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BackgroundUrinary 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.MethodsUrinary 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.ResultsIn 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.ConclusionsHigher 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 registrationThe MESA cohort design is registered at clinicaltrials.gov as follows: https://clinicaltrials.gov/ct2/show/NCT00005487.

Background Sleep irregularity has been linked to incident cardiovascular disease. Less is known about associations of sleep regularity with atherosclerosis. We examined cross-sectional associations of actigraphy-assessed sleep duration and sleep timing regularity with subclinical atherosclerosis in the community-based MESA (Multi-Ethnic Study of Atherosclerosis). Methods and Results MESA Sleep Ancillary Study participants (N=2032; mean age, 68.6±9.2 years; 37.9% White) completed 7-day wrist actigraphy. Participants underwent assessments of coronary artery calcium, carotid plaque presence, carotid intima-media thickness, and the ankle-brachial index. Sleep regularity was quantified by the 7-day with-in person SD of sleep duration and sleep onset timing. Relative risk regression models were used to calculate prevalence ratios and 95% CIs. Models are adjusted for demographics, cardiovascular disease risk factors, and other objectively assessed sleep characteristics including obstructive sleep apnea, sleep duration, and sleep fragmentation. After adjustment, compared with participants with more regular sleep durations (SD ≤60 minutes), participants with greater sleep duration irregularity (SD >120 minutes) were more likely to have high coronary artery calcium burden (>300; prevalence ratio, 1.33 [95% CI, 1.03-1.71]) and abnormal ankle-brachial index (90 minutes) were more likely to have high coronary artery calcium burden (prevalence ratio, 1.39 [95% CI, 1.07-1.82]). Associations persisted after adjustment for cardiovascular disease risk factors and average sleep duration, obstructive sleep apnea, and sleep fragmentation. Conclusions Sleep irregularity, particularly sleep duration irregularity, was associated with several measures of subclinical atherosclerosis. Sleep regularity may be a modifiable target for reducing atherosclerosis risk. Future investigation into cardiovascular risk reduction interventions targeting sleep irregularity may be warranted.

BackgroundObesity 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.ObjectivesTo examine whether adipokines are associated with increased risk of incident VTE.MethodsWe 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.ResultsThe 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.ConclusionHigher resistin levels were independently associated with greater risk of incident VTE. Larger prospective cohort studies are warranted to confirm this association.

BackgroundThis study explored the longitudinal relationship of Lp(a) (lipoprotein[a]) and hypertension to cardiovascular outcomes in a large multiethnic cohort free of baseline cardiovascular disease.MethodsIndividuals from the MESA (Multi-Ethnic Study of Atherosclerosis; N=6674) were grouped as follows: group 1: Lp(a)

BackgroundDifferences in sex hormone levels contribute to differences in cardiovascular disease (CVD) risk. Adipokines play a role in cardiometabolic pathways and have differing associations with CVD. Adipokine levels differ by sex; however, the association between sex hormone profiles and adipokines is not well established. We hypothesized that a more androgenic sex hormone profile would be associated with higher leptin and resistin and lower adiponectin levels among postmenopausal women, with the opposite associations in men.MethodsWe performed an analysis of 1,811 adults in the Multi-Ethnic Study of Atherosclerosis who had both sex hormones and adipokines measured an average of 2.6 years apart. Sex hormones [Testosterone (T), estradiol (E2), sex hormone binding globulin (SHBG), and dehydroepiandrosterone (DHEA)] were measured at exam 1; free T was estimated. Serum adipokines (leptin, resistin, adiponectin) were measured at exams 2 or 3. We used multivariable linear regression to examine the cross-sectional associations between sex hormones and adipokines.ResultsThe mean (SD) age was 63 (10) years, 48% were women; 59% non-White participants. For leptin, after adjusting for demographics only, higher free T and lower SHBG, were associated with higher leptin in women; this association was attenuated after further covariate adjustment. However in men, higher free T and lower SHBG were associated with greater leptin levels in fully adjusted models. For adiponectin, lower free T and higher SHBG were associated with greater adiponectin in both women and men after adjustment for CVD risk factors. For resistin, no significant association was found women, but an inverse association with total T and bioT was seen in men.ConclusionOverall, these results further suggest a more androgenic sex profile (higher free T and lower SHBG) is associated with a less favorable adipokine pattern. These findings may provide mechanistic insight into the interplay between sex hormones, adipokines, and CVD risk.

The prognostic value of traditional atherosclerotic cardiovascular disease (ASCVD) risk factors may decrease with age. We sought to determine whether the association between traditional ASCVD risk factors and incident coronary artery calcium (CAC) differs for younger versus older persons. We included 5,108 participants with baseline CAC = 0. Repeat CAC scoring occurred over 3 to 11 years of follow-up. Multivariable Cox proportional hazards regression assessed the association between traditional risk factors and incident CAC in young (32 to 45 years), middle-aged (46 to 64 years), and older adults (65 to 84 years). A total of 61% of the participants were women and 37% were Black. The proportion with incident CAC ranged from 22% among young adults, 34% for middle-aged adults, and 45% for older adults. In young adults, traditional risk factors were significantly associated with incident CAC except for diastolic blood pressure and high-density lipoprotein (HDL) cholesterol, whereas only total cholesterol/HDL cholesterol ≥3.5 (p = 0.04) was significantly associated with incident CAC in older persons. Non-HDL cholesterol (p = 0.02) was more strongly associated with incident CAC in young (hazard ratio [HR] 1.20, 95% confidence interval [CI] 1.09 to 1.31) and middle aged (HR 1.14, 95% CI 1.07 to 1.23) compared to older adults (HR 1.11, 95% CI 0.99 to 1.23). When added to demographics, traditional risk factors provided a greater C-statistic improvement for incident CAC prediction in young (0.752, +0.070, p

More than half of U.S. young adults have low ten-year but high lifetime risk of cardiovascular disease (CVD). Improving primary prevention in young adulthood may help reduce persistent CVD disparities and overall CVD morbidity and mortality. The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop in 2021 to identify potential trial opportunities in CVD prevention in young adults. The workshop identified promising interventions that could be tested, including interventions that focus on a single cardiovascular risk factor (e.g., lipids or inflammation) to multiple risk factor interventions (e.g., multicomponent lifestyle interventions or fixed-low dose combination of medications). Given the sample size and duration for a trial with hard endpoints, more research is needed on the utility of intermediate endpoints identified noninvasively such as subclinical coronary atherosclerosis as a surrogate endpoint. For now, clinical outcomes trials with hard endpoints will more likely change clinical practice. Trial efficiency depends on accurate identification of high-risk young adults, which can potentially be done using traditional risk equations, coronary artery calcium screening, computerized tomography coronary angiography, and polygenic risk scores. Trials in young adults should include enhanced recruitment strategies with intense community engagement to enroll a trial population that is racially, ethnically, geographically, and socially diverse. Despite the challenges in conducting large prevention trials in young adults, recent advances including innovation in clinical trial conduct, new therapies and successful interventions in older populations, and an increasing recognition of a lifespan approach to risk assessment have made such trials more feasible than ever.DisclosuresThe views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.

