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Background: Medication nonadherence is associated with worse outcomes in patients with atherosclerotic cardiovascular disease (ASCVD), a group who requires long-term therapy for secondary prevention. It is important to understand to what extent drug costs, which are potentially actionable factors, contribute to medication nonadherence., Methods: In a nationally representative survey of US adults in the National Health Interview Survey (2013-2017), we identified individuals ≥18 years with a reported history of ASCVD. Participants were considered to have experienced cost-related nonadherence (CRN) if in the preceding 12 months they reported skipping doses to save money, taking less medication to save money, or delaying filling a prescription to save money. We used survey analysis to obtain national estimates., Results: Of the 14 279 surveyed individuals with ASCVD, a weighted 12.6% (or 2.2 million [95% CI, 2.1-2.4]) experienced CRN, including 8.6% or 1.5 million missing doses, 8.8% or 1.6 million taking lower than prescribed doses, and 10.5% or 1.9 million intentionally delaying a medication fill to save costs. Age <65 years, female sex, low family income, lack of health insurance, and high comorbidity burden were independently associated with CRN, with >1 in 5 reporting CRN in these subgroups. Survey respondents with CRN compared with those without CRN had 10.8-fold higher odds of requesting low-cost medications and 8.9-fold higher odds of using alternative, nonprescription, therapies., Conclusions: One in 8 patients with ASCVD reports nonadherence to medications because of cost. The removal of financial barriers to accessing medications, particularly among vulnerable patient groups, may help improve adherence to essential therapy to reduce ASCVD morbidity and mortality.

Importance: Health insurance is effective in preventing financial hardship from unexpected major health care events. However, it is also essential to assess whether vulnerable patients, particularly those from low-income families, are adequately protected from longitudinal health care costs for common chronic conditions such as atherosclerotic cardiovascular disease (ASCVD)., Objective: To examine the annual burden of total out-of-pocket health expenses among low-income families that included a member with ASCVD., Design, Setting, and Participants: In this cross-sectional study of the Medical Expenditure Panel Survey from January 2006 through December 2015, all families with 1 or more members with ASCVD were identified. Families were classified as low income if they had an income under 200% of the federal poverty limit. Analyses began December 2017., Main Outcomes and Measures: Total annual inflation-adjusted out-of-pocket expenses, inclusive of insurance premiums, for all patients with ASCVD. We compared these expenses against annual family incomes. Out-of-pocket expenses of more than 20% and more than 40% of family income defined high and catastrophic financial burden, respectively., Results: We identified 22 521 adults with ASCVD, represented in 20 600 families in the Medical Expenditure Panel Survey. They correspond to an annual estimated 23 million or 9.9% of US adults with a mean (SE) age of 65 (0.2) years and included 10.9 million women (47.1%). They were represented in 21 million or 15% of US families. Of these, 8.2 million families (39%) were low income. The mean annual family income was $57 143 (95% CI, $55 377-$58 909), and the mean out-of-pocket expense was $4415 (95% CI, $3735-$3976). While financial burden from health expenses decreased throughout the study, even in 2014 and 2015, low-income families had 3-fold higher odds than mid/high-income families of high financial burden (21.4% vs 7.6%; OR, 3.31; 95% CI, 2.55-4.31) and 9-fold higher odds of catastrophic financial burden (9.8% vs 1.2%; OR, 9.35; 95% CI, 5.39-16.20), representing nearly 2 million low-income families nationally. Further, even among the insured, 1.6 million low-income families (21.8%) experienced high financial burden and 721 000 low-income families (9.8%) experienced catastrophic out-of-pocket health care expenses in 2014 and 2015., Conclusions and Relevance: One in 4 low-income families with a member with ASCVD, including those with insurance coverage, experience a high financial burden, and 1 in 10 experience a catastrophic financial burden due to cumulative out-of-pocket health care expenses. To alleviate economic disparities, policy interventions must extend focus to improving not only access, but also quality of coverage, particularly for low-income families.

