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1.  Family History of Coronary Heart Disease and the Incidence and Progression of Coronary Artery Calcification: Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2013;232(2):369-376.
Objective
We evaluated family history as a predictor of incident and progressive coronary artery calcium (CAC) using data from the Multi-Ethnic Study of Atherosclerosis (MESA).
Background
MESA is a multi-center prospective study of 6,814 asymptomatic individuals. The relationship between family history of coronary heart disease (CHD) and CAC incidence or progression has not been described previously.
Methods
A total of 5,099 participants had detailed information about family history of CHD (late versus premature and parental versus sibling history). The mean time between CAC scans was 3.1 ± 1.3 years. The association of late versus premature family history was assessed against CAC change using multivariate regression model adjusted for demographics and cardiac risk factors.
Results
A family history of premature CHD was associated with an odds ratio (OR) of 1.55 (p < 0.01) for incident development of CAC after adjusting for risk factors and demographics. A premature family history was associated with 14.4 units (p < 0.01) greater volume scores compared to those with no family history in similarly adjusted models by median regression analysis. A combined parental and sibling family history was associated with the greatest incidence and progression in demographic-adjusted models. Caucasians demonstrated the most consistent predictive relationship between family history of premature CHD and incidence (p < 0.01) and progression (p < 0.05) of CAC, though no significant interaction with ethnicity was noted.
Conclusions
Family history of premature CHD is associated with enhanced development and progression of subclinical disease, independent of other risk factors, in a multiethnic, population-based study.
doi:10.1016/j.atherosclerosis.2013.11.042
PMCID: PMC4491495  PMID: 24468150
Subclinical atherosclerosis; coronary calcium; family history
2.  Associations of Pentraxin 3 with Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis 
Objective
Pentraxin 3 (PTX3) is likely a specific marker of vascular inflammation. However, associations of PTX3 with cardiovascular disease (CVD) risk have not been well studied in healthy adults or multi-ethnic populations. We examined associations of PTX3 with CVD risk factors, measures of subclinical CVD, coronary artery calcification (CAC) and CVD events in the Multi-Ethnic Study of Atherosclerosis (MESA).
Approach and Results
2838 participants free of prevalent CVD with measurements of PTX3 were included in the present study. Adjusting for age, sex and ethnicity, PTX3 was positively associated with age, obesity, insulin, systolic blood pressure, C-reactive protein (CRP) and carotid intima media thickness (all p<0.045). A one standard deviation increase in PTX3 (1.62 ng/ml) was associated with the presence of CAC in fully adjusted models including multiple CVD risk factors (relative risk; 95% confidence interval 1.05; 1-01-1.08). In fully adjusted models, a standard deviation higher level of PTX3 was associated with an increased risk of myocardial infarction (hazard ratio; 95% confidence interval 1.51; 1.16-1.97), combined CVD events (1.23; 1.05-1.45) and combined CHD events (1.33; 1.10-1.60) but not stroke, CVD-related mortality or all cause death.
Conclusions
In these apparently healthy adults, PTX3 was associated with CVD risk factors, subclinical CVD, CAC and incident coronary heart disease events independent of CRP and CVD risk factors. These results support the hypothesis that PTX3 reflects different aspects of inflammation than CRP and may provide additional insight into the development and progression of atherosclerosis.
doi:10.1111/jth.12557
PMCID: PMC4055511  PMID: 24628740
Atherosclerosis; Cardiovascular Diseases; Epidemiology; Inflammation; Pentraxin 3
3.  Baseline Subclinical Atherosclerosis Burden and Distribution are Associated with the Frequency and Mode of Future Coronary Revascularization: Multi-Ethnic Study of Atherosclerosis (MESA) 
JACC. Cardiovascular imaging  2014;7(5):476-486.
Objectives
We sought to evaluate the impact of coronary artery calcium (CAC) burden and regional distribution on the need for and type of future coronary revascularization (percutaneous [PCI] vs. surgical [CABG]) among asymptomatic individuals.
Background
The need for coronary revascularization and the chosen mode of revascularization are thought to be a function of disease burden and anatomic distribution. The association between the baseline burden and regional distribution of CAC and the risk and type of future coronary revascularization remains unknown.
Methods
6,540 MESA participants (individuals aged 45-84 years, free of known baseline cardiovascular disease) with vessel-specific CAC measurement were followed for median 8.5 (7.7 – 8.6) years. Annualized rates and multivariable adjusted hazard ratios for revascularization and revascularization type were analyzed according to CAC score category, number of vessels with CAC (0-4, including the left main), and by involvement of individual coronary arteries.
Results
A total of 265 revascularizations (4.2%) occurred during follow-up, and 206 (78% of total) were preceded by adjudicated symptoms. Revascularization was uncommon when CAC=0 (0.6%), with graded increase over both rising CAC burden and increasingly diffuse CAC distribution. The revascularization rate per 1,000 person-years for CAC 1-100, 101-400, and >400 was 4.9, 11.7 and 25.4; for 1, 2, 3, and 4 vessels with CAC the rates were 3.0, 8.0, 16.1, and 24.8. In multivariable models adjusting for CAC score, number of vessels with CAC remained predictive of mode of revascularization. Independent predictors of CABG vs. PCI included 3 or 4 vessel CAC, higher CAC burden, and involvement of the left main. Risk for CABG was extremely low with <3 vessel baseline CAC. Results were similar when considering only symptom-driven revascularizations.
Conclusions
In this multi-ethnic cohort of asymptomatic individuals, baseline CAC was highly predictive of future coronary revascularization procedures, with measures of CAC burden and distribution each independently predicting need for PCI vs. CABG over 8.5 year follow-up.
doi:10.1016/j.jcmg.2014.03.005
PMCID: PMC4024837  PMID: 24831208
cardiac CT; coronary artery calcium; coronary artery disease; revacularization
4.  Lower extremity peripheral artery disease in the absence of traditional risk factors. The Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2010;214(1):169-173.