Studies on associations between biomarkers of vitamin D metabolism and fracture risk have focused predominantly on White or elderly populations and may not be generalizable to relatively healthy multiethnic populations. We tested associations of total 25-hydroxyvitamin D (25[OH]D), the ratio of 24,25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 (vitamin D metabolite ratio, VDMR), parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF-23) concentrations measured in serum with risk of hip and vertebral fractures in the Multi-Ethnic Study of Atherosclerosis (MESA). Serum 25-hydroxyvitamin D2 and D3 and 24,25-dihydroxyvitamin D3 were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The study cohort of 6466 participants was without clinically apparent cardiovascular disease and was 39% White, 27% Black, 22% Hispanic, and 12% Chinese. The mean age was 62 years, and 53% were female. There were 128 hip and vertebral fractures over a mean follow-up of 14.2 years. 25(OH)D, the VDMR, PTH, and FGF-23 were not significantly associated with fracture risk after adjustment for demographics, diabetes, smoking, systolic blood pressure, body mass index, medication use, albuminuria, and estimated glomerular filtration rate. Principal component analysis did not suggest differences in linear combinations of 25(OH)D, the VDMR, PTH, and FGF-23 between participants who experienced fractures and those who did not. We did not observe significant interaction between race and ethnicity and any biomarker of vitamin D metabolism on fracture risk. In conclusion, none of the four serum biomarkers of vitamin D metabolism investigated showed a significant association with fracture risk in relatively healthy multiethnic populations. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Background and aimsWe aimed to determine the utility of coronary artery calcium (CAC) for atherosclerotic cardiovascular disease (ASCVD) risk stratification in women with and without early menopause (EM).MethodsTo examine the association between CAC and incident ASCVD, we performed Kaplan-Meier survival analysis and multivariable Cox proportional hazards modeling using data from 2,456 postmenopausal women in the Multi-Ethnic Study of Atherosclerosis (MESA) with or without EM, defined as occurring at 50% of middle-aged postmenopausal women with EM had CAC = 0, similar to those without EM. Among women with CAC = 0, those with EM had a low to borderline 10-year risk of ASCVD, but the 15-year risk was significantly higher for women with EM versus those without EM. When CAC ≥ 1, the incidence of ASCVD was similar for women with and without EM. These findings support the use of CAC to help improve ASCVD risk stratification in women with EM.Condensed abstractThis study investigated the association between coronary artery calcium (CAC) and incident atherosclerotic cardiovascular disease (ASCVD) in postmenopausal women with and without early menopause (EM). We found that >50% of women had CAC = 0 and an associated low-to-borderline 10-year cumulative incidence of ASCVD. However, the risk for ASCVD was significantly higher for women with EM after 15-years follow-up. Additional research is needed to better understand the differences in long-term ASCVD risk between women with and without EM who have CAC = 0.

Despite numerous advances in all areas of cardiovascular care, cardiovascular disease (CVD) is the leading cause of death in the United States (US). There is compelling evidence that interventions to improve diet are effective in cardiovascular disease prevention. This clinical practice statement emphasizes the importance of evidence-based dietary patterns in the prevention of atherosclerotic cardiovascular disease (ASCVD), and ASCVD risk factors, including hyperlipidemia, hypertension, diabetes, and obesity. A diet consisting predominantly of fruits, vegetables, legumes, nuts, seeds, plant protein and fatty fish is optimal for the prevention of ASCVD. Consuming more of these foods, while reducing consumption of foods with saturated fat, dietary cholesterol, salt, refined grain, and ultra-processed food intake are the common components of a healthful dietary pattern. Dietary recommendations for special populations including pediatrics, older persons, and nutrition and social determinants of health for ASCVD prevention are discussed.

Risk for atherosclerotic cardiovascular disease (ASCVD) shows considerable heterogeneity both in generally healthy persons and in those with known ASCVD. The foundation of preventive cardiology begins with assessing baseline ASCVD risk using global risk scores based on standard office-based measures. Persons at low risk are generally recommended for lifestyle management only and those at highest risk are recommended for both lifestyle and pharmacologic therapy. Additional "risk enhancing" factors, including both traditional risk factors and novel biomarkers and inflammatory factors can be used to further assess ASCVD risk, especially in those at borderline or intermediate risk. There are also female-specific risk enhancers, social determinants of health, and considerations for high-risk ethnic groups. Screening for subclinical atherosclerosis, especially with the use of coronary calcium screening, can further inform the treatment decision if uncertain based on the above strategies. Persons with pre-existing ASCVD also have variable risk, affected by the number of major ASCVD events, whether recurrent events have occurred recently, and the presence of other major risk factors or high-risk conditions. Current guidelines define high to very high risk ASCVD accordingly. Accurate ASCVD risk assessment is crucial for the appropriate targeting of preventive therapies to reduce ASCVD risk. Finally, the clinician-patient risk discussion focusing on lifestyle management and the risks and benefits of evidence-based pharmacologic therapies to best lower ASCVD risk is central to this process. This clinical practice statement provides the preventive cardiology specialist with guidance and tools for assessment of ASCVD risk with the goal of appropriately targeting treatment approaches for prevention of ASCVD events.

Background: Multiparity is a risk factor for cardiovascular disease (CVD). However, the mechanisms of this relationship are unknown. Adipokines may predispose multiparous women to certain cardiometabolic complications that can increase their risk of future CVD. Materials and Methods: We studied 973 female participants of the Multi-Ethnic Study of Atherosclerosis free of CVD, who had complete data on parity and adipokines measured at Examination 2 or 3 (randomly assigned). Parity was categorized as nulliparity, 1-2, 3-4, and ≥5 live births. Multivariable linear regression was used to evaluate the association of parity with leptin, resistin, and adiponectin levels. Results: The women had mean age of 65 ± 9 years. After adjustment for age, race/ethnicity, study site, education, menopause status, smoking, physical activity, use of hormone therapy, and waist circumference, a history of grand multiparity (≥5 live births) was associated with 11% higher resistin levels (95% confidence interval [CI] 0-23) and 3-4 live births was associated with 23% higher leptin levels (95% CI 7-42), compared with nulliparity. After adjustment for computed tomography-measured visceral fat, the association of 3-4 live births with leptin remained significant. There were no significant associations of parity with adipokines after further adjustment for additional CVD risk factors. Multigravidity (but not parity) was inversely associated with adiponectin levels. Conclusions: In a multiethnic cohort of women, greater parity was associated with resistin and leptin; however, this association was attenuated after accounting for CVD risk factors. Dysregulation of adipokines could contribute to the excess CVD risk associated with multiparity. Further studies are needed to determine whether adipokines independently mediate the relationship between multiparity and CVD. Clinical trials registration: The MESA cohort is registered at NCT00005487.

