Associations of carotid intima media thickness with gene expression in whole blood and genetically predicted gene expression across 48 tissues.

Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study (GWAS) of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent GWAS on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL and TLN2 as new candidate genes whose differential expression might modulate cIMT.

Interleukin-6 Predicts Carotid Plaque Severity, Vulnerability, and Progression.

BACKGROUND: IL-6 (interleukin-6) has important roles in atherosclerosis pathophysiology. To determine if anti-IL-6 therapy warrants evaluation as an adjuvant stroke prevention strategy in patients with carotid atherosclerosis, we tested whether circulating IL-6 levels predict carotid plaque severity, vulnerability, and progression in the prospective population-based CHS (Cardiovascular Health Study). METHODS: Duplex carotid ultrasound was performed at baseline and 5 years. Baseline plaque severity was scored 0 to 5 based on North American Symptomatic Carotid Endarterectomy Trial grade of stenosis. Plaque vulnerability at baseline was the presence of markedly irregular, ulcerated, or echolucent plaques. Plaque progression at 5 years was a ≥1 point increase in stenosis severity. The relationship of baseline plasma IL-6 levels with plaque characteristics was modeled using multivariable linear (severity) or logistic (vulnerability and progression) regression. Risk factors of atherosclerosis were included as independent variables. Stepwise backward elimination was used with P>0.05 for variable removal. To assess model stability, we computed the E-value or minimum strength of association (odds ratio scale) that unmeasured confounders must have with log IL-6 and the outcome to suppress the association. We performed internal validation with 100 bootstrap samples. RESULTS: There were 4334 participants with complete data (58.9% women, mean age: 72.7±5.1 years), including 1267 (29.2%) with vulnerable plaque and 1474 (34.0%) with plaque progression. Log IL-6 predicted plaque severity (ß=0.09, P=1.3×10-3), vulnerability (OR, 1.21 [95% CI, 1.05-1.40]; P=7.4×10-3, E-value=1.71), and progression (OR, 1.44 [95% CI, 1.23-1.69], P=9.1×10-6, E-value 2.24). In participants with >50% predicted probability of progression, mean log IL-6 was 0.54 corresponding to 2.0 pg/mL. Dichotomizing IL-6 levels did not affect the performance of prediction models. CONCLUSIONS: Circulating IL-6 predicts carotid plaque severity, vulnerability, and progression. The 2.0 pg/mL cutoff could facilitate the selection of individuals that would benefit from anti-IL-6 drugs for stroke prevention.

Accuracy of the Society of Radiologists in Ultrasound (SRU) Carotid Doppler Velocity Criteria for Grading North American Symptomatic Carotid Endarterectomy Trial (NASCET) Stenosis: A Meta-Analysis.

PURPOSE: The Society of Radiologists in Ultrasound (SRU) consensus panel proposed six Doppler velocity cut points for classifying internal carotid artery (ICA) stenosis of 50% and 70% according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method. Their relative accuracies have not been compared. MATERIALS AND METHODS: Meta-analysis performed following comprehensive literature review and identification of manuscripts with graphs of individual patient NASCET ICA stenosis measured by arteriography versus ICA peak-systolic velocity (PSV), end-diastolic velocity (EDV) and ICA PSV to common carotid artery (CCA) PSV. True positives, true negatives, false positives, and false negatives were calculated and used in two-level mixed effects models. Hierarchical summary receiver operating characteristic (ROC) curves were generated. Areas under the ROC curves were estimated. RESULTS: Nine studies performed between 1993 and 2016 were identified after review of 337 manuscripts. There were 1738 bifurcation data points extracted for PSV, 1026 for EDV, and 775 for ICA/CCA ratio. The highest sensitivity was 96% (95% CI: 93%, 98%) for PSV of 125 cm/s (50% stenosis) and highest specificity 86% (95% CI: 71%, 93%) for PSV of 230 cm/s (70% stenosis). Areas under the ROC curves ranged from a high of 0.93 (95% CI: 0.92, 0.95) for PSV (50% stenosis) to a low of 0.86 (95% CI: 0.84, 0.88) for EDV (70% stenosis). CONCLUSIONS: The SRU consensus Doppler cut points vary in their accuracies for predicting ICA stenosis. The PSV cut points have tradeoffs: high sensitivity/low specificity for 50% stenosis and high specificity/moderate sensitivity for 70% stenosis.