Objective
Lower-extremity peripheral artery disease (LE-PAD), is strongly related to traditional risk factors (smoking, hypertension, dyslipidemia, diabetes). We hypothesized that the prevalence of LE-PAD in the absence of traditional CVD risk factors is not negligible, and that this condition would remain associated with subclinical atherosclerosis in other territories.
Methods
In the Multi-Ethnic Study of Atherosclerosis, we classified participants without any traditional risk factor according to their ankle-brachial index (ABI) into 3 groups: low (<1.00), normal (1.00–1.30) and high (>1.30) ABI. Coronary or carotid artery diseases were defined by the presence of any coronary artery calcification (CAC score > 0) or carotid plaque, respectively.
Results
Among the 6814 participants, 1932 had no traditional risk factors. A low- and high ABI were found in 176 (9%) and 149 (7.8%) cases, respectively. Lower glomerular filtration rate (OR: 0.88/10 units, p = 0.04) and higher Interleukin-6 levels (OR: 1.42/natural-log unit, p = 0.02) were associated with low ABI. Past smoking (cessation > 10 years) and pulse pressure had borderline association with low ABI. In adjusted models, low-ABI was significantly associated with CAC prevalence (OR: 1.22, p < 0.03). No significant association was found with carotid plaque.
Conclusion
In the absence of traditional CVD risk factors, LE-PAD is still common and associated with coronary artery disease.
doi:10.1016/j.atherosclerosis.2010.10.011
PMCID: PMC4415364  PMID: 21067754
Atherosclerosis; Peripheral artery disease; Risk; Subclinical
5.  Ethnic and Gender Differences in Liver Fat on Cardiac Computed Tomography: The Multi-Ethnic Study of Atherosclerosis 
Mayo Clinic proceedings  2014;89(4):493-503.
Objective
To describe ethnic and gender differences in the prevalence and determinants of fatty liver in a multi-ethnic cohort.
Patients and Methods
We studied participants from the Multi-Ethnic Study of Atherosclerosis who underwent baseline non-contrast cardiac CT between July 2000-August 2002, and had adequate hepatic and splenic imaging for fatty liver determination (n=4088). Fatty liver was diagnosed by a liver/spleen attenuation ratio <1. We compared the prevalence and severity of fatty liver, among four ethnicities (White, Chinese, African American, Hispanic), stratifying by obesity and metabolic syndrome. Multivariable ordinal logistic regression was employed to determine the impact of cardio-metabolic risk factors on fatty liver prevalence in different ethnicities.
Results
The prevalence of fatty liver varied significantly by ethnicity (White 15%, Chinese 20%, African-American 11%, Hispanic 27%, p<0.001). Although African-Americans had the highest prevalence of obesity, a smaller percentage of obese African Americans were diagnosed with fatty liver compared to other ethnicities (African American 17%, White 31%, Chinese 37%, Hispanic 39%, p<0.001). Hispanics demonstrated the highest prevalence of fatty liver, including among the obese and metabolic syndrome population. An increase in insulin resistance predicted a two-fold increased prevalence of fatty liver in all ethnicities after multi-variable adjustment.
Conclusion
African-Americans have a lower prevalence, and Hispanic Americans a higher prevalence of fatty liver compared to other ethnicities. There are distinct ethnic variations in the prevalence of fatty liver even among patients with the metabolic syndrome or obesity, suggesting that genetic factors may play a significant role in the phenotypic expression of fatty liver.
doi:10.1016/j.mayocp.2013.12.015
PMCID: PMC4410019  PMID: 24613289
Non-alcoholic Fatty Liver Disease; Ethnicity; Computed Tomography
6.  A Comparison of Mortality Rates in a Large Population of Smokers and Non-smokers: based on the Presence or Absence of Coronary Artery Calcification 
JACC. Cardiovascular imaging  2012;5(10):1037-1045.
Objectives
To further study the interplay between smoking status, Coronary Artery Calcium (CAC) and all-cause mortality.
Background
Prior studies have not directly compared the relative prognostic impact of CAC in smokers versus non-smokers. In particular, while zero CAC is a known favorable prognostic-marker, whether smokers without CAC have as good a prognosis as non-smokers without CAC is unknown. Given computed tomography (CT) screening for lung cancer appears effective in smokers, the relative prognostic implications of visualizing any CAC versus no CAC on such screening also deserve study.
Methods
Our study cohort consisted of 44,042 asymptomatic individuals referred for non-contrast cardiac CT (age 54±11 years, 54% males). Subjects were followed for a mean of 5.6 years. The primary endpoint was all-cause mortality.
Results
Approximately 14% (n=6020) of subjects were active smokers at enrollment. There were 901 deaths (2.05%) overall, with increased mortality in smokers vs. non-smokers (4.3% vs. 1.7%, p<0.0001). Smoking remained a risk factor for mortality across increasing strata of CAC scores (1-100, 101-400, and >400). In multivariable analysis within these strata, we found mortality hazard ratios (HRs) of 3.8 (95% CI, 2.8-5.2), 3.5 (2.6-4.9), and 2.7 (2.1-3.5), respectively, in smokers compared to nonsmokers. At each stratum of elevated CAC score, mortality in smokers was consistently higher than mortality in non-smokers from the CAC stratum above. However, among the 19,898 individuals with CAC=0, the mortality HR for smokers without CAC was 3.6 (95% CI, 2.3-5.7), compared to non-smokers without CAC.
