 0.009 cm] vs -0.006 cm [95% CI, -0.004 to -0.009 cm]; P = .003), time-domain heart rate variability (-7.2 ms [95% CI, -10.5 to -3.7 ms] vs 3.6 ms [95% CI, 1.6-9.3 ms]; P = .001), and FEV 1 (ENDS: -4.1 [95% CI, -5.4 to -2.8] vs control participants: -1.1 [95% CI, -2.7 to 0.6]; P = .005) with values similar to those of cigarette users. ENDS users performed worse than control participants on all exercise parameters, notably metabolic equivalents (METs; adjusted mean difference, 1.28 METs [95% CI, 0.73-1.83 METs]; P < .001) and 60-s heart rate recovery (adjusted mean difference, 2.9 beats/min [95% CI, 0.7-5.0 beats/min]; P = .008)., Interpretation: ENDS users had acute worsening of blood pressure, heart rate, and heart rate variability, as well as vasoconstriction, impaired exercise tolerance, and increased airflow obstruction after vaping, compared to control participants., Trial Registry: ClinicalTrials.gov; No.: NCT03863509; URL: www., Clinicaltrials: gov., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: In humans, arterial grayscale ultrasound texture features independently predict adverse cardiovascular disease (CVD) events and change with medical interventions. We performed this study to examine how grayscale ultrasound texture features and elastin fibers change in plaque-free segments of the arterial wall in a murine model prone to atherosclerosis., Methods: A total of 10 Apoe tm1Unc/J mice ( n  = 5 male, n  = 5 female) were imaged at 6, 16, and 24 weeks of age. Two mice were euthanized at 6 and 16 weeks and the remaining mice at 24 weeks. Texture features were extracted from the ultrasound images of the distal 1.0 mm of the common carotid artery wall, and elastin measures were extracted from histology images. Two-way analysis of variance was used to evaluate associations between week, sex, and grayscale texture features. Texture feature and elastin number comparisons between weeks were conducted using the sex-by-week two-way interaction contrasts. Sex-specific correlations between the number of elastin fibers and grayscale texture features were analyzed by conducting non-parametric Spearman's rank correlation analyses., Results: Arterial wall homogeneity changed significantly in male mice from 6 to 24 weeks, with a mean (SD) of 0.14 (0.03) units at 6 weeks and 0.18 (0.03) units at 24 weeks ( p  = 0.026). Spatial gray level dependence matrices-homogeneity (SGLD-HOM) also correlated with carotid artery plaque score ( r s  = 0.707, p  = 0.033). Elastin fibers in the region of interest decreased from 6 to 24 weeks for both male and female mice, although only significantly in male mice. The mean (SD) number of elastin fibers for male mice was 5.32 (1.50) at 6 weeks and 3.59 (0.38) at 24 weeks ( p  = 0.023). For female mice, the mean (SD) number of elastin fibers was 3.98 (0.38) at 6 weeks and 3.46 (0.19) at 24 weeks ( p  = 0.051)., Conclusion: Grayscale ultrasound texture features that are associated with increased risk for CVD events in humans were used in a murine model, and the grayscale texture feature SGLD-HOM was shown to change in male mice from 6 weeks to 24 weeks. Structural alterations of the arterial wall (change in elastin fiber number) were observed during this time and may differ by sex., Competing Interests: CM: W. L. Gore & Associates contracted research grants to the University of Wisconsin-Madison, consulting Acoustic Range Estimates. TV: Research agreement with Fujifilm VisualSonics (Toronto, CA) to acquire photoacoustic radiofrequency data not used in this paper. 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., (© 2023 Mitchell, Al Mukaddim, Liu, Graham, Eickhoff, Weichmann, Tattersall, Korcarz, Stein, Varghese and Eliceiri.)

Arterial stiffness progresses with age and is a predictor of adverse cardiovascular disease events. Studies examining associations of statin therapy with arterial stiffness have yielded mixed results. Associations between the duration and intensity of statin therapy and arterial stiffness have not been studied in a prospective multiethnic cohort. MESA participants (n = 1242) with statin medication use data at each exam (1-5) and who had undergone B-mode carotid ultrasound at baseline and at Exam 5 after (mean ± [SD]) 9.4 ± 0.5 years were analyzed. Carotid arterial stiffness was measured using the distensibility coefficient (DC) and Young's elastic modulus (YEM). Linear regression models were used to evaluate associations between DC and YEM and statin treatment duration and intensity. At baseline, participants were 66.5 ± 8.1 years old, 41% female, 36% White, 30% African American, 14% Chinese American, and 20% Hispanic. The mean baseline low-density lipoprotein cholesterol (LDL-C) was 149.5 ± 14.5 mg/dL. After adjusting for age, sex, race/ethnicity, and CVD risk factors, the percent changes in DC and YEM were found to not be significantly different in individuals on statin therapy at any combination of visits (1-4) compared to participants never on statin therapy (all p > 0.32). There were also no differences in the percent change in DC and YEM based on statin therapy intensity by quartile (all p > 0.14) over the 10-year follow-up period. Based on the aforementioned results, statin therapy was not associated with changes in carotid artery stiffness over nearly a decade of follow-up regardless of therapy duration or intensity., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Rationale: Extrapulmonary manifestations of asthma, including fatty infiltration in tissues, may reflect systemic inflammation and influence lung function and disease severity. Objectives: To determine if skeletal muscle adiposity predicts lung function trajectory in asthma. Methods: Adult SARP III (Severe Asthma Research Program III) participants with baseline computed tomography imaging and longitudinal postbronchodilator FEV 1 % predicted (median follow-up 5 years [1,132 person-years]) were evaluated. The mean of left and right paraspinous muscle density (PSMD) at the 12th thoracic vertebral body was calculated (Hounsfield units [HU]). Lower PSMD reflects higher muscle adiposity. We derived PSMD reference ranges from healthy control subjects without asthma. A linear multivariable mixed-effects model was constructed to evaluate associations of baseline PSMD and lung function trajectory stratified by sex. Measurements and Main Results: Participants included 219 with asthma (67% women; mean [SD] body mass index, 32.3 [8.8] kg/m 2 ) and 37 control subjects (51% women; mean [SD] body mass index, 26.3 [4.7] kg/m 2 ). Participants with asthma had lower adjusted PSMD than control subjects (42.2 vs. 55.8 HU; P  < 0.001). In adjusted models, PSMD predicted lung function trajectory in women with asthma (β = -0.47 Δ slope per 10-HU decrease; P  = 0.03) but not men (β = 0.11 Δ slope per 10-HU decrease; P  = 0.77). The highest PSMD tertile predicted a 2.9% improvement whereas the lowest tertile predicted a 1.8% decline in FEV 1 % predicted among women with asthma over 5 years. Conclusions: Participants with asthma have lower PSMD, reflecting greater muscle fat infiltration. Baseline PSMD predicted lung function decline among women with asthma but not men. These data support an important role of metabolic dysfunction in lung function decline.

