B-type natriuretic peptide (BNP) and C-reactive protein (CRP) predict atrial fibrillation (AF) risk. However, their risk stratification abilities in the broad community remain uncertain. We sought to improve risk stratification for AF using biomarker information.
Methods and results
We ascertained AF incidence in 18 556 Whites and African Americans from the Atherosclerosis Risk in Communities Study (ARIC, n=10 675), Cardiovascular Health Study (CHS, n = 5043), and Framingham Heart Study (FHS, n = 2838), followed for 5 years (prediction horizon). We added BNP (ARIC/CHS: N-terminal pro-B-type natriuretic peptide; FHS: BNP), CRP, or both to a previously reported AF risk score, and assessed model calibration and predictive ability [C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI)]. We replicated models in two independent European cohorts: Age, Gene/Environment Susceptibility Reykjavik Study (AGES), n = 4467; Rotterdam Study (RS), n = 3203. B-type natriuretic peptide and CRP were significantly associated with AF incidence (n = 1186): hazard ratio per 1-SD ln-transformed biomarker 1.66 [95% confidence interval (CI), 1.56–1.76], P < 0.0001 and 1.18 (95% CI, 1.11–1.25), P < 0.0001, respectively. Model calibration was sufficient (BNP, χ2 = 17.0; CRP, χ2 = 10.5; BNP and CRP, χ2 = 13.1). B-type natriuretic peptide improved the C-statistic from 0.765 to 0.790, yielded an IDI of 0.027 (95% CI, 0.022–0.032), a relative IDI of 41.5%, and a continuous NRI of 0.389 (95% CI, 0.322–0.455). The predictive ability of CRP was limited (C-statistic increment 0.003). B-type natriuretic peptide consistently improved prediction in AGES and RS.
B-type natriuretic peptide, not CRP, substantially improved AF risk prediction beyond clinical factors in an independently replicated, heterogeneous population. B-type natriuretic peptide may serve as a benchmark to evaluate novel putative AF risk biomarkers.
Atrial fibrillation; Risk prediction; Epidemiology; Biomarker; B-type natriuretic peptide; C-reactive protein
Background and Purpose
Emerging data suggest that left atrial disease may cause ischemic stroke in the absence of atrial fibrillation or flutter (AF). If true, this condition may provide an etiology for many strokes currently classified as cryptogenic.
Among 6,741 participants in the Multi-Ethnic Study of Atherosclerosis who were free of clinically apparent cerebrovascular or cardiovascular disease (including AF) at baseline, we examined the association between markers of left atrial abnormality on a standard 12-lead electrocardiogram (ECG)—specifically, P-wave area, duration, and terminal force in lead V1 (PTFV1)—and the subsequent risk of ischemic stroke while accounting for incident AF.
During a median follow-up of 8.5 years, 121 participants (1.8%) suffered a stroke and 541 participants (8.0%) were diagnosed with AF. In Cox proportional hazards models adjusting for potential baseline confounders, PTFV1 was more strongly associated with incident stroke (hazard ratio [HR] per 1-SD increase, 1.21; 95% confidence interval [CI], 1.02–1.44) than with incident AF (HR per 1-SD, 1.11; 95% CI, 1.03–1.21). The association between PTFV1 and stroke was robust in numerous sensitivity analyses accounting for AF, including analyses that excluded those with any incident AF or modeled any incident AF as having been present from baseline.
We found an association between baseline P-wave morphology and incident stroke even after accounting for AF. This association may reflect an atrial cardiopathy that leads to stroke in the absence of AF.
Arrhythmia; atrium; electrocardiography; embolism; stroke
To determine the association of HIV, immunologic, and inflammatory factors on coronary artery calcium (CAC), a marker of subclinical atherosclerosis.
Cross-sectional study comparing baseline data of males from Hawaii Aging with HIV –Cardiovascular Study (HAHCS) with the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. The cohorts were pooled to determine effects of HIV on CAC and explore immunologic and inflammatory factors that may explain development of CAC in HIV. Multivariable regression models compared CAC prevalence in HAHCS with MESA adjusting for coronary heart disease (CHD) risk profiles.
