The discrimination of a risk prediction model measures that model's ability to distinguish between subjects with and without events. The area under the receiver operating characteristic curve (AUC) is a popular measure of discrimination. However, the AUC has recently been criticized for its insensitivity in model comparisons in which the baseline model has performed well. Thus, 2 other measures have been proposed to capture improvement in discrimination for nested models: the integrated discrimination improvement and the continuous net reclassification improvement. In the present study, the authors use mathematical relations and numerical simulations to quantify the improvement in discrimination offered by candidate markers of different strengths as measured by their effect sizes. They demonstrate that the increase in the AUC depends on the strength of the baseline model, which is true to a lesser degree for the integrated discrimination improvement. On the other hand, the continuous net reclassification improvement depends only on the effect size of the candidate variable and its correlation with other predictors. These measures are illustrated using the Framingham model for incident atrial fibrillation. The authors conclude that the increase in the AUC, integrated discrimination improvement, and net reclassification improvement offer complementary information and thus recommend reporting all 3 alongside measures characterizing the performance of the final model.
area under curve; biomarkers; discrimination; risk assessment; risk factors
The purpose of this study was to assess the prevalence and distribution of coronary artery calcium (CAC) across Framingham Risk Score (FRS) strata and therefore determine FRS levels at which asymptomatic, young to early middle-age individuals could potentially benefit from CAC screening.
High CAC burden is associated with increased risk of coronary events beyond the FRS. Expert panel recommendations for CAC screening are based on data obtained in middle-age and older individuals.
We included 2,831 CARDIA (Coronary Artery Risk Development in Young Adults) study participants with an age range of 33 to 45 years. The number needed to screen ([NNS] number of people in each FRS stratum who need to be screened to detect 1 person with a CAC score above the specified cut point) was used to assess the yield of screening for CAC. CAC prevalence was compared across FRS strata using a chi-square test.
CAC scores >0 and ≥100 were present in 9.9% and 1.8% of participants, respectively. CAC prevalence and amount increased across higher FRS strata. A CAC score >0 was observed in 7.3%, 20.2%, 19.1%, and 44.8% of individuals with FRSs of 0 to 2.5%, 2.6% to 5%, 5.1% to 10%, and >10%, respectively (NNS = 14, 5, 5, and 2, respectively). A CAC score of ≥100 was observed in 1.3%, 2.4%, and 3.5% of those with FRSs of 0 to 2.5%, 2.6% to 5%, and 5.1% to 10%, respectively (NNS = 79, 41, and 29, respectively), but in 17.2% of those with an FRS >10% (NNS = 6). Similar trends were observed when findings were stratified by sex and race.
In this young to early middle-age cohort, we observed concordance between CAC prevalence/amount and FRS strata. Within this group, the yield of screening and possibility of identifying those with a high CAC burden (CAC score of ≥100) is low in those with an FRS of ≤10%, but considerable in those with an FRS >10%.
coronary artery calcium; coronary heart disease; Framingham Risk Score; number needed to screen; risk factors
Return of individual genetic results to research participants, including participants in archives and biorepositories, is receiving increased attention. However, few groups have deliberated on specific results or weighed deliberations against relevant local contextual factors.
The Electronic Medical Records and GEnomics (eMERGE) network, which includes five biorepositories conducting genome-wide association studies, convened a Return of Results Oversight Committee (RROC) to identify potentially returnable results. Network-wide deliberations were then brought to local constituencies for final decision-making.
Defining results that should be considered for return required input from clinicians with relevant expertise and much deliberation. The RROC identified two sex chromosomal anomalies, Klinefelter Syndrome and Turner Syndrome, as well as homozygosity for Factor V Leiden, as findings that could warrant reporting. Views about returning HFE gene mutations associated with hemochromatosis were mixed due to low penetrance. Review of EMRs suggested that most participants with detected abnormalities were unaware of these findings. Local considerations relevant to return varied and, to date, four sites have elected not to return findings (return was not possible at one site).
The eMERGE experience reveals the complexity of return of results decision-making and provides a potential deliberative model for adoption in other collaborative contexts.