Background: Excess adipose tissue has been implicated in the pathogenesis of insulin resistance and atherosclerosis and is a key risk factor for blood pressure (BP) elevation. However, circulating levels of adiponectin, a protein produced by adipose tissue and widely implicated in the pathogenesis of insulin resistance and atherosclerosis, are inversely proportional to adiposity. The relationship between adiponectin and incident hypertension has not been determined in the general US population., Methods: Normotensive participants (n = 1233) enrolled in the Dallas Heart Study, a multiethnic, probability-based population sample of Dallas County adults were followed for median of 7 years. Retroperitoneal, intraperitoneal, visceral, and subcutaneous adipose tissue were measured at baseline by magnetic resonance imaging. Liver fat content was measured by 1 H-magnetic resonance spectroscopy. Relative risk regression was used to determine the association of adiponectin with incident hypertension after adjustment for age, race, sex, BMI, smoking, diabetes, baseline systolic BP, total cholesterol, and regional fat depot., Results: Of the 1233 study participants (median age 40 years, 40% black, and 56% women), 391 (32%) had developed hypertension over a median follow-up of 7 years. Adiponectin levels were associated with reduced risk of incident hypertension (RR 0.81, 95% CI [0.68-0.96]) in the fully adjusted model, which included liver fat. Similar results were observed after adjustment for subcutaneous or visceral fat depots when tested individually or simultaneously in the model., Conclusion: Our study suggested a protective role of adiponectin against incident hypertension independent of body fat distribution., (Copyright © 2016 John Wiley & Sons, Ltd.)

Therapies targeting high-density lipoprotein cholesterol content (HDL-C) have not improved coronary heart disease (CHD) outcomes. High-density lipoprotein particle concentration (HDL-P) may better predict CHD. However, the impact of race/ethnicity on the relations between HDL-P and subclinical atherosclerosis and incident CHD events has not been described. Participants from the Dallas Heart Study (DHS), a multiethnic, probability-based, population cohort of Dallas County adults, underwent the following baseline measurements: HDL-C, HDL-P by nuclear magnetic resonance imaging, and coronary artery calcium by electron-beam computed tomography. Participants were followed for a median of 9.3 years for incident CHD events (composite of first myocardial infarction, stroke, coronary revascularization, or cardiovascular death). The study comprised 1,977 participants free of CHD (51% women, 46% black). In adjusted models, HDL-C was not associated with prevalent coronary artery calcium (p = 0.13) or incident CHD overall (hazard ratio [HR] per 1 SD 0.89, 95% confidence interval [CI] 0.76 to 1.05). However, HDL-C was inversely associated with incident CHD among nonblack (adjusted HR per 1 SD 0.67, 95% CI 0.46 to 0.97) but not black participants (HR 0.94, 95% CI 0.78 to 1.13, pinteraction = 0.05). Conversely, HDL-P, adjusted for risk factors and HDL-C, was inversely associated with prevalent coronary artery calcium (p = 0.009) and with incident CHD overall (adjusted HR per 1 SD 0.73, 95% CI 0.62 to 0.86), with no interaction by black race/ethnicity (pinteraction = 0.57). In conclusion, in contrast to HDL-C, the inverse relation between HDL-P and incident CHD events is consistent across ethnicities. These findings suggest that HDL-P is superior to HDL-C in predicting prevalent atherosclerosis as well as incident CHD events across a diverse population and should be considered as a therapeutic target., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Visceral (VAT) and abdominal subcutaneous (SAT) adipose tissues contribute to obesity but may have different metabolic and atherosclerosis risk profiles. We sought to determine the associations of abdominal VAT and SAT mass with markers of cardiac and metabolic risk in a large, multiethnic, population-based cohort of obese adults., Design and Methods: Among obese participants in the Dallas Heart Study, we examined the cross-sectional associations of abdominal VAT and SAT mass, assessed by magnetic resonance imaging (MRI) and indexed to body surface area (BSA), with circulating biomarkers of insulin resistance, dyslipidemia, and inflammation (n = 942); and with aortic plaque and liver fat by MRI and coronary calcium by computed tomography (n = 1200). Associations of VAT/BSA and SAT/BSA were examined after adjustment for age, sex, race, menopause, and body mass index., Results: In multivariable models, VAT significantly associated with the homeostasis model assessment of insulin resistance (HOMA-IR), lower adiponectin, smaller LDL and HDL particle size, larger VLDL size, and increased LDL and VLDL particle number (p < 0.001 for each). VAT also associated with prevalent diabetes, metabolic syndrome, hepatic steatosis, and aortic plaque (p < 0.001 for each). VAT independently associated with C-reactive protein but not with any other inflammatory biomarkers tested. In contrast, SAT associated with leptin and inflammatory biomarkers, but not with dyslipidemia or atherosclerosis. Associations between SAT and HOMA-IR were significant in univariable analyses but attenuated after multivariable adjustment., Conclusion: VAT associated with an adverse metabolic, dyslipidemic, and atherogenic obesity phenotype. In contrast, SAT demonstrated a more benign phenotype, characterized by modest associations with inflammatory biomarkers and leptin, but no independent association with dyslipidemia, insulin resistance, or atherosclerosis in obese individuals. These findings suggest that abdominal fat distribution defines distinct obesity sub-phenotypes with heterogeneous metabolic and atherosclerosis risk., (Copyright © 2012 The Obesity Society.)