Conclusion
Smoking is a risk factor for death across the entire spectrum of subclinical coronary atherosclerosis. Smokers with any coronary calcification are at significantly increased future mortality risk than smokers without CAC. However, the absence of CAC may not be as useful a “negative risk factor” in active smokers; as this group has mortality rates similar to non-smokers with mild to moderate atherosclerosis.
doi:10.1016/j.jcmg.2012.02.017
PMCID: PMC4405129  PMID: 23058072
Smoking; Subclinical Atherosclerosis; Coronary artery calcification; Cardiac CT; Prognosis
7.  CORONARY ARTERY CALCIUM IN RELATION TO INITIATION AND CONTINUATION OF CARDIOVASCULAR PREVENTIVE MEDICATIONS: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) 
Background
Whether measuring and reporting of coronary artery calcium scores (CACS) might lead to changes in cardiovascular risk management is not established. In this observational study we examined whether high baseline CACS were associated with the initiation as well continuation of new lipid lowering medication (LLM), blood pressure lowering medication (BPLM) and regular aspirin (ASA) use in a multi-ethnic population-based cohort.
Methods and Results
MESA is a prospective cohort study of 6814 participants free of clinical cardiovascular disease at entry who underwent CAC testing at baseline examination (exam 1). Information on LLM, BPLM and regular ASA usage was also obtained at baseline, and at exams 2 and 3 (average of 1.6 and 3.2 years after baseline respectively). In this study we examined: 1) initiation of these medications at exam 2 among participants not taking these medications at baseline; and 2) continuation of medication use to exam 3 among participants already on medication at baseline. Among MESA participants, initiation of LLM, BPLM and ASA was greater in those with higher CACS After taking into account age, gender, race, MESA site, LDL cholesterol, diabetes mellitus, BMI, smoking status, hypertension, systolic blood pressure, and SES (income, education and health insurance), the risk ratios for medication initiation comparing those with CACS>400 vs. CACS=0 were 1.53 (95% CI: 1.08, 2.15) for LLM, 1.55 (1.10-- 2.17) for BPLM, and 1.32 (1.03–1.69) for ASA initiation, respectively. The risk ratios for medication continuation among those with CAC>400 vs. CACS=0 were 1.10 (95% CI: 1.01–1.20) for LLM, 1.05 (1.02–1.08) for BPLM, and 1.14 (1.04- 1.25) for ASA initiation, respectively.
Conclusion
CACS>400 was associated with a higher likelihood of initiation and continuation of LLM, BPLM and ASA. The association was weaker for continuation than for initiation of these preventive therapies.
doi:10.1161/CIRCOUTCOMES.109.893396
PMCID: PMC4402976  PMID: 20371760
Coronary artery calcification; Computed tomography; Medications; Adherence; Prevention
8.  Cost-Effectiveness of Coronary Artery Calcium Testing for Coronary Heart and Cardiovascular Disease Risk Prediction to Guide Statin Allocation: The Multi-Ethnic Study of Atherosclerosis (MESA) 
PLoS ONE  2015;10(3):e0116377.
Background
The Multi-Ethnic Study of Atherosclerosis (MESA) showed that the addition of coronary artery calcium (CAC) to traditional risk factors improves risk classification, particularly in intermediate risk asymptomatic patients with LDL cholesterol levels <160 mg/dL. However, the cost-effectiveness of incorporating CAC into treatment decision rules has yet to be clearly delineated.
Objective
To model the cost-effectiveness of CAC for cardiovascular risk stratification in asymptomatic, intermediate risk patients not taking a statin. Treatment based on CAC was compared to (1) treatment of all intermediate-risk patients, and (2) treatment on the basis of United States guidelines.
Methods
We developed a Markov model of first coronary heart disease (CHD) and cardiovascular disease (CVD) events. We modeled statin treatment in intermediate risk patients with CAC≥1 and CAC≥100, with different intensities of statins based on the CAC score. We compared these CAC-based treatment strategies to a “treat all” strategy and to treatment according to the Adult Treatment Panel III (ATP III) guidelines. Clinical and economic outcomes were modeled over both five- and ten-year time horizons. Outcomes consisted of CHD and CVD events and Quality-Adjusted Life Years (QALYs). Sensitivity analyses considered the effect of higher event rates, different CAC and statin costs, indirect costs, and re-scanning patients with incidentalomas.
Results
We project that it is both cost-saving and more effective to scan intermediate-risk patients for CAC and to treat those with CAC≥1, compared to treatment based on established risk-assessment guidelines. Treating patients with CAC≥100 is also preferred to existing guidelines when we account for statin side effects and the disutility of statin use.
Conclusion
Compared to the alternatives we assessed, CAC testing is both effective and cost saving as a risk-stratification tool, particularly if there are adverse effects of long-term statin use. CAC may enable providers to better tailor preventive therapy to patients' risks of CVD.
doi:10.1371/journal.pone.0116377
PMCID: PMC4364761  PMID: 25786208
9.  Obesity and Metabolic Phenotypes (Metabolically Healthy and Unhealthy Variants) Are Significantly Associated with Prevalence of Elevated C-Reactive Protein and Hepatic Steatosis in a Large Healthy Brazilian Population 
Journal of Obesity  2015;2015:178526.
