Ideal cardiovascular health and resting heart rate in the Multi-Ethnic Study of Atherosclerosis.

Elevated resting heart rate (RHR) is associated with an increased cardiovascular disease (CVD) risk, but little is known about its association with cardiovascular health (CVH), assessed by the Life's Simple 7 (LS7) metrics. We explored whether ideal CVH was associated with RHR in a cohort free from clinical CVD. We conducted a cross-sectional analysis of baseline data (2000-2002) of 6457 Multi-Ethnic Study of Atherosclerosis participants in 2018. Each LS7 metric (smoking, physical activity, diet, body mass index, blood pressure, cholesterol and glucose) was scored 0-2. Total score ranged from 0 to 14. Scores of 0-8 indicate inadequate, 9-10 average, and 11-14 optimal CVH. RHR was categorized as <60, 60-69, 70-79 and ≥80 bpm. We used multinomial logistic regression to determine associations between CVH score and RHR, adjusting for age, sex, race/ethnicity, education, income, health insurance, and atrioventricular nodal blockers. Mean age of participants (standard deviation) was 62 (10) years; 53% were women; 47% had inadequate CVH, 33% average, and 20% optimal. Favorable CVH was associated with lower odds of having higher RHR. Compared to RHR <60 bpm, participants with optimal CVH had adjusted odds ratio (95% CI) of 0.55 (0.46-0.64) for RHR of 60-69 bpm, 0.34 (0.28-0.43) for 70-79 bpm, and 0.14 (0.09-0.22) for ≥80 bpm. A similar pattern was observed in the stratified analysis by sex, race/ethnicity and age. Favorable CVH was less likely to be associated with elevated RHR irrespective of sex, race/ethnicity and age. More research is needed to explore the usefulness of promoting ideal CVH to reduce elevated RHR, a known risk factor for CVD.

Mid-life serum Vitamin D concentrations were associated with incident dementia but not late-life neuropsychological performance in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Activated Vitamin D has anti-inflammatory properties and adequate 25-hydroxyvitamin D [25(OH)D] concentrations may be important for neurocognitive function and protection against neurologic injury. We examined whether mid-life 25(OH) D concentrations were associated with later-life performance on neuropsychological testing, functional ability, depressive symptoms, and incident dementia. METHODS: We studied 13,039 white and black ARIC participants who had serum 25(OH) D measured mid-life at visit 2 (1990-1992). Over the next ~ 20 years through visit 5 (2011-2013), participants underwent 3 additional in-person visits, annual telephone calls, and hospitalization surveillance. An extensive battery of neuropsychological outcomes were assessed at visit 5 using standardized protocols. Incident dementia was ascertained through a formal algorithm that included data from in-person cognitive testing, telephone interviews, hospital discharge codes, and death certificate codes. Diagnoses of dementia were adjudicated by expert clinician committee. For the primary cognitive analyses, we imputed for missing covariates and outcomes and used linear regression to evaluate non-concurrent cross-sectional associations of mid-life 25(OH) D (visit 2) with late-life neuropsychological outcomes (visit 5). We also used Cox regression models to examine associations of mid-life 25(OH) D and incident dementia. RESULTS: In mid-life, the mean (SD) age of participants was 57 (6) years, 57% were women, and 24% black. Mean (SD) 25(OH) D was 24.3 (8.6) ng/mL; 33% had deficient (< 20 ng/mL), 44% intermediate (20- < 30 ng/mL), and 23% sufficient (≥30 ng/mL) 25(OH) D concentrations. Association between mid-life 25(OH) D and late-life performance on neuropsychological testing were mostly null. There was no significant association with functional ability or depressive symptoms. Results were similar in a sensitivity analysis using complete-case data (no imputation). However, after a median follow-up of 20 years, low 25(OH) D concentrations were associated with increased risk for incident dementia (p = 0.01 for trend across categories), with HR of 1.26 (95% CI 1.06, 1.49) for participants with deficient 25(OH) D, compared to sufficient concentrations. CONCLUSION: In this community cohort, mid-life serum 25(OH) D concentrations were associated with incident dementia but not with performance on neuropsychological testing, functional ability, or depressive symptoms, 20 years later. Whether serum 25(OH) D concentrations are causally related to dementia or confounded by poorer health status remains uncertain. TRIAL REGISTRATION: Registered on clinicaltrials.gov NCT00005131 .

