Incident Clinical Cardiovascular Disease Research Articles

Abstract 15482: Trends in Cardiovascular Health Among Older Adults With and Without Cardiovascular Diseases: National Health and Nutrition Examination Survey (NHANES), 2013-2018

Introduction: American Heart Association’s (AHA) Life’s Essential 8 (LE8) is a framework for quantifying cardiovascular health (CVH). Prior studies have focused on individuals without clinical cardiovascular disease (CVD). We sought to examine recent trends in LE8 scores among older adults with prevalent CVD. Methods: We included non-institutionalized older US adults (ages 65+) from NHANES (2013-18). Overall LE8 scores (range 0-100; higher = better CVH) were calculated for all participants with or without CVD, using methods recommended by the AHA. CVD diagnoses were self-reported, including coronary heart disease (CHD), stroke, heart failure (HF), hypertension (HTN), angina, and myocardial infarction (MI). Percent change in LE8 scores from 2013-18 was calculated for each diagnosis group, and a linear regression tested for significance of changes within groups. Results: The 3,050 participants represented 37,908,305 adults (54.7% women; mean age 72.6 y); 3.4% self-identified as Asian, 7.2% Black, 3.9% Mexican, 3.3% Other Hispanic, 2.4% Multi-racial, and 79.9% Non-Hispanic White. Overall LE8 scores tended to stay stable or decline between 2013-14 and 2017-18 for individuals with and without CVD (Figure 1). Significant decreases in mean LE8 scores occurred in those with HTN, with a 4.1% decline from 2013-18 (from 59.6 [95% CI: 58.4-60.8] to 57.1 [55.9-58.4]), stroke, with a 11.5% decline (from 60.6 [56.0-65.2] to 53.6 [50.7-56.5]), and HF, with a 15.2% decline (from 60.9 [57.2-64.6] to 51.6 [48.0-55.2]). Conclusions: Recent LE8 scores remained stable or declined for older US adults even before the pandemic. In particular, individuals with HTN, stroke, and HF had significant declines in LE8 scores. Since LE8 metrics include behavioral and physiologic metrics associated with CVD risk, these data indicate concerning trends and primary and secondary prevention opportunities in older US adults, who are at highest risk for incident and recurrent CVD events.

Abstract P606: Effectiveness of Randomized Dietary Interventions for the Primary Prevention of Incident Cardiovascular Disease and Type 2 Diabetes

Objective: Randomized controlled trials (RCTs) provide opportunities to estimate the causal effects of interventions on disease risk; however, large-scale, long-term RCTs of diet for the prevention of major chronic disease endpoints are sparse. We sought to summarize RCTs comparing the effectiveness of dietary interventions for the primary prevention of clinical cardiovascular disease (CVD) events and type 2 diabetes (T2D) in adults. Methods: We conducted a systematic review and meta-analysis (PROSPERO #CRD42021283728) of RCTs exclusively with dietary interventions with outcomes of incident primary CVD events and/or T2D among adults. We searched MEDLINE and other databases and references. Eligible interventions included those providing instruction, education, and/or provisions to modify intakes of nutrients, foods, or overall dietary patterns. We excluded meal replacement products, dietary supplements, interventions with concomitant comprehensive lifestyle programs, exercise regimens, etc., trials in secondary prevention populations, and trials assessing risk factor or biomarker changes only, rather than clinical events. Two investigators performed screening and data extraction in parallel. We conducted a random effects meta-analysis to estimate the pooled effectiveness of dietary interventions compared with usual diet or low-fat control groups for CVD and T2D outcomes, separately. Results: Among the 5365 citations generated in our searches, we identified 4 eligible RCTs, representing 56,721 participants with mean ages ranging from 44.7 to 67.9 years. Mean intervention duration was 2.3 to 8.1 years, resulting in 3,151 CVD events and 3,603 T2D cases. Compared with the control diets, the various healthy dietary patterns were related to a combined 7% (relative risk [RR] = 0.93, confidence interval [CI] = 0.87-1.00) lower CVD risk and 8% (RR = 0.92, CI = 0.86-0.98) lower T2D risk. Conclusion: Despite major morbidity and mortality from CVD and T2D, there have been few large, population-based, long-term RCTs assessing the exclusive effectiveness of dietary modification for the primary prevention of clinical CVD events or T2D. Results, however, indicate that various healthy diets may be modestly effective for primary prevention.

Association of Cardiovascular Health Through Young Adulthood With Genome-Wide DNA Methylation Patterns in Midlife: The CARDIA Study.