We studied 100 men from HAHCS and 2733 men from MESA. Positive CAC was seen in 58% HAHCS participants and 57% MESA participants. Mean CAC was 260.8 in HAHCS and 306.5 in MESA. Using relative risk (RR) regression, HAHCS participants had a greater risk (RR=1.20, P<0.05) of having positive CAC than MESA when adjusting for age, smoking status, diabetes, antihypertensive therapy, BMI, systolic blood pressure, total cholesterol, and HDL cholesterol. Among participants with positive CAC, HIV infection was not associated with larger amounts of CAC. Among HAHCS participants, current HIV viral load, CD4, length of HIV, interleukin 6 (IL-6), fibrinogen, C-reactive protein (CRP), and D-dimer were not associated with the presence or amount of CAC.
HIV was independently associated with a positive CAC in men with increased likelihood occurring between 45 and 50 years of age. Current HIV viral load, CD4 count, length of HIV, and inflammatory markers were unrelated to either presence or amount of CAC.
Antiviral therapy; Coronary artery calcium; MESA; Framingham Risk Score
Rationale: Computed tomography (CT)-based lung density is used to quantitate the percentage of emphysema-like lung (hereafter referred to as percent emphysema), but information on its distribution among healthy nonsmokers is limited.
Objectives: We evaluated percent emphysema and total lung volume on CT scans of healthy never-smokers in a multiethnic, population-based study.
Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study investigators acquired full-lung CT scans of 3,137 participants (ages 54–93 yr) between 2010–12. The CT scans were taken at full inspiration following the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) protocol. “Healthy never-smokers” were defined as participants without a history of tobacco smoking or respiratory symptoms and disease. “Percent emphysema” was defined as the percentage of lung voxels below −950 Hounsfield units. “Total lung volume” was defined by the volume of lung voxels.
Measurements and Main Results: Among 854 healthy never-smokers, the median percent emphysema visualized on full-lung scans was 1.1% (interquartile range, 0.5–2.5%). The percent emphysema values were 1.2 percentage points higher among men compared with women and 0.7, 1.2, and 1.2 percentage points lower among African Americans, Hispanics, and Asians compared with whites, respectively (P < 0.001). Percent emphysema was positively related to age and height and inversely related to body mass index. The findings were similar for total lung volume on CT scans and for percent emphysema defined at −910 Hounsfield units and measured on cardiac scans. Reference equations to account for these differences are presented for never, former and current smokers.
Conclusions: Similar to lung function, percent emphysema varies substantially by demographic factors and body size among healthy never-smokers. The presented reference equations will assist in defining abnormal values for percent emphysema and total lung volume on CT scans, although validation is pending.
emphysema; lung volumes; quantitative computed tomography; reference equations
Whereas low lung function is known to predict mortality in the general population, the prognostic significance of emphysema on computed tomography (CT) in persons without chronic obstructive pulmonary disease (COPD) remains uncertain.
To determine whether greater emphysema-like lung on CT is associated with all-cause mortality among persons without airflow obstruction or COPD in the general population.
Prospective cohort study.
Population-based, multiethnic sample from 6 US communities.
2965 participants ages 45-84 years without airflow obstruction on spirometry.
Emphysema-like lung was defined on cardiac CT as the number of lung voxels less than -950 Hounsfield Units, and was adjusted for the number of total imaged lung voxels.
Among 2965 participants, 50.9% of whom never smoked, there were 186 deaths over a median of 6.2 years. Greater emphysema-like lung was independently associated with increased mortality (adjusted hazard ratio [HR]1.14 per one-half of the interquartile range, 95% CI 1.04-1.24, P=0.004), adjusting for potential confounders including cardiovascular risk factors and the forced expiratory volume in one second. Generalized additive models supported a linear association between emphysema-like lung and mortality without evidence for a threshold. The association was of greatest magnitude among smokers, although multiplicative interaction terms did not support effect modification by smoking status.
Cardiac CT scans did not include lung apices. The number of deaths was limited among subgroup analyses.
Emphysema-like lung on CT was associated with all-cause mortality among persons without airflow obstruction or COPD in a general population sample, particularly among smokers. Recognition of the independent prognostic significance of emphysema on CT among patients without COPD on spirometry is warranted.
Primary Funding Source
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.
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.
Atherosclerosis; Cardiovascular Diseases; Epidemiology; Inflammation; Pentraxin 3
Previous epidemiologic studies have shown that low-density lipoprotein is an independent risk factor for prevalent aortic valve calcification (AVC); however, to our knowledge, the interactions between plasma lipoprotein concentrations and age on the relative risks (RRs) for AVC prevalence and severity have not been examined in a large, racially and ethnically diverse cohort.
Using stepwise RR regression, the relationships of baseline fasting lipid levels and lipoprotein levels to baseline prevalence and severity of AVC were determined in 5801 non–statin-using participants in the Multi-Ethnic Study of Atherosclerosis (MESA).