Result return; biorepository; electronic medical records; deliberation; context
We sought to determine whether novel markers not involving ionizing radiation could predict CAC progression in a low-risk population.
Increase in coronary artery calcium (CAC) scores over time (CAC progression) improves prediction of coronary heart disease (CHD) events. Due to radiation exposure, CAC measurement represents an undesirable method for repeated risk assessment, particularly in low predicted risk individuals (Framingham Risk Score [FRS] <10%).
From 6814 MESA participants, 2620 individuals were classified as low risk for CHD events (FRS <10%), and had follow-up CAC measurement. In addition to traditional risk factors [(RFs) - base model], various combinations of novel-marker models were selected based on data-driven, clinical, or backward stepwise selection techniques.
Mean follow-up was 2.5 years. CAC progression occurred in 574 participants (22% overall; 214 of 1830 with baseline CAC =0, and 360 of 790 with baseline CAC >0). Addition of various combinations of novel markers to the base model (c-statistic =0.711), showed improvements in discrimination of approximately only 0.005 each (c-statistics 0.7158, 0.7160 and 0.7164) for the best-fit models. All 3 best-fit novel-marker models calibrated well but were similar to the base model in predicting individual risk probabilities for CAC progression. The highest prevalence of CAC progression occurred in the highest compared to the lowest probability quartile groups (39.2–40.3% versus 6.4–7.1%).
In individuals at low predicted risk by FRS, traditional RFs predicted CAC progression in the short term with good discrimination and calibration. Prediction improved minimally when various novel markers were added to the model.
coronary calcium; Framingham risk score; risk factors; progression
Genome wide association studies identified several single nucleotide polymorphisms (SNPs) associated with prevalent coronary heart disease (CHD) but less is known of associations with incident CHD. The association of thirteen published CHD SNPs was examined in five ancestry groups of four large US prospective cohorts.
Methods and Results
The analyses included incident coronary events over 9.1 to 15.7 average follow-up times in up to 26,617 white individuals (6,626 events), 8,018 African Americans (914 events), 1,903 Hispanics (113 events), 3,669 American Indians (595 events) and 885 Asian/Pacific Islanders (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex and ancestry (as needed). Nine loci were statistically associated with incident CHD events in whites: 9p21 (rs10757278, p=4.7 × 10−41), 16q23.1 (rs2549513, p=0.0004), 6p24.1 (rs499818, p=0.0002), 2q36.3 (rs2943634, p=6.7 × 10−6), MTHFDIL (rs6922269, p=5.1 × 10−10), APOE (rs429358, p=2.7 × 10−18), ZNF627 (rs4804611, p=5.0 × 10−8), CXCL12 (rs501120, p=1.4 × 10−6) and LPL (rs268, p=2.7 × 10−17). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals aged 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in African Americans and associations varied in other US minorities.
Prospective analyses of white individuals replicated several reported cross-sectional CHD-SNP associations.
9p21 locus; incident coronary heart disease; genetic polymorphisms
Functional biomarkers like large artery elasticity (LAE) and small artery elasticity (SAE) may predict cardiovascular disease (CVD) events beyond blood pressure. The authors examined the prognostic value of LAE and SAE for clinical CVD events among 6,235 Multi-Ethnic Study of Atherosclerosis participants who were initially aged 45–84 years and without symptomatic CVD. LAE and SAE were derived from diastolic pulse contour analysis. During a median 5.8 years of follow-up between 2000 and 2008, 454 adjudicated CVD events occurred, including 256 cases of coronary heart disease (CHD), 93 strokes, and 126 heart failures (multiple diagnoses were possible). After adjustment for age, race/ethnicity, sex, clinic, height, heart rate, body mass index, systolic and diastolic blood pressure, use of antihypertensive and cholesterol-lowering medications, smoking, total cholesterol, high density lipoprotein cholesterol, triglycerides, diabetes, and high-sensitivity C-reactive protein, the hazard ratio for any CVD per standard-deviation increase in SAE was 0.71 (95% confidence interval: 0.61, 0.83; P < 0.0001). The lowest (stiffest) SAE quartile had a hazard ratio of 2.28 (95% confidence interval: 1.55, 3.36) versus the highest (most elastic) quartile. The net reclassification index, conditional on base risk, was 0.11. SAE was significantly associated with future CHD, stroke, and heart failure. After adjustment, LAE was not significantly related to CVD. In asymptomatic participants free of overt CVD, lower SAE added prognostic information for CVD, CHD, stroke, and heart failure events.
arteries; cardiovascular diseases; elasticity; risk factors
To evaluate independent associations of high density lipoprotein cholesterol (HDL-C) and particle (HDL-P) concentrations with carotid intima-media thickness (cIMT) and incident coronary heart disease (CHD).