Cardiovascular health (CVH) from young adulthood is strongly associated with an individual's future risk of cardiovascular disease (CVD) and total mortality. Defining epigenomic biomarkers of lifelong CVH exposure and understanding their roles in CVD development may help develop preventive and therapeutic strategies for CVD. In 1085 CARDIA study (Coronary Artery Risk Development in Young Adults) participants, we defined a clinical cumulative CVH score that combines body mass index, blood pressure, total cholesterol, and fasting glucose measured longitudinally from young adulthood through middle age over 20 years (mean age, 25-45). Blood DNA methylation at >840 000 methylation markers was measured twice over 5 years (mean age, 40 and 45). Epigenome-wide association analyses on the cumulative CVH score were performed in CARDIA and compared in the FHS (Framingham Heart Study). We used penalized regression to build a methylation-based risk score to evaluate the risk of incident coronary artery calcification and clinical CVD events. We identified 45 methylation markers associated with cumulative CVH at false discovery rate <0.01 (P=4.7E-7-5.8E-17) in CARDIA and replicated in FHS. These associations were more pronounced with methylation measured at an older age. CPT1A, ABCG1, and SREBF1 appeared as the most prominent genes. The 45 methylation markers were mostly located in transcriptionally active chromatin and involved lipid metabolism, insulin secretion, and cytokine production pathways. Three methylation markers located in genes SARS1, SOCS3, and LINC-PINT statistically mediated 20.4% of the total effect between CVH and risk of incident coronary artery calcification. The methylation risk score added information and significantly (P=0.004) improved the discrimination capacity of coronary artery calcification status versus CVH score alone and showed association with risk of incident coronary artery calcification 5 to 10 years later independent of cumulative CVH score (odds ratio, 1.87; P=9.66E-09). The methylation risk score was also associated with incident clinical CVD in FHS (hazard ratio, 1.28; P=1.22E-05). Cumulative CVH from young adulthood contributes to midlife epigenetic programming over time. Our findings demonstrate the role of epigenetic markers in response to CVH changes and highlight the potential of epigenomic markers for precision CVD prevention, and earlier detection of subclinical CVD, as well.

Omega-3 fatty acids, subclinical atherosclerosis, and cardiovascular events: Implications for primary prevention

Background and aimsHigh-dose eicosapentaenoic acid (EPA) therapy was beneficial in high-risk patients without clinical cardiovascular disease (CVD). Whether higher plasma levels of EPA and docosahexaenoic acid (DHA) have similar benefits in those without subclinical CVD is unclear. We aim to evaluate the interplay between plasma omega-3 fatty acids and coronary artery calcium (CAC) in relation to CVD events. MethodsWe examined 6568 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with plasma EPA and DHA levels and CAC measured at baseline. The primary outcome was incident CVD events (myocardial infarction, angina, cardiac arrest, stroke, CVD death). Hazard ratios for the primary outcome were adjusted for potential confounder using Cox regression. ResultsMean ± SD age was 62.1 ± 10.2 years and 52.9% were females. The median follow-up time was 15.6 years. Higher loge(EPA) (adjusted hazard ratio, aHR = 0.83; 95% CI, 0.74–0.94) and loge(DHA) (aHR = 0.79; 95% CI, 0.66–0.96) were independently associated with fewer CVD events. The difference in absolute CVD event rates between lowest vs. highest EPA tertile increased at higher CAC levels. The adjusted HR for highest vs. lowest EPA tertile within CAC = 0 was 1.02 (95% CI, 0.72–1.46), CAC = 1–99 was 0.71 (95% CI, 0.51–0.99), and CAC≥100 was 0.67 (95% CI, 0.52–0.84). A similar association was seen in tertiles of DHA by CAC category. ConclusionsIn an ethnically diverse population free of clinical CVD, higher plasma omega-3 fatty acid levels were associated with fewer long-term CVD events. The absolute decrease in CVD events with higher omega-3 fatty acid levels was more apparent at higher CAC scores.

Abstract P040: Dyslipidemia And The Incidence Of Subclinical And Clinical Cardiovascular Disease In Adolescents And Young Adults: The Strong Heart Family Study (SHFS)

Introduction: Dyslipidemia is characterized by high levels of total cholesterol (TC), LDL cholesterol (LDL-C), triglycerides (TG), or low levels of HDL cholesterol (HDL-C) and is an established risk factor for subclinical and clinical cardiovascular disease (CVD) among adults. Although several investigations exist in older American Indian (AI) adults, the data on AI adolescents and young adults are scarce. Hypothesis: Dyslipidemia will be prevalent, and the incidence of subclinical and clinical CVD will be higher in young AI with than without baseline dyslipidemia. Methods: We evaluated AI participants from the SHFS, who were 14-39 years old at the baseline examination, 2001-2003 (n=1,436). To measure lipids, we drew blood after a 12-hour fast and defined dyslipidemia as any of the following: TC ≥ 200 mg/dL, LDL-C ≥ 100 mg/dL, TG ≥ 150 mg/dL, HDL-C &lt; 40 mg/dL for men, HDL-C &lt; 50mg/dL for women, non-HDL-C ≥ 130 mg/dL or taking lipid lowering medication. We used carotid ultrasound to detect atherosclerotic plaque at baseline and at the follow-up examination, 2006-2009. We identified CVD events through 2019 with a median follow-up of 17.8 years. We used log-rank tests to determine if the incidence of plaque or CVD events differed according to different categories of dyslipidemia. Results: Prevalence of dyslipidemia was 42%, 65%, and 73% for participants &lt;20, 20-29, and 30-39 years old, respectively. During follow-up, 109 (9.9%) participants had incident plaque (of 1,107 plaque free participants) and 128 (9%) had a fatal or non-fatal CVD event (of 1,424 CVD free participants). Plaque incidence was higher in participants with high TC, LDL-C, TG, non-HDL-C, and dyslipidemia at baseline. CVD incidence was higher for participants with high TC, TG, and non-HDL-C (Table 1). Conclusions: AI adolescents and young adults have an unexpectedly high prevalence of dyslipidemia, which leads to higher incident plaque and CVD events later in life. These data provide evidence for the benefits of lipid screening and intervention among this population.