Background. Among the obese, the so-called metabolically healthy obese (MHO) phenotype is thought to confer a lower CVD risk as compared to obesity with typical associated metabolic changes. The present study aims to determine the relationship of different subtypes of obesity with inflammatory-cardiometabolic abnormalities. Methods. We evaluated 5,519 healthy, Brazilian subjects (43 ± 10 years, 78% males), free of known cardiovascular disease. Those with <2 metabolic risk factors (MRF) were considered metabolically healthy, and those with BMI ≥ 25 kg/m2 and/or waist circumference meeting NCEP criteria for metabolic syndrome as overweight/obese (OW). High sensitivity C reactive protein (hsCRP) was measured to assess underlying inflammation and hepatic steatosis (HS) was determined via abdominal ultrasound. Results. Overall, 40% of OW individuals were metabolically healthy, and 12% normal-weight had ≥2 MRF. The prevalence of elevated CRP (≥3 mg/dL) and HS in MHO versus normal weight metabolically healthy group was 22% versus 12%, and 40% versus 8% respectively (P < 0.001). Both MHO individuals and metabolically unhealthy normal weight (MUNW) phenotypes were associated with elevated hsCRP and HS. Conclusion. Our study suggests that MHO and MUNW phenotypes may not be benign and physicians should strive to treat individuals in these subgroups to reverse these conditions.
doi:10.1155/2015/178526
PMCID: PMC4369939  PMID: 25838943
11.  Association between inflammatory markers and liver fat: The Multi-Ethnic Study of Atherosclerosis 
BACKGROUND
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease. Data is emerging that an independent association between markers of subclinical atherosclerosis and NAFLD exists and it may be considered as an independent predictor of cardiovascular (CV) outcomes. We aim to better characterize the relationship between NAFLD and inflammatory markers in a multi-ethnic cohort by assessing fatty liver on computed tomography (CT) scans.
METHODS
The Multi-Ethnic Study of Atherosclerosis (MESA) is a longitudinal, population-based study from four ethnic groups free of CV disease at baseline. The inflammatory markers studied include: C-reactive protein (CRP) and interleukin 6 (IL-6). On CT scans liver-to-spleen ratio (LSR: Hounsfield Units (HU) of the liver divided by HU of spleen) of <1 and liver attenuation of <40 HU were used as criteria for fatty liver. Unadjusted and adjusted multivariate linear and logistic regression analysis was performed.
RESULTS
4038 participants amongst 6814 MESA population with visible spleen on the CT scan, available CRP and IL-6 levels and no reported liver cirrhosis were included. The average age was 61 +/− 10 years, 37% Caucasians and 45% were males. Mean CRP and IL-6 were 2.36 mg/dl and 1.37 pg/ml respectively. 696 participants (17%) had LSR of <1 and 253 (6%) had liver attenuation of <40 HU. When using LSR <1 as a continuous variable, the correlation (adjusted odds ratio (OR)) with CRP >2.0 was 0.037 (95% CI: 0.02-0.054) and with IL-6 was 0.014 (95% CI: 0.004-0.023). On the other hand when presence and absence of LSR <1 was considered, higher ORs for association with CRP >2: 1.41 (95% CI: 1.16 to 1.73) and IL6:1.18 (95% CI: 1.05 to 1.31) were found. Similarly, the adjusted association of per unit decrease in liver attenuation with CRP>2 was 1.92 (95% CI: 1.20 to 2.63) while for IL-6 was 1.08 (95% CI: 0.69 to 1.47). When considering presence and absence of liver attenuation <40 HU the OR for CRP >2 was 2.27 (95% CI: 1.62 to 3.16) and for IL-6 was 1.33 (95% CI: 1.13 to 1.58).
CONCLUSION
CRP and IL-6 levels were found to be significantly associated with liver fat assessed on CT scan after adjusting for other risk factors for atherosclerosis.
doi:10.4172/2155-9880.1000344
PMCID: PMC4296580  PMID: 25598995
Inflammation; Non-alcoholic fatty liver disease; computed tomography scan; C reactive protein
12.  Dyslipidemia, Coronary Artery Calcium, and Incident Atherosclerotic Cardiovascular Disease: Implications for Statin Therapy from the Multi-Ethnic Study of Atherosclerosis 
Circulation  2013;129(1):77-86.
Background
Worldwide clinical practice guidelines for dyslipidemia emphasize allocating statin therapy to those at the highest absolute atherosclerotic cardiovascular disease (CVD) risk.
Methods and Results
We examined 5,534 MESA participants who were not on baseline medications for dyslipidemia. Participants were classified by baseline CAC score (>0, ≥100) and the common clinical scheme of counting lipid abnormalities (LA), including LDL-C ≥3.36 mmol/L (130 mg/dL), HDL-C <1.03 mmol/L (40 mg/dL) for men or <1.29 mmol/L (50 mg/dL) for women, and triglycerides ≥1.69 mmol/L (150 mg/dL). Our main outcome measure was incident CVD (myocardial infarction, angina resulting in revascularization, resuscitated cardiac arrest, stroke, cardiovascular death). Over a median follow-up of 7.6 years, more than half of events (55%) occurred in the 21% of participants with CAC≥100. Conversely, 65% of events occurred in participants with zero or one LA. In those with CAC≥100, CVD rates ranged from 22.2 to 29.2 per 1,000 person-years across LA categories. In contrast, with CAC=0, CVD rates ranged from 2.4 to 6.2 per 1,000 person-years across LA categories. Individuals with zero LA and CAC≥100 had a higher event rate compared to individuals with three LA but CAC=0 (22.2 vs 6.2 per 1,000 person-years). Similar results were obtained when classifying LA using dataset-quartiles of TC/HDL-C, LDL-C, non-HDL-C, or LDL particle concentration and guideline-categories of LDL-C or non-HDL-C.
Conclusions
CAC may have the potential to help match statin therapy to absolute CVD risk. Across the spectrum of dyslipidemia, event rates similar to secondary prevention populations were observed for patients with CAC≥100.
doi:10.1161/CIRCULATIONAHA.113.003625
PMCID: PMC3919521  PMID: 24141324
Atherosclerosis; Cardiovascular disease risk factors; Cholesterol; Computed tomography
13.  Relation of Thoracic Aortic Distensibility to Left Ventricular Area (From the Multi-ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2013;113(1):178-182.