HDL-C is inversely related to CHD, but also to triglycerides, LDL particles (LDL-P), and related metabolic risk. HDL-P associations with CHD may be partially independent of these factors.
In a multi-ethnic study of 5598 men and women ages 45-84, without baseline CHD, excluding subjects on lipid-lowering medications, triglycerides >400 mg/dl or missing values, we evaluated associations of HDL-C and NMR-spectroscopy-measured HDL-P with cIMT and incident CHD (myocardial infarction, CHD death, angina, n=227 events, 6.0 years mean follow-up). All models were adjusted for age, sex, ethnicity, hypertension and smoking.
HDL-C and HDL-P correlated with each other (π=0.69) and LDL-P (π = −0.38, −0.25, respectively), p<0.05 for all. For (1-SD) higher HDL-C (15 mg/dl) or HDL-P (6.64 μmol/l), cIMT differences (95%CI) were −26.1(−34.7,−17.4) and −30.1 (−38.8,−21.4) μm, and CHD hazard ratios (HR (95%CI)) were 0.74 (0.63, 0.88) and 0.70 (0.59, 0.82), respectively. Adjusted for each other and LDL-P, HDL-C was no longer associated with cIMT (2.3 (−9.5, 14.2) μm) or CHD (0.97(0.77, 1.22)), but HDL-P remained independently associated with cIMT (−22.2(−33.8,−10.6) μm) and CHD (0.75 (0.61, 0.93)). Interactions by sex, ethnicity, diabetes and high-sensitivity C-reactive protein were not significant.
Adjusting for each other and LDL-P substantially attenuated associations of HDL-C, but not HDL-P, with cIMT and CHD. Potential confounding by related lipids or lipoproteins should be carefully considered when evaluating HDL-related risk.
Lipids; lipoproteins; high-density lipoprotein cholesterol; high-density lipoprotein particles; cardiovascular disease
The lifetime risks of cardiovascular disease have not been reported across the age spectrum in black adults and white adults.
We conducted a meta-analysis at the individual level using data from 18 cohort studies involving a total of 257,384 black men and women and white men and women whose risk factors for cardiovascular disease were measured at the ages of 45, 55, 65, and 75 years. Blood pressure, cholesterol level, smoking status, and diabetes status were used to stratify participants according to risk factors into five mutually exclusive categories. The remaining lifetime risks of cardiovascular events were estimated for participants in each category at each age, with death free of cardiovascular disease treated as a competing event.
We observed marked differences in the lifetime risks of cardiovascular disease across risk-factor strata. Among participants who were 55 years of age, those with an optimal risk-factor profile (total cholesterol level, <180 mg per deciliter [4.7 mmol per liter]; blood pressure, <120 mm Hg systolic and 80 mm Hg diastolic; nonsmoking status; and nondiabetic status) had substantially lower risks of death from cardiovascular disease through the age of 80 years than participants with two or more major risk factors (4.7% vs. 29.6% among men, 6.4% vs. 20.5% among women). Those with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal myocardial infarction (3.6% vs. 37.5% among men, <1% vs. 18.3% among women) and fatal or nonfatal stroke (2.3% vs. 8.3% among men, 5.3% vs. 10.7% among women). Similar trends within risk-factor strata were observed among blacks and whites and across diverse birth cohorts.
Differences in risk-factor burden translate into marked differences in the lifetime risk of cardiovascular disease, and these differences are consistent across race and birth cohorts. (Funded by the National Heart, Lung, and Blood Institute.)