High-Density Lipoprotein Subspecies Defined by Presence of Apolipoprotein C-III and Incident Coronary Heart Disease in Four Cohorts.

BACKGROUND: The causal role of high-density lipoprotein (HDL) cholesterol in cardioprotection has been questioned by genetic and randomized studies. Novel measures that relate to HDL function may contribute new information to the prediction of cardiovascular risk. Apolipoprotein C-III (apoC-III) is a key regulator of lipoprotein metabolism. We investigated whether subspecies of HDL defined by apoC-III are associated with coronary heart disease (CHD). METHODS: We used immunoaffinity chromatography to measure the apoA-I concentrations of HDL that contains and lacks apoC-III in 2 prospective studies of adults free of CHD. In MESA (Multi-Ethnic Study of Atherosclerosis), 5657 participants (52% women, 52-72 years of age) were followed for risk of CHD from 2000 to 2002 through 2013. In a case-cohort study nested within the DCH study (Danish Diet, Cancer, and Health), 3642 participants (47% women, 51-64 years of age) were followed from 1994 to 1997 through 2010. Subsequently, we conducted a meta-analysis that combined these results with the previously published findings from 2 cohort studies that used similar laboratory methodology to measure lipoproteins, totaling 2997 incident cases. RESULTS: ApoC-III was found on 6% to 8% of apoA-I. The 2 HDL subspecies showed opposing associations, with risk of CHD in each of the individual cohorts and in the meta-analysis (P heterogeneity between the 2 subspecies <0.01). HDL that contains apoC-III was associated with a higher risk of CHD (pooled relative risk per standard deviation, 1.09; 95% confidence interval, 1.01-1.18), whereas HDL that lacks apoC-III was associated with lower risk (relative risk, 0.76; 95% confidence interval, 0.70-0.83). The relative risk for HDL lacking apoC-III was even more negative than the relative risk for total HDL (relative risk, 0.80; 95% confidence interval, 0.74-0.87). CONCLUSIONS: Our findings from 4 prospective studies support the hypothesis that apoC-III may mark a subfraction of HDL that is associated with higher risk of CHD. New measures reflecting HDL structure and function may provide novel insights for cardiovascular risk that extend beyond traditional plasma HDL cholesterol concentrations.

Associations of edge-detected and manual-traced common carotid artery intima-media thickness with incident peripheral artery disease: The Multi-Ethnic Study of Atherosclerosis.

Common carotid artery (CCA) intima-media thickness (IMT) is associated with coronary heart disease and can be measured on ultrasound images either by hand or with an automated edge detector. The association of CCA IMT with incident peripheral artery disease (PAD) is poorly studied. We studied 5467 participants of the Multi-Ethnic Study of Atherosclerosis composed of non-Hispanic white, Chinese, Hispanic, and African American participants with a mean age of 61.9 years (47.8% men). Framingham Risk Factors, manual-traced IMT (mt-IMT), and edge-detected IMT (ed-IMT) were entered into multivariable Cox proportional hazards models with incident PAD as the outcome. There were 87 events during a median follow-up of 12.2 years. In fully adjusted models and expressing the hazard ratios (HR) as an increment in SD values, both mt-IMT and ed-IMT were significantly associated with incident PAD: HR 1.36 (95% CI: 1.15, 1.61) and 1.29 (95% CI: 1.04, 1.60), respectively. We conclude that ed- and mt-CCA IMT measurements are associated with incident PAD. ClinicalTrials.gov Identifier: NCT00063440.

Ankle-brachial index and incident heart failure with reduced versus preserved ejection fraction: The Multi-Ethnic Study of Atherosclerosis.