Decreased arterial compliance is an early manifestation of adverse structural and functional changes within the vessel wall. Its correlation with left ventricular (LV) area on computed tomography (CT), a marker of LV remodeling, has not been well demonstrated. We tested the hypothesis that decreasing aortic compliance and increasing arterial stiffness is independently associated with increased LV area. The study population consisted of 3,540 (61±10 years, 46% men) from the MESA study who underwent aortic distensibility (AD) assessment on magnetic resonance imaging (MRI) and LV area measurement on CT (adjusted to body surface area). Multivariable logistic regression was performed to assess the association between body surface area (BSA) normalized LV area >75th percentile and AD after adjusting for baseline clinical, historical and imaging covariates. The mean LV area /BSA was 2,153 cm2 and mean AD was 1.84 mm Hg−1 x103. Subjects in the lowest AD quartile were older with higher prevalence of hypertension, diabetes, and hypercholesterolemia (p<0.05 for all comparisons). Using multivariate linear regression adjusting for demographics, traditional risk factors, coronary artery calcium and C-reactive protein, each standard deviation decrease was associated with 18 cm2 increase in the LV area. In addition, decreasing AD quartiles were independently associated with increased BSA LV area defined as >75th percentile. In this multi-ethnic cohort, reduced AD was associated with increased LV area. Longitudinal studies are needed to determine if decreased distensibility precedes and directly influences increased LV area.
doi:10.1016/j.amjcard.2013.09.039
PMCID: PMC3912190  PMID: 24210674
Arterial compliance; Left ventricular area; Computed tomography; Aortic Distensibility
14.  Headed in the Right Direction But at Risk for Miscalculation 
The newly released 2013 ACC/AHA Guidelines for Assessing Cardiovascular Risk makes progress compared with previous cardiovascular risk assessment algorithms. For example, the new focus on total atherosclerotic cardiovascular diseases (ASCVD) is now inclusive of stroke in addition to hard coronary events, and there are now separate equations to facilitate estimation of risk in non-Hispanic white and black individuals and separate equations for women. Physicians may now estimate lifetime risk in addition to 10-year risk. Despite this progress, the new risk equations do not appear to lead to significantly better discrimination than older models. Because the exact same risk factors are incorporated, using the new risk estimators may lead to inaccurate assessment of atherosclerotic cardiovascular risk in special groups such as younger individuals with unique ASCVD risk factors. In general, there appears to be an overestimation of risk when applied to modern populations with greater use of preventive therapy, although the magnitude of overestimation remains unclear. Because absolute risk estimates are directly used for treatment decisions in the new cholesterol guidelines, these issues could result in overuse of pharmacologic management. The guidelines could provide clearer direction on which individuals would benefit from additional testing, such as coronary calcium scores, for more personalized preventive therapies. We applaud the advances of these new guidelines, and we aim to critically appraise the applicability of the risk assessment tools so that future iterations of the estimators can be improved to more accurately assess risk in individual patients.
doi:10.1016/j.jacc.2014.04.010
PMCID: PMC4280905  PMID: 24814487
coronary artery calcium; guidelines; preventive cardiology; risk assessment
15.  Association Between Resting Heart Rate and Inflammatory Biomarkers (High-Sensitivity C-Reactive Protein, Interleukin-6, and Fibrinogen) (from the Multi-Ethnic Study of Atherosclerosis) 
The American journal of cardiology  2013;113(4):644-649.
Heart rate (HR) at rest is associated with adverse cardiovascular events; however, the biologic mechanism for the relation is unclear. We hypothesized a strong association between HR at rest and subclinical inflammation, given their common interrelation with the autonomic nervous system. HR at rest was recorded at baseline in the Multi-Ethnic Study of Atherosclerosis, a cohort of 4 racial or ethnic groups without cardiovascular disease at baseline and then divided into quintiles. Subclinical inflammation was measured using high-sensitivity C-reactive protein, interleukin-6, and fibrinogen. We used progressively adjusted regression models with terms for physical activity and atrioventricular nodal blocking agents in the fully adjusted models. We examined inflammatory markers as both continuous and categorical variables using the clinical cut point of ≥3 mg/L for high-sensitivity C-reactive protein and the upper quartiles of fibrinogen (≥389 mg/dl) and interleukin-6 (≥1.89 pg/ml). Participants had a mean age of 62 years (SD 9.7), mean resting heart rate of 63 beats/min (SD 9.6) and were 47% men. Increased HR at rest was significantly associated with higher levels of all 3 inflammatory markers in both continuous (p for trend <0.001) and categorical (p for trend <0.001) models. Results were similar among all 3 inflammatory markers, and there was no significant difference in the association among the 4 racial or ethnic groups. In conclusion, an increased HR at rest was associated with a higher level of inflammation among an ethnically diverse group of subjects without known cardiovascular disease.
doi:10.1016/j.amjcard.2013.11.009
PMCID: PMC4280910  PMID: 24393259
16.  CPAP versus Oxygen in Obstructive Sleep Apnea 
The New England journal of medicine  2014;370(24):2276-2285.
Background
Obstructive sleep apnea is associated with hypertension, inflammation, and increased cardiovascular risk. Continuous positive airway pressure (CPAP) reduces blood pressure, but adherence is often suboptimal, and the benefit beyond management of conventional risk factors is uncertain. Since intermittent hypoxemia may underlie cardiovascular sequelae of sleep apnea, we evaluated the effects of nocturnal supplemental oxygen and CPAP on markers of cardiovascular risk.
