Objective

Lower C2, a continuous blood pressure waveform characteristic asserted to represent small artery elasticity, predicts future cardiovascular disease events. It is hypothesized that the paradoxical positive association between body mass index (BMI) and C2 may reflect muscle instead of excess fat.

Methods

In a multi-ethnic, community-living cohort of 1,960 participants, computed tomography scans of the abdomen were used to measure visceral adipose tissue (VAT) and total abdominal muscle tissue (TAMT), and applanation tonometry of the radial arteries was used to assess C2. The period cross-sectional associations between BMI, TAMT, and VAT with C2 were ascertained.

Results

The mean age was 62 ± 9 years and 51% were male. After adjustments for age, gender, ethnicity, pack years smoking cigarettes, diabetes, hypertension, and total and HDL cholesterol, higher BMI (standardized beta = 0.09, P-value < 0.01) and more TAMT (standardized beta = 0.12, P-value < 0.01) were significantly associated with higher C2. In contrast, more VAT (standardized beta = -0.09, P-value < 0.01) was associated with lower C2.

Conclusions

In multivariable analysis, VAT, in contrast to TAMT and BMI, was associated with less compliant small arteries. Visceral fat may be a better marker for detrimental excess body fat than BMI.

Objectives

This study assessed the utility of the pooled cohort equation (PCE) and/or coronary artery calcium (CAC) for atherosclerotic cardiovascular disease (ASCVD) risk assessment in smokers, especially those who were lung cancer screening eligible (LCSE).

Background

The U.S. Preventive Services Task Force recommended and the Centers for Medicare & Medicaid Services currently pays for annual screening for lung cancer with low-dose computed tomography scans in a specified group of cigarette smokers. CAC can be obtained from these low-dose scans. The incremental utility of CAC for ASCVD risk stratification remains unclear in this high-risk group.

Methods

Of 6,814 MESA (Multi-Ethnic Study of Atherosclerosis) participants, 3,356 (49.2% of total cohort) were smokers (2,476 former and 880 current), and 14.3% were LCSE. Kaplan-Meier, Cox proportional hazards, area under the curve, and net reclassification improvement (NRI) analyses were used to assess the association between PCE and/or CAC and incident ASCVD. Incident ASCVD was defined as coronary death, nonfatal myocardial infarction, or fatal or nonfatal stroke.

Results

Smokers had a mean age of 62.1 years, 43.5% were female, and all had a mean of 23.0 pack-years of smoking. The LCSE sample had a mean age of 65.3 years, 39.1% were female, and all had a mean of 56.7 pack-years of smoking. After a mean of 11.1 years of follow-up 13.4% of all smokers and 20.8% of LCSE smokers had ASCVD events; 6.7% of all smokers and 14.2% of LCSE smokers with CAC = 0 had an ASCVD event during the follow-up. One SD increase in the PCE 10-year risk was associated with a 68% increase risk for ASCVD events in all smokers (hazard ratio: 1.68; 95% confidence interval: 1.57 to 1.80) and a 22% increase in risk for ASCVD events in the LCSE smokers (hazard ratio: 1.22; 95% confidence interval: 1.00 to 1.47). CAC was associated with increased ASCVD risk in all smokers and in LCSE smokers in all the Cox models. The C-statistic of the PCE for ASCVD was higher in all smokers compared with LCSE smokers (0.693 vs. 0.545). CAC significantly improved the C-statistics of the PCE in all smokers but not in LCSE smokers. The event and nonevent net reclassification improvements for all smokers and LCSE smokers were 0.018 and -0.126 versus 0.16 and -0.196, respectively.

Conclusions

In this well-characterized, multiethnic U.S. cohort, CAC was predictive of ASCVD in all smokers and in LCSE smokers but modestly improved discrimination over and beyond the PCE. However, 6.7% of all smokers and 14.2% of LCSE smokers with CAC = 0 had an ASCVD event during follow-up.

Background

Assessment of coronary artery calcium (CAC) during lung cancer screening chest computed tomography (CT) represents an opportunity to identify asymptomatic individuals at increased coronary heart disease (CHD) risk. We determined the improvement in CHD risk prediction associated with the addition of CAC testing in a population recommended for lung cancer screening.

Methods

We included 484 out of 6814 Multi-Ethnic Study of Atherosclerosis (MESA) participants without baseline cardiovascular disease who met U.S. Preventive Service Task Force CT lung cancer screening criteria and underwent gated CAC testing. 10 year-predicted CHD risks with and without CAC were calculated using a validated MESA-based risk model and categorized into low (<5%), intermediate (5%-10%), and high (≥10%). The net reclassification improvement (NRI) and change in Harrell's C-statistic by adding CAC to the risk model were subsequently determined.