This study investigated the relationship between ankle-brachial index (ABI) and risk for heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). ABI has previously been associated with mortality, cardiovascular disease (CVD), and overall HF but the relationship between ABI and risk of HF stratified by EF has not been well characterized. We analyzed data from 6553 participants (53% female; mean age 62 ± 10 years) enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) who were free of known clinical CVD/HF at baseline (2000-2002) and had baseline ABI measured. Participants were classified as low (≤ 0.90), borderline-low (0.91-1.00), normal (1.01-1.40), and high (> 1.40) ABI. Incident hospitalized HF was determined over a median follow-up of 14 years; we classified HF events (n = 321) as HFrEF with EF < 50% (n = 155, 54%) or HFpEF with EF ⩾ 50% (n = 133, 46%). Low ABI was associated with incident HFrEF (hazard ratio (HR): 2.02, 95% CI 1.19-3.40, p = 0.01) and had no significant association with HFpEF (HR: 0.67, 95% CI 0.30-1.48, p = 0.32). Borderline-low and high ABI were not significantly associated with HFrEF or HFpEF. Cubic spline analyses showed association with both low and high ABI for HFrEF and high ABI for HFpEF. A 1 SD lower ABI (for ABI < 1.1) was associated with incident HFrEF in multivariable analysis (HR: 1.27, 95% CI 1.05-1.54) but was not significant after additionally adjusting for interim myocardial infarction (HR: 1.21, 95% CI 0.99-1.48). Low ABI was associated with higher risk for incident HFrEF but not HFpEF in persons free of known CVD. Future studies of a larger size are needed for high ABI analyses.

Doppler Velocity Estimates of Internal Carotid Artery Stenosis: Angle Correction Parallel to the Color Doppler Lumen Versus Parallel to the Artery Wall.

OBJECTIVES: We compared internal carotid artery Doppler peak systolic velocities (PSVs) measured with angle correction parallel to the artery wall (// wall) on grayscale images and parallel to the direction of blood flow (// flow) on color Doppler images. METHODS: We studied 25 internal carotid lesions with PSVs higher than 125 cm/s. The PSVs were measured in the same imaging plane, at the stenosis orifice (0 cm) and at 0.5 and 1 cm downstream by both methods. Linear regression and correlation analyses were used to study the effects of the angle correction method on changes in PSVs as a function of the differences in angle adjustment and distance from the stenosis. RESULTS: The 23 patients studied included 9 women and 14 men. There was a mean difference in absolute PSVs ± SD of -17.2 ± 29.5 cm/s (P < .008) between methods at the stenosis. The difference in the PSVs was associated with the angle difference between the flow jet and the artery wall (P < .01). At 1 cm from the stenosis, // flow PSVs were more strongly correlated with PSVs at the stenosis (r = 0.61; 95% confidence interval, 0.28, 0.82; P = .001) than // wall PSVs (r = 0.39; 95% confidence interval, -0.003, 0.68; P = .052). CONCLUSIONS: Blood flow velocity measurements made with angle correction parallel to the direction of the color Doppler blood flow lumen remain more consistent with the distance from the stenosis than blood flow velocity measurements made with angle correction parallel to the outer artery walls.

Carotid Artery Wall Thickness and Incident Cardiovascular Events: A Comparison between US and MRI in the Multi-Ethnic Study of Atherosclerosis (MESA).

Purpose To compare common carotid artery (CCA) wall thickness measured manually by using US and semiautomatically by using MRI, and to examine their associations with incident coronary heart disease and stroke. Materials and Methods This prospective study enrolled 698 participants without a history of clinical cardiovascular disease (CVD) from the Multi-Ethnic Study of Atherosclerosis (MESA) from July 2000 to December 2013 (mean age, 63 years; range, 45 to 84 years; same for men and women). All participants provided written informed consent. CCA wall thickness was measured with US as well as both noncontrast proton-density-weighted and intravenous gadolinium-enhanced MRI. Cox proportional hazards models were used to assess the associations between wall thickness measurements by using US and MRI with CVD outcomes. Results The adjusted hazard ratios for coronary heart disease, stroke, and CVD associated with per standard deviation increase in intima-media thickness were 1.10, 1.08, and 1.14, respectively. The corresponding associations for mean wall thickness measured with proton-density-weighted MRI were 1.32, 1.48, and 1.37, and for mean wall thickness measured with gadolinium-enhanced MRI were 1.27, 1.58, and 1.38. When included simultaneously in the same model, MRI wall thickness, but not intima-media thickness, remained associated with outcomes. Conclusion For individuals without known cardiovascular disease at baseline, wall thickness measurements by using MRI were more consistently associated with incident cardiovascular disease, particularly stroke, than were intima-media thickness by using US. © RSNA, 2018 Online supplemental material is available for this article.

Alcohol Consumption and Common Carotid Intima-Media Thickness: The USE-IMT Study.