Galectin-3 and incidence of atrial fibrillation: The Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Galectin-3, a ß-galactoside binding lectin involved in important regulatory roles in adhesion, inflammation, immunity, and fibrosis, may be relevant to atrial fibrillation (AF) etiology. METHODS: We included 8,436 participants free of AF at baseline (1996-1998) and with measures of plasma galectin-3 from the Atherosclerosis Risk in Communities study. We ascertained incident AF through 2013 from study visit electrocardiograms, hospitalizations, and death certificates. Multivariable Cox proportional hazards models, adjusted for AF risk factors plus incident heart failure (HF) and coronary heart disease (CHD), were used to estimate hazard ratios for the association between galectin-3 and incident AF. RESULTS: The mean age (SD) of participants was 62.6 (5.6) years, and the sample was comprised of 58.7% women and 21.2% blacks. During a median follow-up of 15.7 years, 1,185 incident cases of AF were observed. After adjusting for AF risk factors, participants with galectin-3 levels ≥90th percentile (19.5 ng/mL) had a significantly higher risk of incident AF when compared with the lowest quartile (4.4-11.9 ng/mL), with hazard ratios (95% CI) of 1.40 (1.04-1.89) for the 90th-<95th percentile and 1.51 (1.11-2.06) for the 95th-100th percentile. This association was attenuated and no longer statistically significant after accounting for incident CHD and HF as time-dependent variables. CONCLUSIONS: Elevated plasma galectin-3 is associated with increased risk of incident AF. Galectin-3 may increase AF risk via pathways involving CHD and HF.

Association between body mass index and liver stiffness measurement using transient elastography in patients with non-alcoholic fatty liver disease in a hepatology clinic: a cross sectional study.

Background: Transient elastography (TE) is an FDA approved, non-invasive tool to estimate liver stiffness measurement (LSM) in patients with non-alcoholic fatty liver disease (NAFLD). Our aim was to analyze if body mass index (BMI) would predict the severity of liver stiffness using TE scores. Methods: We performed a cross-sectional study of patients with NAFLD who presented to the hepatology clinic between January 2019 through January 2021. Fibrosis severity was divided into the following categories: F0 to F1 (2-7 kPa), F2 (>7 to 10 kPa), F3 (>10 to 14 kPa) and F4 (>14 kPa). We used ordered logistic regression models to determine the odds ratio (OR) and 95% confidence interval (CI) of having a higher LSM severity compared to lower associated with BMI. Models were adjusted for patient demographics and comorbidities. Results: Among 284 patients, 56.7% were females, and the median (interquartile range, IQR) age was 62 [51-68] years and BMI 31.9 (28.1, 36.2) kg/m2; 47% of patients were in the F0 to F1 stage, 24% F2, 16% F3, and 13% F4. The correlation between BMI and TE score was 0.31 (P<0.001). With 1 kg/m2 increase in BMI there was 1.10 times higher odds of having a higher LSM severity (adjusted OR, 1.10; 95% CI: 1.05-1.14). Compared to patients with BMI <25 kg/m2, the adjusted OR (95% CI) of having a higher fibrosis stage was 1.82 (0.61-5.44), 5.93 (2.05-17.13), and 8.56 (2.51-29.17) for patients with BMI of 25 to <30, 30 to <40, and ≥40 respectively. Conclusions: BMI correlates with the severity of LSM using TE scores in NAFLD patients even after adjusting for potential confounding variables. This suggests TE as an appreciable study for liver stiffness even in obese individuals.

Adipokines and incident venous thromboembolism: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Obesity leads to adipocyte hypertrophy and adipokine dysregulation and is an independent risk factor for venous thromboembolism (VTE). However, the association between adipokines and VTE is not well established. OBJECTIVES: To examine whether adipokines are associated with increased risk of incident VTE. METHODS: We studied 1888 participants of the Multi-Ethnic Study of Atherosclerosis cohort who were initially free of VTE and had adipokine (adiponectin, leptin, and resistin) levels measured at either examination 2 or 3 (2002-2004 or 2004-2005, respectively). During follow-ups, VTE was ascertained through hospitalization records and death certificates by using ICD-9 and 10 codes. We used multivariable Cox proportional hazards regression to assess the association between 1 standard deviation (SD) log-transformed increments in adipokines and incident VTE. RESULTS: The mean ± SD age was 64.7 ± 9.6 years, and 49.8% of participants were women. Medians (interquartile range) of adiponectin, leptin, and resistin were 17.3 (11.8-26.2) mcg/mL, 13.5 (5.6-28.2) ng/mL, and 15.0 (11.9-19.0) ng/mL, respectively. There were 78 incident cases of VTE after a median of 9.7 (5.0-12.4) years of follow-up. After adjusting for sociodemographics, smoking, and physical activity, the hazard ratios (95% CIs) per 1 SD increment of adiponectin, leptin, and resistin were 1.14 (0.90-1.44), 1.29 (1.00-1.66), and 1.38 (1.09-1.74), respectively. The association for resistin persisted after further adjustments for body mass index and computed tomography-derived total visceral adipose tissue area. CONCLUSION: Higher resistin levels were independently associated with greater risk of incident VTE. Larger prospective cohort studies are warranted to confirm this association.