Whether fish or the fatty acids they contain are independently associated with risk for incident heart failure (HF) among postmenopausal women is unclear.
Methods and Results
The baseline Women’s Health Initiative Observational Study (WHI-OS) cohort consisted of 93,676 women aged 50–79 of diverse ethnicity and background of which 84,493 were eligible for analyses. Intakes of baked/broiled fish, fried fish and omega-3 fatty acid (eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), α-linolenic acid (ALA)), and trans fatty acid (TFA) were determined from the WHI food frequency questionnaire. Baked/broiled fish consumption was divided into 5 frequency categories: <1/mo (referent), 1–3/mo, 1–2/wk, 3–4/wk, ≥5/wk. Fried fish intake was grouped into 3 frequency categories: <1/mo (referent), 2) 1–3/mo, and 3) ≥1/wk. Associations between fish or fatty acid intake and incident HF were determined using Cox models adjusting for HF risk factors and dietary factors. Baked/broiled fish consumption (≥5 servings/wk at baseline) was associated with a hazard ratio (HR) of 0.70 (95% CI: 0.51, 0.95) for incident HF. In contrast, fried fish consumption (≥1 serving/wk at baseline) was associated with a HR of 1.48 (95% CI: 1.19, 1.84) for incident HF. No significant associations were found between EPA+DHA, ALA, or TFA intake and incident HF.
Increased baked/broiled fish intake may lower HF risk, while increased fried fish intake may increase HF risk in postmenopausal women.
heart failure; epidemiology; nutrition; women
Peripheral arterial disease patients are less likely than other high-risk patients to achieve ideal low density lipoprotein cholesterol (LDL-cholesterol) levels. This randomized controlled trial assessed whether a telephone counseling intervention, designed to help peripheral arterial disease patients request more intensive cholesterol lowering therapy from their physician, achieves lower LDL-cholesterol levels than two control conditions.
355 peripheral arterial disease participants with baseline LDL-cholesterol ≥ 70 mg/dl were enrolled. The primary outcome was change in LDL-cholesterol level at twelve-month follow-up. There were three parallel arms: telephone counseling intervention, attention control condition, and usual care. The intervention consisted of patient-centered counseling, delivered every six weeks, encouraging participants to request increases in cholesterol-lowering therapy from their physician. The attention control condition consisted of telephone calls every six weeks providing information only. The usual care condition participated in baseline and follow-up testing.
At 12-month follow-up, participants in the intervention improved their LDL-cholesterol level, compared to those in attention control (−18.4 mg/dl vs. −6.8 mg/dl, p= 0.010) but not compared to those in usual care (−18.4 mg/dl vs. −11.1 mg/dl, p= 0.208). Intervention participants were more likely to start a cholesterol-lowering medication or increase their cholesterol-lowering medication dose than those in the attention control (54% vs. 18%, p=0.001) and usual care (54% vs. 31%, P<0.001) conditions.
Telephone counseling that helped peripheral arterial disease patients request more intensive cholesterol-lowering therapy from their physician achieved greater LDL-cholesterol declines than an attention control arm that provided health information alone.
Intermittent claudication; secondary prevention; peripheral arterial disease
By examining the distribution of CAC across FRS strata in a large, multi-ethnic, community-based sample of men and women, we sought to determine if lower risk persons could potentially benefit from CAC screening.
The 10-year Framingham risk scores (FRS) and coronary artery calcium (CAC) are predictors of coronary heart disease (CHD). CAC ≥300 is associated with the highest risk for CHD even in low risk (FRS <10%) persons; however expert groups have suggested CAC screening only in intermediate risk (FRS 10–20%) groups.
We included 5660 MESA participants. The number needed to screen [number of people that need to be screened to detect one person with CAC above the specified cut-point (NNS)] was used to assess the yield of screening for CAC. CAC prevalence was compared across FRS strata using chi-square tests.
CAC >0, ≥100 and ≥300 were present in 46.4%, 20.6% and 10.1% of participants, respectively. Prevalence and amount of CAC increased with higher FRS. CAC ≥300 was observed in 1.7% and 4.4% of those with FRS 0–2.5% and 2.6–5%, respectively (NNS =59.7 and 22.7). Likewise, CAC ≥300 was observed in 24% and 30% of those with FRS 15.1–20% and >20%, respectively (NNS =4.2 and 3.3). Trends were similar when stratified by age, gender and race/ethnicity.