Asthma and cardiovascular disease (CVD) pose significant public health burdens. Airway inflammation is central to asthma pathophysiology and systemic inflammation, which occurs in asthma, is central to CVD pathophysiology. Numerous robust epidemiological studies have demonstrated deleterious systemic cardiovascular effects associated with the asthma syndrome. The cardiovascular effects associated with asthma include arterial injury, atherosclerotic CVD events, atrial fibrillation, and hypertension. Asthma is a heterogeneous disease, however, and the risk of CVD is not homogeneous across the various clinical phenotypes and molecular endotypes, highlighting prior inconsistent associations of asthma and its subtypes with various forms of CVD. The mechanistic underpinnings of the increased CVD risk in asthma remain multifactorial and undefined. Collectively, this supports the need for a precision approach in the identification of individuals with asthma who remain at elevated risk of development of cardiovascular diseases to guide both diagnostic and preventive interventions to decrease CVD risk among individuals living with asthma., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background Asthma and atherosclerotic cardiovascular disease share an underlying inflammatory pathophysiology. We hypothesized that persistent asthma is associated with carotid plaque burden, a strong predictor of atherosclerotic cardiovascular disease events. Methods and Results The MESA (Multi-Ethnic Study of Atherosclerosis) enrolled adults free of known atherosclerotic cardiovascular disease at baseline. Subtype of asthma was determined at examination 1. Persistent asthma was defined as asthma requiring use of controller medications, and intermittent asthma was defined as asthma without controller medications. B-mode carotid ultrasound was performed to detect carotid plaques (total plaque score [TPS], range 0-12). Multivariable regression modeling with robust variances evaluated the association of asthma subtype and carotid plaque burden. The 5029 participants were a mean (SD) age of 61.6 (10.0) years (53% were women, 26% were Black individuals, 23% were Hispanic individuals, and 12% were Chinese individuals). Carotid plaque was present in 50.5% of participants without asthma (TPS, 1.29 [1.80]), 49.5% of participants with intermittent asthma (TPS, 1.25 [1.76]), and 67% of participants with persistent asthma (TPS, 2.08 [2.35]) ( P ≤0.003). Participants with persistent asthma had higher interleukin-6 (1.89 [1.61] pg/mL) than participants without asthma (1.52 [1.21] pg/mL; P =0.02). In fully adjusted models, persistent asthma was associated with carotid plaque presence (odds ratio, 1.83 [95% confidence interval, 1.21-2.76]; P <0.001) and TPS (β=0.66; P <0.01), without attenuation after adjustment for baseline interleukin-6 ( P =0.02) or CRP (C-reactive protein) ( P =0.01). Conclusions Participants with persistent asthma had higher carotid plaque burden and higher levels of inflammatory biomarkers, compared with participants without asthma. Adjustment for baseline inflammatory biomarkers did not attenuate the association between carotid plaque and asthma subtype, highlighting the increased atherosclerotic cardiovascular disease risk among those with persistent asthma may be multifactorial.

Rationale: The role of obesity-associated insulin resistance (IR) in airflow limitation in asthma is uncertain. Objectives: Using data in the Severe Asthma Research Program 3 (SARP-3), we evaluated relationships between homeostatic measure of IR (HOMA-IR), lung function (cross-sectional and longitudinal analyses), and treatment responses to bronchodilators and corticosteroids. Methods: HOMA-IR values were categorized as without (<3.0), moderate (3.0-5.0), or severe (>5.0). Lung function included FEV 1 and FVC measured before and after treatment with inhaled albuterol and intramuscular triamcinolone acetonide and yearly for 5 years. Measurements and Main Results: Among 307 participants in SARP-3, 170 (55%) were obese and 140 (46%) had IR. Compared with patients without IR, those with IR had significantly lower values for FEV 1 and FVC, and these lower values were not attributable to obesity effects. Compared with patients without IR, those with IR had lower FEV 1 responses to β-adrenergic agonists and systemic corticosteroids. The annualized decline in FEV 1 was significantly greater in patients with moderate IR (-41 ml/year) and severe IR (-32 ml/year,) than in patients without IR (-13 ml/year, P  < 0.001 for both comparisons). Conclusions: IR is common in asthma and is associated with lower lung function, accelerated loss of lung function, and suboptimal lung function responses to bronchodilator and corticosteroid treatments. Clinical trials in patients with asthma and IR are needed to determine if improving IR might also improve lung function.

Background: Transesophageal echocardiography (TEE) is the gold standard for the detection of valvular vegetations (VV). Differentiating small VV from degenerative changes is challenging and prone to inter-observer variability. We evaluated inter-observer agreement regarding aortic (AV) and mitral valve (MV) findings on TEEs ordered for suspected infective endocarditis (IE)., Methods: A total of 349 consecutive TEEs were evaluated. Studies were classified as "definite, possible, or no" IE with valve masses classified further by morphology. Nine faculty echocardiographers scored randomly selected TEEs of the AV (N = 38) and MV (N = 35). Inter-reader variability was calculated using the Fleiss/Scott Kappa (Kf)., Results: Positive blood cultures were present in 81% and 45% had definite IE by the modified Duke criteria. There was moderate reader agreement regarding the presence of a valvular mass for both the AV (Kf = .41, 95% CI [.30-.53]) and MV (Kf = .49, 95% CI [.34-.65]). For diagnosis of IE, there was fair agreement for the AV (Kf = .29, 95% CI [.18-.42]) and moderate agreement for the MV (Kf = .53, 95% CI [.36-.70]). Masses described as large, multi-lobulated, or pedunculated were more frequently categorized as clinical IE, (p < .006, both valves), however those with filamentous lesions were not (p < .001, both valves)., Conclusions: In a large academic center, the inter-observer agreement for the presence of a left sided valvular mass was moderate and agreement regarding the final diagnosis of IE was fair to moderate, with better agreement among readers evaluating the MV. Lesion morphology is associated with the clinical diagnosis of IE., (© 2022 The Authors. Echocardiography published by Wiley Periodicals LLC.)

Elastic arteries stiffen via 2 main mechanisms: (1) load-dependent stiffening from higher blood pressure and (2) structural stiffening due to changes in the vessel wall. Differentiating these closely coupled mechanisms is important to understanding vascular aging. MESA (Multi-Ethnic Study of Atherosclerosis) participants with B-mode carotid ultrasound and brachial blood pressure at exam 1 and exam 5 (year 10) were included in this study (n=2604). Peterson and Young elastic moduli were calculated to represent total stiffness. Structural stiffness was calculated by adjusting Peterson and Young elastic moduli to a standard blood pressure of 120/80 mm Hg with participant-specific models. Load-dependent stiffness was the difference between total and structural stiffness. Changes in carotid artery stiffness mechanisms over 10 years were compared by age groups with ANCOVA models adjusted for baseline cardiovascular disease risk factors. The 75- to 84-year age group had the greatest change in total, structural, and load-dependent stiffening compared with younger groups ( P <0.05). Only age and cessation of antihypertensive medication were predictive of structural stiffening, whereas age, race/ethnicity, education, blood pressure, cholesterol, and antihypertensive medication were predictive of increased load-dependent stiffening. On average, structural stiffening accounted for the vast majority of total stiffening, but 37% of participants had more load-dependent than structural stiffening. Rates of structural and load-dependent carotid artery stiffening increased with age. Structural stiffening was consistently observed, and load-dependent stiffening was highly variable. Heterogeneity in arterial stiffening mechanisms with aging may influence cardiovascular disease development.

Background: Absence of coronary artery calcium (CAC) identifies asymptomatic individuals at low cardiovascular disease risk. Carotid artery plaque is a marker of increased risk, but its association with cardiovascular risk and incident CAC in people without CAC is unclear., Methods: Multi-Ethnic Study of Atherosclerosis participants with CAC score of 0 at enrollment who also underwent carotid plaque measurement using B-mode ultrasonography were prospectively followed for incident coronary heart disease, stroke, and cardiovascular disease events, and CAC (score >0 on up to 3 serial computed tomography scans). The association of carotid plaque presence and plaque score (Ln[score+1]) at baseline with cardiovascular events and incident CAC was evaluated with Cox proportional hazards regression models adjusted for demographics, risk factors, and statin use., Results: Among these 2673 participants (58 years, 64% women, 34% White, 30% Black, 24% Hispanic, and 12% Chinese), carotid plaque at baseline was observed in 973 (36%) and the median plaque score (range, 1-12) among those with plaque was 1. A total of 79 coronary heart disease, 80 stroke, and 151 cardiovascular disease events were observed during 16.1 years of follow-up. Carotid plaque presence and plaque score were independently associated with coronary heart disease risk (HRs, 1.66 [95% CI, 1.04-2.66]; and 1.48 [95% CI, 1.01-2.17], respectively) but not with stroke and cardiovascular disease risk. A total of 973 (36.4%) participants developed CAC over the evaluation period (median 9.3 years). Carotid plaque presence and plaque score were independently associated with incident CAC (HRs, 1.34 [95% CI, 1.18-1.54]; and 1.37 [95% CI, 1.21-1.54]), respectively., Conclusions: The presence and extent of carotid plaque are associated with long-term coronary heart disease risk and incident CAC among middle-aged asymptomatic individuals with an initial CAC score of 0.