BackgroundHepatocyte growth factor (HGF) is a biomarker with potential for use in the diagnosis, treatment and prognostication of cardiovascular disease (CVD). Elevated HGF is associated with calcification in the coronary arteries. However, knowledge is limited on the role HGF may play in extracoronary calcification (ECC). This study examined whether HGF is associated with ECC in the aortic valve (AVC), mitral annulus (MAC), ascending thoracic aorta and descending thoracic aortic (DTAC).MethodsAt baseline, adults aged 45-84 years, free of CVD, in the Multi-Ethnic Study of Atherosclerosis had HGF and ECC measured by ELISA and cardiac CT scan, respectively. ECC measurements were repeated after an average of 2.4 years of follow-up. Prevalent ECC was defined as Agatston score >0 at baseline. Incident ECC was defined as Agatston score >0 at follow-up among participants with Agatston score=0 at baseline. We used Poisson and linear mixed-effects regression models to estimate the association between HGF and ECC, adjusted for sociodemographic and CVD risk factors.ResultsOf 6648 participants, 53% were women. Mean (SD) age was 62 (10) years. Median (IQR) of HGF was 905 (757-1087) pg/mL. After adjustment for CVD risk factors, the highest HGF levels (tertile 3) were associated with greater prevalence and extent of AVC, MAC and DTAC at baseline compared with the lowest tertile (tertile 1). Additionally, the risk of incident AVC and MAC increased by 62% and 45%, respectively, in demographic-adjusted models. However, the associations were not statistically significant in fully adjusted models. The highest HGF levels were also associated with 10% and 13% increase in MAC and DTAC progression, respectively, even after adjustment for CVD risk factors.ConclusionHigher HGF levels were significantly associated with a greater risk of calcification at some extracoronary sites, suggesting an alternate biological pathway that could be targeted to reduce CVD risk.

BackgroundAdipokines play a role in cardiometabolic pathways. Coronary artery calcium (CAC) progression prognosticates cardiovascular disease (CVD) risk. However, the association of adipokines with CAC progression is not well established. We examined the association of adipokines with CAC progression in a multi-ethnic cohort free of CVD at baseline.MethodsWe included 1,904 randomly-selected adults enrolled in the Multi-Ethnic Study of Atherosclerosis who had both adipokine levels [leptin, resistin, adiponectin] and CAC by CT measured at either exam 2 (2002-2004) or exam 3 (2004-2005). CAC was previously measured at exam 1 (2000-2002) and a subset (n=566) had CAC measured at exam 5 (2010-2012). We used logistic regression to examine odds of CAC progression between exam 1 and 2/3 (defined as >0 Agatston units of change/year). We used linear mixed effect models to examine CAC progression from exam 2/3 to 5.ResultsAt exam 2/3, the mean age was 65(10) yrs; 50% women. In models adjusted for sociodemographic factors and BMI, the highest tertile of leptin, compared to lowest, was associated with an increased odds of CAC progression over the preceding 2.6yrs [OR 1.60 (95% CI: 1.10-2.33)]. In models further adjusted for visceral fat and CVD risk factors, the highest tertile of leptin was statistically significantly associated with a 4% (1-7%) greater CAC progression over an average of 7yrs. No associations were seen for resistin and adiponectin.ConclusionsHigher leptin levels were independently, but modestly, associated with CAC progression. Atherosclerosis progression may be one mechanism through which leptin confers increased CVD risk.

BackgroundDifferent 25-hydroxyvitamin D [25(OH)D] thresholds for treatment with vitamin D supplementation have been suggested and are derived almost exclusively from observational studies. Whether other characteristics, including race/ethnicity, BMI, and estimated glomerular filtration rate (eGFR), should also influence the threshold for treatment is unknown.ObjectivesThe aim was to identify clinical and biomarker characteristics that modify the response to vitamin D supplementation.MethodsA total of 666 older adults in the Multi-Ethnic Study of Atherosclerosis (MESA) were randomly assigned to 16 wk of oral vitamin D3 (2000 IU/d; n = 499) or placebo (n = 167). Primary outcomes were changes in serum parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations from baseline to 16 wk.ResultsAmong 666 participants randomly assigned (mean age: 72 y; 53% female; 66% racial/ethnic minority), 611 (92%) completed the study. The mean (SD) change in PTH was -3 (16) pg/mL with vitamin D3 compared with 2 (18) pg/mL with placebo (estimated mean difference: -5; 95% CI: -8, -2 pg/mL). Within the vitamin D3 group, lower baseline 25-hydroxyvitamin D [25(OH)D] was associated with a larger decline in PTH in a nonlinear fashion. With baseline 25(OH)D ≥30 ng/mL as the reference, 25(OH)D

In this clinical practice statement, we represent a summary of the current evidence and clinical applications of cardiac computed tomography (CT) in evaluation of coronary artery disease (CAD), from an expert panel organized by the American Society for Preventive Cardiology (ASPC), and appraises the current use and indications of cardiac CT in clinical practice. Cardiac CT is emerging as a front line non-invasive diagnostic test for CAD, with evidence supporting the clinical utility of cardiac CT in diagnosis and prevention. CCTA offers several advantages beyond other testing modalities, due to its ability to identify and characterize coronary stenosis severity and pathophysiological changes in coronary atherosclerosis and stenosis, aiding in early diagnosis, prognosis and management of CAD. This document further explores the emerging applications of CCTA based on functional assessment using CT derived fractional flow reserve, peri‑coronary inflammation and artificial intelligence (AI) that can provide personalized risk assessment and guide targeted treatment. We sought to provide an expert consensus based on the latest evidence and best available clinical practice guidelines regarding the role of CCTA as an essential tool in cardiovascular prevention - applicable to risk assessment and early diagnosis and management, noting potential areas for future investigation.

BackgroundIdeal cardiovascular health (CVH) is associated with a lower incidence of cardiovascular disease. Extracoronary calcification (ECC)-measured at the aortic valve, mitral annulus, ascending thoracic aorta, and descending thoracic aorta-is an indicator of systemic atherosclerosis. This study examined whether favorable CVH was associated with a lower risk of ECC.MethodsWe analyzed data from MESA (Multi-Ethnic Study of Atherosclerosis) participants aged 45 to 84 years without cardiovascular disease at baseline. ECC was measured by noncontrast cardiac computed tomography scan at baseline and after an average of 2.4 years. Prevalent ECC was defined as an Agatston score >0 at the baseline scan. Incident ECC was defined as Agatston score >0 at the follow-up scan among participants with Agatston score of 0 at the baseline scan. Each CVH metric (smoking, physical activity, body mass index, diet, blood pressure, total cholesterol, and blood glucose) was scored 0 to 2 points, with 2 indicating ideal; 1, intermediate; and 0, poor. The aggregated CVH score was 0 to 14 points (0-8, inadequate; 9-10, average; 11-14, optimal). We used Poisson and linear mixed-effects regression models to examine the association between CVH and ECC adjusted for sociodemographic factors.ResultsOf 6504 participants, 53% were women with a mean age (SD) of 62 (10) years. Optimal and average CVH scores were associated with lower ECC prevalence, incidence, and extent. For example, optimal CVH scores were associated with 57%, 56%, 70%, and 54% lower risk of incident aortic valve calcification, mitral annulus calcification, ascending thoracic aorta calcification, and descending thoracic aorta calcification, respectively. In addition, optimal and average CVH scores were associated with lower ECC progression at 2 years, although these associations were only significant for mitral annulus calcification and descending thoracic aorta calcification.ConclusionsIn this multiethnic cohort, favorable CVH was associated with a lower risk of extracoronary atherosclerosis. These findings emphasize the importance of primordial prevention as an intervention to reduce the burden of cardiovascular disease.