Our study suggests that in very low risk individuals (FRS ≤5%), the yield of screening and probability of identifying persons with clinically significant levels of CAC is low, but becomes greater in low and intermediate risk persons (FRS 5.1–20%).
Framingham risk score; coronary calcium; coronary heart disease; number needed to screen; risk factors; population; atherosclerosis; low risk
Even among asymptomatic people at low risk (<10%) by Framingham Risk Score (FRS), high coronary artery calcium (CAC) scores signify higher predicted risk of coronary heart disease (CHD) events. We sought to determine non-invasive factors (without radiation exposure) significantly associated with CAC in low-risk, asymptomatic persons. In a cross-sectional analysis, we studied 3046 participants from MESA at low 10-year predicted risk (FRS <10%) for CHD events. Multivariable logistic regression was used to assess the association of novel markers with presence of any CAC (CAC >0) and advanced CAC (CAC ≥ 300). CAC >0 and CAC ≥ 300 were present in 30% and 3.5% of participants, respectively. Factor VIIIc, fibrinogen and sICAM were each associated with CAC presence (P ≤ 0.02); and C-reactive protein, D-dimer and carotid intima-media thickness (CIMT) with advanced CAC (P ≤ 0.03). The base model combining traditional risk factors had excellent discrimination for advanced CAC (C-statistic, 0.808). Addition of the 2 best-fit models combining biomarkers plus/minus CIMT improved the c-statistics to 0.822 and 0.820, respectively. All 3 models calibrated well, but were similar in estimating individual risk probabilities for advanced CAC (prevalence = 9.97%, 10.63% and 10.10% in the highest quartiles of predicted probabilities versus 0.26%, 0.26% and 0.26% in the lowest quartiles, respectively). In conclusion, in low risk individuals, traditional risk factors alone predicted advanced CAC with high discrimination and calibration. Biomarker combinations +/− CIMT were also significantly associated with advanced CAC, but improvement in prediction and estimation of clinical risk were modest compared to traditional risk factors alone.
coronary calcium; biomarkers; novel markers; low-risk; risk factors
The amount of cholesterol per LDL particle is variable and related in part to particle size, with smaller particles carrying less cholesterol. This variability causes concentrations of LDL cholesterol (LDL-C) and LDL particles (LDL-P) to be discordant in many individuals.
LDL-P measured by nuclear magnetic resonance (NMR) spectroscopy, calculated LDL-C, and carotid intima-media thickness (IMT) were assessed at baseline in the Multi-Ethnic Study of Atherosclerosis (MESA), a community-based cohort of 6814 persons free of clinical CVD at entry and followed for CVD events (n=319 during 5.5-year follow-up). Discordance, defined as values of LDL-P and LDL-C differing by ≥ 12 percentile units to give equal-sized concordant and discordant subgroups, was related to CVD events and to carotid IMT in models predicting outcomes for a 1 SD difference in LDL-C or LDL-P, adjusted for age, sex and race.
LDL-C and LDL-P were associated with incident CVD overall: hazard ratios (HR [95% CI]) 1.20 [1.08, 1.34] and 1.32 [1.19, 1.47], respectively, but for those with discordant levels, only LDL-P was associated with incident CVD (HR: 1.45 [1.19, 1.78]) (LDL-C HR: 1.07 [0.88, 1.30])). IMT also tracked with LDL-P rather than LDL-C, i.e., adjusted mean IMT of 958, 932, and 917 μm in the LDL-P > LDL-C discordant, concordant, and LDL-P < LDL-C discordant subgroups, respectively, with the difference persisting after adjustment for LDL-C (p=0.002) but not LDL-P (p=0.60).
For individuals with discordant LDL-C and LDL-P levels, the LDL-attributable atherosclerotic risk is better indicated by LDL-P.