Background: In asthma, IL-6 is a potential cause of enhanced inflammation, tissue damage and airway dysfunction. IL-6 signalling is regulated by its receptor, which is composed of two proteins, IL-6R and GP130. In addition to their membrane form, these two proteins may be found as extracellular soluble forms. The interaction of IL-6 with soluble IL-6R (sIL-6R) can trigger IL-6 trans-signalling in cells lacking IL-6R. Conversely, the soluble form of GP130 (sGP130) competes with its membrane form to inhibit IL-6 trans-signalling., Objectives: We aimed to analyse IL-6 trans-signalling proteins in the airways of subjects after an allergen challenge., Methods: We used a model of segmental bronchoprovocation with an allergen (SBP-Ag) in human subjects with allergy. Before and 48 h after SBP-Ag, bronchoalveolar lavages (BALs) allowed for the analysis of proteins in BAL fluids (BALFs) by ELISA, and membrane proteins on the surface of BAL cells by flow cytometry. In addition, we performed RNA sequencing (RNA-seq) and used proteomic data to further inform on the expression of the IL-6R subunits by eosinophils, bronchial epithelial cells and lung fibroblasts. Finally, we measured the effect of IL-6 trans-signalling on bronchial fibroblasts, in vitro., Results: IL-6, sIL-6R, sGP130 and the molar ratio of sIL-6R/sGP130 increased in the airways after SBP-Ag, suggesting the potential for enhanced IL-6 trans-signalling activity. BAL lymphocytes, monocytes and eosinophils displayed IL-6R on their surface and were all possible providers of sIL-6R, whereas GP130 was highly expressed in bronchial epithelial cells and lung fibroblasts. Finally, bronchial fibroblasts activated by IL-6 trans-signalling produced enhanced amounts of the chemokine, MCP-1 (CCL2)., Conclusion and Clinical Relevance: After a bronchial allergen challenge, we found augmentation of the elements of IL-6 trans-signalling. Allergen-induced IL-6 trans-signalling activity can activate fibroblasts to produce chemokines that can further enhance inflammation and lung dysfunction., (© 2021 John Wiley & Sons Ltd.)

Current risk stratification strategies do not fully explain cardiovascular disease (CVD) risk. We aimed to evaluate the association of low-density lipoprotein (LDL-P) and high-density lipoprotein (HDL-P) particles with progression of coronary artery calcium and carotid wall injury. All participants in the Multi-Ethnic Study Atherosclerosis (MESA) with LDL-P and HDL-P measured by ion mobility, coronary artery calcium score (CAC), carotid intima-media thickness (IMT), and carotid plaque data available at Exam 1 and 5 were included in the study. CAC progression was annualized and treated as a categorical or continuous variable. Carotid IMT and plaque progression were treated as continuous variables. Fully adjusted regression models included established CVD risk factors, as well as traditional lipids. Mean (±SD) follow-up duration was 9.6 ± 0.6 years. All LDL-P subclasses as well as large HDL-P at baseline were positively and significantly associated with annualized CAC progression, however, after adjustment for established risk factors and traditional lipids, only the association with medium and very small LDL-P remained significant (β -0.02, p = 0.019 and β 0.01, p = 0.003, per 1 nmol/l increase, respectively). Carotid plaque score progression was positively associated with small and very small LDL-P (p <0.01 for all) and non-HDL-P (p = 0.013). Only the association with very small LDL-P remained significant in a fully adjusted model (p = 0.035). Mean IMT progression was not associated with any of the lipid particles. In conclusion, in the MESA cohort, LDL-P measured by ion mobility was significantly associated with CAC progression as well as carotid plaque progression beyond the effect of traditional lipids., Competing Interests: Declaration of Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: Influenza is temporally associated with cardiopulmonary morbidity and mortality among those with cardiovascular disease who may mount a less vigorous immune response to vaccination. Higher influenza vaccine dose has been associated with reduced risk of influenza illness., Objective: To evaluate whether high-dose trivalent influenza vaccine compared with standard-dose quadrivalent influenza vaccine would reduce all-cause death or cardiopulmonary hospitalization in high-risk patients with cardiovascular disease., Design, Setting, and Participants: Pragmatic multicenter, double-blind, active comparator randomized clinical trial conducted in 5260 participants vaccinated for up to 3 influenza seasons in 157 sites in the US and Canada between September 21, 2016, and January 31, 2019. Patients with a recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor were eligible., Interventions: Participants were randomly assigned to receive high-dose trivalent (n = 2630) or standard-dose quadrivalent (n = 2630) inactivated influenza vaccine and could be revaccinated for up to 3 seasons., Main Outcomes and Measures: The primary outcome was the time to the composite of all-cause death or cardiopulmonary hospitalization during each enrolling season. The final date of follow-up was July 31, 2019. Vaccine-related adverse events were also assessed., Results: Among 5260 randomized participants (mean [SD] age, 65.5 [12.6] years; 3787 [72%] men; 3289 [63%] with heart failure) over 3 influenza seasons, there were 7154 total vaccinations administered and 5226 (99.4%) participants completed the trial. In the high-dose trivalent vaccine group, there were 975 primary outcome events (883 hospitalizations for cardiovascular or pulmonary causes and 92 deaths from any cause) among 884 participants during 3577 participant-seasons (event rate, 45 per 100 patient-years), whereas in the standard-dose quadrivalent vaccine group, there were 924 primary outcome events (846 hospitalizations for cardiovascular or pulmonary causes and 78 deaths from any cause) among 837 participants during 3577 participant-seasons (event rate, 42 per 100 patient-years) (hazard ratio, 1.06 [95% CI, 0.97-1.17]; P = .21). In the high-dose vs standard-dose groups, vaccine-related adverse reactions occurred in 1449 (40.5%) vs 1229 (34.4%) participants and severe adverse reactions occurred in 55 (2.1%) vs 44 (1.7%) participants., Conclusions and Relevance: In patients with high-risk cardiovascular disease, high-dose trivalent inactivated influenza vaccine, compared with standard-dose quadrivalent inactivated influenza vaccine, did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations. Influenza vaccination remains strongly recommended in this population., Trial Registration: ClinicalTrials.gov Identifier: NCT02787044.