Associations of urinary isoprostanes with measures of subclinical atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA).

Background: Urinary isoprostanes are markers of systemic oxidative stress, which is implicated in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Coronary artery calcium (CAC), thoracic aortic calcium (TAC) and carotid plaque are measure subclinical atherosclerosis and prognosticate ASCVD risk. We examined the associations between urinary isoprostane levels and measures of plaque prevalence, burden, incidence and progression across three vascular beds in a cohort from the Multi-Ethnic Study of Atherosclerosis. Methods: Urinary levels of 8-isoprostane and 2,3-dinor-8-F2-isoprostane were measured in 1089 participants (mean ± SD 62 ± 8 years, 48% women) at baseline. Participants underwent computed tomography for CAC and TAC, and duplex ultrasound for carotid plaque. TAC and CAC were reassessed at 2.4 and 10 years, respectively. Regression models were adjusted for CVD risk factors. Results: In adjusted models, there were no significant associations between isoprostane levels with CAC prevalence or progression. Highest versus lowest tertile of 8-isoprostane was associated with 28% lower prevalence of descending TAC at baseline [prevalence ratio (PR) 0.72 95% CI (0.56, 0.94)], while 1-SD higher 2,3-dinor-8-F2-isoprostane was associated with 96% higher incident ascending TAC at follow-up [Relative Risk 1.96 (1.24, 3.09)]. Highest versus lowest tertile of isoprostane measures were associated with 22% higher prevalence of carotid plaque [(PR 1.22 (1.04, 1.45)] and 14% difference [3,26] in greater extent of carotid plaque at baseline. Conclusions: Higher urinary isoprostanes were inconsistently associated with some measures of subclinical atherosclerosis by imaging. This suggests a limited role of urinary isoprostane levels as a prognostic marker for the development of ASCVD. Trial registration: The MESA cohort design is registered at clinicaltrials.gov as follows: https://clinicaltrials.gov/ct2/show/NCT00005487.

Associations of endogenous sex hormone levels with the prevalence and progression of valvular and thoracic aortic calcification in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND AIMS: Sex hormones (SH) may contribute to sex differences in cardiovascular disease (CVD). High free testosterone (T) and low sex hormone binding globulin (SHBG) have been associated with progression of coronary artery calcification in women. We now examined the association of SH with extra-coronary calcification (ECC) prevalence and progression among MESA participants. METHODS: We studied 2,737 postmenopausal women and 3,130 men free of clinical CVD with baseline SH levels. ECC measurements [ascending and descending thoracic aortic calcification (ATAC, DTAC), mitral annular calcification (MAC), aortic valve calcification (AVC)] were obtained by computed tomography at baseline and after 2.4 ± 0.9 years. We used multivariable Poisson regression to evaluate associations with ECC prevalence and incidence (Agatston scores >0) and linear mixed effects models for ECC progression, per 1-SD increment in log(SH) in women and men separately. RESULTS: The mean age was 65 ± 9 and 62 ± 10 years for women and men, respectively. In women, greater free T and lower SHBG were associated with MAC incidence in a demographic-adjusted model only. In men, lower free T was associated with MAC prevalence, DTAC incidence and progression, while greater SHBG was associated with MAC prevalence and DTAC progression after further adjusting for CVD risk factors. CONCLUSIONS: In this diverse cohort free of CVD, we found some associations of SH with ECC measures. In particular, free T was inversely associated with prevalent MAC and DTAC progression in men independent of CVD risk factors. SH may influence vascular calcification, but further work is needed to understand clinical implications of these findings.

Association between parity and markers of inflammation: The multi-ethnic study of atherosclerosis.