Results

Of 484 included participants (mean age = 65; 39% women; 32% black), 72 (15%) experienced CHD events over the course of follow-up (median = 12.5 years). Adding CAC to the MESA CHD risk model resulted in 17% more participants classified into the highest or lowest risk categories and a NRI of 0.26 (p = 0.001). The C-statistic improved from 0.538 to 0.611 (p = 0.01).

Conclusions

CHD event rates were high in this lung cancer screening eligible population. These individuals represent a high-risk population who merit consideration for CHD prevention measures regardless of CAC score. Although overall discrimination remained poor with inclusion of CAC scores, determining whether those reclassified to an even higher risk would benefit from more aggressive preventive measures may be important.

Low-dose rivaroxaban was effective in secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in the COMPASS trial. There is no established role, however, for oral anticoagulants in primary prevention. We evaluated whether coronary artery calcium (CAC) scoring identifies a high-risk primary prevention adult population who may benefit from low-dose rivaroxaban to prevent ASCVD events. We modeled expected outcomes of low-dose rivaroxaban in 5,196 Multiethnic Study of Atherosclerosis (MESA) cohort participants not already on antiplatelet or anticoagulant therapy. We applied relative risk ratios from COMPASS to absolute MESA event rates in order to estimate number needed to treat (NNT) to avoid a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, as well as number needed to harm (NNH) to cause 1 hospitalized bleed; with both NNT and NNH stratified by calculated ASCVD risk and by baseline CAC. MESA participants with CAC ≥300 had crude ASCVD event rate of 20 per 1000 patient-years, which is comparable to that observed in the COMPASS control-arm. CAC was independently associated with the composite ASCVD outcome (p <0.001 for trend). However, CAC was not independently associated with adjusted hazard ratio for hospitalized major bleeding. Predicted 5-year NNT (modeled from COMPASS) was 75 in persons with CAC 100-299 and 45 with CAC ≥300 despite NNH values of 252 and 98, respectively. In conclusion, CAC helps to distinguish estimated ASCVD benefit from estimated bleeding harm, thereby identifying very high-risk primary prevention adults without established cardiovascular disease who may derive net-benefit from low-dose rivaroxaban.

Background

Recent American College of Cardiology/American Heart Association Primary Prevention Guidelines recommended considering low-dose aspirin therapy only among adults 40 to 70 years of age who are at higher atherosclerotic cardiovascular disease (ASCVD) risk but not at high risk of bleeding. However, it remains unclear how these patients are best identified. The present study aimed to assess the value of coronary artery calcium (CAC) for guiding aspirin allocation for primary prevention by using 2019 aspirin meta-analysis data on cardiovascular disease relative risk reduction and bleeding risk.

Methods

The study included 6470 participants from the MESA Study (Multi-Ethnic Study of Atherosclerosis). ASCVD risk was estimated using the pooled cohort equations, and 3 strata were defined: <5%, 5% to 20%, and >20%. All participants underwent CAC scoring at baseline, and CAC scores were stratified as =0, 1 to 99, ≥100, and ≥400. A 12% relative risk reduction in cardiovascular disease events was used for the 5-year number needed to treat (NNT₅) calculations, and a 42% relative risk increase in major bleeding events was used for the 5-year number needed to harm (NNH₅) estimations.

Results

Only 5% of MESA participants would qualify for aspirin consideration for primary prevention according to the American College of Cardiology/American Heart Association guidelines and using >20% estimated ASCVD risk to define higher risk. Benefit/harm calculations were restricted to aspirin-naive participants <70 years of age not at high risk of bleeding (n=3540). The overall NNT₅ with aspirin to prevent 1 cardiovascular disease event was 476 and the NNH₅ was 355. The NNT₅ was also greater than or similar to the NNH₅ among estimated ASCVD risk strata. Conversely, CAC≥100 and CAC≥400 identified subgroups in which NNT₅ was lower than NNH₅. This was true both overall (for CAC≥100, NNT₅=140 versus NNH₅=518) and within ASCVD risk strata. Also, CAC=0 identified subgroups in which the NNT₅ was much higher than the NNH₅ (overall, NNT₅=1190 versus NNH₅=567).

Conclusions

CAC may be superior to the pooled cohort equations to inform the allocation of aspirin in primary prevention. Implementation of current 2019 American College of Cardiology/American Heart Association guideline recommendations together with the use of CAC for further risk assessment may result in a more personalized, safer allocation of aspirin in primary prevention. Confirmation of these findings in experimental settings is needed.