Background: Inflammation is intimately involved in the pathogenesis of atherosclerosis and is accurately measured by high-sensitivity C-reactive protein (hs-CRP), a sensitive marker for future risk of cardiovascular disease. The Correlation between Oral Health and Systemic Inflammation (COHESION) trial was designed to test the hypothesis that PlaqueHD, a plaque-identifying toothpaste, reduces hs-CRP., Methods: The trial was designed initially to include 132 subjects with hs-CRP between 2.0 and 10.0 mg/L but instead randomized 112 between 0.5 and 10.0, of which 103 had baseline and follow-up data and comprised the intention-to-treat sample. Of these, a prespecified subgroup analysis included 40 with baseline hs-CRP >2.0 and all hs-CRP <10. Because the distribution of hs-CRP was skewed toward higher values, to achieve normality assumptions, the significance of changes in hs-CRP between groups over time was tested on log-transformed data using a mixed effects analysis of variance., Results: The intention-to-treat analysis showed no significant differences between the PlaqueHD and placebo group (P = .615). The prespecified subgroup analysis showed a significant difference between the PlaqueHD and placebo group (P = .047). Results of the analysis showed a reduction in hs-CRP at follow-up of 0.58 in the PlaqueHD and an increase of 0.55 in the placebo group., Conclusions: These findings are compatible with those of a prior pilot trial that also suggested benefits only in subjects with baseline elevations. Future trials targeting reductions of hs-CRP levels should randomize subjects with baseline hs-CRP between 2.0 and 10.0 mg/L., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Asthma and atrial fibrillation (AF) share an underlying inflammatory pathophysiology. We hypothesized that persistent asthmatics are at higher risk for developing AF and that this association would be attenuated by adjustment for baseline markers of systemic inflammation., Methods: The MESA (Multi-Ethnic Study of Atherosclerosis) is a prospective longitudinal study of adults free of cardiovascular disease at baseline. Presence of asthma was determined at exam 1. Persistent asthma was defined as asthma requiring use of controller medications. Intermittent asthma was defined as asthma without use of controller medications. Participants were followed for a median of 12.9 (interquartile range, 10-13.6) years for incident AF. Multivariable Cox regression models were used to assess associations of asthma subtype and AF., Results: The 6615 participants were a mean (SD) 62.0 (10.2) years old (47% male, 27% black, 12% Chinese, and 22% Hispanic). AF incidence rates were 0.11 (95% CI, 0.01-0.12) events/10 person-years for nonasthmatics, 0.11 (95% CI, 0.08-0.14) events/10 person-years for intermittent asthmatics, and 0.19 (95% CI, 0.120.49) events/10 person-years for persistent asthmatics (log-rank P =0.008). In risk-factor adjusted models, persistent asthmatics had a greater risk of incident AF (hazard ratio, 1.49 [95% CI, 1.03-2.14], P =0.03). IL (Interleukin)-6 (hazard ratio, 1.26 [95% CI, 1.13-1.42]), TNF (tumor necrosis factor)-α receptor 1 (hazard ratio, 1.09 [95% CI, 1.08-1.11]) and D-dimer (hazard ratio, 1.10 [95% CI, 1.02-1.20]) predicted incident AF, but the relationship between asthma and incident AF was not attenuated by adjustment for any inflammation marker (IL-6, CRP [C-reactive protein], TNF-α R1, D-dimer, and fibrinogen)., Conclusions: In a large multiethnic cohort with nearly 13 years follow-up, persistent asthma was associated with increased risk for incident AF. This association was not attenuated by adjustment for baseline inflammatory biomarkers.

Background: Relative enlargement of the pulmonary artery (PA) on chest CT imaging is associated with respiratory exacerbations in patients with COPD or cystic fibrosis. We sought to determine whether similar findings were present in patients with asthma and whether these findings were explained by differences in ventricular size., Methods: We measured the PA and aorta diameters in 233 individuals from the Severe Asthma Research Program III cohort. We also estimated right, left, and total epicardial cardiac ventricular volume indices (eERVVI, eELVVI, and eETVVI, respectively). Associations between the cardiac and PA measures (PA-to-aorta [PA/A] ratio, eERVVI-to-eELVVI [eRV/eLV] ratio, eERVVI, eELVVI, eETVVI) and clinical measures of asthma severity were assessed by Pearson correlation, and associations with asthma severity and exacerbation rate were evaluated by multivariable linear and zero-inflated negative binomial regression., Results: Asthma severity was associated with smaller ventricular volumes. For example, those with severe asthma had 36.1 mL/m 2 smaller eETVVI than healthy control subjects (P = .003) and 14.1 mL/m 2 smaller eETVVI than those with mild/moderate disease (P = .011). Smaller ventricular volumes were also associated with a higher rate of asthma exacerbations, both retrospectively and prospectively. For example, those with an eETVVI less than the median had a 57% higher rate of exacerbations during follow-up than those with eETVVI greater than the median (P = .020). Neither PA/A nor eRV/eLV was associated with asthma severity or exacerbations., Conclusions: In patients with asthma, smaller cardiac ventricular size may be associated with more severe disease and a higher rate of asthma exacerbations., Trial Registry: ClinicalTrials.gov; No.: NCT01761630; URL: www.clinicaltrials.gov., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objective- Lp(a) [lipoprotein(a)] is a well-described risk factor for atherosclerosis, but Lp(a)-associated risk may vary by race/ethnicity. We aimed to determine whether race/ethnicity modifies Lp(a)-related risk of carotid atherosclerotic plaque outcomes among black, white, Chinese, and Hispanic individuals. Approach and Results- Carotid plaque presence and score were assessed by ultrasonography at baseline (n=5155) and following a median 9.4 year period (n=3380) in MESA (Multi-Ethnic Study of Atherosclerosis) participants. Lp(a) concentrations were measured by immunoassay and examined as a continuous and categorical variable using clinically-based cutoffs, 30 and 50 mg/dL. Lp(a) was related to greater risk of prevalent carotid plaque at baseline in whites alone (all P<0.001): per log unit (relative risk, 1.05); Lp(a)≥30 mg/dL (relative risk, 1.16); and Lp(a)≥50 mg/dL (relative risk, 1.20). Lp(a) levels over 50 mg/dL were associated with a higher plaque score at baseline in whites (all P<0.001) and Hispanics ( P=0.04). In prospective analyses, whites with Lp(a) ≥50 mg/dL were found to have greater risk of plaque progression (relative risk, 1.12; P=0.03) and higher plaque scores (all P<0.001) over the 9.4-year follow-up. Race-based differences between whites and black participants were significant for cross-sectional associations and for carotid plaque score following the 9.4 year study period. Conclusions- Race was found to be a modifying variable in Lp(a)-related risk of carotid plaque, and Lp(a) levels may have greater influence on plaque burden in whites than in black individuals. Borderline results in Hispanics suggest that elevated Lp(a) may increase the risk of carotid plaque, but follow-up studies are needed.

Background: Asthma is associated with an increased cardiovascular disease (CVD) risk in adults, but the impact of asthma and atopic conditions on CVD risk in children is less well established. We hypothesized that children in the Childhood Origins of Asthma (COAST) Cohort with asthma and atopic conditions would have early carotid arterial injury., Methods: The COAST study is a longitudinal birth cohort of children at increased risk of developing asthma. Children underwent ultrasonography measuring far wall right carotid bifurcation (RCB) and common carotid artery (RCCA) intima-media thickness (IMT; a measure of arterial injury). Multivariable linear regression models adjusted for age, gender, race, blood pressure, and body-mass index were used to assess associations of asthma and markers of arterial injury., Results: The 89 participants were a mean (standard deviation) 15.3 (0.6) years old and 42% were female; 28 asthmatics had atopic disease, 34 asthmatics were without other atopic disease, and 15 non-asthmatics had atopic disease. This study population was compared to 12 controls (participants free of asthma or atopic disease). Compared to controls (589 μm), those with atopic disease (653 μm, p = 0.07), asthma (649 μm, p = 0.05), or both (677 μm, p = 0.005) had progressively higher RCB IMT values (ptrend = 0.011). In adjusted models, asthmatic and/or atopic participants had significantly higher RCB IMT than those without asthma or atopic disease (all p≤0.03). Similar relationships were found for RCCA IMT., Conclusion: Adolescents with asthma and other atopic diseases have an increased risk of subclinical arterial injury compared to children without asthma or other atopic disease., Competing Interests: The authors have declared that no competing interests exist.