In age-stratified, adjusted analyses, the low-density lipoprotein–associated RRs (95%confidence intervals) for prevalent AVC were higher for younger compared with older participants (age 45-54 years, 1.69 [1.19-2.39]; age 55-64 years, 1.48 [1.24-1.76]; age 65-74 years, 1.09 [0.95-1.25]; and age 75-84 years, 1.16 [0.99-1.36]; P interaction=.04]. There was a similar, significant interaction of age with total cholesterol–associated RR for prevalent AVC (P interaction=.04). In contrast, total- to high-density lipoprotein cholesterol ratio RRs were similar across all age strata (P interaction=.68). At multivariate analyses, no lipoprotein parameter was associated with AVC severity.
In this racially and ethnically diverse, preclinical cohort, low-density lipoprotein was a risk factor for AVC only in participants younger than 65 years, whereas the total cholesterol/high-density lipoprotein cholesterol ratio was associated with a modest increased risk of AVC across all ages. These findings may have important implications for the efficacy of and targets for dyslipidemia therapies in calcific aortic valve disease.
To develop and validate 10-year cumulative incidence functions of intracerebral hemorrhage (ICH) and ischemic stroke (IS).
We used data on 27,493 participants from 3 population-based cohort studies: the Atherosclerosis Risk in Communities Study, median age 54 years, 45% male, median follow-up 20.7 years; the Rotterdam Study, median age 68 years, 38% male, median follow-up 14.3 years; and the Cardiovascular Health Study, median age 71 years, 41% male, median follow-up 12.8 years. Among these participants, 325 ICH events, 2,559 IS events, and 9,909 nonstroke deaths occurred. We developed 10-year cumulative incidence functions for ICH and IS using stratified Cox regression and competing risks analysis. Basic models including only established nonlaboratory risk factors were extended with diastolic blood pressure, total cholesterol/high-density lipoprotein cholesterol ratio, body mass index, waist-to-hip ratio, and glomerular filtration rate. The cumulative incidence functions' performances were cross-validated in each cohort separately by Harrell C-statistic and calibration plots.
High total cholesterol/high-density lipoprotein cholesterol ratio decreased the ICH rates but increased IS rates (p for difference across stroke types <0.001). For both the ICH and IS models, C statistics increased more by model extension in the Atherosclerosis Risk in Communities and Cardiovascular Health Study cohorts. Improvements in C statistics were reproduced by cross-validation. Models were well calibrated in all cohorts. Correlations between 10-year ICH and IS risks were moderate in each cohort.
We developed and cross-validated cumulative incidence functions for separate prediction of 10-year ICH and IS risk. These functions can be useful to further specify an individual's stroke risk.
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.
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.
Coronary artery calcification; Computed tomography; Medications; Adherence; Prevention
Sudden cardiac death (SCD) is an important cause of mortality in the adult population. Height has been associated with cardiac hypertrophy and an increased risk of arrhythmias, but also with decreased risk of coronary heart disease, suggesting a complex association with SCD.
We examined the association of adult height with the risk of physician-adjudicated SCD in two large population-based cohorts: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) study.
Over an average follow-up time of 11.7 years in CHS, there were 199 (3.6%) cases of SCD among 5,556 participants. In ARIC, over 12.6 years, there were 227 (1.5%) cases of SCD among 15,633 participants. In both cohorts, there was a trend towards decreased SCD with taller height. In fixed effects meta-analysis, the pooled hazard ratio per 10 cm of height was 0.84 (95%CI 0.73, 0.98, p=0.03). The association of increased height with lower risk of SCD was slightly attenuated after inclusion of risk factors associated with height, such as hypertension and left ventricular hypertrophy. The association appeared stronger among men than women in both cohorts.
In two population-based prospective cohorts of different ages, greater height was associated with lower risk of SCD.
Body height; risk factors; death; sudden; cardiac
Experimental studies demonstrate that high aortic pressure in late systole relative to early systole causes greater myocardial remodeling and dysfunction, for any given absolute peak systolic pressure.