Methods
We conducted a randomized, controlled trial in which patients with cardiovascular disease or multiple cardiovascular risk factors were recruited from cardiology practices. Patients were screened for obstructive sleep apnea with the use of the Berlin questionnaire, and home sleep testing was used to establish the diagnosis. Participants with an apnea–hypopnea index of 15 to 50 events per hour were randomly assigned to receive education on sleep hygiene and healthy lifestyle alone (the control group) or, in addition to education, either CPAP or nocturnal supplemental oxygen. Cardiovascular risk was assessed at baseline and after 12 weeks of the study treatment. The primary outcome was 24-hour mean arterial pressure.
Results
Of 318 patients who underwent randomization, 281 (88%) could be evaluated for ambulatory blood pressure at both baseline and follow-up. On average, the 24-hour mean arterial pressure at 12 weeks was lower in the group receiving CPAP than in the control group (−2.4 mm Hg; 95% confidence interval [CI], −4.7 to −0.1; P = 0.04) or the group receiving supplemental oxygen (−2.8 mm Hg; 95% CI, −5.1 to −0.5; P = 0.02). There was no significant difference in the 24-hour mean arterial pressure between the control group and the group receiving oxygen. A sensitivity analysis performed with the use of multiple imputation approaches to assess the effect of missing data did not change the results of the primary analysis.
Conclusions
In patients with cardiovascular disease or multiple cardiovascular risk factors, the treatment of obstructive sleep apnea with CPAP, but not nocturnal supplemental oxygen, resulted in a significant reduction in blood pressure. (Funded by the National Heart, Lung, and Blood Institute and others; HeartBEAT ClinicalTrials.gov number, NCT01086800.)
doi:10.1056/NEJMoa1306766
PMCID: PMC4172401  PMID: 24918372
17.  Physical Fitness and Hypertension in a Population at Risk for Cardiovascular Disease: The Henry Ford ExercIse Testing (FIT) Project 
Background
Increased physical fitness is protective against cardiovascular disease. We hypothesized that increased fitness would be inversely associated with hypertension.
Methods and Results
We examined the association of fitness with prevalent and incident hypertension in 57 284 participants from The Henry Ford ExercIse Testing (FIT) Project (1991–2009). Fitness was measured during a clinician‐referred treadmill stress test. Incident hypertension was defined as a new diagnosis of hypertension on 3 separate consecutive encounters derived from electronic medical records or administrative claims files. Analyses were performed with logistic regression or Cox proportional hazards models and were adjusted for hypertension risk factors. The mean age overall was 53 years, with 49% women and 29% black. Mean peak metabolic equivalents (METs) achieved was 9.2 (SD, 3.0). Fitness was inversely associated with prevalent hypertension even after adjustment (≥12 METs versus <6 METs; OR: 0.73; 95% CI: 0.67, 0.80). During a median follow‐up period of 4.4 years (interquartile range: 2.2 to 7.7 years), there were 8053 new cases of hypertension (36.4% of 22 109 participants without baseline hypertension). The unadjusted 5‐year cumulative incidences across categories of METs (<6, 6 to 9, 10 to 11, and ≥12) were 49%, 41%, 30%, and 21%. After adjustment, participants achieving ≥12 METs had a 20% lower risk of incident hypertension compared to participants achieving <6 METs (HR: 0.80; 95% CI: 0.72, 0.89). This relationship was preserved across strata of age, sex, race, obesity, resting blood pressure, and diabetes.
Conclusions
Higher fitness is associated with a lower probability of prevalent and incident hypertension independent of baseline risk factors.
doi:10.1161/JAHA.114.001268
PMCID: PMC4338714  PMID: 25520327
cohort; fitness; hypertension; metabolic equivalents; physical activity
18.  Thoracic Aortic Distensibility and Thoracic Aortic Calcium (From the Multi-ethnic Study of Atherosclerosis [MESA]) 
The American journal of cardiology  2010;106(4):575-580.
Decreased arterial distensibility is an early manifestation of adverse structural and functional changes within the vessel wall. Its correlation with thoracic aortic calcium (TAC), a marker of atherosclerosis, has not been well demonstrated. We tested the hypothesis that decreasing aortic compliance and increasing arterial stiffness is independently associated with increased TAC. We included 3,540 (61±10 years, 46% males) subjects from the Multi-ethnic Study of Atherosclerosis (MESA) study who underwent aortic distensibility (AD) assessment on MRI. TAC was calculated using modified Agatston algorithm on non-contrast cardiac CT. Multivariate regression models were calculated for the presence of TAC. Overall, 861 (24%) individuals had detectable TAC. A lower AD was observed among those with vs. without TAC (2.02±1.34 vs. 1.28±0.74, p<0.0001). The prevalence of TAC increased significantly across decreasing quartiles of AD (7%, 17%, 31%, and 42%, p<0.0001). Using multivariate analysis, TAC was independently associated with AD after adjusting for age, gender, ethnicity and other covariates. In conclusion, our analysis demonstrates that increased arterial stiffness is associated with increased TAC independent of ethnicity and other atherosclerotic risk factors.
doi:10.1016/j.amjcard.2010.03.074
PMCID: PMC4228943  PMID: 20691319
19.  Comparison of a Novel Method vs the Friedewald Equation for Estimating Low-Density Lipoprotein Cholesterol Levels From the Standard Lipid Profile 
JAMA  2013;310(19):2061-2068.
IMPORTANCE
In clinical and research settings worldwide, low-density lipoprotein cholesterol (LDL-C) is typically estimated using the Friedewald equation. This equation assumes a fixed factor of 5 for the ratio of triglycerides to very low-density lipoprotein cholesterol (TG:VLDL-C); however, the actual TG:VLDL-C ratio varies significantly across the range of triglyceride and cholesterol levels.
OBJECTIVE
To derive and validate a more accurate method for LDL-C estimation from the standard lipid profile using an adjustable factor for the TG:VLDL-C ratio.