Introduction: Multiparity has been associated with increased risk of cardiovascular disease (CVD). Inflammation may be a mechanism linking parity to CVD. We investigated the association between parity and later-life markers of inflammation. Methods: We studied 3,454 female MESA participants aged 45-84, free of CVD, who had data on parity and inflammatory markers. Parity was categorized as 0 (reference), 1-2, 3-4, or ≥5. Linear regression was used to evaluate the association between parity and natural log-transformed levels of fibrinogen, D-dimer, GlycA, high sensitivity C-reactive protein (hsCRP), and interleukin-6 (IL-6). Results: Mean age was 62 ± 10 years. The proportion of women with nulliparity, 1-2, 3-4, and ≥5 live births were 18, 39, 29, and 14%, respectively. There was no association between parity and fibrinogen. Women with grand multiparity (≥5 live births) had 28, 10, and 18% higher levels of hsCRP, IL-6 and D-dimer, respectively, compared to nulliparous women, after adjustment for demographic factors. After additional adjustment for CVD risk factors, women with 1-2 and 3-4 live births had higher hsCRP and women with 1-2 live births had higher GlycA. Conclusion: In this diverse cohort of middle-to-older aged women, we found that higher parity was associated with some inflammatory markers; however, these associations were largely attenuated after adjustment for CVD risk factors. There was no clear dose-response relationship between parity and these inflammatory markers. Future studies are needed to evaluate how inflammation may influence the link between parity and CVD and whether healthy lifestyle/pharmacotherapies targeting inflammation can reduce CVD risk among multiparous women. Clinical trial registration: The MESA cohort design is registered at clinicaltrials.gov as follows: https://clinicaltrials.gov/ct2/show/NCT00005487.

The association of novel inflammatory marker GlycA and incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Emerging evidence has implicated that inflammation contributes to the pathogenesis of atrial fibrillation (AF). GlycA is a novel marker of systemic inflammation with low intra-individual variability and high analytic precision. GlycA has been associated with incident cardiovascular disease (CVD) independent of other inflammatory markers. However, whether GlycA is associated with AF, specifically, has yet to be established. We examined the association between GlycA and AF in a multi-ethnic cohort. METHODS: We studied 6,602 MESA participants aged 45-85, with no clinical CVD at baseline, with data on GlycA and incident AF. We used multivariable-adjusted Cox models to evaluate the association between GlycA and incident AF. We also examined other inflammatory markers [high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6) and fibrinogen] and incident AF for comparison. RESULTS: The mean (SD) age was 62 (10) years, 53% women. The mean plasma GlycA was 381 (62) µmol/L. Over median follow-up of 12.9 years, 869 participants experienced AF. There was no statistically significant association between GlycA and incident AF after adjusting for sociodemographics, CVD risk factors, and other inflammatory markers [Hazard Ratio (95% CI) per 1 SD increment in GlycA: 0.97 (0.88-1.06)]. Neither hsCRP nor fibrinogen was associated with incident AF in same model. In contrast, IL-6 was independently associated with incident AF [HR 1.12 per 1 SD increment (1.05-1.19)]. CONCLUSIONS: Although GlycA has been associated with other CVD types, we found that GlycA was not associated with AF. More research will be required to understand why IL-6 was associated with AF but not GlycA. CLINICAL TRIAL REGISTRATION: MESA is not a clinical trial. However, the cohort is registered at: URL: https://clinicaltrials.gov/ct2/show/NCT00005487 Unique identifier: NCT00005487.

Associations of adipokine levels with the prevalence and extent of valvular and thoracic aortic calcification: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND AIMS: Extra-coronary calcification (ECC) is a marker of atherosclerosis and independently associated with cardiovascular disease (CVD). Adipokines may mediate the effect of obesity on atherosclerosis. However, the relationship of adipokines with ECC is not well-established. We examined the associations of leptin, resistin and adiponectin with ECC in a diverse community-based cohort. METHODS: We performed a cross-sectional analysis of 1897 adults without clinical CVD in the MESA cohort. Serum adipokine levels and non-contrast cardiac CT scans were obtained at Exam 2 or 3 (randomly assigned). ECC was quantified by Agatston score and included calcification of the mitral annulus (MAC), aortic valve (AVC), ascending thoracic aorta (ATAC) and descending thoracic aorta (DTAC). We used multivariable regression to evaluate the associations between leptin, resistin and adiponectin [per 1 SD ln(adipokine] with ECC prevalence (score >0) and extent [ln(score+1)]. RESULTS: The mean age of participants was 65 ± 10 years; 49% women. After adjusting for demographic factors, adiponectin was inversely associated with AVC prevalence and extent; leptin positively associated with MAC prevalence and extent; and resistin positively associated with ATAC prevalence and extent and DTAC extent. After adjustment for BMI and other CVD risk factors, adiponectin remained inversely associated with AVC prevalence, and resistin remained associated with greater ATAC prevalence and extent. Leptin was not associated with measures of ECC after full adjustment. No adipokine was associated with MAC after full adjustment. CONCLUSIONS: We identified significant associations between select adipokines and specific markers of ECC. Adipokines may play a role in the development of systemic atherosclerosis.

