Skeletal Muscle Adiposity and Lung Function Trajectory in the Severe Asthma Research Program.

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 FEV1% 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/m2) and 37 control subjects (51% women; mean [SD] body mass index, 26.3 [4.7] kg/m2). 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 (ß = -0.47 Δ slope per 10-HU decrease; P = 0.03) but not men (ß = 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 FEV1% 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.

The Impact of Insulin Resistance on Loss of Lung Function and Response to Treatment in Asthma.

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 FEV1 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 FEV1 and FVC, and these lower values were not attributable to obesity effects. Compared with patients without IR, those with IR had lower FEV1 responses to ß-adrenergic agonists and systemic corticosteroids. The annualized decline in FEV1 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.

Asthma as a Systemic Disease: Cardiovascular Effects Associated with Asthma.

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.

Evaluation of inter-observer variability regarding aortic and mitral valve findings on transesophageal echocardiograms ordered for suspected endocarditis.

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.

Increased IL-6 and Potential IL-6 trans-signalling in the airways after an allergen challenge.

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.

Effect of High-Dose Trivalent vs Standard-Dose Quadrivalent Influenza Vaccine on Mortality or Cardiopulmonary Hospitalization in Patients With High-risk Cardiovascular Disease: A Randomized Clinical Trial.

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.

HDL (High-Density Lipoprotein) Metrics and Atherosclerotic Risk in Women.

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.

Change in Neighborhood Characteristics and Change in Coronary Artery Calcium: A Longitudinal Investigation in the MESA (Multi-Ethnic Study of Atherosclerosis) Cohort.

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.

Sex differences in predictors of longitudinal changes in carotid artery stiffness: the Multi-Ethnic Study of Atherosclerosis.

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.

Asthma predicts cardiovascular disease events: the multi-ethnic study of atherosclerosis.

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.

Predictors of carotid thickness and plaque progression during a decade: the Multi-Ethnic Study of Atherosclerosis.

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 (ß=-2.89; P=0.001) and Hispanic participants (ß=-1.81; P=0.02), and with higher baseline high-density lipoprotein cholesterol (per 5 mg/dL; ß=-0.22; P=0.03), antihypertensive use (ß=-2.06; P=0.0004), and time on antihypertensive medications (years; ß=-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.

Longitudinal effects of a decade of aging on carotid artery stiffness: the multiethnic study of atherosclerosis.

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 (ß=360.2 mm Hg; P=0.008). Starting antihypertensive medication after examination 1 was predictive of improvements in distensibility coefficient (ß=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.

Systemic Inflammation in Asthma: What Are the Risks and Impacts Outside the Airway?

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.

Influenza Vaccine Immune Response in Patients With High-Risk Cardiovascular Disease: A Secondary Analysis of the INVESTED Randomized Clinical Trial.

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.

Association of statin therapy with progression of carotid arterial stiffness: the Multi-Ethnic Study of Atherosclerosis (MESA).

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.

In Vivo Adaptive Bayesian Regularized Lagrangian Carotid Strain Imaging for Murine Carotid Arteries and Its Associations With Histological Findings.

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: rs = 0.83, p = 0.01; female mice: correlation between shear MASI and plaque score: rs = 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.

Changes in carotid artery texture by ultrasound and elastin features in a murine model.

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 Apoetm1Unc/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 (rs = 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.

Temporal Association Among Influenza-Like Illness, Cardiovascular Events, and Vaccine Dose in Patients With High-Risk Cardiovascular Disease: Secondary Analysis of a Randomized Clinical Trial.

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.

Cardiovascular and Pulmonary Responses to Acute Use of Electronic Nicotine Delivery Systems and Combustible Cigarettes in Long-Term Users.

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 FEV1 (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.