Abstract P435: Associations of Endogenous Sex Hormone Levels With the Prevalence and Progression of Valvular and Thoracic Aortic Calcification in the Multi-Ethnic Study of Atherosclerosis (MESA)

Background: Sex hormone (SH) levels may contribute to sex differences in cardiovascular disease (CVD) risk among women and men. We previously found that high free testosterone (T) and low sex hormone binding globulin (SHBG) were associated with progression of coronary artery calcification in women. Extra-coronary calcification (ECC) predicts incident clinical CVD independent of traditional risk factors. We examined whether SH were also associated with ECC prevalence and progression among MESA participants free of clinical CVD at baseline. Methods: We studied 2883 postmenopausal women and 3164 men who had endogenous SH levels measured at baseline. ECC was measured by non-contrast cardiac CT at baseline and at a follow-up visit up to 5 years later. ECC included ascending and descending thoracic aortic calcification (ATAC, DTAC), mitral annular calcification (MAC) and aortic valve calcification (AVC). We used multivariable Poisson regression to evaluate associations with ECC prevalence and risk of developing ECC (Agatston scores &gt;0) and linear mixed effects models for ECC progression, per 1 SD increment in log (SH) level in women and men separately. Results: The mean (SD) age was 64 (9) years for women and 62 (10) years for men. In women, greater free T and lower SHBG were associated with MAC incidence in a demographic-adjusted model but were no longer statistically significant after adjustment for CVD risk factors ( Table ). 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 in fully adjusted models. We did not find associations of SH with AVC or ATAC in either men or women. Conclusion: In this diverse cohort free of CVD, we found certain associations of SH with measures of ECC. 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 the clinical implications of these findings.

Association of Insulin Dose, Cardiometabolic Risk Factors, and Cardiovascular Disease in Type 1 Diabetes During 30 Years of Follow-up in the DCCT/EDIC Study.

OBJECTIVEThe Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated the beneficial effects of intensive therapy on atherosclerosis and clinical cardiovascular disease (CVD) outcomes. The current analyses evaluated the relationship between longitudinal changes in insulin dose and CVD risk factors and outcomes.RESEARCH DESIGN AND METHODSA total of 1,441 participants were randomly assigned to intensive or conventional diabetes therapy during the DCCT. After an average of 6.5 years of follow-up, 96% of the surviving cohort enrolled in the EDIC observational study, which included annual visits with detailed medical history, physical examination, and laboratory testing. CVD events were adjudicated by a review committee. Generalized linear mixed models and Cox proportional hazards regression models were used to assess the association between insulin dose and cardiometabolic risk factors and CVD risk, respectively, over a total of 30 years.RESULTSHigher insulin doses were significantly associated with a less favorable cardiometabolic risk profile (higher BMI, pulse rate, and triglycerides and lower HDL cholesterol) with the exception of lower diastolic blood pressure and lower LDL cholesterol. In a minimally adjusted model, a 0.1 unit/kg body wt/day increase in insulin dose was associated with a 6% increased risk of any CVD (95% CI 3, 9). However, the association with insulin dose was no longer significant after adjustment for other CVD risk factors.CONCLUSIONSDuring DCCT/EDIC, higher insulin doses were associated with adverse trends in several cardiometabolic risk factors, even after multivariable adjustment, but not with incident CVD outcomes.

A dose-response meta-analysis of chronic arsenic exposure and incident cardiovascular disease.