Objective: Myeloperoxidase (MPO) is a leukocyte-derived enzyme that appears to be directly involved in atherosclerosis development. We evaluated the association of circulating MPO with coronary and aortic atherosclerosis in a large, multiethnic population., Methods and Results: Plasma levels of MPO were measured in 3294 subjects participating in the Dallas Heart Study, a probability-based population sample. Coronary artery calcification (CAC) was measured by EBCT, and abdominal aorta plaque prevalence (AP) and burden (APB), as well as abdominal aorta wall thickness (AWT) were determined by MRI. Associations between MPO and atherosclerosis phenotypes were assessed in multivariable analyses adjusting for traditional atherosclerosis risk factors. MPO levels in the 4th compared with 1st quartile independently associated with prevalent AP (OR 1.41, 95% CI 1.08-1.84), APB (beta coefficient 0.23, p = 0.02), and AWT (beta coefficient 0.04, p = 0.03), but not with prevalent CAC (OR 0.84, 95% CI 0.61-1.17). MPO remained associated with aortic atherosclerosis phenotypes but not coronary calcification after adjustment for other inflammatory biomarkers. A significant interaction was observed between race/ethnicity, MPO and AP (p(interaction) = 0.038), such that MPO levels in the 4th vs 1st quartile associated with prevalent AP in African Americans, (OR 1.81, 95% CI 1.23-2.65) but not in White or Hispanic participants (OR 0.99, 95% CI 0.68-1.44)., Conclusion: Higher levels of MPO associated with aortic but not coronary atherosclerosis, with significant associations limited to African American participants. These findings suggest that MPO might be a novel risk factor contributing to racial disparities in peripheral vascular disease., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: Pulmonary surfactant protein B (SP-B), an alveolar protein normally detectable at only very low concentrations in blood, circulates at higher levels among smokers and those with alveolar injury and inflammation. We hypothesized that SP-B may serve as a marker of the vascular effects of smoking and would thus be associated with subclinical measures of atherosclerosis., Methods and Results: Plasma levels of SP-B were measured in 3294 subjects, ages 30 to 65, enrolled in the Dallas Heart Study, a probability-based population sample of Dallas County adults. Coronary artery calcium (CAC) was measured by computed tomography and abdominal aortic plaque (AP) by magnetic resonance imaging. The cohort comprised 29% current and 17% former smokers. The overall prevalence of CAC was 22%, and that of AP was 39%. Median SP-B levels were 5-fold higher among current versus never smokers (P<0.0001) and were significantly correlated with estimated pack-years smoked (Spearman ρ=0.35, P<0.0001). Increasing levels of SP-B also associated with other traditional cardiac risk factors and higher levels of inflammatory biomarkers. In univariable analyses, increasing SP-B quartiles associated with higher prevalence of both CAC and AP (P(trend)<0.0001 for each). In multivariable analyses adjusting for traditional cardiovascular risk factors, SP-B remained associated with AP (OR 1.87 for the 4th versus 1st quartiles, 95% confidence interval 1.39 to 2.51; P<0.0001) but not CAC. An interaction was observed between SP-B, smoking status, and AP (P(interaction)=0.01), such that SP-B associated with AP in current smokers (adjusted OR 2.15 for the 4th versus 1st quartile, 95% confidence interval 1.26 to 3.67; P=0.005) but not in former or never smokers., Conclusions: Circulating levels of SP-B increase with greater smoking burden and independently associate with abdominal AP among current smokers. Our findings support further investigation of the role of SP-B as a marker of the vascular effects of smoking.