Objective- HDL-C (high-density lipoprotein cholesterol) may not always be cardioprotective in postmenopausal women. HDL particles (HDL-P) via ion-mobility may better reflect the antiatherogenicity of HDL. Objectives were (1) to evaluate associations of HDL-C and ion-mobility HDL-P with carotid intima-media thickness (cIMT) and carotid plaque separately and jointly in women; and (2) to assess interactions by age at and time since menopause. Approach and Results- Analysis included 1380 females from the MESA (Multi-Ethnic Study of Atherosclerosis; age: 61.8±10.3; 61% natural-, 21% surgical-, and 18% peri-menopause). Women with unknown or early menopause (age at nonsurgical menopause ≤45 years) were excluded. Adjusting for each other, higher HDL-P but not HDL-C was associated with lower cIMT ( P=0.001), whereas higher HDL-C but not HDL-P was associated with greater risk of carotid plaque presence ( P=0.04). Time since menopause significantly modified the association of large but not small HDL-P with cIMT; higher large HDL-P was associated with higher cIMT close to menopause but with lower cIMT later in life. The proatherogenic association reported for HDL-C with carotid plaque was most evident in women with later age at menopause who were >10 years postmenopausal. Conclusions- Elevated HDL-C may not always be cardioprotective in postmenopausal women. The cardioprotective capacity of large HDL-P may adversely compromise close to menopause supporting the importance of assessing how the menopause transition might impact HDL quality and related cardiovascular disease risk later in life.

Objective: This pilot study determined if the ultrasound texture feature "contrast" was associated with cardiovascular disease (CVD) risk factors and subclinical arterial disease., Methods: We evaluated ultrasound images of the right common carotid artery (CCA) from a convenience sample of 151 participants and examined relationships between contrast, CVD risk factors, carotid intima-media thickness (IMT) and coronary artery calcium (CAC). Grey level difference statistics algorithms were used to evaluate the texture feature "contrast" from carotid ultrasound images. Right CCA IMT measurements were made in triplicate in the distal 1 cm segment of the far wall of the artery and CAC score was measured using the Agatston scoring method., Results: In individual models that included age, sex and race, grey level difference statistics contrast (outcome) was associated independently with age [beta (standard error) = -0.87 (0.38) per year; p = 0.02], C-reactive protein [-2.22 (0.96) per mg dl -1 ; p = 0.02], high-density lipoprotein cholesterol [0.61 (0.24) per mg dl -1 ; p = 0.01] and CCA IMT [-0.06 (0.02) microns; p = 0.001]. Other CVD risk factors and CAC were not associated independently with contrast., Conclusion: These findings support the potential use of the ultrasound texture contrast for evaluating arterial injury and CVD risk. Advances in knowledge: This paper contributes to the literature in that it describes how the greyscale texture feature "contrast" is related to CVD risk factors.

Background: Apolipoprotein C-III (apoC-III), a small proinflammatory protein present on 6% to 7% of high-density lipoprotein (HDL) particles, defines a subspecies of HDL adversely associated with coronary heart disease in primarily white cohorts. In a multi-ethnic population free of clinical cardiovascular disease, we evaluated the relationship between apoC-III-defined HDL subspecies and subclinical markers of atherosclerotic pathology., Methods and Results: We investigated cross-sectional associations between apolipoprotein A-I concentrations of apoC-III-defined HDL subspecies, measured via ELISA and imaging measures of subclinical atherosclerosis, among 4659 participants in the MESA (The Multi-Ethnic Study of Atherosclerosis) at baseline (2000-2002). HDL particles containing and lacking apoC-III were divergently associated with coronary artery calcification in women ( P -heterogeneity=0.002) but not in men ( P -heterogeneity=0.31) and with carotid plaque score ( P -heterogeneity=0.02) and intima-media thickness ( P -heterogeneity=0.06) in the overall study population. HDL lacking apoC-III was inversely associated with all outcome measures (coronary artery calcification, women: odds ratio per SD=0.81 [95% confidence interval [CI], 0.73-0.90]; carotid plaque, overall: odds ratio per SD=0.92 [95% CI, 0.84-1.00]; intima-media thickness, overall: mean difference per SD=-14.0 µm [95% CI, -21.1 to -6.7 μm]), whereas HDL containing apoC-III was positively associated (coronary artery calcification, women: odds ratio=1.10 [95% CI, 0.99-1.22]; plaque, overall: odds ratio=1.10 [95% CI, 1.01-1.19]) or unassociated. Neither total HDL nor HDL subspecies was associated with changes in subclinical atherosclerosis measures up to 10 years later., Conclusions: The presence of apoC-III defined a subspecies of HDL not inversely associated with baseline measures of subclinical atherosclerosis, supporting a role of apoC-III in the pathophysiology of cardiovascular disease., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Objective: ω-3 (n-3) fatty acids (FAs) have long been considered healthful dietary components, yet recent clinical trials have questioned their cardiovascular benefits. By contrast, the ω-6 (n-6) FAs have been considered harmful, proatherogenic macronutrients, despite an absence of empirical evidence supporting this hypothesis. We aimed to determine whether plasma n-3 and n-6 FAs are related to risk of carotid plaque and its progression in 3327 participants of MESA (Multi-Ethnic Study of Atherosclerosis)., Approach and Results: Carotid plaque was assessed using ultrasonography at baseline and after a median period of 9.5 years. Plasma phospholipid n-3 and n-6 FAs were determined using gas chromatography-flame ionization detection. Relative risk regression analyses assessed the relations of FAs with the presence or progression of carotid plaque adjusted for typical cardiovascular disease risk factors. At baseline, it was found that participants in the fourth quartile of n-3 docosahexaenoic acid showed a 9% lower risk of carotid plaque ( P =0.05), whereas those in the second quartile of n-3 α-linolenic acid showed an 11% greater risk compared with respective referent quartiles ( P =0.02). In prospective analyses, individuals in the top quartile of docosahexaenoic acid showed a 12% lower risk of carotid plaque progression during 9.5 years compared with those in the referent quartile ( P =0.002). No significant relations were observed among n-6 FAs and plaque outcomes. No significant race/ethnicity interactions were found., Conclusions: These findings support docosahexaenoic acid as an atheroprotective macronutrient, whereas null findings for n-6 FAs challenge the view that they promote atherosclerosis., (© 2018 American Heart Association, Inc.)

Background: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in heart failure patients with reduced left ventricular function and intraventricular conduction delay. However, individual outcomes vary significantly. This study sought to use a machine learning algorithm to develop a model to predict outcomes after CRT., Methods and Results: Models were developed with machine learning algorithms to predict all-cause mortality or heart failure hospitalization at 12 months post-CRT in the COMPANION trial (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure). The best performing model was developed with the random forest algorithm. The ability of this model to predict all-cause mortality or heart failure hospitalization and all-cause mortality alone was compared with discrimination obtained using a combination of bundle branch block morphology and QRS duration. In the 595 patients with CRT-defibrillator in the COMPANION trial, 105 deaths occurred (median follow-up, 15.7 months). The survival difference across subgroups differentiated by bundle branch block morphology and QRS duration did not reach significance ( P =0.08). The random forest model produced quartiles of patients with an 8-fold difference in survival between those with the highest and lowest predicted probability for events (hazard ratio, 7.96; P <0.0001). The model also discriminated the risk of the composite end point of all-cause mortality or heart failure hospitalization better than subgroups based on bundle branch block morphology and QRS duration., Conclusions: In the COMPANION trial, a machine learning algorithm produced a model that predicted clinical outcomes after CRT. Applied before device implant, this model may better differentiate outcomes over current clinical discriminators and improve shared decision-making with patients., (© 2018 American Heart Association, Inc.)