Remdesivir for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The nucleotide analogue prodrug remdesivir was among the first antiviral therapies to be tested in randomized controlled trials (RCTs) for COVID-19. We performed a meta-analysis to understand efficacy and safety. METHODS: We searched PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov databases (from January 1, 2020 to November 5, 2020). We included RCTs comparing the efficacy and safety of remdesivir to control/placebo in COVID-19. Two independent investigators abstracted data, assessed the quality of evidence, and rated the certainty of evidence. RESULTS: A total of 4 RCTs with 7334 patients with COVID-19 were included. At a follow-up of 28-29 days from randomization, very low certainty evidence showed that use of remdesivir compared with control group (placebo and/or standard of care) was not associated with a significant decrease in time to clinical improvement (standardized mean difference -0.80 day; [CI, -2.12, 0.53]). However, moderate certainty of evidence showed that remdesivir was associated with higher rates of recovered patients (risk difference [RD] 0.07 [0.05, 0.08]) and discharged patients (RD 0.07 [0.03, 0.11]) and lower rates of developing serious adverse events (RD -0.05 [-0.10, -0.01]) compared with control. Moderate and very low certainty of evidence showed there was no significant difference in deaths at 28-29 days follow-up (RD -0.01 [-0.03, 0.01]) and developing any adverse events (RD 0.01 [-0.17, 0.19]) between both groups, respectively. CONCLUSION: Patients given remdesivir are more likely to demonstrate recovery and were associated with higher rates of hospital discharge, but not with significant reduction in mean time to clinical improvement or mortality.

Effect of Progression of Valvular Calcification on Left Ventricular Structure and Frequency of Incident Heart Failure (from the Multiethnic Study of Atherosclerosis).

Heart failure (HF) is a leading cause of morbidity. Strategies for preventing HF are paramount. Prevalent extracoronary calcification is associated with HF risk but less is known about progression of mitral annular (MAC) and aortic valve calcification (AVC) and HF risk. Progression of valvular calcification (VC) [interval change of >0 units/yr] was assessed by 2 cardiac computed tomography scans over a median of 2.4 years. We used Cox regression to determine the risk of adjudicated HF and linear mixed effects models to determine 10-year change in left ventricular (LV) parameters measured by cardiac magnetic resonance imaging associated with VC progression. We studied 5,591 MESA participants free of baseline cardiovascular disease. Mean ± SD age was 62 ± 10 years; 53% women; 83% had no VC progression, 15% progressed at 1 site (AVC or MAC) and 3% at both sites. There were 251 incident HF over 15 years. After adjusting for cardiovascular risk factors, the hazard ratios (95% confidence interval) of HF associated with VC progression at 1 and 2 sites were 1.62 (1.21 to 2.17) and 1.88 (1.14 to 3.09), respectively, compared with no progression (p-for-trend <0.001). Hazard ratios were higher for HFpEF (2.52 [1.63 to 3.90] and 2.49 [1.19 to 5.25]) but nonsignificant for HFrEF. Both AVC (1.61 [1.19 to 2.19]) and MAC (1.50 [1.09 to 2.07]) progression were associated with HF. VC was associated with worsening of some LV parameters over 10 years. In conclusion, VC progression was associated with increased risk of HF and change in LV function. Interventions targeted at reducing VC progression may also impact HF risk, particularly HFpEF.

Resting heart rate and incidence of venous thromboembolism.