Type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF)-along with their associated risk factors-have overlapping etiologies, and two or more of these conditions frequently occur in the same patient. Many recent cardiovascular outcome trials (CVOTs) have demonstrated the benefits of agents originally developed to control T2D, ASCVD, or CKD risk factors, and these agents have transcended their primary indications to confer benefits across a range of conditions. This evolution in CVOT evidence calls for practice recommendations that are not constrained by a single discipline to help clinicians manage patients with complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. The ultimate goal for these recommendations is to be comprehensive yet succinct and easy to follow by the nonexpert-whether a specialist or a primary care clinician. To meet this need, we formed a volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM Practice Recommendations, a multispecialty consensus on the comprehensive management of the patient with complicated metabolic disease. The task force recommendations are based on strong evidence and incorporate practical guidance that is clinically relevant and simple to implement, with the aim of improving outcomes in patients with DCRM. The recommendations are presented as 18 separate graphics covering lifestyle therapy, patient self-management education, technology for DCRM management, prediabetes, cognitive dysfunction, vaccinations, clinical tests, lipids, hypertension, anticoagulation and antiplatelet therapy, antihyperglycemic therapy, hypoglycemia, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), ASCVD, HF, CKD, and comorbid HF and CKD, as well as a graphical summary of medications used for DCRM.

ObjectiveTo understand the relationship between cardiovascular disease (CVD) risk and frailty among men (MWH) and women living with HIV (WWH), or at risk for HIV.DesignWe considered 10-year coronary heart disease and atherosclerotic CVD risk by Framingham risk score (FRS, 2001 National Cholesterol Education Program Adult Treatment Program III) and Pooled Cohort Equations (PCE, 2013 American College of Cardiology/American Heart Association) in relation to the Fried Frailty Phenotype (FFP) in the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS).MethodsFFP was ascertained in MACS from 2004 to 2019 and in WIHS from 2005 to 2006 and 2011-2019. FFP score at least three of five components defined frailty. Repeated measures logistic regression (both cohorts) and Cox proportional hazards regression (MACS) were performed, controlled for education, income, cholesterol medication and hepatitis C virus serostatus, and among MWH and WWH, CD4+ cell count/μl, antiretroviral therapy, and HIV viral load.ResultsThere were 5554 participants (1265 HIV seronegative/1396 MWH; 768 seronegative/1924 WWH) included. Among men, high-risk FRS was associated with increased risk of incident frailty among seronegative [adjusted hazard ratio (aHR)) = 2.12, 95% confidence interval (CI):1.22-3.69] and MWH (aHR = 2.19, 95% CI: 1.33-3.61). Similar associations were seen with high-risk PCE and incident frailty among SN (aHR = 1.88, 95% CI: 1.48-2.39) and MWH (aHR = 1.59, 95% CI: 1.26-2.00). Among women, high-risk PCE was associated with frailty in SN [adjusted odds ratio (aOR) = 1.43, 95% CI: 1.02-2.00] and WWH (aOR = 1.36, 95% CI: 1.08-1.71); however, high-risk FRS was not (seronegative: aOR = 1.03, 95% CI: 0.30-3.49; WWH: aOR = 0.86, 95% CI: 0.23-3.20).ConclusionHigher CVD risk was associated with increased frailty regardless of HIV serostatus among men and women. These findings may inform clinical practices of screening for frailty.

BackgroundThe 2018 American Heart Association/American College of Cardiology/Multisociety cholesterol guideline states that statin therapy may be withheld or delayed among intermediate-risk individuals in the absence of coronary artery calcium (CAC=0). We evaluated whether traditional cardiovascular risk factors are associated with incident atherosclerotic cardiovascular disease (ASCVD) events among individuals with CAC=0 over long-term follow-up.MethodsWe included participants with CAC=0 at baseline from the MESA (Multi-Ethnic Study of Atherosclerosis), a prospective cohort study of individuals free of clinical ASCVD at baseline. We used multivariable-adjusted Cox proportional hazards models to study the association between cardiovascular risk factors (cigarette smoking, diabetes, hypertension, preventive medication use [aspirin and statin], family history of premature ASCVD, chronic kidney disease, waist circumference, lipid and inflammatory markers) and adjudicated incident ASCVD outcomes.ResultsWe studied 3416 individuals (mean [SD] age 58 [9] years; 63% were female, 33% White, 31% Black, 12% Chinese American, and 24% Hispanic). Over a median follow-up of 16 years, there were 189 ASCVD events (composite of coronary heart disease and stroke) of which 91 were coronary heart disease, 88 were stroke, and 10 were both coronary heart disease and stroke events. The unadjusted event rates of ASCVD were ≤5 per 1000 person-years among individuals with CAC=0 for most risk factors with the exception of current cigarette smoking (7.3), diabetes (8.9), hypertension (5.4), and chronic kidney disease (6.8). After multivariable adjustment, risk factors that were significantly associated with ASCVD included current cigarette smoking: hazard ratio, 2.12 (95% CI, 1.32-3.42); diabetes: hazard ratio, 1.68 (95% CI, 1.01-2.80); and hypertension: hazard ratio, 1.57 (95% CI, 1.06-2.33).ConclusionsCurrent cigarette smoking, diabetes, and hypertension are independently associated with incident ASCVD over a 16-year follow-up among those with CAC=0.

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

Background and aimsSex 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.MethodsWe 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.ResultsThe 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.ConclusionsIn 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.

Background and aimsExtra-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.MethodsWe 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)].ResultsThe 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.ConclusionsWe identified significant associations between select adipokines and specific markers of ECC. Adipokines may play a role in the development of systemic atherosclerosis.

BackgroundAbsence 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.MethodsMulti-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.ResultsAmong 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.ConclusionsThe 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.

The INdividual response to VITamin D (INVITe) trial was a randomized, placebo-controlled, parallel group trial of vitamin D3 supplementation (2000 IU daily) designed to determine clinical and genetic characteristics that modify the response to vitamin D supplementation. To enhance internal and external validity and reduce cost, the INVITe trial was nested within the Multi-Ethnic Study of Atherosclerosis (MESA), an ongoing prospective observational cohort study. The INVITe trial enrolled a community-based population of 666 racially and ethnically diverse participants from January 2017 to April 2019. This represents 30% of 2210 MESA participants approached for screening, and 96% of those found to be eligible. Barriers to enrollment included delayed initiation of the trial relative to scheduled MESA study visits, a lower number of available MESA participants than expected, and a high prevalence (18%) of high-dose vitamin D supplementation (>1000 IU daily, an exclusion criterion). The final study visit was attended by 611 participants (92%), and median adherence was 98%. Our experience suggests that integration of a randomized trial into an existing observational cohort study may leverage strengths of the source population and enhance enrollment, retention, and adherence, although with limited enrollment capacity. The INVITe trial will use rigorously-collected data to advance understanding of individual determinants of vitamin D response.