Background: High blood cholesterol contributes to atherosclerosis, yet reliance on the lipid panel alone may mischaracterize individuals with elevated lipoprotein particle numbers., Objective: The aim of the article was to determine whether elevated lipoprotein or apolipoprotein measures are associated with carotid atherosclerosis and plaque progression independent of cardiovascular (CV) risk factors including standard lipids in a subcohort of 2228 Multi-Ethnic Study of Atherosclerosis participants., Methods: Ultrasonography assessed carotid artery plaque and common carotid intima-media thickness (cIMT) at baseline and after a median period of 9.4 years. Nuclear magnetic resonance spectroscopy estimated lipoprotein particle concentrations. Apolipoprotein B (ApoB) and apolipoprotein A-I were measured using an automated immunoassay. Regression analysis determined associations of apolipoprotein and lipoprotein measurements with cIMT and relative risk regression determined associations with carotid plaque progression., Results: After adjustment for typical CV risk factors, individuals in top quartiles of ApoB, ApoB/apolipoprotein A-I, low-density lipoprotein particles (LDL-P), small LDL-P, and total LDL-P/high-density lipoprotein (HDL) particles showed similar risks of carotid plaque and cIMT progression as LDL-C, non-HDL cholesterol (HDL-C), total cholesterol (TC), and TC/HDL-C. A significant association with plaque progression remained in the top ApoB quartile after further adjustment for LDL-C (P = .02) or TC + HDL-C (P = .04), but was nonsignificant when adjusted for all lipid covariates (P = .086). Those in the top quartile of small LDL-P concentrations showed greater cIMT progression than those in the referent after adjustment for LDL-C, but this was nonsignificant after adjustment for TC + HDL-C., Conclusion: When coupled with evidence that apolipoprotein testing identifies lipid-lipoprotein discordance, these findings suggest that ApoB and small LDL-P provide atherosclerosis risk information that is not revealed by typical CV risk factors., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Associations with antihypertensive medication classes and progression of arterial stiffness have not been studied in a prospective multiethnic cohort. All participants had hypertension at baseline, defined as blood pressure ≥140/90 mm Hg or use of antihypertensive medications. Medication use and blood pressure were assessed at 5 time points. Young's elastic modulus and distensibility coefficient of the right common carotid artery were obtained by ultrasound at baseline and after a mean (SD) follow-up period of 9.4 (0.5) years. Associations with changes in Young's elastic modulus and distensibility coefficient, baseline antihypertensive medication use, number of visits each medication class was reported, and blood pressure control (<140/90 mm Hg) were assessed using multiple linear regression models. At baseline, mean age of participants (n=1206) was 63.2 (9.0) years (55% female; 35% African American, 19% Hispanic, 12% Chinese). Mean systolic blood pressure was 136.5 (20.6) mm Hg. Greater progression of arterial stiffness was associated with older age, African American ethnicity, and baseline calcium channel blocker use. There were no other associations between changes in Young's elastic modulus or distensibility coefficient and use of other medication classes (all P>0.4). Achieving blood pressure control (<140/90 mm Hg) at all visits was associated with slower progression of arterial stiffness (Young's elastic modulus: β=-790.1 mm Hg, P=0.01; distensibility coefficient: β=7.34×10 - 4 mm Hg - 1 , P=0.001). Blood pressure control, rather than use of any particular antihypertensive medication class, was associated most strongly with slowing arterial stiffness progression. Over nearly a decade of follow-up, no consistent associations between any specific antihypertensive medication class and progressive carotid arterial stiffening were identified., (© 2016 American Heart Association, Inc.)

Background: Asthma is a heterogeneous syndrome with different clinical subtypes that is associated with an increased risk for cardiovascular disease (CVD). We hypothesized that the late-onset subtype of asthma is associated with a higher risk of incident CVD., Methods and Results: Participants from the Wisconsin Sleep Cohort free of CVD at baseline were followed for a mean (SD) of 13.9 (5.9) years for development of CVD (myocardial infarction, angina, stroke, coronary revascularization, heart failure, or CVD death). Late-onset asthma was defined as physician-diagnosed asthma at age ≥18 years. Multivariable Cox regression models adjusted for age, sex, and CVD risk factors were used to assess associations of late-onset asthma and incident CVD. The 1269 participants were 47.3 (8.0) years old; 166 participants had asthma (111 late-onset, 55 early-onset). Participants with late-onset asthma compared to nonasthmatics were more likely to be female (67% versus 44%) and to have a higher body-mass index (32.2 versus 29.4 kg/m(2)) (P<0.05). Mean age of asthma diagnosis in the late-onset group was 39.5 (9.6) years versus 8.9 (5.7) years in the early-onset group (P<0.0001). Late-onset asthmatics had a higher adjusted risk of incident CVD than nonasthmatics (hazard ratio 1.57, 95% CI 1.01-2.45, P=0.045). There was no interaction between body-mass index and age of asthma diagnosis on incident CVD (P=0.83)., Conclusions: In a large cohort study of adults followed prospectively for over a decade, late-onset asthmatics had an increased risk of incident CVD events that persisted after adjustment for age, sex, and CVD risk factors., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Although some evidence shows that neighborhood deprivation is associated with greater subclinical atherosclerosis, prior studies have not identified what aspects of deprived neighborhoods were driving the association., Methods: We investigated whether social and physical neighborhood characteristics are related to the progression of subclinical atherosclerosis in 5950 adult participants of the MESA (Multi-Ethnic Study of Atherosclerosis) during a 12-year follow-up period. We assessed subclinical disease using coronary artery calcium (CAC). Neighborhood features examined included density of recreational facilities, density of healthy food stores, and survey-based measures of availability of healthy foods, walking environment, and social environment. We used econometric fixed-effects models to investigate how change in a given neighborhood exposure is related to simultaneous change in subclinical atherosclerosis., Results: Increases in density of neighborhood healthy food stores were associated with decreases in CAC (mean changes in CAC Agatston units per 1-SD increase in neighborhood exposures, -19.99; 95% confidence interval, -35.21 to -4.78) after adjustment for time-varying demographic confounders and computed tomography scanner type. This association remained similar in magnitude after additional adjustment for time-varying behavioral risk factors and depression. The addition of time-varying biomedical factors attenuated associations with CAC slightly (mean changes in CAC per 1-SD increase in neighborhood exposures, -17.60; 95% confidence interval, -32.71 to -2.49). Changes across time in other neighborhood measures were not significantly associated with within-person change in CAC., Conclusions: Results from this longitudinal study provide suggestive evidence that greater access to neighborhood healthy food resources may slow the development of coronary atherosclerosis in middle-aged and older adults., (© 2016 American Heart Association, Inc.)

Objectives: To identify and characterize an association between persistent asthma and cardiovascular disease (CVD) risk in the Multi-Ethnic Study of Atherosclerosis (MESA)., Approach and Results: MESA is a longitudinal prospective study of an ethnically diverse cohort of individuals free of known CVD at its inception. The presence and severity of asthma were assessed in the MESA at examination 1. Persistent asthma was defined as asthmatics using controller medications (inhaled corticosteroids, leukotriene inhibitors, and oral corticosteroids) and intermittent asthma as asthmatics not using controller medications. Participants were followed up for a mean (SD) of 9.1 (2.8) years for development of incident CVD (coronary death, myocardial infarction, angina, stroke, and CVD death). Multivariable Cox regression models were used to assess associations of asthma and CVD. The 6792 participants were 62.2 (SD, 10.2) years old: 47% men (28% black, 22% Hispanic, and 12% Chinese). Persistent asthmatics (n=156), compared with intermittent (n=511) and nonasthmatics (n=6125), respectively, had higher C-reactive protein (1.2 [1.2] versus 0.9 [1.2] versus 0.6 [1.2] mg/L) and fibrinogen (379 [88] versus 356 [80] versus 345 [73] mg/dL) levels. Persistent asthmatics had the lowest unadjusted CVD-free survival rate of 84.1%, 95% confidence interval (78.9%-90.3%) compared with intermittent asthmatics 91.1% (88.5%-93.8%) and nonasthmatics 90.2% (89.4%-91%). Persistent asthmatics had greater risk of CVD events than nonasthmatics (hazard ratio [95% confidence interval], 1.6 [1.01-2.5]; P=0.040]), even after adjustment for age, sex, race, CVD risk factors, and antihypertensive and lipid medication use., Conclusions: In this large multiethnic cohort, persistent asthmatics had a higher CVD event rate than nonasthmatics., (© 2015 American Heart Association, Inc.)