AIMS: Epidemiological evidence indicates a protective effect of light to moderate alcohol consumption compared to non-drinking and heavy drinking. Although several mechanisms have been suggested, the effect of alcohol on atherosclerotic changes in vessel walls is unclear. Therefore, we explored the relationship between alcohol consumption and common carotid intima media thickness, a marker of early atherosclerosis in the general population. METHODS: Individual participant data from eight cohorts, involving 37,494 individuals from the USE-IMT collaboration were used. Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) with alcohol consumption. RESULTS: The mean age was 57.9 years (SD 8.6) and the mean CIMT was 0.75 mm (SD 0.177). About, 40.5% reported no alcohol consumed, and among those who drank, mean consumption was 13.3 g per day (SD 16.4). Those consuming no alcohol or a very small amount (<5 g per day) had significantly lower common CIMT values than those consuming >10 g per day, after adjusting for a range of confounding factors. CONCLUSION: In this large CIMT consortium, we did not find evidence to support a protective effect of alcohol on CIMT.

Comparing Arterial Function Parameters for the Prediction of Coronary Heart Disease Events: The Multi-Ethnic Study of Atherosclerosis (MESA).

Arterial dysfunction has been linked to decline in cardiac function and increased risk of cardiovascular disease events. We calculated the value of arterial function, measured at baseline (2000-2002), in predicting time to first coronary heart disease (CHD) event (median follow-up, 10.2 years) among participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Measures included the following: C1 and C2, derived from diastolic pulse contour analysis from the radial artery blood pressure waveform obtained by tonometry (n = 6,336); carotid distensibility and Young's elastic modulus at the carotid artery, derived from carotid artery ultrasonography (n = 6,531 and 6,528); and aortic distensibility, measured using cardiac magnetic resonance imaging (n = 3,677). After adjustment, the hazard ratio for a CHD event per standard-deviation increment in arterial function was 0.97 (95% confidence interval (CI): 0.86, 1.10) for C1, 0.73 (95% CI: 0.63, 0.86) for C2, 0.98 (95% CI: 0.86, 1.11) for carotid distensibility, 0.99 (95% CI: 0.90, 1.09) for Young's modulus, and 0.90 (95% CI: 0.74, 1.10) for aortic distensibility. We examined the area under the receiver operating characteristic curve for the model with full adjustment plus the addition of each measure individually. C2 provided additional discrimination for the prediction of CHD (area under the curve = 0.736 vs. 0.743; P = 0.04). Lower C2 was associated with a higher risk of future CHD events.

Relationship of cigarette smoking with inflammation and subclinical vascular disease: the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: We sought to assess the impact of smoking status, cumulative pack-years, and time since cessation (the latter in former smokers only) on 3 important domains of cardiovascular disease: inflammation, vascular dynamics and function, and subclinical atherosclerosis. APPROACH AND RESULTS: The Multi-Ethnic Study of Atherosclerosis (MESA) cohort enrolled 6814 adults without prior cardiovascular disease. Smoking variables were determined by self-report and confirmed with urinary cotinine. We examined cross-sectional associations between smoking parameters and (1) inflammatory biomarkers (high-sensitivity C-reactive protein [hsCRP], interleukin-6, and fibrinogen); (2) vascular dynamics and function (brachial flow-mediated dilation and carotid distensibility by ultrasound, as well as aortic distensibility by MRI); and (3) subclinical atherosclerosis (coronary artery calcification, carotid intima-media thickness, and ankle-brachial index). We identified 3218 never smokers, 2607 former smokers, and 971 current smokers. Mean age was 62 years and 47% were male. There was no consistent association between smoking and vascular distensibility or flow-mediated dilation outcomes. However, compared with never smokers, the adjusted association between current smoking and measures of either inflammation or subclinical atherosclerosis was consistently stronger than for former smoking (eg, odds ratio for hsCRP>2 mg/L of 1.7 [95% confidence interval, 1.5-2.1] versus 1.2 [1.1-1.4], odds ratio for coronary artery calcification>0 of 1.8 [1.5-2.1] versus 1.4 [1.2-1.6], respectively). Similar associations were seen for interleukin-6, fibrinogen, carotid intima-media thickness, and ankle-brachial index. A monotonic association was also found between higher pack-year quartiles and increasing inflammatory markers. Furthermore, current smokers with hsCRP>2 mg/L were more likely to have increased carotid intima-media thickness, abnormal ankle-brachial index, and coronary artery calcification>75th percentile for age, sex, and race (relative to smokers with hsCRP<2 mg/L, interaction P<0.05 for all 3 outcomes). In contrast, time since quitting in former smokers was independently associated with lower inflammation and atherosclerosis (eg, odds ratio for hsCRP>2 mg/L of 0.91 [0.88-0.95] and odds ratio for coronary artery calcification>0 of 0.94 [0.90-0.97] for every 5-year cessation interval). CONCLUSIONS: These findings expand our understanding of the harmful effects of smoking and help explain the cardiovascular benefits of smoking cessation.