DESIGN, SETTING, AND PARTICIPANTS
We used a convenience sample of consecutive clinical lipid profiles obtained from 2009 through 2011 from 1 350 908 children, adolescents, and adults in the United States. Cholesterol concentrations were directly measured after vertical spin density-gradient ultracentrifugation, and triglycerides were directly measured. Lipid distributions closely matched the population-based National Health and Nutrition Examination Survey (NHANES). Samples were randomly assigned to derivation (n = 900 605) and validation (n = 450 303) data sets.
MAIN OUTCOMES AND MEASURES
Individual patient-level concordance in clinical practice guideline LDL-C risk classification using estimated vs directly measured LDL-C (LDL-CD).
RESULTS
In the derivation data set, the median TG:VLDL-C was 5.2 (IQR, 4.5–6.0). The triglyceride and non–high-density lipoprotein cholesterol (HDL-C) levels explained 65% of the variance in the TG:VLDL-C ratio. Based on strata of triglyceride and non–HDL-C values, a 180-cell table of median TG:VLDL-C values was derived and applied in the validation data set to estimate the novel LDL-C (LDL-CN). For patients with triglycerides lower than 400 mg/dL, overall concordance in guideline risk classification with LDL-CD was 91.7% (95% CI, 91.6%–91.8%) for LDL-CN vs 85.4% (95% CI, 85.3%–85.5%) for Friedewald LDL-C (LDL-CF) (P < .001). The greatest improvement in concordance occurred in classifying LDL-C lower than 70 mg/dL, especially in patients with high triglyceride levels. In patients with an estimated LDL-C lower than 70 mg/dL, LDL-CD was also lower than 70 mg/dL in 94.3% (95% CI, 93.9%–94.7%) for LDL-CN vs 79.9% (95% CI, 79.3%–80.4%) for LDL-CF in samples with triglyceride levels of 100 to 149 mg/dL; 92.4% (95% CI, 91.7%–93.1%) for LDL-CN vs 61.3% (95% CI, 60.3%–62.3%) for LDL-CF in samples with triglyceride levels of 150 to 199 mg/dL; and 84.0% (95% CI, 82.9%–85.1%) for LDL-CN vs 40.3% (95% CI, 39.4%–41.3%) for LDL-CF in samples with triglyceride levels of 200 to 399 mg/dL (P < .001 for each comparison).
CONCLUSIONS AND RELEVANCE
A novel method to estimate LDL-C using an adjustable factor for the TG:VLDL-C ratio provided more accurate guideline risk classification than the Friedewald equation. These findings require external validation, as well as assessment of their clinical importance. The implementation of these findings into clinical practice would be straightforward and at virtually no cost.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT01698489
doi:10.1001/jama.2013.280532
PMCID: PMC4226221  PMID: 24240933
20.  The prevalence of the metabolically healthy obese phenotype in an aging population and its association with subclinical cardiovascular disease: The Brazilian study on healthy aging 
Background
Current literature has elucidated a new phenotype, metabolically healthy obese (MHO), with risks of cardiovascular disease similar to that of normal weight individuals. Few studies have examined the MHO phenotype in an aging population, especially in association with subclinical CVD.
Research design and methods
This cross sectional study population consisted of 208 octogenarians and older. Anthropometrics, biochemical, and radiological parameters were measured to assess obesity, metabolic health (assessed by the National Cholesterol Education Program –Adult Treatment Panel (NCEP-ATP III) criteria), and subclinical measures of CVD.
Results
The prevalence of MHO was 13.5% (N = 28). No significant association with MHO was noted for age, coronary artery calcium score, cIMT, or hs-CRP > 3 mg/dl (p = NS).
Conclusions
Our results suggest that the MHO phenotype exists in the elderly; however, subclinical CVD measures were not different in sub-group analysis suggesting traditional metabolic risk factor algorithms may not be accurate in the very elderly.
doi:10.1186/1758-5996-6-121
PMCID: PMC4236419  PMID: 25411583
Obesity; Aging; Metabolic Syndrome; Subclinical CVD
21.  Should Statin Therapy Be Allocated on the Basis of Global Risk or on the Basis of Randomized Trial Evidence? 
The American journal of cardiology  2010;106(6):905-909.
Current clinical guidelines recommend the use of a global risk assessment tool, such as those pioneered by the Framingham Heart Study, to determine eligibility for statin therapy in patients with absolute risk levels greater than a certain threshold. In support of this approach, several randomized trials have reported that patients with high absolute risk clearly benefit from statin therapy. Therefore, the guideline recommendations would seem intuitive and effective, albeit on the core assumption that the mortality and morbidity benefits associated with statin therapy would be greatest in those with high predicted absolute risk. However, if this assumption is incorrect, using predicted absolute risk to guide statin therapy could easily result in underuse in some groups and overuse in others. Herein, the authors question the utility of global risk assessment strategies based on the Framingham risk score for guiding statin therapy in light of current data that have become available from more recent and robust prospective randomized clinical trials since the publication of the National Cholesterol Education Program Adult Treatment Panel III guidelines. Moreover, the Adult Treatment Panel III guidelines do not support treatment of some patients who may benefit from statin therapy. In conclusion, the authors propose an alternative approach for incorporating more recent randomized trial data into future statin allocation algorithms and treatment guidelines.
doi:10.1016/j.amjcard.2010.05.015
PMCID: PMC4201182  PMID: 20816135
22.  Computed Tomography-Derived Cardiovascular Risk Markers, Incident Cardiovascular Events, and All-Cause Mortality in Non- Diabetics. The Multi-Ethnic Study of Atherosclerosis 
AIM
We assess the improvement in discrimination afforded by the addition thoracic aorta calcium (TAC), aortic valve calcification (AVC), mitral annular calcification (MAC), pericardial adipose tissue volume (PAT) and liver attenuation (LA) to Framingham risk score(FRS) + coronary artery calcium (CAC) for incident CHD/CVD in a multi ethnic cohort.