Objective: Lymphotoxin β receptor (LTβR), a member of the tumor necrosis factor superfamily, binds ligands expressed by activated lymphocytes. Interruption of LTβR signaling improves autoimmune diseases and alters lipid homeostasis. We assayed circulating LTβR and examined its association with atherosclerosis phenotypes in a population-based sample., Methods and Results: Plasma LTβR was measured by ELISA in 3215 subjects enrolled in the Dallas Heart Study. Atherosclerosis was assessed using CT measurements of coronary calcium (CAC) and abdominal MRI measurements of aortic plaque (AP) (n=2252) and aortic wall thickness (AWT) (n=2265). We analyzed associations between LTβR and atherosclerosis using multivariable logistic and linear regression methods. Higher levels of LTβR associated with most traditional cardiovascular risk factors, multiple inflammatory markers, and markers of cardiac injury. Univariable analyses demonstrated significant associations of LTβR with CAC, AP, and AWT (p<0.0001 for each). In multivariable models adjusted for traditional risk factors, the 4th vs. the 1st quartile of LTβR remained associated with prevalent CAC, AP, and increased AWT (all p<0.05). Similar associations were observed when LTβR was modeled as a log-transformed continuous variable., Conclusion: LTβR levels are independently associated with atherosclerosis in multiple vascular beds. These findings support further investigation of the lymphotoxin/LTβR pathway in atherosclerosis., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Specific chemokines contribute to vascular inflammation and may be useful biomarkers to detect atherosclerosis. The chemokines CXCL1 and CCL11 have previously been studied in animal or human models of atherosclerosis, while CXCL2 and CCL23 have not. Among 2,454 subjects enrolled in the Dallas Heart Study, a multi-ethnic population-based sample, we measured plasma CCL11, CCL23, CXCL1, and CXCL2, and associated levels with coronary artery calcium (CAC) by computed tomography, and aortic wall thickness, plaque burden, and compliance by magnetic resonance imaging. Elevated chemokine levels were defined as greater than or equal to the median for CCL11 and CCL23 and greater than or equal to the upper detection limit for CXCL1 and CXCL2. Elevated CCL23 (P < 0.01) and CXCL1 (P = 0.01), but not CCL11 and CXCL2, associated with CAC in univariable analyses. After adjustment for traditional risk factors, elevated CCL23 remained associated with CAC (OR 1.3, 95% CI 1.0-1.7; P = 0.02), while the association with CXCL1 was modestly attenuated (OR 1.4, 95% CI 1.0-2.1; P = 0.06). CCL23 also associated with aortic wall thickness, plaque, and compliance in univariable analyses (P < 0.05 for each), but these associations were attenuated after multivariable adjustment. The novel chemotactic protein, CCL23, which has not been previously studied in atherosclerosis, is independently associated with coronary atherosclerosis, suggesting that this chemokine merits further study in animal and human models.