Consistent evidence at high levels of water arsenic (≥100 µg/l), and growing evidence at low-moderate levels (<100 µg/l), support a link with cardiovascular disease (CVD). The shape of the dose-response across low-moderate and high levels of arsenic in drinking water is uncertain and critical for risk assessment.We conducted a systematic review of general population epidemiological studies of arsenic and incident clinical CVD (all CVD, coronary heart disease (CHD) and stroke) with three or more exposure categories. In a dose-response meta-analysis, we estimated the pooled association between log-transformed water arsenic (log-linear) and restricted cubic splines of log-transformed water arsenic (non-linear) and the relative risk of each CVD endpoint.Twelve studies (pooled N = 408 945) conducted at high (N = 7) and low-moderate (N = 5) levels of water arsenic met inclusion criteria, and 11 studies were included in the meta-analysis. Compared with 10 µg/l, the estimated pooled relative risks [95% confidence interval (CI)] for 20 µg/l water arsenic, based on a log-linear model, were 1.09 (1.03, 1.14) (N = 2) for CVD incidence, 1.07 (1.01, 1.14) (N = 6) for CVD mortality, 1.11 (1.05, 1.17) (N = 4) for CHD incidence, 1.16 (1.07, 1.26) (N = 6) for CHD mortality, 1.08 (0.99, 1.17) (N = 2) for stroke incidence and 1.06 (0.93, 1.20) (N = 6) for stroke mortality. We found no evidence of non-linearity, although these tests had low statistical power.Although limited by the small number of studies, this analysis supports quantitatively including CVD in inorganic arsenic risk assessment, and strengthens the evidence for an association between arsenic and CVD across low-moderate to high levels.

Role of Fibroblast Growth Factor- 23 in Coronary Artery Diseases and its Association with Apolipoprotein A1

Coronary artery disease (CAD) is a clinical manifestation resulting from a narrowing of epicardial coronary arteries that supply blood and oxygen to the heart. Coronary artery disease is mostcommonlydue to atherosclerotic occlusion of the coronary arteries.Fibroblast growth factor 23 (FGF23) is a circulating peptide hormone secreted by bone cells,regulating phosphate and vitamin D metabolism. Several recent observational studies reported an independent association of circulating FGF23 with several cardiovascular disease (CVD) risk factors including left ventricular hypertrophy and vascular dysfunction,CVD progression and incident clinical CVD eventsand mortality.Apolipoprotein A1 (ApoA1) is the primary protein associated with high-density lipoprotein (HDL) particles,and plays a central role in reverse cholesterol transport. HDL cholesterol (HDL-C) and ApoA1 concentrations are inverlassely related to the risk for coronary artery disease. To find the role of fibroblast growth factor-23 in coronary artery disease and its associationwith Apolipoprotein-A1.This ccross –sectionalstudyincluded 42 elective patients attending the cardiology unit and the results of those patients were compared with 40 healthy control group. Blood samples were obtained for measurements of (FGF-23,troponin I,Apo-A1,total creatine kinase activity,urea,creatinine and lipid profile).The obtained results showed that there was a significant difference in serum FGF-23 in coronary artery disease (367.52 ± 128.52 pg/ml) as compared with the control (165.41 ± 53.65 pg/ml) (p&lt; 0.05). There was a significant differences in Apo-A1 in coronary artery disease (2.03±0.90 mg/ml) as compared with the control (1.49 ± 0.25 mg/ml) (P = 0.014).There was a significant difference in age between CAD (58.66±8.85) and control group (51.125 ± 11.71) (P&lt;0.005).There was a significant difference in TG where control (99.50 ± 21.59) differ from CAD (142.05 ± 66.24) (P = 0.006).According to the results that were shown in the tables, we can be conclude that higher levels of FGF23 and Apo-A1 may be associated with complications and mortality of CAD beside its associating with atherosclerosis in the Iraqi patients.

A dose-response meta-analysis of chronic arsenic exposure and incident cardiovascular disease.

Consistent evidence at high levels of water arsenic (≥100 µg/l), and growing evidence at low-moderate levels (<100 µg/l), support a link with cardiovascular disease (CVD). The shape of the dose-response across low-moderate and high levels of arsenic in drinking water is uncertain and critical for risk assessment. We conducted a systematic review of general population epidemiological studies of arsenic and incident clinical CVD (all CVD, coronary heart disease (CHD) and stroke) with three or more exposure categories. In a dose-response meta-analysis, we estimated the pooled association between log-transformed water arsenic (log-linear) and restricted cubic splines of log-transformed water arsenic (non-linear) and the relative risk of each CVD endpoint. Twelve studies (pooled N = 408 945) conducted at high (N = 7) and low-moderate (N = 5) levels of water arsenic met inclusion criteria, and 11 studies were included in the meta-analysis. Compared with 10 µg/l, the estimated pooled relative risks [95% confidence interval (CI)] for 20 µg/l water arsenic, based on a log-linear model, were 1.09 (1.03, 1.14) (N = 2) for CVD incidence, 1.07 (1.01, 1.14) (N = 6) for CVD mortality, 1.11 (1.05, 1.17) (N = 4) for CHD incidence, 1.16 (1.07, 1.26) (N = 6) for CHD mortality, 1.08 (0.99, 1.17) (N = 2) for stroke incidence and 1.06 (0.93, 1.20) (N = 6) for stroke mortality. We found no evidence of non-linearity, although these tests had low statistical power. Although limited by the small number of studies, this analysis supports quantitatively including CVD in inorganic arsenic risk assessment, and strengthens the evidence for an association between arsenic and CVD across low-moderate to high levels.