Methods and Results
We tested the hypothesis that late systolic hypertension, defined as the ratio of late (last one third of systole) to early (first two thirds of systole) pressure–time integrals (PTI) of the aortic pressure waveform, independently predicts incident heart failure (HF) in the general population. Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded noninvasively from 6124 adults. The late/early systolic PTI ratio (L/ESPTI) was assessed as a predictor of incident HF during median 8.5 years of follow‐up. The L/ESPTI was predictive of incident HF (hazard ratio per 1% increase=1.22; 95% CI=1.15 to 1.29; P<0.0001) even after adjustment for established risk factors for HF (HR=1.23; 95% CI=1.14 to 1.32: P<0.0001). In a multivariate model that included brachial systolic and diastolic blood pressure and other standard risk factors of HF, L/ESPTI was the modifiable factor associated with the greatest improvements in model performance. A high L/ESPTI (>58.38%) was more predictive of HF than the presence of hypertension. After adjustment for each other and various predictors of HF, the HR associated with hypertension was 1.39 (95% CI=0.86 to 2.23; P=0.18), whereas the HR associated with a high L/E was 2.31 (95% CI=1.52 to 3.49; P<0.0001).
Independently of the absolute level of peak pressure, late systolic hypertension is strongly associated with incident HF in the general population.
arterial hemodynamics; heart failure; late systolic load; left ventricular afterload
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.
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.
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).
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.
Inflammation; Non-alcoholic fatty liver disease; computed tomography scan; C reactive protein
Significant cardiovascular morbidity has been associated with mitral annulus calcification (MAC), but limited data exist regarding its progression. The purpose of this study was to examine the natural history of and risk factors for MAC progression.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a longitudinal cohort study of participants aged 45–84 years without clinical cardiovascular disease who underwent serial cardiac computed tomography studies with quantification of MAC. Regression models were used to identify risk factors associated with MAC incidence and progression.
Prevalent MAC was observed in 534 of 5,895 (9%) participants. Over a median 2.3 years, 280 (5%) developed incident MAC. After adjustment, age was the strongest predictor of incident MAC (adjusted OR, 2.25 per 10 yrs; 95% CI, 1.97 to 2.58; P<0.0001). Female gender, white ethnicity, body mass index, diabetes, hypertension, hyperlipidemia, serum cholesterol, smoking, and interleukin-6 were also significant predictors of incident MAC. In participants with prevalent MAC, the median rate of change was 10.1 [IQR, −6.7, 60.7] Agatston units (AU)/year. Baseline MAC severity was the predominant predictor of rate of MAC progression (β-coefficient per 10 AU, 0.88; 95% CI, 0.85 to 0.91; P<0.0001), although ethnicity and smoking status possessed modest influence.
Several cardiovascular risk factors predicted incident MAC, as did female gender. Severity of baseline MAC was the primary predictor of MAC progression, suggesting that, while atherosclerotic processes may initiate MAC, they are only modestly associated with its progression over these time frames.
calcification; mitral valve; progression; risk factors; gender
Inflammation contributes to the pathogenesis of disease associated with the left ventricle (LV); yet, our understanding of the effect of inflammation on the right ventricle (RV) is quite limited.
Methods and results
The relationships of C-reactive protein (CRP), interleukin-6 (IL-6) and fibrinogen with RV morphology and function (from cardiac MRI) were examined in participants free of clinical cardiovascular disease (n=4,009) from the Multi-Ethnic Study of Atherosclerosis (MESA)-RV study. Multivariable regressions (linear, quantile [25th and 75th] and generalized additive models [GAM]) were used to examine the independent association of CRP, IL-6 and fibrinogen with RV mass, RV end-diastolic volume (RVEDV), RV end-systolic volume (RVESV), RV stroke volume (RVSV) and RV ejection fraction (RVEF). Unadjusted and adjusted analyses revealed strong inverse associations between both CRP and IL-6 with RV mass, RVEDV, RVESV and RVSV (all p<0.01); there were no associations with RVEF. These relationships remained significant after adjustment for the respective LV parameters and lung function. However, GAM models suggested that extreme values of CRP and IL-6 might have positive associations with RV parameters. Fibrinogen showed significant associations in unadjusted models, but no associations after adjustment or in sensitivity analyses.
Levels of CRP and IL-6 are independently associated with RV morphology even after adjustment for the respective LV measure in this multi-ethnic population free of cardiovascular disease. Systemic inflammation may contribute to RV structural changes independent of effects on the LV.
Systemic inflammation; right ventricle; heart failure; Multi-Ethnic Study of Atherosclerosis
Recent reports have linked variability in visit-to-visit systolic blood pressure (SBP) to risk of mortality and stroke, independent of the effect of mean SBP level. This study aimed to evaluate whether variability in SBP is associated with all-cause mortality, incident myocardial infarction (MI), and incident stroke, independent of mean SBP or trends in SBP levels over time.