The Go Red for Women movement was initiated by the American Heart Association (AHA) in the early 2000s to raise awareness concerning cardiovascular disease (CVD) risk in women. In 2016, the AHA funded 5 research centers across the United States to advance our knowledge of the risks and presentation of CVD that are specific to women. This report highlights the findings of the centers, showing how insufficient sleep, sedentariness, and pregnancy-related complications may increase CVD risk in women, as well as presentation and factors associated with myocardial infarction with nonobstructive coronary arteries and heart failure with preserved ejection fraction in women. These projects were augmented by collaborative ancillary studies assessing the relationships between various lifestyle behaviors, including nightly fasting duration, mindfulness, and behavioral and anthropometric risk factors and CVD risk, as well as metabolomic profiling of heart failure with preserved ejection fraction in women. The Go Red for Women Strategically Focused Research Network enhanced the evidence base related to heart disease in women, promoting awareness of the female-specific factors that influence CVD.

Given rapid advancements in medical science, it is often challenging for the busy clinician to remain up-to-date on the fundamental and multifaceted aspects of preventive cardiology and maintain awareness of the latest guidelines applicable to cardiovascular disease (CVD) risk factors. The "American Society for Preventive Cardiology (ASPC) Top Ten CVD Risk Factors 2021 Update" is a summary document (updated yearly) regarding CVD risk factors. This "ASPC Top Ten CVD Risk Factors 2021 Update" summary document reflects the perspective of the section authors regarding ten things to know about ten sentinel CVD risk factors. It also includes quick access to sentinel references (applicable guidelines and select reviews) for each CVD risk factor section. The ten CVD risk factors include unhealthful nutrition, physical inactivity, dyslipidemia, hyperglycemia, high blood pressure, obesity, considerations of select populations (older age, race/ethnicity, and sex differences), thrombosis/smoking, kidney dysfunction and genetics/familial hypercholesterolemia. For the individual patient, other CVD risk factors may be relevant, beyond the CVD risk factors discussed here. However, it is the intent of the "ASPC Top Ten CVD Risk Factors 2021 Update" to provide a succinct overview of things to know about ten common CVD risk factors applicable to preventive cardiology.

BackgroundDue to the overlapping clinical features of coronavirus disease 2019 (COVID-19) and influenza, parallels are often drawn between the two diseases. Patients with pre-existing cardiovascular diseases (CVD) are at a higher risk for severe manifestations of both illnesses. Considering the high transmission rate of COVID-19 and with the seasonal influenza approaching in late 2020, the dual epidemics of COVID-19 and influenza pose serious cardiovascular implications. This review highlights the similarities and differences between influenza and COVID-19 and the potential risks associated with coincident pandemics.Main bodyCOVID-19 has a higher mortality compared to influenza with case fatality rate almost 15 times more than that of influenza. Additionally, a significantly increased risk of adverse outcomes has been noted in patients with CVD, with ~ 15 to 70% of COVID-19 related deaths having an underlying CVD. The critical care need have ranged from 5 to 79% of patients hospitalized due to COVID-19, a proportion substantially higher than with influenza. Similarly, the frequency of vascular thrombosis including deep venous thrombosis and pulmonary embolism is markedly higher in COVID-19 patients compared with influenza in which vascular complications are rarely seen. Unexpectedly, while peak influenza season is associated with increased cardiovascular hospitalizations, a decrease of ~ 50% in cardiovascular hospitalizations has been observed since the first diagnosed case of COVID-19, owing in part to deferred care.ConclusionIn the coming months, increasing efforts towards evaluating new interventions will be vital to curb COVID-19, especially as peak influenza season approaches. Currently, not enough data exist regarding co-infection of COVID-19 with influenza or how it would progress clinically, though it may cause a significant burden on an already struggling health care system. Until an effective COVID-19 vaccination is available, high coverage of influenza vaccination should be of utmost priority.

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

Background and aimsSouth Asians are at increased risk for cardiovascular disease (CVD). Aortic valve calcium (AVC) is associated with CVD risk and aortic stenosis. Elevated Lp(a) is a heritable risk factor for CVD and AVC. AVC prevalence and its association with Lp(a) have not been studied in South Asians.MethodsAmong participants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study (n = 695), AVC prevalence and extent were compared to four race/ethnic groups in the Multi-Ethnic Study of Atherosclerosis (MESA) (n = 4671). Multivariable regression was performed to evaluate associations between Lp(a) and AVC stratified by race/ethnic groups, adjusting for cardiovascular risk factors.ResultsAfter age and sex adjustment, South Asians had higher median Lp(a) (17.0 mg/dL) compared to Whites (12.9 mg/dL), Hispanics (13.1 mg/dL) and Chinese Americans (12.9 mg/dL), and Blacks had highest Lp(a) levels (35.1 mg/dL). There were no differences in the odds of AVC in South Asians compared with Whites or Hispanics, after age and sex adjustment (p = 0.64 and 0.63, respectively). Odds of AVC was lower in Chinese (OR 0.35; 95%CI 0.23-0.54) and somewhat lower in Blacks compared with South Asians (OR 0.76; 0.56-1.04). There were no associations between Lp(a) and AVC presence or extent in South Asians. Lp(a) was associated with AVC only among Blacks and Whites.ConclusionsAlthough present in Whites and Blacks, there were no associations between Lp(a) and AVC in South Asians. These differences may be due to statistic power or race specific modifying factors that influences the effect of Lp(a) particles on AVC pathogenesis.

Background and aimsPrevalent valvular calcification (VC) is associated with stroke but little is known about associations of VC progression with stroke.MethodsProgression (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.ResultsWe 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.ConclusionsProgression of MAC but not AVC over 2.4 years is associated with increased risk of total and ischemic stroke.

The coronavirus disease 2019 (COVID-19) pandemic has consumed our healthcare system, with immediate resource focus on the management of high numbers of critically ill patients. Those that fare poorly with COVID-19 infection more commonly have cardiovascular disease (CVD), hypertension and diabetes. There are also several other conditions that raise concern for the welfare of patients with and at high risk for CVD during this pandemic. Traditional ambulatory care is disrupted and many patients are delaying or deferring necessary care, including preventive care. New impediments to medication access and adherence have arisen. Social distancing measures can increase social isolation and alter physical activity and nutrition patterns. Virtually all facility based cardiac rehabilitation programs have temporarily closed. If not promptly addressed, these changes may result in delayed waves of vulnerable patients presenting for urgent and preventable CVD events. Here, we provide several recommendations to mitigate the adverse effects of these disruptions in outpatient care. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers should be continued in patients already taking these medications. Where possible, it is strongly preferred to continue visits via telehealth, and patients should be counselled about promptly reporting new symptoms. Barriers to medication access should be reviewed with patients at every contact, with implementation of strategies to ensure ongoing provision of medications. Team-based care should be leveraged to enhance the continuity of care and adherence to lifestyle recommendations. Patient encounters should include discussion of safe physical activity options and access to healthy food choices. Implementation of adaptive strategies for cardiac rehabilitation is recommended, including home based cardiac rehab, to ensure continuity of this essential service. While the practical implementation of these strategies will vary by local situation, there are a broad range of strategies available to ensure ongoing continuity of care and health preservation for those at higher risk of CVD during the COVID-19 pandemic.