Ideal cardiovascular health: associations with biomarkers and subclinical disease and impact on incidence of cardiovascular disease in the Framingham Offspring Study.

BACKGROUND: The American Heart Association Cardiovascular Health score (CVH score) is inversely associated with cardiovascular disease (CVD) incidence, but the mechanisms underlying this association warrant exploration. METHODS AND RESULTS: We related the CVH score to circulating biomarkers and prevalent subclinical CVD (defined as ≥1 of the following: increased carotid intima-media thickness or stenosis, left ventricular hypertrophy [by ECG or echocardiography], left ventricular systolic dysfunction, microalbuminuria, and a reduced ankle-brachial index) in 2680 Framingham Study participants (mean age, 58 years; 55% women). After adjustment for age and sex, an ideal CVH score (nonsmoking status, ideal body mass index, regular physical activity, healthy diet, and an optimal profile of serum cholesterol, blood pressure, and glucose; 1 point for each) was associated with higher circulating concentrations of natriuretic peptides (N-terminal pro-atrial natriuretic peptide and B-type natriuretic peptide) and lower blood concentrations of plasminogen activator inhibitor-1, aldosterone, C-reactive protein, D-dimer, fibrinogen, homocysteine, and growth differentiation factor-15 levels (P<0.001 for all), as well as lower odds of subclinical disease (odds ratio, 0.74 per 1-unit increase in CVH score; 95% confidence interval, 0.68-0.80). The incidence of CVD (267 events over 16 years) was inversely associated with the CVH score in age- and sex-adjusted models (hazard ratio, 0.77 per 1-unit increase in CVH score; 95% confidence interval, 0.70-0.86), which was slightly attenuated upon adjustment for biomarkers and subclinical disease (hazard ratio, 0.87; 95% confidence interval, 0.78-0.97). CONCLUSION: In our prospective community-based study, the inverse association between an ideal cardiovascular health score and CVD incidence was partly attributable to its favorable impact on CVD biomarker levels and subclinical disease.

Healthy lifestyle change and subclinical atherosclerosis in young adults: Coronary Artery Risk Development in Young Adults (CARDIA) study.

BACKGROUND: The benefits of healthy habits are well established, but it is unclear whether making health behavior changes as an adult can still alter coronary artery disease risk. METHODS AND RESULTS: The Coronary Artery Risk Development in Young Adults (CARDIA) prospective cohort study (n=3538) assessed 5 healthy lifestyle factors (HLFs) among young adults aged 18 to 30 years (year 0 baseline) and 20 years later (year 20): not overweight/obese, low alcohol intake, healthy diet, physically active, nonsmoker. We tested whether change from year 0 to 20 in a continuous composite HLF score (HLF change; range, -5 to +5) is associated with subclinical atherosclerosis (coronary artery calcification and carotid intima-media thickness) at year 20, after adjustment for demographics, medications, and baseline HLFs. By year 20, 25.3% of the sample improved (HLF change ≥+1); 40.4% deteriorated (had fewer HLFs); 34.4% stayed the same; and 19.2% had coronary artery calcification (>0). Each increase in HLFs was associated with reduced odds of detectable coronary artery calcification (odds ratio=0.85; 95% confidence interval, 0.74-0.98) and lower intima-media thickness (carotid bulb ß=-0.024, P=0.001), and each decrease in HLFs was predictive to a similar degree of greater odds of coronary artery calcification (odds ratio=1.17; 95% confidence interval, 1.02-1.33) and greater intima-media thickness (ß=+0.020, P<0.01). CONCLUSIONS: Healthy lifestyle changes during young adulthood are associated with decreased risk and unhealthy lifestyle changes are associated with increased risk for subclinical atherosclerosis in middle age.

Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis.

OBJECTIVE: To estimate atherosclerosis progression and identify influencing factors in rheumatoid arthritis (RA). METHODS: We used carotid ultrasound to measure intima-media thickness (IMT) in RA patients, and ascertained cardiovascular (CV) risk factors, inflammation markers and medications. A second ultrasound was performed approximately 3 years later. We calculated the progression rate by subtracting the baseline from the follow-up IMT, divided by the time between the two scans. We used logistic regression to identify baseline factors predictive of rapid progression. We tested for interactions of erythrocyte sedimentation rate (ESR) with CV risk factors and medication use. RESULTS: Results were available for 487 RA patients. The mean (SD) common carotid IMT at baseline was 0.571 mm (0.151). After a mean of 2.8 years, the IMT increased by 0.050 mm (0.055), p≤0.001, a progression rate of 0.018 mm/year (95% CI 0.016 to 0.020). Baseline factors associated with rapid progression included the number of CV risk factors (OR 1.27 per risk factor, 95% CI 1.01 to 1.61), and the ESR (OR 1.12 per 10 mm/h, 95% CI 1.02 to 1.23). The ESR×CV risk factor and ESR×medication product terms were significant, suggesting these variables modify the association between the ESR and IMT progression. CONCLUSIONS: Systemic inflammation and CV risk factors were associated with rapid IMT progression. CV risk factors may modify the role of systemic inflammation in determining IMT progression over time. Methotrexate and antitumour necrosis factor agents may influence IMT progression by reducing the effect of the systemic inflammation on the IMT.

Mediation of cardiovascular risk factor effects through subclinical vascular disease: the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: It is unclear to what extent subclinical cardiovascular disease (CVD) such as coronary artery calcium (CAC), carotid intima-media thickness (CIMT), and brachial flow-mediated dilation (FMD) are mediators of the known associations between traditional cardiovascular risk factors and incident CVD events. We assessed the portion of the effects of risk factors on incident CVD events that are mediated through CAC, CIMT, and FMD. APPROACH AND RESULTS: Six thousand three hundred fifty-five of 6814 Multi-Ethnic Study of Atherosclerosis participants were included. Nonlinear implementation of structural equation modeling (STATA mediation package) was used to assess whether CAC, CIMT, or FMD are mediators of the association between traditional risk factors and incident CVD event. Mean age was 62 years, with 47% men, 12% diabetics, and 13% current smokers. After a mean follow-up of 7.5 years, there were 539 CVD adjudicated events. CAC showed the highest mediation while FMD showed the least. Age had the highest percent of total effect mediated via CAC for CVD outcomes, whereas current cigarette smoking had the least percent of total effect mediated via CAC (percent [95% confidence interval]: 80.2 [58.8-126.7] versus 10.6 [6.1-38.5], respectively). Body mass index showed the highest percent of total effect mediated via CIMT (17.7 [11.6-38.9]); only a negligible amount of the association between traditional risk factors and CVD was mediated via FMD. CONCLUSIONS: Many of the risk factors for incident CVD (other than age, sex, and body mass index) showed a modest level of mediation via CAC, CIMT, and FMD, suggesting that current subclinical CVD markers may not be optimal intermediaries for gauging upstream risk factor modification.

Left Ventricular Ejection Time Derived From the Common Carotid Artery Doppler Waveform: Association With Left Ventricular Ejection Fraction and Prediction of Heart Failure.

OBJECTIVES: Left ventricular ejection time (LVET) is measured from blood pressure tracings as the interval from end diastole to the dicrotic notch and shows associations with left ventricular ejection fraction (LVEF) and heart failure. LVET can be measured on common carotid artery Doppler waveforms. We therefore studied the possible associations of common carotid artery LVET with LVEF measured by echocardiography and heart failure. METHODS: We performed a retrospective study of 110 patients who had transthoracic echocardiography and carotid Doppler evaluations within 1 day of each other. LVEF was determined by the biplane modified Simpson method. LVET was measured from left common carotid artery Doppler tracings. Linear regression was used to evaluate associations between LVET and LVEF. We also used logistic regression with LVEF of less than 40% as a cut point for heart failure to generate a receiver operating characteristic curve, estimate the area under the curve, and calculate sensitivity and specificity. RESULTS: LVET was associated with LVEF (P < .0001). The area under the curve of LVET for heart failure was 0.81 (95% confidence interval [CI], 0.72-0.87), and the sensitivity and specificity were 76.9% (95% CI, 65.4%-88.4%) and 65.5% (95% CI, 53.4%-77.8%), respectively, for LVET of 321 milliseconds. CONCLUSIONS: LVET measured on common carotid artery Doppler tracings decreases with LVEF and is strongly associated with prevalent heart failure. Based on what is known of blood pressure-measured LVET, common carotid artery Doppler waveform-derived LVET could be used to serially monitor cardiac function.