BACKGROUND/OBJECTIVES: Higher resting heart rate is a risk factor for arterial cardiovascular diseases. We assessed whether higher heart rate is a risk factor for venous thromboembolism (VTE). METHODS: In a prospective epidemiologic cohort, the Atherosclerosis Risk in Communities (ARIC) Study, we associated resting heart rate by electrocardiogram with physician-validated incident hospitalized VTE through 2015. We also examined whether lower heart rate variability (HRV), a marker of cardiac autonomic imbalance, might be a risk factor for VTE. RESULTS: Resting heart rate at Visit 1 (1987-1989), when participants were 45 to 64 years old (mean, 54 years), was not associated with incidence of VTE (n = 882 cases). However, heart rate at Visit 4 (1996-1998; mean age, 63 years) was associated positively with VTE (n = 557 cases). The adjusted hazard ratios (95% confidence intervals) of VTE across Visit 4 heart rate categories of <60, 60 to 69, 70 to 79, and ≥80 bpm were 1 (reference), 1.22 (1.01-1.49), 1.39 (1.09-1.78), and 1.44 (1.01-2.06), respectively, and when evaluated continuously 1.11 (1.02-1.21) per 10 bpm greater heart rate. For the most part, HRV indices were not associated with VTE or associations were explained by inverse correlations of HRV indices with heart rate. CONCLUSION: We found a significant positive and independent association of resting heart rate at ARIC Visit 4 with incidence of VTE. The reason why high heart rate is a risk marker for VTE warrants further exploration.

Resting heart rate and incident venous thromboembolism: the Multi-Ethnic Study of Atherosclerosis.

Objective: Venous thromboembolism (VTE) is associated with significant morbidity and mortality. Resting heart rate (RHR), which may be modifiable through lifestyle changes, has been shown to be associated with cardiovascular disease risk and with inflammatory markers that have been predictive of VTE incidence. Methods: We examined whether RHR is also associated with VTE incidence independent of these risk factors. We studied 6479 Multi-Ethnic Study of Atherosclerosis participants free from clinical VTE at baseline who had baseline RHR ascertained by 12-lead ECG. VTE events were recorded from hospital records and death certificates using International Classification of Diseases (ICD)-9 and ICD-10 codes. We categorised RHR as <60, 60-69, 70-79 and ≥80 bpm. We used Cox hazard models to determine the association of incident VTE by RHR. Results: Participants had mean (SD) age of 62 (10) years and RHR of 63 (10) bpm. RHR was cross-sectionally correlated with multiple inflammatory and coagulation factors. There were 236 VTE cases after a median follow-up of 14 years. Compared with those with RHR<60 bpm, the HR (95% CI) for incident VTE for RHR≥80 bpm was 2.08 (1.31 to 3.30), after adjusting for demographics, physical activity, smoking, diabetes and use of atrioventricular (AV)-nodal blockers, aspirin and anticoagulants, and remained significant after further adjustment for inflammatory markers (2.05 (1.29 to 3.26)). Results were similar after excluding those taking AV-nodal blocker medications. There was no effect modification of these associations by sex or age. Conclusion: Elevated RHR was positively associated with VTE incidence after a median of 14 years; this association was independent of several traditional VTE and inflammatory markers.

Progression of valvular calcification and risk of incident stroke: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND AIMS: Prevalent valvular calcification (VC) is associated with stroke but little is known about associations of VC progression with stroke. METHODS: Progression (interval increase >0 Agatston units/year) of aortic valvular calcification (AVC) and mitral annular calcification (MAC) was assessed by two cardiac CTs over a median of 2.4 years. We determined the risk of adjudicated total and ischemic stroke using Cox regression adjusted for cardiovascular disease (CVD) risk factors. RESULTS: We studied 5,539 MESA participants free of baseline CVD and atrial fibrillation. Baseline mean ± SD age was 62 ± 10 years; 53% were women; 83% had no progression of VC; 15%, progression at one site (AVC or MAC), and 3%, progression at both sites. Over a median of 12 years, 211 total and 167 ischemic strokes occurred. The number of sites with VC progression (range 0-2) was not associated with total and ischemic stroke (all p > 0.05). We found MAC progression to be associated with increased risk of total stroke [adjusted hazard ratio (95% CI) 1.59 (1.11, 2.28)] and ischemic stroke [1.64 (1.10, 2.45)]. Results remained significant after further adjustment for baseline coronary artery calcification. After excluding participants with interim atrial fibrillation and coronary heart disease, findings were no longer statistically significant in fully-adjusted models. There was no interaction by age, sex, or race/ethnicity. There was no association with AVC progression and stroke. CONCLUSIONS: Progression of MAC but not AVC over 2.4 years is associated with increased risk of total and ischemic stroke.