Objective: We aimed to examine associations of lipoprotein(a) (Lp(a)) concentrations with coronary heart disease (CHD) and determine whether current Lp(a) clinical laboratory cut points identify risk of disease incidence in 4 races/ethnicities of the Multi-Ethnic Study of Atherosclerosis (MESA)., Approach and Results: A subcohort of 1323 black, 1677 white, 548 Chinese American, and 1044 Hispanic MESA participants were followed up during a mean 8.5-year period in which 235 incident CHD events were recorded. Lp(a) mass concentrations were measured using a turbidimetric immunoassay. Cox regression analysis determined associations of Lp(a) with CHD risk with adjustments for lipid and nonlipid variables. Lp(a) concentrations were continuously associated with risk of CHD incidence in black (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.09-2.04] and white participants (HR, 1.22; 95% CI, 1.02-1.45). Examining Lp(a) risk by the 50 mg/dL cut point revealed higher risks of incident CHD in all races except Chinese Americans: blacks (HR, 1.69; 95% CI, 1.03-2.76), whites (HR, 1.82; 95% CI, 1.15-2.88); Hispanics (HR, 2.37; 95% CI, 1.17-4.78). The lower Lp(a) cut point of 30 mg/dL identified higher risk of CHD in black participants alone (HR, 1.87; 95% CI, 1.08-3.21)., Conclusions: Our findings suggest that the 30 mg/dL cutoff for Lp(a) is not appropriate in white and Hispanic individuals, and the higher 50 mg/dL cutoff should be considered. In contrast, the 30 mg/dL cutoff remains suitable in black individuals. Further research is necessary to develop the most clinically useful Lp(a) cutoff values in individual races/ethnicities., (© 2015 American Heart Association, Inc.)

Background: The role of atherosclerosis in the progression of global left ventricular dysfunction and cardiovascular events has been well recognized. Left ventricular (LV) dyssynchrony is a measure of regional myocardial dysfunction. Our objective was to investigate the relationship of subclinical atherosclerosis with mechanical LV dyssynchrony in a population-based asymptomatic multi-ethnic cohort., Methods and Results: Participants of the Multi-Ethnic Study of Atherosclerosis (MESA) at exam 5 were evaluated using 1.5T cardiac magnetic resonance (CMR) imaging, carotid ultrasound (n = 2062) for common carotid artery (CCA) and internal carotid artery (ICA) intima-media thickness (IMT), and cardiac computed tomography (n = 2039) for coronary artery calcium (CAC) assessment (Agatston method). Dyssynchrony indices were defined as the standard deviation of time to peak systolic circumferential strain (SD-TPS) and the difference between maximum and minimum (max-min) time to peak strain using harmonic phase imaging in 12 segments (3-slices × 4 segments). Multivariable regression analyses were performed to assess associations after adjusting for participant demographics, cardiovascular risk factors, LV mass, and ejection fraction. In multivariable analyses, SD-TPS was significantly related to measures of atherosclerosis, including CCA-IMT (8.7 ms/mm change in IMT, p = 0.020), ICA-IMT (19.2 ms/mm change in IMT, p < 0.001), carotid plaque score (1.2 ms/unit change in score, p < 0.001), and log transformed CAC+1 (0.66 ms/unit log-CAC+1, p = 0.018). These findings were consistent with other parameter of LV dyssynchrony i.e. max-min., Conclusion: In the MESA cohort, measures of atherosclerosis are associated with parameters of subclinical LV dyssynchrony in the absence of clinical coronary event and left-bundle-branch block., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To identify sex differences in predictors of longitudinal changes in carotid arterial stiffness in a multiethnic cohort., Approach and Results: Carotid artery distensibility coefficient (DC) and Young's elastic modulus (YEM) were measured in 2650 Multi-Ethnic Study of Atherosclerosis participants (45-84 years old and free of cardiovascular disease) at baseline and after a mean of 9.4 years. Predictors of changes in DC and YEM for each sex were evaluated using multivariable linear regression models. The 1236 men (46.6%) were 60.0 (SD, 9.3) years: 40% were white, 22% black, 16% Chinese, and 22% Hispanic. The 1414 (53.4%) women were 59.8 (9.4) years old with a similar race distribution. Despite similar rates of change in DC and YEM, predictors of changes in distensibility markers differed by sex. In men, Chinese (P=0.002) and black (P=0.003) race/ethnicity, systolic blood pressure (P=0.012), and diabetes mellitus (P=0.05) were associated with more rapidly decreasing DC (accelerated stiffening). Starting antihypertensive medication was associated with improved DC (P=0.03); stopping antihypertensives was associated with more rapid stiffening (increased YEM, P=0.05). In women, higher education was associated with slower stiffening (DC, P=0.041; YEM, P<0.001) as was use of lipid-lowering medication (P=0.03), whereas baseline use of antihypertensive medications (YEM, P=0.01) and systolic blood pressure (DC, P=0.02; P=0.04) predicted increasing stiffening in women., Conclusions: Longitudinal changes in carotid artery stiffness are associated with systolic blood pressure and antihypertensive therapy in both sexes; however, race/ethnicity (in men) and level of education (in women) may have different contributions between the sexes., (© 2014 American Heart Association, Inc.)

Background: Presence of coronary artery calcium (CAC), carotid plaque, and increased carotid intima-media thickness (IMT) may indicate elevated cardiovascular disease (CVD) risk; however, no large studies have compared them directly. This study compares predictive uses of CAC presence, carotid artery plaque presence, and high IMT for incident CVD events., Methods and Results: Participants were from the Multi-Ethnic Study of Atherosclerosis (MESA). Predictive values of carotid plaque, IMT, and CAC presence were compared using Cox proportional hazards models, c-statistics, and net reclassification indices. The 6779 participants were mean (SD) 62.2 (10.2) years old; 49.9% had CAC, and 46.7% had carotid plaque. The mean left and right IMT were 0.754 (0.210) mm and 0.751 (0.187) mm, respectively. After 9.5 years (mean), 538 CVD events, 388 coronary heart disease (CHD) events, and 196 stroke/transient ischemic attacks were observed. CAC presence was a stronger predictor of incident CVD and CHD than carotid ultrasound measures. Mean IMT≥75th percentile (for age, sex, and race) alone did not predict events. Compared with traditional risk factors, c-statistics for CVD (c=0.756) and CHD (c=0.752) increased the most by the addition of CAC presence (CVD, 0.776; CHD, 0.784; P<0.001) followed by carotid plaque presence (CVD, c=0.760; CHD, c=0.757; P<0.05). Compared with risk factors (c=0.782), carotid plaque presence (c=0.787; P=0.045) but not CAC (c=0.785; P=0.438) improved prediction of stroke/transient ischemic attacks., Conclusions: In adults without CVD, CAC presence improves prediction of CVD and CHD more than carotid plaque presence or high IMT. CAC and carotid ultrasound parameters performed similarly for stroke/transient ischemic attack event prediction., (© 2015 American Heart Association, Inc.)

Background and Purpose: Carotid artery intima-media thickness (IMT) and plaque are noninvasive markers of subclinical arterial injury that predict incident cardiovascular disease. We evaluated predictors of longitudinal changes in IMT and new plaque during a decade in a longitudinal multiethnic cohort., Methods: Carotid IMT and plaque were evaluated in Multi-Ethnic Study of Atherosclerosis (MESA) participants at exams 1 and 5, a mean (standard deviation) of 9.4 (0.5) years later. Far wall carotid IMT was measured in both common and internal carotid arteries. A plaque score was calculated from all carotid segments. Mixed-effects longitudinal and multivariate regression models evaluated associations of baseline risk factors and time-updated medication use with IMT progression and plaque formation., Results: The 3441 MESA participants were aged 60.3 (9.4) years (53% women; 26% blacks, 22% Hispanic, 13% Chinese); 1620 (47%) had carotid plaque. Mean common carotid artery IMT progression was 11.8 (12.8) μm/year, and 1923 (56%) subjects developed new plaque. IMT progressed more slowly in Chinese (β=-2.89; P=0.001) and Hispanic participants (β=-1.81; P=0.02), and with higher baseline high-density lipoprotein cholesterol (per 5 mg/dL; β=-0.22; P=0.03), antihypertensive use (β=-2.06; P=0.0004), and time on antihypertensive medications (years; β=-0.29; P<0.0001). Traditional risk factors were associated with new plaque formation, with strong associations for cigarette use (odds ratio, 2.31; P<0.0001) and protection by black ethnicity (odds ratio, 0.68; P<0.0001)., Conclusions: In a large, multiethnic cohort with a decade of follow-up, ethnicity was a strong, independent predictor of carotid IMT and plaque progression. Antihypertensive medication use was associated with less subclinical disease progression., (© 2014 American Heart Association, Inc.)