Background and aimsThe long-term associations between zero, minimal coronary artery calcium (CAC) and cause-specific mortality are currently unknown, particularly after accounting for competing risks with other causes of death.MethodsWe evaluated 66,363 individuals from the CAC Consortium (mean age 54 years, 33% women), a multi-center, retrospective cohort study of asymptomatic individuals undergoing CAC scoring for clinical risk assessment. Baseline evaluations occurred between 1991 and 2010.ResultsOver a mean of 12 years of follow-up, individuals with CAC = 0 (45% prevalence, mean age 45 years) had stable low rates of coronary heart disease (CHD) death, cardiovascular disease (CVD) death (ranging 0.32 to 0.43 per 1000 person-years), and all-cause death (1.38-1.62 per 1000 person-years). Cancer was the predominant cause of death in this group, yet rates were also very low (0.47-0.79 per 1000 person-years). Compared to CAC = 0, individuals with CAC 1-10 had an increased multivariable-adjusted risk of CVD death only under age 40. Individuals with CAC>10 had multivariable-adjusted increased risks of CHD death, CVD death and all-cause death at all ages, and a higher proportion of CVD deaths.ConclusionsCAC = 0 is a frequent finding among individuals undergoing CAC scanning for risk assessment and is associated with low rates of all-cause death at 12 years of follow-up. Our results support the emerging consensus that CAC = 0 represents a unique population with favorable all-cause prognosis who may be considered for more flexible treatment goals in primary prevention. Detection of any CAC in young adults could be used to trigger aggressive preventive interventions.

AimsThe benefits of physical activity (PA) on cardiovascular disease (CVD) are well known. However, studies suggest PA is associated with coronary artery calcium (CAC), a subclinical marker of CVD. In this study, we evaluated the associations of self-reported recreational and non-recreational PA with CAC composition and incident CVD events. Prior studies suggest high CAC density may be protective for CVD events.Methods and resultsWe evaluated 3393 participants of the Multi-Ethnic Study of Atherosclerosis with prevalent CAC. After adjusting for demographics, the highest quintile of recreational PA was associated with 0.07 (95% confidence interval 0.01-0.13) units greater CAC density but was not associated with CAC volume. In contrast, the highest quintile of non-recreational PA was associated with 0.08 (0.02-0.14) units lower CAC density and a trend toward 0.13 (-0.01 to 0.27) log-units higher CAC volume. There were 520 CVD events over a 13.7-year median follow-up. Recreational PA was associated with lower CVD risk (hazard ratio 0.88, 0.79-0.98, per standard deviation), with an effect size that was not changed with adjustment for CAC composition or across levels of prevalent CAC.ConclusionRecreational PA may be associated with a higher density but not a higher volume of CAC. Non-recreational PA may be associated with lower CAC density, suggesting these forms of PA may not have equivalent associations with this subclinical marker of CVD. While PA may affect the composition of CAC, the associations of PA with CVD risk appear to be independent of CAC.

IntroductionPhysical activity (PA) is inversely associated with risk of heart failure and cardiovascular disease (CVD), whereas increased left ventricular (LV) mass and mass to volume (m:v) ratio are unfavorable CVD risk factors. We assessed whether changes in leisure time PA were associated with longitudinal changes in cardiac structure in a community-based population.MethodsWe included 2779 Multi-Ethnic Study of Atherosclerosis participants, free of baseline CVD, who had available data on PA and cardiac magnetic resonance imaging at examinations 1 (2000-2002) and 5 (2010-2012). Physical activity was measured by a Typical Week PA Survey and converted to MET-minutes per week of moderate+vigorous activity. We used linear mixed effect models to estimate the associations of baseline and change in PA with baseline and change in cardiac structure, adjusting for CVD risk factors and body size.ResultsAt baseline, the mean age was 59 yr, 53% were women, and 58% of nonwhite race/ethnicity. During average 10-yr follow-up, and after accounting for baseline PA levels, the highest quintiles of PA increase were significantly associated with increases in LV mass (2.3 g; 95% confidence interval [CI], 0.4-4.2), LV end-diastolic volume (4.7 mL; 95% CI, 2.4-7.0), and stroke volume (3.3 mL; 95% CI, 1.6-5.1), but lower M:V ratio (-2.9; 95% CI, -5.0 to -0.8) compared with the lowest quintiles. Increasing exercise PA was associated with increases in LV diameter and reductions in M:V ratio, whereas occupational PA was associated with increases in m:v ratio. Increasing PA over 10 yr was also associated with greater risk of eccentric dilated LV hypertrophy at examination 5.ConclusionsAfter accounting for baseline PA, greater positive changes in leisure-time PA levels were associated with a more eccentric-type of LV remodeling pattern over 10 yr. The clinical implications of such findings remain to be determined.

Low-dose rivaroxaban was effective in secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in the COMPASS trial. There is no established role, however, for oral anticoagulants in primary prevention. We evaluated whether coronary artery calcium (CAC) scoring identifies a high-risk primary prevention adult population who may benefit from low-dose rivaroxaban to prevent ASCVD events. We modeled expected outcomes of low-dose rivaroxaban in 5,196 Multiethnic Study of Atherosclerosis (MESA) cohort participants not already on antiplatelet or anticoagulant therapy. We applied relative risk ratios from COMPASS to absolute MESA event rates in order to estimate number needed to treat (NNT) to avoid a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, as well as number needed to harm (NNH) to cause 1 hospitalized bleed; with both NNT and NNH stratified by calculated ASCVD risk and by baseline CAC. MESA participants with CAC ≥300 had crude ASCVD event rate of 20 per 1000 patient-years, which is comparable to that observed in the COMPASS control-arm. CAC was independently associated with the composite ASCVD outcome (p