The Cardiovascular Health Study is a longitudinal cohort study of vascular risk factors and disease in the elderly. Participants who attended their first 5 annual clinic visits and experienced no event before the 5th visit were eligible (n = 3,852). Primary analyses were restricted to participants not using antihypertensive medications throughout the first 5 clinic visits (n = 1,642). Intraindividual SBP variables were defined using each participant’s 5-visit blood pressure measures. Cox proportional hazards models estimated adjusted hazard ratios (HRs) per SD increase in intraindividual SBP variability, adjusted for intraindividual SBP mean and change over time.
Over a mean follow-up of 9.9 years, there were 844 deaths, 203 MIs, and 195 strokes. Intraindividual SBP variability was significantly associated with increased risk of mortality (HR = 1.13; 95% confidence interval (CI) = 1.05–1.21) and of incident MI (HR = 1.20; 95%CI = 1.06–1.36), independent of the effect from adjustment factors. Intraindividual SBP variability was not associated with risk of stroke (HR = 1.03; 95% CI = 0.89–1.21).
Long-term visit-to-visit SBP variability was independently associated with a higher risk of subsequent mortality and MI but not stroke. More research is needed to determine the relationship of BP variability with cardiovascular risk and the clinical implications.
blood pressure; blood pressure variability; hypertension; mortality; myocardial infarction; stroke.
Dyslipidemia is a major contributor to the development of atherosclerosis and coronary disease. Its role in the etiology of atrial fibrillation (AF) is uncertain.
Methods and Results
We studied 7142 men and women from the Multi‐Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study who did not have prevalent AF at baseline and were not on lipid‐lowering medications. Total cholesterol, high‐density lipoprotein and low‐density lipoprotein cholesterol, and triglycerides were measured using standard procedures. Incident AF during follow‐up was identified from hospital discharge codes; review of medical charts; study electrocardiograms; and, in MESA only, Medicare claims. Multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals of AF by clinical categories of blood lipids in each cohort. Study‐specific results were meta‐analyzed using inverse of variance weighting. During 9.6 years of mean follow‐up, 480 AF cases were identified. In a combined analysis of multivariable‐adjusted results from both cohorts, high levels of high‐density lipoprotein cholesterol were associated with lower AF risk (hazard ratio 0.64, 95% CI 0.48 to 0.87 in those with levels ≥60 mg/dL versus <40 mg/dL), whereas high triglycerides were associated with higher risk of AF (hazard ratio 1.60, 95% CI 1.25 to 2.05 in those with levels ≥200 mg/dL versus <150 mg/dL). Total cholesterol and low‐density lipoprotein cholesterol were not associated with the risk of AF.
In these 2 community‐based cohorts, high‐density lipoprotein cholesterol and triglycerides but not low‐density lipoprotein cholesterol or total cholesterol were associated with the risk of AF, accounting for other cardiometabolic risk factors.
atrial fibrillation; cholesterol; epidemiology; lipids; risk factors
Coronary artery calcium (CAC) predicts coronary heart disease (CHD) events and serial measurement of CAC has been proposed to evaluate atherosclerosis progression. We examined whether progression of CAC is a predictor of future CHD events.
Methods and Results
We studied 6,778 persons (52.8% female) aged 45–84 years from the Multi-Ethnic Study of Atherosclerosis. 5,682 persons had baseline and follow-up CAC scans approximately 2.5 ± 0.8 years apart; multiple imputation was used to account for the remainder (n=1,096) missing follow-up scans. Median follow-up duration from the baseline was 7.6 (max=9.0) years. CAC change was assessed by absolute change between baseline and follow-up CAC. Cox proportional hazards regression providing hazard ratios (HR) examined the relation of change in CAC with CHD events, adjusting for age, gender, ethnicity, baseline calcium score, and other risk factors. 343 total and 206 hard CHD events occurred. The annual change in CAC averaged 24.9 ± 65.3 units. Among persons without CAC at baseline (n=3,396), a 5 unit annual change in CAC was associated with an adjusted HR of 1.4 (1.0–1.9) for total and 1.5 (1.1–2.1) for hard CHD. Among those with CAC>0 at baseline HR’s (per 100 unit annual change) were 1.2 (1.1–1.4) and 1.3 (1.1–1.5), respectively. Among participants with baseline CAC, those with annual progression of ≥300 units had adjusted HR’s of 3.8 (1.5–9.6) for total and 6.3 (1.9–21.5) for hard CHD compared to those without progression.