Association of the Novel Inflammatory Marker GlycA and Incident Heart Failure and Its Subtypes of Preserved and Reduced Ejection Fraction: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: GlycA, a nuclear magnetic resonance composite marker of systemic inflammation, reflects serum concentration and glycosylation state of main acute phase reactants. Prior studies have shown plasma GlycA levels were associated with cardiovascular disease even after adjusting for other inflammatory markers. However, little is known about the association of GlycA with the heart failure (HF) subtypes: heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction. We examined the association of GlycA with incident HF and its subtypes in a multiethnic cohort. METHODS: We studied 6507 Multi-Ethnic Study of Atherosclerosis participants aged 45 to 84 without baseline cardiovascular disease or HF who had data on GlycA and incident hospitalized HF. We used multivariable-adjusted Cox hazards models to evaluate the association of GlycA with incident total HF, HFpEF, and heart failure with reduced ejection fraction. Models were adjusted for sociodemographics, cardiovascular disease risk factors, and inflammatory biomarkers. RESULTS: The mean (SD) for age was 62 (10) years and for GlycA was 375 (82) µmol/L; 53% women. Over a median follow-up of 14.0 years, participants in the highest quartile of GlycA, compared with the lowest, experienced increased risk of developing any HF (hazard ratio, 1.48 [95% CI, 1.01-2.18]) in fully adjusted models. However, this increased risk was only seen for HFpEF (2.18 [1.15-4.13]) and not heart failure with reduced ejection fraction [1.06 (0.63-1.79)]. There was no significant interaction by sex, age, or race/ethnicity. CONCLUSIONS: GlycA was associated with an increased risk of any HF, and in particular, HFpEF. Future studies should examine mechanisms that might explain differential association of GlycA with HF subtypes, and whether therapeutic lowering of GlycA can prevent HFpEF development. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005487.

The novel inflammatory marker GlycA and the prevalence and progression of valvular and thoracic aortic calcification: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: GlycA is a novel composite biomarker of systemic inflammation reflecting posttranslational glycosylation of acute phase reactants. GlycA has been associated with coronary artery calcium, cardiovascular disease (CVD) events and mortality. Vascular calcifications outside of the coronary arteries are risk markers of CVD and mortality. Whether GlycA is linked to extra-coronary calcifications (ECC) is not well established. METHODS: We studied 6462 MESA participants free of clinical CVD who had plasma GlycA measured at baseline. ECCs [calcification in aortic valve (AVC), mitral annulus (MAC), ascending and descending thoracic aorta (ATAC, DTAC)] were ascertained at baseline and follow-up visit (median 2.3-yrs later) by cardiac CT. Poisson regression models with robust variance estimation assessed associations of GlycA with prevalent and incident ECC. Linear mixed models assessed the cross-sectional and 2-year change in ECC. Models were adjusted for demographic and lifestyle factors. RESULTS: In cross-sectional analysis, GlycA (per SD increment) was positively associated with prevalent AVC, ATAC and DTAC with adjusted prevalence ratios (95% CI) of 1.08 (1.01-1.14), 1.18 (1.03-1.34) and 1.10 (1.06-1.14), respectively. There was also a significant association between GlycA and baseline extent of both ATAC and DTAC. Longitudinally, GlycA was positively associated with incident MAC and DTAC, with adjusted incidence ratios of 1.18 (1.03-1.37) and 1.17 (1.07-1.28), respectively. GlycA was also associated with 2-year change in MAC and DTAC extent. CONCLUSIONS: In this diverse cohort free from clinical CVD, we found GlycA was positively associated with prevalent and incident ECC measures, in particular for progression of MAC and DTAC.

Relation of Elevated Resting Heart Rate in Mid-Life to Cognitive Decline Over 20 Years (from the Atherosclerosis Risk in Communities [ARIC] Study).