Background and Purpose: Arterial stiffening is associated with hypertension, stroke, and cognitive decline; however, the effects of aging and cardiovascular disease risk factors on carotid artery stiffening have not been assessed prospectively in a large multiethnic longitudinal study., Methods: Distensibility coefficient and the Young's elastic modulus (YEM) of the right common carotid artery were calculated at baseline and after a mean of 9.4 (standard deviation [SD], 0.5) years in 2650 participants. Effects of age and cardiovascular disease risk factors were evaluated by multivariable mixed regression and ANCOVA models., Results: At baseline, participants were 59.9 (SD, 9.4) years old (53% women; 25% black, 22% Hispanic, 14% Chinese). YEM increased from 1581 (SD, 927) to 1749 (SD, 1306) mm Hg (P<0.0001), and distensibility coefficient decreased from 3.1 (SD, 1.3) to 2.7 (SD, 1.1)×10(-3) mm Hg(-1) (P<0.001), indicating progressive arterial stiffening. YEM increased more among participants who were aged>75 years old at baseline (P<0.0001). In multivariable analyses, older age and less education independently predicted worsening YEM and distensibility coefficient. Stopping antihypertensive medication during the study period predicted more severe worsening of YEM (β=360.2 mm Hg; P=0.008). Starting antihypertensive medication after examination 1 was predictive of improvements in distensibility coefficient (β=1.1×10(-4) mm Hg(-1); P=0.024)., Conclusions: Arterial stiffening accelerates with advanced age. Older individuals experience greater increases in YEM than do younger adults, even after considering the effects of traditional risk factors. Treating hypertension may slow the progressive decline in carotid artery distensibility observed with aging and improve cerebrovascular health.

Atherosclerotic lower extremity peripheral arterial disease (PAD) is a highly prevalent condition associated with a significant increase in risk of all-cause mortality and cardiovascular morbidity and mortality. PAD is underdiagnosed and undertreated. Treatment is focused on (1) lowering cardiovascular risk and cardiovascular disease event rates and (2) improvement in symptoms and quality of life. Multidisciplinary and intersociety guidelines guide optimal medical therapy. Substantial evidence supports implementation of tobacco cessation counseling and pharmacotherapy to help achieve tobacco abstinence, antiplatelet therapy, HMG-CoA reductase inhibitors (statins) therapy, and antihypertensive therapy for the purpose of lowering cardiovascular event rates and improving survival., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Previous studies have demonstrated gaps in achievement of low-density lipoprotein-cholesterol (LDL-C) goals among U.S. individuals at high cardiovascular disease risk; however, recent studies in selected populations indicate improvements., Objective: We sought to define the longitudinal trends in achieving LDL-C goals among high-risk United States adults from 1999-2008., Methods: We analyzed five sequential population-based cross-sectional National Health and Nutrition Examination Surveys 1999-2008, which included 18,656 participants aged 20-79 years. We calculated rates of LDL-C goal achievement and treatment in the high-risk population., Results: The prevalence of high-risk individuals increased from 13% to 15.5% (p = 0.046). Achievement of LDL-C <100 mg/dL increased from 24% to 50.4% (p<0.0001) in the high-risk population with similar findings in subgroups with (27% to 64.8% p<0.0001) and without (21.8% to 43.7%, p<0.0001) coronary heart disease (CHD). Achievement of LDL-C <70 mg/dL improved from 2.4% to 17% (p<0.0001) in high-risk individuals and subgroups with (3.4% to 21.4%, p<0.0001) and without (1.7% to 14.9%, p<0.0001) CHD. The proportion with LDL-C ≥130 mg/dL and not on lipid medications decreased from 29.4% to 18% (p = 0.0002), with similar findings among CHD (25% to 11.9% p = 0.0013) and non-CHD (35.8% to 20.8% p<0.0001) subgroups., Conclusion: The proportions of the U.S. high-risk population achieving LDL-C <100 mg/dL and <70 mg/dL increased over the last decade. With 65% of the CHD subpopulation achieving an LDL-C <100 mg/dL in the most recent survey, U.S. LDL-C goal achievement exceeds previous reports and approximates rates achieved in highly selected patient cohorts.

Background: The Reynolds Risk Score (RRS) is one alternative to the Framingham Risk Score (FRS) for cardiovascular risk assessment. The Adult Treatment Panel III (ATP III) integrated the FRS a decade ago, but with the anticipated release of ATP IV, it remains uncertain how and which risk models will be integrated into the recommendations. We sought to define the effects in the United States population of a transition from the FRS to the RRS for cardiovascular risk assessment., Methods: Using the National Health and Nutrition Examination Surveys, we assessed FRS and RRS in 2,502 subjects representing approximately 53.6 Million (M) men (ages 50-79) and women (ages 45-79), without cardiovascular disease or diabetes. We calculated the proportion reclassified by RRS and the subset whose LDL-C goal achievement changed., Results: Compared to FRS, the RRS assigns a higher risk category to 13.9% of women and 9.1% of men while assigning a lower risk to 35.7% of men and 2% of women. Overall, 4.7% of women and 1.1% of men fail to meet newly intensified LDL-C goals using the RRS. Conversely, 10.5% of men and 0.6% of women now meet LDL-C goal using RRS when they had not by FRS., Conclusion: In the U.S. population the RRS assigns a new risk category for one in six women and four of nine men. In general, women increase while men decrease risk. In conclusion, adopting the RRS for the 53.6 million eligible U.S. adults would result in intensification of clinical management in 1.6 M additional women and 2.10 M fewer men.

Background: The Framingham Global Cardiovascular Disease (FRS-CVD) risk assessment is a proposed alternative for the assessment of hard coronary heart disease (FRS-CHD) event risk. Beyond heart attack and death, FRS-CVD risk adds the end points of cerebrovascular disease, angina, heart failure, and peripheral vascular disease., Objective: We sought to estimate the population impact of using FRS-CVD instead of FRS-CHD risk prediction on U.S. adults., Methods: We analyzed FRS-CHD and FRS-CVD risk in men age 45-74 and women age 55-74 without cardiovascular disease or diabetes, using the National Health and Nutrition Examination Survey 2005-2006. We stratified the population into 10-year risk categories: low: <6%, moderate ≥ 6 to <10%, moderate high ≥ 10 to <20%, and high ≥ 20% by both risk models, and assessed change in risk category distribution and achievement of lipid goals., Results: We analyzed 1020 subjects who statistically represent approximately 50 million U.S. adults. When the FRS-CVD was used, we found that 63% of men and 74% of women increase at least one risk category compared with when the FRS-CHD is used. Overall, the low-risk population decreases from 52% to 16% and the high-risk group increases from 4% to 20%. Of the subjects changing risk categories, 30% will now fail to meet their new corresponding lipid goals., Conclusions: FRS-CVD end points are more comprehensive, yet the population implications of such a change may be profound. The use of a FRS-CVD risk model significantly increases the intermediate and high-risk groups, thus increasing the number of individuals eligible for novel risk assessment tools such as high-sensitivity C-reactive protein, coronary calcium scoring, and more frequent use of pharmacotherapy., (Copyright © 2011 National Lipid Association. Published by Elsevier Inc. All rights reserved.)