Increased carotid intima-media thickness (cIMT) is associated with heart failure (HF) in previous studies, but it is not known whether the association of cIMT differs between HF with reduced (HFrEF) versus preserved ejection fraction (HFpEF). We studied 6699 participants (mean age 62 ± 10 years, 47% male, and 38% white) from the Multi-Ethnic Study of Atherosclerosis (MESA) with baseline cIMT measurements. We classified HF events as HFrEF (EF <50%) or HFpEF (EF ≥ 50%) at the time of diagnosis. Cox proportional hazard regression was used to compute hazard ratios (HR), and 95% confidence intervals (CI) for the association between the IMT Z-score (measured maximum IMT of Internal Carotid (IC) and Common Carotid (CC) sites as the mean of the maximum IMT of the near and far walls of right and left sides), and incident HFrEF or HFpEF. Models were adjusted for covariates and interim coronary artery disease (CAD) events. A total of 191 HFrEF and 167 HFpEF events occurred during follow-up. In multivariable analysis, each 1 standard deviation increase in the measured maximum IMT (Z-score) was associated with both HFrEF and HFpEF in the unadjusted and demographically adjusted models [HR, 95% CI 1.57 (1.43 to 1.73)] and [HR, 95% CI 1.61 (1.47 to 1.77)] but not in the fully adjusted models [HR, 95% CI 1.11 (0.96 to 1.28)] and [HR, 95% CI 1.13 (0.98 to 1.30)]. In conclusion, cIMT was significantly associated with incident HF, but the association is partially attenuated with adjustment for demographic factors and becomes non-significant after adjustment for other traditional heart failure risk factors and interim CAD events. There was no difference in the association of IMT measures with HFrEF versus HFpEF.

Background

The use of atherosclerotic cardiovascular disease (ASCVD) risk to personalize systolic blood pressure (SBP) treatment goals is a topic of increasing interest. Therefore, we studied whether coronary artery calcium (CAC) can further guide the allocation of anti-hypertensive treatment intensity.

Methods

We included 3733 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with SBP between 120 and 179 mm Hg. Within subgroups categorized by both SBP (120-139 mm Hg, 140-159 mm Hg, and 160-179 mm Hg) and estimated 10-year ASCVD risk (using the American College of Cardiology/American Heart Assocation pooled-cohort equations), we compared multivariable-adjusted hazard ratios for the composite outcome of incident ASCVD or heart failure after further stratifying by CAC (0, 1-100, or >100). We estimated 10-year number-needed-to-treat for an intensive SBP goal of 120 mm Hg by applying the treatment benefit recorded in meta-analyses to event rates within CAC strata.

Results

The mean age was 65 years, and 642 composite events took place over a median of 10.2 years. In persons with SBP <160 mm Hg, CAC stratified risk for events. For example, among those with an ASCVD risk of <15% and who had an SBP of either 120 to 139 mm Hg or 140 to 159 mm Hg, respectively, we found increasing hazard ratios for events with CAC 1 to 100 (1.7 [95% confidence interval, 1.0-2.6] or 2.0 [1.1-3.8]) and CAC >100 (3.0 [1.8-5.0] or 5.7 [2.9-11.0]), all relative to CAC=0. There appeared to be no statistical association between CAC and events when SBP was 160 to 179 mm Hg, irrespective of ASCVD risk level. Estimated 10-year number-needed-to-treat for a SBP goal of 120mmHg varied substantially according to CAC levels when predicted ASCVD risk <15% and SBP <160mmHg (eg, 10-year number-needed-to-treat of 99 for CAC=0 and 24 for CAC>100, when SBP 120-139mm Hg). However, few participants with ASCVD risk <5% had elevated CAC. Furthermore, 10-year number-needed-to-treat estimates were consistently low and varied less among CAC strata when SBP was 160 to 179 mm Hg or when ASCVD risk was ≥15% at any SBP level.

Conclusions

Combined CAC imaging and assessment of global ASCVD risk has the potential to guide personalized SBP goals (eg, choosing a traditional goal of 140 or a more intensive goal of 120 mm Hg), particularly among adults with an estimated ASCVD risk of 5% to 15% and prehypertension or mild hypertension.

Background

The prognostic value of hsCRP in contemporary multi-ethnic populations is unclear, particularly in statin users. The aim of this study was to characterize the prognostic utility of hsCRP for atherosclerotic CVD (ASCVD) risk prediction in a multi-ethnic population including non-users and users of statins followed for >13 years. Associations with heart failure (HF), atrial fibrillation (AF), venous thromboembolism (VTE), cancer, and all-cause death were also examined.