Progression of CAC is associated with an increased risk for future hard and total CHD events.
coronary calcification; atherosclerosis; imaging; coronary heart disease
In 2006, the US FDA issued a ‘Guidance for Industry’ regarding submission of New Drug Applications for pancreatic enzyme replacement therapy (PERT) products. Five oral delayed-release PERT products have been approved by the FDA, and several others are under development and/ or evaluation for New Drug Application submission. We present in this paper recommendations of the Cystic Fibrosis Foundation's Cystic Fibrosis (CF) Therapeutics Development Network and Data Safety Monitoring Board regarding study design considerations for evaluating PERT products in patients with CF. Careful attention to study design and accuracy of the outcome measures has confirmed our understanding of the efficacy and safety of PERT for the treatment of exocrine pancreatic insufficiency of CF.
coefficient of fat absorption; cystic fibrosis; pancreatic enzyme replacement therapy; pancreatic insufficiency; study design
Atrial fibrillation (AF), the most common cardiac rhythm abnormality, is associated with significant morbidity, mortality, and health care expenditures. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure, atrial fibrillation, and mortality.
Methods and Results
The relation between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and AF was studied in 5,445 Cardiovascular Health Study participants, using relative risk regression for predicting prevalent AF, and Cox proportional hazards for predicting incident AF. NT-proBNP levels were strongly associated with prevalent AF, with an unadjusted prevalence ratio of 128 for the highest quintile (95%CI 17.9, 913.3, p< 0.001); and adjusted prevalence ratio of 147 for the highest quintile (95% CI 20.4, 1064.3, p<0.001) compared to the lowest. After a median follow up of 10 years (maximum of 16 years), there were 1,126 cases of incident AF (a rate of 2.2 per 100 person years). NT-proBNP was highly predictive of incident AF with an unadjusted hazard ratio of 5.2 (95% CI 4.3, 6.4, p < 0.001) for the development of AF for the highest quintile compared to the lowest; for the same contrast, NT-proBNP remained the strongest predictor of incident AF after adjustment for an extensive number of covariates, including age, sex, medication use, blood pressure, echocardiographic parameters, diabetes, and heart failure; with an adjusted hazard ratio of 4.0 (CI 3.2, 5.0, p< 0.001).
In a community based population of older adults, NT-pro BNP was a remarkable predictor of incident AF, independent of any other previously described risk factor.
B-type natriuretic peptide; atrial fibrillation; BNP; NT-proBNP
The association between non-steroidal anti-inflammatory drugs (NSAIDs) and the incidence of valvular and arterial calcification is not well established despite known associations between these drugs and cardiovascular events.
To compare the association between the baseline use of aspirin with other NSAID class medications with the incidence and prevalence of aortic valve calcification (AVC) and coronary artery calcium (CAC).
The relationship of NSAID use to AVC and CAC detected by computed tomography was assessed in 6,814 participants within the Multi-Ethnic Study of Atherosclerosis (MESA) using regression modeling. Results were adjusted for age, sex, ethnicity, study site, anti-hypertensive medication use, education, income, health insurance status, diabetes, smoking, exercise, body mass index, blood pressure, serum lipids, inflammatory markers, fasting glucose, statin medication use, and a simple diet score. Medication use was assessed by medication inventory at baseline which includes the use of non-prescription NSAIDs. MESA collects information on both incident and prevalent calcification. The 4,814 participants of the Heinz Nixdorf Recall (HNR) Study, a German prospective cohort study with similar measures of calcification, were included in this analysis to enable replication.
Mean age of the MESA participants was 62 years (51% female). After adjustment for possible confounding factors, a possible association between aspirin use and incident AVC (Relative Risk(RR): 1.60; 95%Confidence Interval (CI): 1.19–2.15) did not replicate in the HNR cohort (RR: 1.06; 95%CI: 0.87–1.28). There was no significant association between aspirin use and incident CAC in the MESA cohort (RR 1.08; 95%CI: 0.91–1.29) or in the HNR cohort (RR 1.24; 95%CI: 0.87–1.77). Non-aspirin NSAID use was not associated with either AVC or CAC in either cohort. There were no associations between regular cardiac dose aspirin and incident calcification in either cohort.
Baseline NSAID use, as assessed by medication inventory, appears to have no protective effect regarding the onset of calcification in either coronary arteries or aortic valves.