Circulating Vitamin K Is Inversely Associated with Incident Cardiovascular Disease Risk among Those Treated for Hypertension in the Health, Aging, and Body Composition Study (Health ABC)

Background: A role for vitamin K in coronary artery calcification (CAC), a subclinical manifestation of cardiovascular disease (CVD), has been proposed because vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein (MGP), are present in vascular tissue. Observational studies found that low circulating phylloquinone (vitamin K-1) was associated with increased CAC progression, especially in persons treated for hypertension. It is unknown whether hypertension treatment modifies this putative role of vitamin K in clinical CVD risk.Objective: We determined the association between vitamin K status and incident clinical CVD in older adults in the Health ABC (Health, Aging, and Body Composition Study) and whether the association differed by hypertension treatment status.Methods: Plasma phylloquinone was measured in 1061 participants free of CVD (70-79 y of age, 58% women, 39% black). Plasma uncarboxylated MGP [(dp)ucMGP] was measured in a subset of 635 participants. Multivariate Cox models estimated the HR for incident CVD over 12.1 follow-up years. Effect modification by hypertension was tested with the use of interaction terms.Results: Neither low plasma phylloquinone (<0.2 nmol/L) nor elevated (dp)ucMGP (≥574 pmol/L) was significantly associated with incident CVD [respective HRs (95% CIs): 1.27 (0.75, 2.13) and 1.02 (0.72, 1.45)]. In participants treated for hypertension (n = 489; 135 events), low plasma phylloquinone was associated with higher CVD risk overall (HR: 2.94; 95% CI: 1.41, 6.13). In those with untreated hypertension (n = 153; 48 events) and without hypertension (n = 418; 92 events), low plasma phylloquinone was not associated with incident CVD. The association between high (dp)ucMGP did not differ by hypertension treatment status (P-interaction = 0.72).Conclusions: Vitamin K status was not significantly associated with CVD risk overall, but low plasma phylloquinone was associated with a higher CVD risk in older adults treated for hypertension. Additional evidence from larger clinical studies is needed to clarify the importance of vitamin K to CVD in persons treated for hypertension, a segment of the population at high risk of clinical CVD events.

Abstract MP011: Cardiac Markers and Risk for Hospitalization with Infection: The Atherosclerosis Risk in Communities (ARIC) Study

Background: Clinical cardiovascular disease (CVD) is a risk factor for infection, but the association may be confounded by other comorbidities. To better understand the underlying pathophysiology, we explored whether subclinical cardiac biomarkers were associated with infection risk in the general population. Methods: Using 8,588 individuals free of clinical CVD in the biracial ARIC Study in 1996-98 (mean age 62 years and 22% African American), we assessed the association of high-sensitivity cardiac troponin T (hs-cTnT) and natriuretic peptide (NTproBNP) with risk of hospitalization through 2013 with an infection ICD code anywhere among the listed discharge diagnoses. Cox proportional hazards models were used to estimate hazard ratios (HRs). Results: During follow-up (median, 15.2 years), 3,308 individuals were discharged with an infection ICD code. The incidence rate increased proportionally with higher hs-cTnT and NTproBNP (Table1). The association did not change in multivariable Cox proportional analyses, and was consistent after further accounting for incident CVD during follow-up (Table1) or restricting to hospitalizations with infection as the primary diagnosis. No interaction was observed for subgroup analysis by age, sex, race, and status of diabetes or chronic kidney disease (eGFR &lt;60 vs. ≥60 ml/min/1.73m 2 ). Although both cardiac markers were associated with different types of infection (pneumonia, urinary tract infections, bloodstream infections, and cellulitis), the association appeared strongest for cellulitis (HR, 1.41 [95%CI, 1.00-2.00] for hsTnT ≥4 vs. &lt;3ng/L; and 1.51 [1.08-2.11] for NTproBNP ≥69 vs. &lt;68 pg/mL). Conclusions: Higher hs-cTnT and NTproBNP concentrations were independently associated with increased risk for hospitalization with infection, suggesting a potential relationship between cardiac damage/overload and infection.

Abstract P363: Circulating Soluble CD163 and Risk of Cardiovascular Disease and All-Cause Mortality in Older Persons: The Cardiovascular Heart Study (CHS)