Methods and results

We evaluated 6757 participants from the Multi-Ethnic Study of Atherosclerosis (MESA; 1002 using statins at baseline), median follow-up 13.2 years. Higher levels of hsCRP were associated with a higher risk of all study endpoints in the unadjusted Cox Proportional Hazards regression analyses, except AF. Among non-users of statins, hsCRP only remained associated with VTE after adjusting for ASCVD risk factors, and did not improve risk prediction. Among users of statins, hsCRP did not improve ASCVD risk prediction either, although it was strongly associated with incident HF (HR for hsCRP ≥ 2 vs <2 mg/L 3.99; 95% CI 2.02, 7.90) and all-cause death (HR 1.52; 95% CI 1.11, 2.08) in multivariable analyses, and hsCRP significantly improved prediction of HF (area under the curve [AUC] basic model 0.741, AUC basic + hsCRP 0.788).

Conclusions

The utility of hsCRP for ASCVD prediction was modest. On the other hand, hsCRP was associated with incident VTE in statin non-users, and all-cause mortality and HF in statin users. In the latter, hsCRP improved the prediction of incident HF events. This finding should be replicated in larger cohorts.

Objective

We develop a new diabetes CHD risk estimator using traditional risk factors plus coronary artery calcium (CAC), ankle-brachial index (ABI), high sensitivity C-reactive protein, family history of CHD, and carotid intima-media thickness and compared it with United Kingdom Prospective Diabetes study (UKPDS), Framingham risk and the NCEP/ATP III risk scores in type 2 diabetes mellitus (T2DM).

Methods and results

We combined data from T2DM without clinical CVD in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (N = 1343). After a mean follow-up of 8.5 years, 85 (6.3%) participants had incident CHD. Among the novel risk markers, CAC best predicted CHD independent of the FRS [hazard ratio: HR (95% CI): log (CAC +25):1.69 (1.45-1.97), p < 0.0001; CAC categories: CAC ≤ 25 as reference, >25 and ≤125:2.29 (0.87-5.95), >125 and ≤400: 3.87 (1.57-9.57), >400: 5.97 (2.57-13.84), respectively). The MESA-HNR diabetes CHD risk score has better accuracy for the main outcome versus the FRS or UKPDS [area under curve (AUC) of 0.76 vs. 0.70 and 0.69, respectively; all p < 0.05]. The MESA-HNR risk score improved risk classification versus the FRS (net reclassification improvement (NRI) = 0.19 and integrated discrimination improvement (IDI) = 0.046, p < 0.05) and UKPDS (NRI = 0.215 and IDI = 0.046, p < 0.05). Compared with the ATP III guidelines, the MESA-HNR score has an NRI of 0.74 for the main outcome.

Conclusions

This new CHD risk estimator has better discriminative ability for incident CHD than the FRS, UKPDS, and the ATP III/NCEP recommendations in a multi-ethnic cohort with T2DM.

Arterial calcification reflects an atherosclerotic process associated with vascular stiffness. Whether baseline coronary artery calcium (CAC) and extra-coronary calcium (ECC), measured using noncontrast computed tomography imaging, are associated with incident hypertension is poorly understood. We studied participants from the Multi-Ethnic Study of Atherosclerosis without measured or self-reported hypertension at baseline. Incident hypertension was defined by blood pressure criteria (BP, ≥140/90 mmHg), BP medication use, or both, and was assessed at in-person visits. We analyzed incident hypertension using multivariable-adjusted discrete-time proportional hazards models. Net reclassification improvement (NRI) assessed whether CAC reclassified hypertension risk when added to the Framingham hypertension risk score. Among 3,304 subjects analyzed, mean age was 59 ± 10 years; 48% were male and 42% were white. There were 1,283 incident hypertension cases over a median (interquartile range) follow-up time of 10.6 (4.5, 11.5) years. Each 1-unit increase in ln(CAC+1) was independently associated with a 12% higher risk of hypertension (95% confidence interval [CI] 9% to 16%). Relative to CAC = 0, patients with CAC >400 had a hazard ratio for incident hypertension of 2.2 (95% CI 1.8 to 2.9). There was no interaction by age, gender, or baseline BP (p = 0.43, 0.19, 0.09, respectively). Continuous NRI analyses demonstrated that CAC can reclassify risk of incident hypertension; NRI = 0.19 (95% CI 0.10 to 0.26). Furthermore, all measurements of ECC were significantly associated with incident hypertension, even after adjustment for CAC (hazard ratios ranging from 1.36 to 1.38). In conclusion, patients with CAC and ECC are at markedly higher risk of incident hypertension and may benefit from more intensified prevention efforts.