ImportanceThe level of coronary artery calcium (CAC) can effectively stratify cardiovascular risk in middle-aged and older adults, but its utility for young adults is unclear.ObjectivesTo determine the prevalence of CAC in adults aged 30 to 49 years and the subsequent association of CAC with coronary heart disease (CHD), cardiovascular disease (CVD), and all-cause mortality.Design, setting, and participantsA multicenter retrospective cohort study was conducted among 22 346 individuals from the CAC Consortium who underwent CAC testing (baseline examination, 1991-2010, with follow-up through June 30, 2014; CAC quantified using nonconrast, cardiac-gated computed tomography scans) for clinical indications and were followed up for cause-specific mortality. Participants were free of clinical CVD at baseline. Statistical analysis was performed from June 1, 2017, to May 31, 2018.Main outcomes and measuresThe prevalence of CAC and the subsequent rates of CHD, CVD, and all-cause mortality. Competing risks regression modeling was used to calculate multivariable-adjusted subdistribution hazard ratios for CHD and CVD mortality.ResultsThe sample of 22 346 participants (25.0% women and 75.0% men; mean [SD] age, 43.5 [4.5] years) had a high prevalence of hyperlipidemia (49.6%) and family history of CHD (49.3%) but a low prevalence of current smoking (11.0%) and diabetes (3.9%). The prevalence of any CAC was 34.4%, with 7.2% having a CAC score of more than 100. During follow-up (mean [SD], 12.7 [4.0] years), there were 40 deaths related to CHD, 84 deaths related to CVD, and 298 total deaths. A total of 27 deaths related to CHD (67.5%) occurred among individuals with CAC at baseline. The CHD mortality rate per 1000 person-years was 10-fold higher among those with a CAC score of more than 100 (0.69; 95% CI, 0.41-1.16) compared with those with a CAC score of 0 (0.07; 95% CI, 0.04-0.12). After multivariable adjustment, those with a CAC score of more than 100 had a significantly increased risk of CHD (subdistribution hazard ratio, 5.6; 95% CI, 2.5-12.7), CVD (subdistribution hazard ratio, 3.3; 95% CI, 1.8-6.2), and all-cause mortality (hazard ratio, 2.6; 95% CI, 1.9-3.6) compared with those with a CAC score of 0.Conclusions and relevanceIn a large sample of young adults undergoing CAC testing for clinical indications, 34.4% had CAC, and those with elevated CAC scores had significantly higher rates of CHD and CVD mortality. Coronary artery calcium may have potential utility for clinical decision-making among select young adults at elevated risk of cardiovascular disease.

Background and aimsGlycA 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.MethodsWe 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.ResultsIn 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.ConclusionsIn 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.

ObjectiveGlycA, a novel NMR biomarker of inflammation, has been associated with incident cardiovascular disease (CVD) in the general population, but its association with CVD among HIV-infected individuals is unknown. We examined the associations between GlycA and subclinical coronary plaque among HIV-infected and HIV-uninfected men participating in Multicenter AIDS Cohort Study (MACS).DesignCross-sectional analysis of 935 men with plasma measurement of GlycA and noncontrast cardiac computed tomography (CT) and/or coronary CT angiography.MethodsWe used multivariable Poisson and linear regression to assess associations of GlycA with prevalent coronary atherosclerosis and plaque extent, respectively.ResultsMean ± SD age was 54 ± 7 years; 31% were black; 63% HIV-infected. GlycA levels were higher in HIV-infected compared with HIV-uninfected men (397 ± 68 vs. 380 ± 60 μmol/l, P = 0.0001) and higher for men with detectable viral load vs. undetectable (413 ± 79 vs. 393 ± 65 μmol/l, P = 0.004). After adjusting for HIV serostatus, demographic and CVD risk factors, every 1SD increment in GlycA level was associated with a higher prevalence of coronary artery calcium (CAC >0) [prevalence ratio 1.09 (95% CI 1.03-1.15)] and coronary stenosis at least 50% [1.20 (1.02-1.41)]. These associations were not significantly altered after adjusting for traditional inflammatory biomarkers or differ by HIV serostatus. Among men with plaque, GlycA was positively associated with the extent of CAC and total plaque.ConclusionHIV infection was associated with higher GlycA levels. In both HIV-infected and HIV-uninfected individuals, GlycA was significantly associated with several measures of subclinical coronary atherosclerosis, independent of other CVD risk factors and inflammatory biomarkers. These findings suggest the potential role of GlycA in CVD risk stratification among HIV patients.

BackgroundHigher fibroblast growth factor-23 (FGF23) concentrations have been found to be associated with incident heart failure (HF). Experimental data suggest FGF23 directly stimulates myocardial hypertrophy. FGF23 may also enhance renin-angiotensin-aldosterone system activity. Whether FGF23 is associated with increased HF risk in populations with hypertension and whether this association is weaker in the presence of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy is unknown.MethodsWe studied 2,858 adults with hypertension free of cardiovascular disease at baseline (65.6 ± 9.5 years, 46.2% male) participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We investigated the association of baseline serum intact FGF23 with incident HF over a 14-year median follow-up and whether ACEI/ARB therapy modified this risk. We also investigated the relationship of FGF23 with aldosterone and plasma renin activity in a random subgroup of the entire MESA cohort with available assays (N = 1,642).ResultsIn adjusted Cox regression models, higher FGF23 was associated with a 63% greater hazard of incident HF (hazard ratio: 1.63, 95% confidence interval: [1.13-2.36] per 1-unit increase in log-transformed FGF23), which persisted after exclusion of participants with chronic kidney disease (hazard ratio: 1.94 [1.10-3.43]). There was no heterogeneity by ACEI/ARB use (Pinteraction = 0.438). FGF23 improved model fit over covariables (likelihood ratio χ2 = 6.67, P = 0.010). In multivariable linear regression models, there was no association between FGF23 and aldosterone or plasma renin activity.ConclusionsHigher FGF23 concentrations are associated with a significantly increased risk of HF in hypertension but this risk did not differ by ACEI/ARB treatment status. FGF23 may be a useful biomarker for HF risk in hypertensive populations.

BackgroundSex differences in the incidence and manifestation of cardiovascular disease (CVD) suggest the involvement of sex hormones in disease pathogenesis. Coronary artery calcium (CAC) and its progression, measured by non-contrast cardiac computed tomography, are markers of subclinical atherosclerosis and predict CVD, even among low-risk women. We hypothesized that sex hormone levels were associated with CAC progression among women in the Multi-Ethnic Study of Atherosclerosis.MethodsWe studied 2759 post-menopausal women (age 65 ± 9 years), free of baseline CVD, with baseline serum sex hormones and CAC measured at Exam 1 (2000-2002). Of this sample, 2427 had ≥1 follow-up CAC measurement through Exam 5 (2010-2012). Using mixed effects linear regression methods, we tested change in log[CAC+1] score by log[sex hormone] levels (continuous, comparing the 90th versus 10th percentiles). Models adjusted for demographics, lifestyle factors, cardiovascular risk factors, hormone therapy, and years since menopause.ResultsAt baseline, we found no associations between sex hormones and prevalent CAC. Over a median of 4.7 years, in fully-adjusted models, women with higher free testosterone levels had relatively greater CAC progression [Ratio 1.26 (95% CI 1.01-1.56)], whereas higher sex hormone binding globulin (SHBG) was associated with lower progression risk [0.80 (0.64-0.99). No associations were seen for total testosterone, estradiol, or dehydroepiandrosterone.ConclusionA more androgenic hormone profile of higher free testosterone and lower SHBG is associated with a greater CAC progression up to 10-years in post-menopausal women. Sex hormone levels may help identify women at increased risk for CVD who may benefit from additional risk-reducing strategies.