LDL particle number; LDL cholesterol; cardiovascular disease risk; NMR; lipoproteins
The National Heart, Lung, and Blood Institute convened working group to provide basic and clinical research recommendations to the National Heart, Lung, and Blood Institute on the development of an integrated approach for identifying those individuals who are at high risk for cardiovascular event such as acute coronary syndromes (ACS) or sudden cardiac death in the “near term.” The working group members defined near-term as occurring within 1 year of the time of assessment. The participants reviewed current clinical cardiology practices for risk assessment and state-of-the-science techniques in several areas, including biomarkers, proteomics, genetics, psychosocial factors, imaging, coagulation, and vascular and myocardial susceptibility. This report presents highlights of these reviews and a summary of suggested research directions.
cardiovascular diseases; death, sudden; myocardial infarction; risk factors; risk prediction
Coronary artery calcium score (CACS) has been shown to predict future coronary heart disease (CHD) events. However, the extent to which adding CACS to traditional CHD risk factors improves classification of risk is unclear.
To determine whether adding CACS to a prediction model based on traditional risk factors improves classification of risk.
Design, Setting and Participants
CACS was measured by computed tomography on 6,814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based cohort without known cardiovascular disease. Recruitment spanned July 2000 to September 2002; follow-up extended through May 2008. Participants with diabetes were excluded for the primary analysis. Five-year risk estimates for incident CHD were categorized as 0-<3%, 3-<10%, and ≥10% using Cox proportional hazards models. Model 1 used age, gender, tobacco use, systolic blood pressure, antihypertensive medication use, total and high-density lipoprotein cholesterol, and race/ethnicity. Model 2 used these risk factors plus CACS. We calculated the net reclassification improvement (NRI) and compared the distribution of risk using Model 2 versus Model 1.
Main Outcome Measures
Incident CHD events
Over 5.8 years median follow-up, 209 CHD events occurred, of which 122 were myocardial infarction, death from CHD, or resuscitated cardiac arrest. Model 2 resulted in significant improvements in risk prediction compared to Model 1 (NRI=0.25, 95% confidence interval 0.16-0.34, P<0.001). With Model 1, 69% of the cohort was classified in the highest or lowest risk categories, compared to 77% with Model 2. An additional 23% of those who experienced events were reclassified to high risk, and an additional 13% without events were reclassified to low risk using Model 2.
In the MESA cohort, addition of CACS to a prediction model based on traditional risk factors significantly improved the classification of risk and placed more individuals in the most extreme risk categories.
There is increasing interest in utilizing novel markers of cardiovascular disease risk, and consequently, there is a need to assess the value of their use. This scientific statement reviews current concepts of risk evaluation and proposes standards for the critical appraisal of risk assessment methods. An adequate evaluation of a novel risk marker requires a sound research design, a representative at-risk population, and an adequate number of outcome events. Studies of a novel marker should report the degree to which it adds to the prognostic information provided by standard risk markers. No single statistical measure provides all the information needed to assess a novel marker, so measures of both discrimination and accuracy should be reported. The clinical value of a marker should be assessed by its effect on patient management and outcomes. In general, a novel risk marker should be evaluated in several phases, including initial proof of concept, prospective validation in independent populations, documentation of incremental information when added to standard risk markers, assessment of effects on patient management and outcomes, and ultimately, cost-effectiveness.