Objective: Endothelial cell-selective adhesion molecule (ESAM) is a junctional-type cellular adhesion molecule (CAM) that is uniquely expressed in vascular endothelium and activated platelets and mediates neutrophil and monocyte diapedesis across the endothelium. Given its role in endothelial pathobiology, we hypothesized that soluble ESAM (sESAM) would be independently associated with atherosclerosis and vascular stiffness., Methods and Results: We measured sESAM, soluble intercellular adhesion molecule (sICAM)-1, and soluble vascular cell adhesion molecule (sVCAM)-1 in 3222 subjects participating in the Dallas Heart Study, a probability-based population sample. Coronary artery calcium (CAC) was measured by electron beam computed tomography, and abdominal aortic wall thickness (AWT), aortic plaque burden (APB), and aortic compliance (AC) by MRI. Increasing levels of sESAM were associated with all major cardiovascular risk factors as well as with inflammatory markers such as monocyte chemoattractant protein-1, but only weakly correlated with sICAM-1 and sVCAM-1. In multivariate analyses, sESAM was independently associated with prevalent CAC (OR 1.2 per SD increase, 95% CI 1.1 to 1.3; P=0.005), AWT (P=0.035), and AC (P=0.006), but not APB (P=0.15). In contrast, no independent associations were observed between sICAM-1 or sVCAM-1 and any of the atherosclerosis phenotypes., Conclusions: In this first reported clinical study of sESAM in humans, sESAM levels were independently associated with CAC, AWT, and AC, whereas sICAM-1 and sVCAM-1 were not. These findings support a unique role of this cellular adhesion molecule in atherosclerosis and suggest the need for further exploration of sESAM as a predictive biomarker and potential mediator of atherosclerosis.

Background: Peptidoglycan recognition protein-1 (PGLYRP-1) is part of the innate immune system and binds to peptidoglycan, a component of bacterial cell walls that has been found in human atherosclerotic lesions. Chronic exposure to bacterial antigens may cause or exacerbate the inflammatory response to lipid deposition within arterial walls. We hypothesized that PGLYRP-1 is associated with subclinical atherosclerosis as measured by computed tomography and magnetic resonance imaging., Methods and Results: PGLYRP-1 was measured in 3222 subjects in the Dallas Heart Study, a probability-based population sample age 30-65 including 50% African-Americans and 56% women. Coronary artery calcium (CAC) was measured by electron beam computed tomography (n=2467), abdominal aortic wall thickness (AWT) by magnetic resonance imaging (MRI) (n=2270), and abdominal aortic plaque burden (APB) by MRI (n=2256). In univariable analyses, increasing levels of PGLYRP-1 were associated with all major cardiovascular risk factors, with inflammatory markers such as C-reactive protein, and with CAC, AWT, and APB (p<0.0001 for each). In multivariable models adjusted for traditional risk factors, logPGLYRP-1 remained significantly associated with CAC (OR 1.1, 95% CI 1.01-1.3 per S.D.; p=0.04) and AWT (p=0.009) but not APB (p=0.09). Further adjustment for novel biomarkers associated with PGLYRP-1 and atherosclerosis attenuated the association with CAC (p=0.18) but not with AWT (p=0.01) or APB (p=0.037)., Conclusion: In this first reported clinical study of PGLYRP-1 in humans, PGLYRP-1 levels were independently associated with atherosclerosis phenotypes that represent different vascular beds and stages of atherosclerosis.

Background: Caspase-3, an apoptosis protease, is expressed in atherosclerotic plaques. We examined the relationship between plasma caspase-3 levels, aortic compliance, and atherosclerosis., Methods: Caspase-3 was measured in 3,221 subjects from the Dallas Heart Study. Electron beam computed tomography measures of coronary calcium (CAC) (n = 2,404) and magnetic resonance imaging (MRI) measures of abdominal aortic wall thickness (AWT) (n = 2,208) and aortic compliance (AC) (n = 2,328) were obtained. Multivariate analyses were performed, adjusting for age, sex, ethnicity, body mass index (BMI), traditional cardiovascular risk factors, and cardiac medications., Results: In univariable analysis, caspase-3 associated with CAC (P < 0.0001), AWT (P = 0.002), and AC (P < 0.0001). After multivariable adjustment, 4th quartile caspase-3 (compared to 1st quartile) was significantly associated with CAC (P = 0.004), AWT (P = 0.02), and AC (P < 0.0001) with similar findings for caspase-3 as a continuous variable., Conclusions: Caspase-3 independently associates with CAC, AWT, and AC, suggesting a link between apoptosis and atherosclerosis.