AimsLittle is known regarding the risk of atherosclerotic cardiovascular disease (ASCVD) conferred by changes in the volume and density of ascending thoracic aorta calcium (ATAC) over time. We evaluated changes in ATAC volume and density scores and incident ASCVD events.Methods and resultsThe Multi-Ethnic Study of Atherosclerosis is a prospective cohort study of individuals without baseline clinical ASCVD. Ascending thoracic aorta calcium was measured from baseline and follow-up (mean interval 2.4 years) cardiac computed tomography (CT). Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) per standard deviation for events after the follow-up exam adjusted for ASCVD risk factors, baseline ATAC and coronary artery calcium (CAC) volume and density, and changes in CAC volume and density. Among 5887 participants, 296 (5.0%) had detectable ATAC at baseline, follow-up, or both exams. A total of 403 events occurred over 9.5 years. An increase in ATAC volume was associated with coronary heart disease (CHD) (HR 1.90, 95% CI 1.14-3.16), ASCVD (HR 1.93, 95% CI 1.26-2.94), and ischaemic stroke (HR 2.14, CI 1.21-3.78). An increase in ATAC density was inversely associated with CHD (HR 0.29, 95% CI 0.14-0.60) and ASCVD (HR 0.42, 95% CI 0.23-0.76), but not stroke (HR 0.61, CI 0.23-1.61).ConclusionAscending thoracic aorta calcium is uncommon on serial cardiac CT. However, changes in ATAC volume and density are both associated with incident ASCVD events, but in opposite directions. Serial assessments in those with baseline ATAC may provide insight into an individual's trajectory of ASCVD risk.

ObjectivesThis study sought to compare various measures of adiposity with risk for incident hospitalized heart failure (HF) with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF).BackgroundObesity is a risk factor for HF, particularly HFpEF. It is unknown which measures of adiposity, including anthropometrics and computed tomography (CT)-measured fat area, are most predictive of HF subtypes.MethodsThe authors studied 1,806 participants of the MESA (Multi-Ethnic Study of Atherosclerosis) study without baseline cardiovascular disease who underwent anthropometrics (body mass index [BMI] and waist circumference) and an abdominal CT. Subcutaneous and visceral adipose tissue (VAT) were measured from a single CT slice at L2-L3. Cox hazard models were used to examine associations of adiposity with incident hospitalized HFpEF and HFrEF events. Fully adjusted models included demographics, HF risk factors, and N-terminal pro-B-type natriuretic peptide.ResultsOver a mean follow-up of 11 years, there were 34 HFpEF and 36 HFrEF events. The fully adjusted hazard ratio (95% confidence interval [CI]) per 1-SD higher of each anthropometric and CT-measured adiposity measures for incident HFpEF were as follows: BMI HR: 1.66; 95% CI: 1.12 to 2.45; waist circumference HR: 1.59; 95% CI: 1.05 to 2.40; and VAT HR: 2.24; 95% CI: 1.44 to 3.49. None of these adiposity measures were associated with HFrEF. Even among overweight/obese adults (BMI ≥25 kg/m2), assessment of VAT (per 1-SD) was strongly associated with HFpEF (HR: 2.78; 95% CI: 1.62 to 4.76). Subcutaneous adipose tissue was neither associated with HFpEF nor HFrEF.ConclusionsIn a multiethnic cohort free of cardiovascular disease, CT-measured VAT was independently associated with incident hospitalized HFpEF but not HFrEF. Measuring visceral fat at the time of CT imaging for other indications may offer additional prognostication of HF risk. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487).

BackgroundSedentary behaviors (SB) may exacerbate loss of muscle mass and function, independent of physical activity levels. This study examined the associations of SB with abdominal muscle area and density, a marker of muscle quality, in adults.MethodsA total of 1895 participants from the Multi-Ethnic Study of Atherosclerosis completed detailed health history, physical activity and SB questionnaires, computed tomography to quantify body composition, and measurements of inflammatory markers. Analyses included linear and nonlinear regression.ResultsThe mean age and body mass index were 64.6 years and 28 kg·m-2, respectively, and 50% were women. On average, participants engaged in 28 metabolic equivalent hours·week-1 of SB. With adjustment for age, sex, race/ethnicity, physical activity, cardiovascular disease risk factors, and inflammation, multivariable regression modeling revealed a nonlinear (quadratic) relationship between SB and locomotor, stability, and total abdominal muscle density (P

Objective- Arterial calcification is highly correlated with underlying atherosclerosis. Arterial calcification of the thoracic aorta is evident in many older individuals at high susceptibility to aging-related diseases and non-cardiovascular disease (CVD)-related mortality. In this study, we evaluated the association of thoracic aorta calcification (TAC) with non-CVD morbidity and mortality. Approach and Results- We analyzed data from participants in the Multi-Ethnic Study of Atherosclerosis, a prospective cohort study of subclinical atherosclerosis, in which participants underwent cardiac computed tomography at baseline and were followed longitudinally for incident CVD events and non-CVD events. Using modified proportional hazards models accounting for the competing risk of CVD death and controlling for demographics, CVD risk factors, coronary artery calcium, and CVD events, we evaluated whether TAC was independently associated with non-CVD morbidity and mortality. Among 6765 participants (mean age, 62 years), 704 non-CVD deaths occurred for a median follow-up of 12.2 years. Compared with no TAC, the highest tertile of TAC volume was associated with a higher risk of non-CVD mortality (hazard ratio, 1.56; 95% confidence interval, 1.23-1.97), as well as several non-CVD diagnoses, including hip fracture (2.14; 1.03-4.46), chronic obstructive pulmonary disease (2.06; 1.29-3.29), and pneumonia (1.79; 1.30-2.45), with magnitudes of association that were larger than for those of coronary artery calcium. Conclusions- TAC is associated with non-CVD morbidity and non-CVD mortality, potentially through a pathway that is unrelated to atherosclerosis. TAC may be a general marker of biological aging and an indicator of increased risk of non-CVD and death.

BackgroundWomen experience a steeper decline in aortic elasticity related to aging compared to men. We examined whether sex hormone levels were associated with ascending aortic distensibility (AAD) in the Multi-Ethnic Study of Atherosclerosis.MethodsWe studied 1,345 postmenopausal women and 1,532 men aged 45-84 years, who had serum sex hormone levels, AAD measured by phase-contrast cardiac magnetic resonance imaging, and ejection fraction>50% at baseline. Among these participants, 457 women and 548 men returned for follow-up magnetic resonance imaging 10-years later. Stratified by sex, and using mixed effects linear regression methods, we examined associations of sex hormones (as tertiles) with baseline and annual change in log-transformed AAD (mm Hg-110-3), adjusting for demographics, body size, lifestyle factors, mean arterial pressure, heart rate, hypertensive medication use (and in women, for hormone therapy use and years since menopause).ResultsThe mean (SD) age was 65 (9) for women and 62 (10) years for men. AAD was lower in women than men (P < 0.001). In adjusted cross-sectional analysis, the highest tertile of free testosterone (compared to lowest) in women was significantly associated with lower AAD [-0.10 (-0.19, -0.01)] and the highest tertile of estradiol in men was associated with greater AAD [0.12 (0.04, 0.20)]. There were no associations of sex hormones with change in AAD over 10 years, albeit in a smaller sample size.ConclusionsLower free testosterone in women and higher estradiol in men were associated with greater aortic distensibility at baseline, but not longitudinally. Sex hormone levels may account for differences in AAD between women and men.