Non-steroidal anti-inflammatory drugs; aspirin; aortic valve calcification; coronary artery calcification; Multi-Ethnic Study of Atherosclerosis; Heinz Nixdorf Recall Study
The presence and extent of coronary artery calcium (CAC) is an independent predictor of coronary heart disease (CHD) morbidity and mortality. Few studies have evaluated interactions or independent incremental risk for coronary and thoracic aortic calcification (TAC). The independent predictive value of TAC for CHD events is not well-established.
This study used risk factor and computed tomography scan data from 6,807 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Using the same images for each participant, TAC and CAC were each computed using the Agatston method. The study subjects were free of incident CHD at entry into the study.
The mean age of the study population (n=6807) was 62±10 years (47% males). At baseline, the prevalence of TAC and CAC was 28 % (1,904/6,809) and 50% (3393/6809), respectively. Over 4.5±0.9 years, a total of 232 participants (3.41%) had CHD events, of which 132 (1.94%) had a hard event (myocardial infarction, resuscitated cardiac arrest, or CHD death). There was a significant interaction between gender and TAC for CHD events (p<0.05). Specifically, in women, the risk of all CHD event was nearly 3-fold greater among those with any TAC (hazard ratio: 3.04, 95% CI; 1.60–5.76). After further adjustment for increasing CAC score, this risk was attenuated but remained robust (HR: 2.15, 95% CI: 1.10–4.17). Conversely, there was no significant association between TAC and incident CHD in men. In women, the likelihood ratio chi square statistics indicate that the addition of TAC contributed significantly to predicting incident CHD event above that provided by traditional risk factors alone (chi square= 12.44, p=0.0004) as well as risk factors + CAC scores (chi square= 5.33, p=0.02) . On the other hand, addition of TAC only contributed in the prediction of hard CHD events to traditional risk factors (chi-square=4.33, p=0.04) in women, without contributing to the model containing both risk factors and CAC scores (chi square=1.55, p=0.21).
Our study indicates that TAC is a significant predictor of future coronary events only in women, independent of CAC. On studies obtained for either cardiac or lung applications, determination of TAC may provide modest supplementary prognostic information in women with no extra cost or radiation.
atherosclerosis; cardiac CT; coronary calcium; multi-detector CT; prognosis; thoracic atherosclerosis
To study the association between serum C-reactive protein (CRP) and urinary albumin excretion in the Multi-Ethnic Study of Atherosclerosis and to assess whether the association is modified by ethnicity, sex, or systolic blood pressure.
This was a cross-sectional study of 6675 participants who were free from macro albuminuria and clinical cardiovascular disease (mean age 62.1 years, 53% female; 39% White, 27% African American, 22% Hispanic, and 12% Chinese). Urinary albumin excretion was measured by spot urine albumin-to-creatinine ratio (ACR). Effect modifications were tested after adjusting for age, diabetes, body mass index, smoking, use of angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, other antihypertensive drugs, estrogens, statins, and high-density lipoprotein cholesterol and triglyceride levels.
The association between CRP and ACR was modified by ethnicity (P=.01) and sex (P<.001), but not by systolic blood pressure. After multivariate adjustment, the association remained in Chinese, African American, and Hispanic men and African American women (P<.02 for African American men, and P<.04 for the other subgroups).
The association between CRP and ACR was modified by ethnicity and sex; it was stronger in non-White men and African American women. These interactions have not been reported before, and future studies should consider them.
Albuminuria; C-Reactive Protein; Ethnicity; Gender
Cigarette smoking is the major cause of chronic obstructive pulmonary disease and emphysema. Recent studies suggest that susceptibility to cigarette smoke may vary by race/ethnicity; however, they were generally small and relied on self-reported race/ethnicity.
To test the hypothesis that relationships of smoking to lung function and percent emphysema differ by genetic ancestry and self-reported race/ethnicity among Whites, African-Americans, Hispanics and Chinese-Americans.
Cross-sectional population-based study of adults age 45-84 years in the United States
Principal components of genetic ancestry and continental ancestry estimated from one-million genome-wide single nucleotide polymorphisms. Pack-years calculated as years smoking cigarettes-per-day/20. Spirometry measured for 3,344 and percent emphysema on computed tomography for 8,224 participants.