Introduction: Macrophages play important roles in atherosclerotic plaque formation and stability. CD163 is a macrophage specific receptor involved in the clearance and endocytosis of hemoglobin-haptoglobin complexes; soluble CD163 (sCD163) may be a useful biomarker to assess macrophage activation. We are not aware of epidemiologic studies of sCD163 levels and cardiovascular disease (CVD) risk. Also it is not known whether common genetic variants are associated with sCD163. Methods: We tested whether sCD163 was associated with carotid intima-media thickness (IMT) and incident clinical events (overall mortality, coronary heart disease [CHD], myocardial infarction [MI], stroke, and congestive heart failure [CHF]) in 4,577 Cardiovascular Health Study (CHS) participants (95% white, 5% black; age range 65-100 y). We used linear regression with adjustment for sex, age, race, study site, current smoking, BMI, hypertension status, systolic blood pressure (SBP) and LDL cholesterol to test for association between sCD163 and IMT. We used 2 Cox proportional hazards models for incident events analyses: (1) adjusting for sex, age, race, study site, and current smoking; (2) model 1 plus BMI, hypertension status, SBP, LDL-cholesterol, C-reactive protein (CRP), interleukin-6 (IL6), and fibrinogen. We also performed a genome-wide association study (GWAS) for sCD163 in 2,769 unrelated CHS white participants, using Hapmap 2 imputed SNPs. Results: sCD163 was positively associated with female sex, white race, age, BMI, SBP, CRP, IL6 and fibrinogen, negatively associated with current smoking status (p&amp;lt0.0001), and not associated with LDL cholesterol or hypertension status. After adjustment for traditional CVD risk factors, sCD163 was positively associated with carotid IMT (p=0.027). In model 1, increased sCD163 levels were associated with overall mortality (p&amp;lt0.0001), incident CHD (p=0.0034), incident stroke (p=0.016), and incident CHF (p&amp;lt0.0001), but not incident MI (p=0.069). None of the model 2 analyses resulted in significant associations (all p&amp;gt0.05). Five variants upstream of chromosome 2q gene MGAT5 (top result rs4954118, p=7.1x10-14) and a single variant (rs314253, p=6.0x10-13) on chromosome 17p between ASGR1 and DLG4 were significantly (p&amp;lt5x10-8) associated with sCD163. The top result near the CD163 gene was for upstream variant rs6488429 (p=8.2x10-5). Conclusions: sCD163 was associated with carotid IMT after accounting for established CVD risk factors. There were associations of sCD163 with mortality and incident clinical CVD, although associations were attenuated after adjustment for other risk factors. Additional studies are needed to evaluate whether results are similar in younger age groups and other populations. The significant results in the GWAS for sCD163 implicate novel molecular pathways that warrant future fine-mapping and functional studies.

Endogenous testosterone and its relationship to preclinical and clinical measures of cardiovascular disease in the atherosclerosis risk in communities study.

Epidemiologic studies suggest that endogenous testosterone (T) levels in males may be implicated in cardiovascular disease (CVD), however further clarification is needed. We assessed the cross-sectional relationship between endogenous plasma T and mean carotid intima media thickness (cIMT), and the longitudinal relationship with incident clinical CVD events, cardiac mortality, and all-cause mortality using male participants in the Atherosclerosis Risk in Communities (ARIC) study. This study involved a subset of men from visit 4 of the ARIC study. The study was conducted in a community based cohort. Males who provided a morning blood sample excluding those taking androgen therapy, with prevalent coronary heart disease (CHD), stroke, or heart failure (HF) (n = 1558). None. Plasma T by liquid chromatography mass spectrometry and carotid IMT using high resolution B-mode ultrasound were obtained at visit 4. Incident CHD, HF, cardiac mortality, and all-cause mortality were identified by surveillance through 2010 (median 12.8 years). Lower T was significantly associated with higher body mass index, greater waist circumference, diabetes, hypertension, lower HDL, and never smoking (P = 0.01). T was not associated with mean cIMT in unadjusted or adjusted analyses. Following multivariable adjustment, there was no association of quartile (Q) of T with incident CHD [hazard ratio (HR) = 0.87 (95% CI = 0.60-1.26) for Q1; 0.97 (95% CI = 0.69-1.38) for Q2; 0.97 (95% CI = 0.69-1.36) for Q3 compared to reference of Q4] or for incident HF [HR = 0.77 (95% CI = 0.46-1.29) for Q1; 0.72 (95% CI = 0.43-1.21) for Q2; 0.87 (95% CI = 0.53-1.42) for Q3 compared to reference of Q4]. Similarly there was no association of Q of T with mortality or cardiac-associated mortality. Low male plasma T is cross-sectionally associated with key CVD risk factors, but after adjustment there was no association with mean cIMT, incident cardiac events, or mortality. Our results are reassuring that neither high nor low T levels directly predict atherosclerosis, but are a marker for other cardiovascular risk factors.

Association of exhaled carbon monoxide with subclinical cardiovascular disease and their conjoint impact on the incidence of cardiovascular outcomes

Whereas endogenous carbon monoxide (CO) is cytoprotective at physiologic levels, excess CO concentrations are associated with cardiometabolic risk and may represent an important marker of progression from subclinical to clinical cardiovascular disease (CVD). In 1926 participants of the Framingham Offspring Study (aged 57 ± 10 years, 46% women), we investigated the relationship of exhaled CO, a surrogate of blood CO concentration, with both prevalent subclinical CVD and incident clinical CVD events. Presence of subclinical CVD was determined using a comprehensive panel of diagnostic tests used to assess cardiac and vascular structure and function. Individuals with the highest (>5 p.p.m.) compared with lowest (≤4 p.p.m.) CO exposure were more likely to have subclinical CVD [odds ratios (OR): 1.67, 95% CI: 1.32-2.12; P < 0.001]. During the follow-up period (mean 5 ± 3 years), 193 individuals developed overt CVD. Individuals with both high CO levels and any baseline subclinical CVD developed overt CVD at an almost four-fold higher rate compared with those with low CO levels and no subclinical disease (22.1 vs. 6.3%). Notably, elevated CO was associated with incident CVD in the presence [hazards ration (HR): 1.83, 95% CI: 1.08-3.11; P = 0.026] but not in the absence (HR: 0.80, 95% CI: 0.42-1.53; P = 0.51) of subclinical CVD (Pinteraction = 0.019). Similarly, subclinical CVD was associated with incident CVD in the presence of high but not low CO exposure. Our findings in a community-based sample suggest that elevated CO is a marker of greater subclinical CVD burden and, furthermore, a potential key component in the progression from subclinical to clinical CVD.