AHA Scientific Statements; risk assessment; models, statistical; evaluation studies
Isolated minor non-specific ST-segment and T-wave (NSSTA), minor and major electrocardiographic (ECG) abnormalities are established, independent risk markers for incident cardiovascular events. Their association with subclinical atherosclerosis has been postulated but is not clearly defined. The aim of this study is to define the association between ECG abnormalities and measures of subclinical atherosclerosis. We studied participants from MESA, a multi-ethnic sample of men and women aged 45–84 and free of clinical cardiovascular disease at enrollment. Baseline examination included measurement of traditional risk factors, resting 12-lead electrocardiograms, coronary artery calcium (CAC) measurement and common carotid intima-media thickness (CCIMT). Electrocardiograms were coded using Novacode criteria and were defined as having either minor abnormalities (e.g., minor non-specific STTA, first degree atrioventricular block, and QRS axis deviations) or major abnormalities (e.g., pathologic Q waves, major ST-segment and T-wave abnormalities, significant dysrhythmias and conduction system delays). Multivariable logistic and linear regressions were used to determine the cross-sectional associations of ECG abnormalities with CAC and common carotid-IMT. Among 6710 participants, 52.7% were women, with a mean age of 62 years. After multivariable-adjustment, isolated minor STTA, minor and major ECG abnormalities were not associated with the presence of CAC (>0) among men (OR 1.04, 95% CI 0.81–1.33; 1.10, 0.91–1.32; and 1.03, 0.81–1.31, respectively) or women (1.01, 0.82–1.24; 1.04, 0.87–1.23; and 0.94, 0.73–1.22, respectively). Lack of association remained consistent when using both log CAC and CC-IMT as continuous variables. ECG abnormalities are not associated with markers of subclinical atherosclerosis in a large multi-ethnic cohort.
Elevated coronary artery calcium (CAC) is a marker for increase risk of coronary heart disease (CHD). While the majority of CHD events occur among individuals with advanced CAC, CHD can also occur in individuals with little or no calcified plaque. In this study, we sought to evaluate the characteristics associated with incident CHD events in the setting of minimal (score ≤10) or absent CAC (score of zero).
Asymptomatic participants in the Multi-Ethnic Study of Atherosclerosis (MESA) (N=6,809), were followed for occurrence of all CHD events (including myocardial infarction(MI), angina, resuscitated cardiac arrest, or CHD death) and hard CHD events (MI or CHD death). Time to incident CHD was modeled using age-and gender-adjusted Cox regression.
The final study population consisted of 3,923 MESA asymptomatic participants (mean age: 58±9years,39% males) had with CAC scores of 0-10. Overall no detectable CAC was seen in 3415 individuals, whereas 508 had CAC scores of 1-10. During follow up (median 4.1 years) there were 16 incident hard events, and 28 all CHD events in individuals with absent or minimal CAC. In age, gender, race and CHD risk factors adjusted analysis, minimal CAC (1-10) was associated with an estimated 3-fold greater risk of a hard CHD event (HR: 3.23, 95% CI: 1.17-8.95), or of all CHD event (HR: 3.66, 95% CI 1.71-7.85) compared to those with CAC=0. Former smoking (HR=3.57; 1.08-11.77), current smoking (HR=4.93; 1.20-20.30), and diabetes (HR=3.09; 1.07-8.93) were significant risk factors for events in those with CAC=0.
Asymptomatic persons with absent or minimal CAC are at very low risk of future cardiovascular events. Individuals with minimal CAC (1-10) were significantly increased to three fold increased risk for incident CHD events relative to those with CAC scores of zero.
Computed Tomography; Prognosis; Coronary Artery Calcification; Atherosclerosis; Coronary Calcium Score; Cardiac Events
The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms. A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research. The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact. Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation. To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed.
behavioral sciences; epidemiologic methods; evidence-based medicine; genetics; genetic testing; genomics; medicine; public health
Coronary artery calcium (CAC), carotid intimal medial thickness (cIMT), and reduced ankle brachial indices (ABI) are markers of subclinical vascular disease strongly associated with aging. We identified factors associated with low levels of subclinical vascular disease in 1824 participants ≥70 years in the Multi-Ethnic Study of Atherosclerosis. 452 had low CAC (<25th percentile), 441 had low cIMT (<25th percentile), 1636 had normal ABI (>0.9), and 165 had a combination index indicating favorable values for all three parameters. This combination index was independently associated with younger age [OR=2.5 per 1 SD (95%CI 1.8–3.6)], female gender [OR=3.0(1.9–4.8)], lower BMI [OR=1.6 per 1 SD (1.2–2.0)], absence of hypertension [OR=1.8(1.2–2.6)], absence of dyslipidemia [OR=1.6 (1.04–2.4)], and never smoking [OR=1.7(1.1–2.6)]. No significant associations were observed for C-reactive protein, education, diet, or physical activity. Favorable levels of multiple traditional risk factors, but not several novel risk factors, were associated with subclinical markers of successful cardiovascular aging.