Association of common carotid artery Doppler-determined dicrotic notch velocity with the left ventricular ejection fraction.

OBJECTIVES: The appearance of the dicrotic notch on blood pressure tracings is associated with impaired cardiac function. Common carotid artery waveforms have similar fiduciary markers, yet they have not been related to cardiac function. We studied associations of common carotid artery dicrotic notch velocities with the left ventricular ejection fraction (LVEF) determined by echocardiography. METHODS: We conducted a retrospective study of 37 patients who had cardiac echocardiography and carotid Doppler evaluations within 1 day of each other. The LVEF was determined by the biplane modified Simpson rule. Doppler parameters were measured from tracings of the left common carotid artery 4 cm from the flow divider. Linear regression and stepwise multivariable linear regression models were used to evaluate any association between the LVEF and the following variables: age, sex, peak systolic velocity (PSV), end-diastolic velocity (EDV), dicrotic notch velocity, rise time (EDV to PSV), resistive index, and cardiac cycle length. RESULTS: The dicrotic notch velocity was the only variable associated with the LVEF (P = .028) in a bivariate analyses. A backward selection stepwise multivariable equation predicting the LVEF had the dicrotic notch (P = .001) and resistive index (P = .01) as significant predictors, whereas the cardiac cycle length (P = .08) and PSV (P = .08) were borderline not significant. Model goodness of fit was R(2) = 0.37 (P = .004). CONCLUSIONS: Dicrotic notch velocities measured from common carotid artery Doppler waveforms are associated with the LVEF and might offer some clinical value in selected cases.

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

AIMS: 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). METHODS AND RESULTS: 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. CONCLUSION: 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.

Lipoprotein-associated phospholipase A2, a novel cardiovascular inflammatory marker, in HIV-infected patients.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging biomarker of cardiovascular disease. This study was conducted to describe the distribution of Lp-PLA2 in a cohort of human immunodeficiency virus (HIV)-infected adults and to determine associations between Lp-PLA2, cardiometabolic risk factors, and subclinical atherosclerosis in this population. METHODS: Lp-PLA2 was assessed in 341 (25% women, 52% white, 74% on highly active antiretroviral therapy [HAART]) participants of a cohort with detailed characterization of atherogenic risk factors, including surrogate markers of carotid and coronary atherosclerosis. RESULTS: Mean Lp-PLA2 mass was 313 ± 105 ng/mL and activity 173 ± 49 nmol/minute/mL. Seventy-five percent of participants had abnormal Lp-PLA2. Those in the highest Framingham Risk Score tertile had significantly higher Lp-PLA2 activity. Participants with abnormal carotid intima-media thickness (cIMT) had higher Lp-PLA2 mass and activity. Those with coronary artery calcium (CAC) scores >100 had significantly higher Lp-PLA2 mass than those with lower or nondetectable calcium. Those on HAART and protease inhibitor (PI)-based treatment had significantly higher Lp-PLA2 mass and activity than those who were treatment-naive or not on PIs. In multivariate regression, HAART and PI use were positively associated with Lp-PLA2 activity and mass after adjusting for age, race, sex, low-density and high-density lipoprotein cholesterol levels, triglyceride level, and smoking. Adding Lp-PLA2 activity tertiles to the model improved the predictive value for abnormal common cIMT, but not internal cIMT or CAC score. CONCLUSIONS: Lp-PLA2 is highly abnormal in HIV-infected patients and is associated with several cardiovascular and HIV treatment-specific risk factors. Lp-PLA2 may be used as an additional and more vascular specific biomarker for cardiovascular risk stratification in HIV-positive patients.