The prevalence of ever-smoking was: Whites, 57.6%; African-Americans, 56.4%; Hispanics, 46.7%; and Chinese-Americans, 26.8%. Every 10 pack-years was associated with −0.73% (95% CI −0.90%, −0.56%) decrement in the forced expiratory volume in one second to forced vital capacity (FEV1/FVC) and a 0.23% (95% CI 0.08%, 0.38%) increase in percent emphysema. There was no evidence that relationships of pack-years to the FEV1/FVC, airflow obstruction and percent emphysema varied by genetic ancestry (all p>0.10), self-reported race/ethnicity (all p>0.10) or, among African-Americans, African ancestry. There were small differences in relationships of pack-years to the FEV1 among male Chinese-Americans and to the FEV1/FVC with African and Native American ancestry among male Hispanics only.
In this large cohort, there was little-to-no evidence that the associations of smoking to lung function and percent emphysema differed by genetic ancestry or self-reported race/ethnicity.
cigarette smoke; genetic ancestry; lung function; chronic obstructive pulmonary disease; COPD; emphysema; FVC; Forced Vital Capacity; FEV1; Forced Expiratory Volume in 1 second
Experimental and physiologic data mechanistically implicate wave reflections in the pathogenesis of left ventricular failure and cardiovascular disease, but their association with these outcomes in the general population is unclear.
To assess the relationship between central pressure profiles and incident cardiovascular events.
Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded non-invasively from 5,960 participants in the Multiethnic Study of Atherosclerosis (MESA). The central pressure waveform was separated into forward and reflected waves using a physiologic flow waveform. Reflection magnitude (RM=[reflected/forward wave amplitude] ×100), augmentation index (AIx=[second/first systolic peak] ×100) and pulse pressure amplification (PPA=[radial/aortic pulse pressure] ×100) were assessed as predictors of cardiovascular events (CVE) and congestive heart failure (CHF) during median 7.61 years of follow-up.
After adjustment for established risk factors, aortic AIx independently predicted hard CVE (HR per 10%-increase=1.08; 95%CI=1.01-1.14; P=0.016), whereas PPA independently predicted all CVE (HR per 10%-increase=0.82; 95%CI=0.70-0.96; P=0.012). RM was independently predictive of all CVE (hazard ratio [HR] per 10%-increase=1.34; 95%CI=1.08-1.67; P=0.009), hard CVE (HR per 10%-increase=1.46; 95%CI=1.12-1.90; P=0.006) and strongly predictive of new-onset CHF (HR per 10%-increase=2.69; 95%CI=1.79-4.04; P<0.0001), comparing favorably to other risk factors for CHF as judged by various measures of model performance, reclassification and discrimination. In a fully-adjusted model, compared to non-hypertensive subjects with low RM, the HR for hypertensive subjects with low RM, non-hypertensive subjects with high RM and hypertensive subjects with high RM were 1.81 (95%CI=0.85-3.86), 2.16 (95%CI=1.07-5.01) and 3.98 (95%CI=1.96-8.05), respectively.
Arterial wave reflections represent a novel strong risk factor for CHF in the general population.
wave reflections; cardiovascular risk; heart failure. arterial hemodynamics; left ventricular afterload
The Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR)) differed in regards to informing physicians and patients of the results of their subclinical atherosclerosis.
This study investigates whether the association of coronary artery calcium (CAC) with incident non-fatal and fatal cardiovascular (CVD) events is different among these two large, population-based observational studies.
All Caucasian subjects aged 45–75 years, free of baseline cardiovascular disease were included (n=2232 in MESA, n=3119 HNR participants). We studied the association between CAC and event rates at 5 years, including hard cardiac events (MI, cardiac death, resuscitated cardiac arrest), and separately added revascularizations, and strokes (fatal and non-fatal) to determine adjusted hazard ratios (HR).
Both cohorts demonstrated very low CHD (including revascularization) rates with zero calcium (1.13 and 1.16% over 5 years in MESA and HNR respectively) and increasing significantly in both groups with CAC 100–399 (6.71 and 4.52% in MESA and HNR) and CAC >400 (12.5 and 13.54% in MESA and HNR respectively) and demonstrating strong independent predictive values for scores of 100–399 and >400, despite multivariable adjustment for risk factors. Risk factor adjusted five year revascularization rates were nearly identical for HNR and MESA, and generally low for both studies (1.4% [45/3119] for HNR and 1.9% [43/2232] for MESA) over 5 years.
Across two culturally diverse populations, CAC >400 is a strong predictor of events. High CAC did not determininistically result in revascularization and knowledge of CAC did not increase revascularizations.
coronary artery calcification; subclinical atherosclerosis; Multi-Ethnic Study of Atherosclerosis (MESA); Heinz Nixdorf Recall Study (HNR)