Prognostic Value of Frontal QRS-T Angle in Patients Without Clinical Evidence of Cardiovascular Disease (from the Multi-Ethnic Study of Atherosclerosis)

Abnormal frontal QRS-T angle on a 12-lead electrocardiogram is associated with incident coronary heart disease and total mortality in a biracial cohort, but there have been no studies to date examining QRS-T angle's prognostic value across multiple ethnicities. We studied 6,814 participants (52.7% women, mean age 62 years) from Multi-Ethnic Study of Atherosclerosis, a multiethnic cohort aged 45 to 84 years free of clinical cardiovascular disease (CVD) at enrollment. Baseline examination included measurement of traditional risk factors and 12-lead electrocardiograms. Frontal QRS-T axis was defined as normal (less than seventy-fifth percentile), borderline (seventy-fifth to ninety-fifth percentile), or abnormal (ninety-fifth percentile or more), and participants were followed for the composite end point of incident CVD events: cardiovascular death, myocardial infarction, angina pectoris, or heart failure. After 7.6years of follow-up, there were 444 total events. Borderline (HR [hazard ratio] 1.37, 95% confidence interval [CI] 1.10 to 1.70) and abnormal QRS-T angles (HR 2.2, 95% CI 1.63 to 2.97) were associated with incident CVD events in multivariate-adjusted models. However, after adjusting for T-wave abnormalities, there was no statistically significant association of either borderline (HR 1.12, 95% CI 0.90 to 1.41) or abnormal (HR 1.31, 95% CI 0.93 to 1.84) QRS-T angle with incident CVD events. Abnormal frontal QRS-T angle predicts incident CVD events in a multiethnic population, and this increased risk is primarily mediated through T-wave abnormalities. QRS-T angle provides an easily interpretable continuous marker of abnormal ventricular repolarization that can aid the everyday clinician in risk prediction.

Association of sex steroids, gonadotrophins, and their trajectories with clinical cardiovascular disease and all‐cause mortality in elderly men from the Framingham Heart Study

Emerging data from longitudinal studies suggest that low sex steroid concentrations in men are associated with increased cardiovascular risk and mortality. The impact of longitudinal trajectory patterns from serial sex steroid and gonadotrophin measurements on the observed associations is unknown to date. We prospectively evaluated 254 elderly men (mean age, 75·5 years) of the Framingham Heart Study with up to four serial measurements of serum total testosterone (TT), dehydroepiandrosterone sulphate (DHEAS), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and total estradiol (EST); and constructed age- and multivariable-adjusted Cox proportional hazard regression models relating baseline hormone concentrations and their mean, slope and variation over time (modelled as continuous and categorized into quartiles) to the incidence of clinical cardiovascular disease (CVD) and all-cause mortality at 5- and 10-year follow-up. We observed no association between baseline concentrations of sex steroids, gonadotrophins and their trajectories with incident clinical CVD over 5- and 10-year follow-up. Although higher baseline TT concentrations were associated with lower mortality risk at 5 years (hazard ratio per quartile increment, 0·74; 95% confidence interval, 0·56-0·98), correction for multiple statistical testing (P < 0·005) rendered this association statistically nonsignificant. Repeat analyses at the 10-year follow-up time point also demonstrated no significant association between sex steroids, gonadotrophins or their trajectories and mortality. Investigating longitudinal trajectory patterns of serial sex steroid and gonadotrophin measurements, the present study found no consistent associations with incident clinical CVD and all-cause mortality risk in elderly men from the community.

Prognosis of Individuals With Asymptomatic Left Ventricular Systolic Dysfunction in the Multi-Ethnic Study of Atherosclerosis (MESA)