Methods and Results
A total 5745(2710 were intermediate Framingham risk, 210 CVD and 155 CHD events) 251 had adjudicated CHD, 346 had CVD events, 321 died after 9 years of follow-up. Cox proportional hazard, receiver operator curve (ROC) and net reclassification improvement (NRI) analyses.
In the whole cohort and also when the analysis was restricted to only the intermediate risk participants: CAC, TAC, AVC and MAC were all significantly associated with incident CVD/CHD/ mortality; CAC had the strongest association. When added to the FRS, CAC had the highest area under the curve (AUC) for the prediction of incident CHD/CVD; LA had the least. The addition of TAC, AVC, MAC, PAT and LA to FRS + CAC all resulted in a significant reduction in AUC for incident CHD [0.712 vs. 0.646, 0.655, 0.652, 0.648 and 0.569; all p<0.01 respectively] in participants with intermediate FRS. The addition of CAC to FRS resulted in an NRI of 0.547 for incident CHD in the intermediate risk group. The NRI when TAC, AVC, MAC, PAT and LA were added to FRS + CAC were 0.024, 0.026, 0.019, 0.012 and 0.012 respectively, for incident CHD in the intermediate risk group. Similar results were obtained for incident CVD in the intermediate risk group and also when the whole cohort was used instead of the intermediate FRS group.
Conclusion
The addition of CAC to the FRS provides superior discrimination especially in intermediate risk individuals compared with the addition of TAC, AVC, MAC, PAT or LA for incident CHD/CVD. Compared with FRS + CAC, the addition of TAC, AVC, MAC, PAT or LA individually to FRS + CAC worsens the discrimination for incident CHD/CVD. These CT risk markers are unlikely to be useful for improving cardiovascular risk prediction.
doi:10.1177/2047487313492065
PMCID: PMC4150859  PMID: 23689526
cardiac CT derived risk factors; coronary heart disease; cardiovascular events; risk prediction
24.  Polypill Therapy, Subclinical Atherosclerosis, and Cardiovascular Events – Implications for the Use of Preventive Pharmacotherapy: Multi-Ethnic Study of Atherosclerosis (MESA) 
OBJECTIVES
Examine whether the coronary artery calcium score (CAC) can be used to define the target population to treat with a polypill.
BACKGROUND
Prior studies suggested a single polypill to reduce cardiovascular disease (CVD) at the population level.
METHODS
Participants from the Multi-Ethnic Study of Atherosclerosis (MESA) were stratified using the criteria of four polypill studies (TIPS, Poly-Iran, Wald's, and the PILL collaboration). We compared coronary heart disease (CHD) and CVD event rates and calculated 5-year number needed to treat (NNT) after stratification based on the CAC score.
RESULTS
Among MESA participants eligible for the TIPS, Poly-Iran, Wald's and PILL collaboration, a CAC=0 was observed in 58.6%, 54.5%, 38.9% and 40.8%, respectively. The rate of CHD events among those with CAC=0 varied from 1.2 to 1.9 events per 1000 person-years, those with CAC 1- 100 had event rates ranging from 4.1 to 5.5, and in those with CAC>100 the event rate ranged from 11.6 to 13.3. The estimated 5-year NNT to prevent one CVD event ranged from 81 to 130 for individuals with CAC=0, 38 to 54 for those with CAC 1-100, and 18 to 20 for those with CAC>100.
CONCLUSION
Among individuals eligible for treatment with the polypill, the majority of events occurred in those with CAC>100. The group with CAC=0 had a very low event rate and a high projected NNT. The avoidance of treatment in individuals with CAC=0 could allow for significant reductions in the population considered for treatment, with a more selective use of the polypill and as a result, avoiding treatment in those who are unlikely to be benefit
doi:10.1016/j.jacc.2013.08.1640
PMCID: PMC4174413  PMID: 24161320
subclinical atherosclerosis; risk stratification; polypill
25.  Association of resting heart rate with carotid and aortic arterial stiffness: Multi-Ethnic Study of Atherosclerosis (MESA) 
Hypertension  2013;62(3):10.1161/HYPERTENSIONAHA.113.01605.
Resting heart rate is an easily measured, non-invasive vital sign that is associated with cardiovascular disease events. The pathophysiology of this association is not known. We investigated the relationship between resting heart rate and stiffness of the carotid (a peripheral artery) and the aorta (a central artery) in an asymptomatic multi-ethnic population. Resting heart rate was recorded at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA). Distensibility was used as a measure of arterial elasticity, with a lower distensibility indicating an increase in arterial stiffness. Carotid distensibility was measured in 6,484 participants (98% of participants) using B-mode ultrasound and aortic distensibility was measured in 3,512 participants (53% of participants) using cardiac MRI. Heart rate was divided into quintiles and we used progressively adjusted models that included terms for physical activity and AV-nodal blocking agents. Mean resting heart rate of participants (mean age 62 years, 47% male) was 63 beats per minute (SD 9.6 beats per minute). In unadjusted and fully adjusted models, carotid distensibility and aortic distensibility decreased monotonically with increasing resting heart rate (p for trend <0.001 and 0.009 respectively). The relationship was stronger for carotid versus aortic distensibility. Similar results were seen using the resting heart rate taken at the time of MRI scanning. Our results suggest that a higher resting heart rate is associated with an increased arterial stiffness independent of AV-nodal blocker use and physical activity level, with a stronger association for a peripheral (carotid) compared to a central (aorta) artery.
doi:10.1161/HYPERTENSIONAHA.113.01605
PMCID: PMC3838105  PMID: 23836802
heart rate; cardiovascular disease; stiffness; ultrasound; cardiac magnetic resonance imaging

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