Resting heart rate (RHR) is independently associated with cardiovascular disease (CVD) risk. We determined whether RHR, measured in mid-life, is also associated with cognitive decline. We studied 13,720 middle-aged white and black ARIC participants without a history of stroke or atrial fibrillation. RHR was obtained from a 12-lead resting electrocardiogram at the baseline visit (1990 to 1992) and categorized into groups as <60 (reference), 60 to 69, 70 to 79 and ≥80 beats/min. Cognitive scores were obtained at baseline and at up to 2 additional visits (1996 to 1998 and 2011 to 2013). The primary outcome was a global composite cognitive score (Z-score) derived from 3 tests: delayed word recall, digit symbol substitution, and word fluency. The associations of RHR with cognitive decline and incident dementia were examined using linear mixed-effects and Cox hazard models, respectively, adjusting for sociodemographics, CVD risk factors, and AV-nodal blockade use. Multiple imputation methods were used to account for attrition over follow-up. Participants had mean ± SD age of 58 ± 6 years; 56% were women, 24% black. Average RHR was 66 ± 10 beats/min. Over a mean follow-up of 20 years, those with RHR ≥80 beats/min had greater global cognitive decline (average adjusted Z-score difference -0.12 [95% confidence interval -0.21, -0.03]) and increased risk for incident dementia (hazard ratio 1.28 (1.04, 1.57), compared with those with RHR <60 beats/min. In conclusion, elevated RHR is independently associated with greater cognitive decline and incident dementia over 20 years. Further studies are needed to determine whether the associations are causal or secondary to another underlying process, and whether modification of RHR can affect cognitive decline.

GlycA, a Novel Inflammatory Marker and Its Association With Peripheral Arterial Disease and Carotid Plaque: The Multi-Ethnic Study of Atherosclerosis.

GlycA, a composite biomarker of systemic inflammation, is associated with cardiovascular disease (CVD) and mortality, but its relationship with peripheral artery disease (PAD) is unknown. We assessed whether plasma GlycA is associated with ankle-brachial index (ABI), carotid plaque (CP), and incident clinical PAD among 6466 Multi-Ethnic Study of Atherosclerosis participants without CVD at baseline. GlycA, ABI, and CP were measured at baseline. Both ABI and CP were remeasured at 10 years. Incident clinical PAD was ascertained from hospital records. We used logistic, Cox, and linear mixed regression models adjusted for demographic and lifestyle factors. Mean (standard deviation, SD) was 62 (10) years for age and 381 (61) µmol/L for GlycA; 53% were women. GlycA was associated with both prevalent low ABI ≤0.8 (prevalence odds ratio [95% confidence interval, CI] per SD increment in GlycA, 1.65 [1.39-1.97]) and CP (1.19 [1.11-1.27]) at baseline. There were no significant associations of GlycA with incident low ABI, incident CP, or 10-year change in ABI or CP score. We identified 110 incident cases of PAD after 79 590 person-years. The hazard ratio (95% CI) of incident PAD per SD increment in GlycA was 1.38 (1.14-1.66). In conclusion, GlycA was associated with prevalent low ABI, prevalent CP, and incident PAD after a median of 14 years.

A randomized controlled trial of online symptom searching to inform patient generated differential diagnoses.

Patient online health searching is now commonplace, however, the accuracy of patient generated differentials for new symptoms and potential for patient anxiety are concerns. We aimed primarily to determine the accuracy of patient generated differentials for new symptoms with and without online searching, and secondarily, to evaluate the impact of searching on anxiety levels. In the waiting room prior to seeing a clinician, 300 patients with new symptoms were randomly assigned 1:1:1 to Google searching with health related features including a symptom search tool vs Google searching with health related features disabled vs no searching. Participants were 18 years or older and presenting to the emergency department of an urban academic medical center with new low-acuity symptoms that were not due to exacerbation of a chronic condition. Search groups received access on a tablet/smartphone to Google searching with or without health related features. Both search groups could access any websites; health related features led the patient to common diagnoses and physician-validated information. The primary outcome was accuracy of the patient generated differential assessed by matching at least two of the top three diagnoses on the clinician's differential. A secondary outcome was anxiety by a visual analogue scale. Patients were a median of 33.1 (IQI 26.2-45.9) years old, 60% women, 63% black, 82% had a high school education or less, and 45.7% reported having performed an online search prior to presentation. Search group patients spent a median of 3.82 (2.53-5.72) minutes searching online. Similar proportions of patients in each group matched at least two of three clinician diagnoses: 27.0% and 28.3% for Google searching with and without health related features vs 23.8% in the no search group. Patients in the search groups had a similar odds of matching ≥2/3 diagnoses as the no search group [OR (95% CI): 1.23 (0.70-2.13), p = 0.47]. Anxiety was unchanged with online searching. In conclusion, brief online searching in the waiting room did not improve accuracy of patient generated differential diagnoses for new symptoms. The absence of an increase in patient anxiety provides reassurance for subsequent work to refine and investigate online symptom search tools.