Limited data exist on the prevalence, associations, and prognosis of individuals with asymptomatic left ventricular systolic dysfunction (ALVSD), especially in populations without previous clinical cardiovascular disease (CVD). Kaplan-Meier and Cox proportional hazard analyses were used to assess the association between ALVSD, defined as left ventricular ejection fraction <50%, and adjudicated incident congestive heart failure (CHF), all-cause mortality, and CVD events. Of 5004 participants, 112 participants had CHF, 321 had a CVD event, and 278 died after 9 years of follow-up. The overall prevalence of ALVSD was 1.7%, with a higher prevalence in blacks (2.6%). ALVSD had a worse cardiovascular risk profile and was also associated with increased risk in unadjusted and adjusted models for incident CHF (HR [hazard ratio] [95% CI {confidence interval}]: 12.0 [7.04-20.3], P<0.0001 and 8.69 [4.89-15.45], P<0.001 respectively), CVD (HR [95% CI]: 3.32 [1.98-5.58], P<0.001 and 2.21 [1.30-3.73], P=0.003 respectively), and all-cause mortality (HR [95% CI]: 3.47 [2.03-5.94], P<0.0001 and 2.00 [1.13-3.54], P=0.017, respectively). A 10% decrement in left ventricular ejection fraction at baseline was associated with an increase in risk in unadjusted and adjusted models for clinical CHF (HR [95% CI]: 2.17 [1.82-2.63], P<0.0001 and 2.13 [1.73-2.51], P<0.001, respectively) and all-cause mortality (HR [95% CI]: 1.22 [1.05-1.41], P=0.009 and 1.17 [1.00-1.36], P=0.047, respectively). Among the subset of participants with ALVSD, the left ventricular mass index was particularly informative about risk for incident CHF (c-index=0.74). ALVSD is uncommon in individuals without previous clinical CVD, but it is associated with high risk for CHF, CVD, and all-cause mortality. The left ventricular mass index had good discrimination for incident CHF in Multi-Ethnic Study of Atherosclerosis (MESA) participants with ALVSD.

Clinical implications of discordance between low-density lipoprotein cholesterol and particle number

The amount of cholesterol per low-density lipoprotein (LDL) particle is variable and related in part to particle size, with smaller particles carrying less cholesterol. This variability causes concentrations of LDL cholesterol (LDL-C) and LDL particles (LDL-P) to be discordant in many individuals. LDL-P measured by nuclear magnetic resonance spectroscopy, calculated LDL-C, and carotid intima-media thickness (IMT) were assessed at baseline in the Multi-Ethnic Study of Atherosclerosis, a community-based cohort of 6814 persons free of clinical cardiovascular disease (CVD) at entry and followed for CVD events (n = 319 during 5.5-year follow-up). Discordance, defined as values of LDL-P and LDL-C differing by ≥ 12 percentile units to give equal-sized concordant and discordant subgroups, was related to CVD events and to carotid IMT in models predicting outcomes for a 1 SD difference in LDL-C or LDL-P, adjusted for age, gender, and race. LDL-C and LDL-P were associated with incident CVD overall: hazard ratios (HR 1.20, 95% CI [CI] 1.08-1.34; and 1.32, 95% CI 1.19-1.47, respectively, but for those with discordant levels, only LDL-P was associated with incident CVD (HR 1.45, 95% CI 1.19-1.78; LDL-C HR 1.07, 95% CI 0.88-1.30). IMT also tracked with LDL-P rather than LDL-C, ie, adjusted mean IMT of 958, 932, and 917 microm in the LDL-P > LDL-C discordant, concordant, and LDL-P < LDL-C discordant subgroups, respectively, with the difference persisting after adjustment for LDL-C (P = .002) but not LDL-P (P = .60). For individuals with discordant LDL-C and LDL-P levels, the LDL-attributable atherosclerotic risk is better indicated by LDL-P.

Atherosclerosis profile and incidence of cardiovascular events: a population-based survey

BackgroundAtherosclerosis is a chronic progressive disease often presenting as clinical cardiovascular disease (CVD) events. This study evaluated the characteristics of individuals with a diagnosis of atherosclerosis and estimated the incidence of CVD events to assist in the early identification of high-risk individuals.MethodsRespondents to the US SHIELD baseline survey were followed for 2 years to observe incident self-reported CVD. Respondents had subclinical atherosclerosis if they reported a diagnosis of narrow or blocked arteries/carotid artery disease without a past clinical CVD event (heart attack, stroke or revascularization). Characteristics of those with atherosclerosis and incident CVD were compared with those who did not report atherosclerosis at baseline but had CVD in the following 2 years using chi-square tests. Logistic regression model identified characteristics associated with atherosclerosis and incident events.ResultsOf 17,640 respondents, 488 (2.8%) reported having subclinical atherosclerosis at baseline. Subclinical atherosclerosis was associated with age, male gender, dyslipidemia, circulation problems, hypertension, past smoker, and a cholesterol test in past year (OR = 2.2) [all p < 0.05]. Incident CVD was twice as high in respondents with subclinical atherosclerosis (25.8%) as in those without atherosclerosis or clinical CVD (12.2%). In individuals with subclinical atherosclerosis, men (RR = 1.77, p = 0.050) and individuals with circulation problems (RR = 2.36, p = 0.003) were at greatest risk of experiencing CVD events in the next 2 years.ConclusionSelf-report of subclinical atherosclerosis identified an extremely high-risk group with a >25% risk of a CVD event in the next 2 years. These characteristics may be useful for identifying individuals for more aggressive diagnostic and therapeutic efforts.