In July of 2008, the National Heart, Lung, and Blood Institute convened experts in noninvasive cardiovascular imaging, outcomes research, statistics, and clinical trials to develop recommendations for future randomized controlled trials of the use of imaging in: 1) screening the asymptomatic patient for coronary artery disease; 2) assessment of patients with stable angina; 3) identification of acute coronary syndromes in the emergency room; and 4) assessment of heart failure patients with chronic coronary artery disease with reduced left ventricular ejection fraction. This study highlights several possible trial designs for each clinical situation.
cardiovascular imaging; chest pain diagnosis; clinical trials
cardiovascular imaging; chest pain diagnosis; clinical trials
The authors assessed associations of body size perception and weight change over 13 years in black men and women and white men and women from the Coronary Artery Risk Development in Young Adults (CARDIA) Study (1992–2005). The perceptions of self and ideal body size were measured by using the Stunkard 9-figure scale at the year 7 examination (1992–1993). Figures were classified into underweight, normal weight, overweight, and obese. Self-ideal discrepancy yielded 4 body size satisfaction categories. Body mass index (BMI) (measured at years 7, 10, 15, and 20) was the dependent variable in gender-specific adjusted multiple regression models stratified by year 7 BMI. Obese women who perceived themselves as obese lost 0.09 BMI units annually, while those who perceived themselves as normal weight gained 0.31 units annually (P = 0.0005); obese women who considered their body size much too large had less annual weight gain than did those who considered their body size a bit too large (0.21 vs. 0.38 BMI units; P = 0.009). Obese women with overweight ideal body size gained less weight annually than did those with normal weight ideal body size (0.12 vs. 0.27 BMI units; P = 0.04). Results for men showed fewer and weaker associations. When obese women perceive themselves as obese and feel that their body size is too large, they gain less weight over time.
body image; body mass index; health status disparities; obesity; psychology; weight gain
Clinical trials of postmenopausal hormone therapy have shown increased risk of coronary heart disease (CHD) in the first few years after initiation of therapy, and no overall benefit.
To evaluate a range of inflammatory, lipid, thrombotic, and genetic markers for their association with CHD and to assess whether any of these markers modified or mediated the initially increased risk associated with hormone therapy
Nested case-control study of biomarkers and genetic variants in the Women’s Health Initiative randomized, controlled trials of hormone therapy in postmenopausal women aged 50–79 years at baseline.
Conjugated equine estrogens 0.625 mg daily or placebo in 10,739 hysterectomized women, and the same estrogen plus medroxy-progesterone acetate 2.5 mg daily in 16,608 women with an intact uterus.
Main outcome measures
Associations between putative biomarkers and genetic markers, hormone treatment, and CHD events during the first 4 years after randomization.
In multivariable-adjusted analyses of 359 cases and 820 controls, in the combined trials baseline levels of 12 of the 23 biomarkers studied were associated with CHD events: interleukin-6, matrix metalloproteinase-9, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides, d-dimer, factor VIII, von Willebrand factor, leukocyte count, homocysteine, and fasting insulin. Biomarkers tended to be more strongly associated with CHD in the initial 2 years after randomization. The genetic polymorphism glycoprotein IIIa leu33pro was significantly associated with CHD. Baseline low-density lipoprotein cholesterol interacted significantly with hormone treatment (particularly with CEE+MPA), so that women with higher levels were at higher risk of CHD when given hormone therapy (p for interaction = 0.03). There was a non-significant interaction of baseline high-density lipoprotein cholesterol with hormone therapy on CHD (p = 0.08). The levels of several biomarkers were changed by hormone therapy, but these changes did not appear to be associated with future CHD events.
The study confirmed that several thrombotic, inflammatory, and lipid biomarkers were associated with CHD events in postmenopausal women, however only low-density cholesterol (an established risk factor) modified the effect of hormone therapy. Further research is needed to identify the mechanisms by which hormone therapy increases the risk of CHD.
biomarkers; risk prediction; hormone therapy; estrogen; medroxy-progesterone; coronary heart disease; stroke; mortality; clinical trials; age; menopause