Ashley E. Giambrone

Long-Term Prognosis After Coronary Artery Calcification Testing in Asymptomatic Patients: A Cohort Study

Context Clinicians use coronary artery calcification scores to predict the risk for myocardial infarction from coronary artery disease. The score also predicts all-cause mortality, but more is known about the accuracy of its short-term predictions than its long-term predictions. Contribution The study found that the score accurately predicted all-cause mortality at 15 years in asymptomatic patients. Caution The study was limited to a single center. Implication Coronary artery calcification scores may help motivate patients with high scores to adopt healthier lifestyles and may help researchers stratify study patients more effectively. A coronary artery calcification (CAC) test is used to estimate cardiovascular prognosis and provides additive information, above and beyond traditional cardiac risk factors, to estimate important clinical outcomes (1, 2). The published data show a strong relationship between the extent of CAC and adverse clinical outcomes across diverse asymptomatic patient subgroups and population cohorts (110). However, most risk-stratification evidence on CAC involves short-term prognosis, with few registries reporting follow-up beyond 5 years (1, 11). For screening with CAC, a large proportion of tested persons is middle-aged and has the possibility for long-term survival. According to published data, CAC incidence increases with age and the potential interaction between CAC and the length of follow-up is important (1, 6, 7). Given the progressive nature of atherosclerotic disease and the prevalence of potentiating cardiac risk factors, an understanding of the long-term sequelae of low- to high-risk CAC scores may prove useful in defining the value of cardiovascular testing for patients of various age groups. Thus, the aim of this report was to describe the prognostic significance of long-term follow-up across an array of CAC scores for asymptomatic patient subgroups of younger and older women and men. Methods Study Population From 1996 to 1999, primary care physicians referred 9715 patients to 1 outpatient clinic as part of a cardiology outreach screening program in the Tricare Healthcare System. These patients did not have symptoms of coronary artery disease and were from the area surrounding Nashville, Tennessee (86% were white, 8% were African American, 4% were Hispanic, and 2% were Asian). The median annual per capita income was

Plaque Echolucency and Stroke Risk in Asymptomatic Carotid Stenosis A Systematic Review and Meta-Analysis

33000. Each patient paid

Silent Brain Infarction and Risk of Future Stroke: A Systematic Review and Meta-Analysis

69 out of pocket for the procedure at the time of service. All patients signed informed consent for the index CAC scan and follow-up procedures; Centennial Medical Center (Nashville, Tennessee) provided institutional approval. Deidentified data were sent to 3 participating institutions (Emory University School of Medicine, Atlanta, Georgia; Cedars-Sinai Medical Center, Los Angeles, California; and Weill Cornell Medical College, New York, New York) for analysis. Institutional review board approval was garnered for data analysis at each institution. Five-year follow-up was previously reported in a subgroup of these patients (3). Cardiac Risk Factor Data A detailed history of cardiac risk factors was ascertained at the time of testing, as previously described (3). In addition to age, a medical history of hypertension was collected and defined as having had a prescription for an antihypertensive medication or documented blood pressure 140/90 mm Hg or higher. A history of diabetes was defined as having had a prescription for an antidiabetic medication or a history of elevated blood glucose levels greater than 7 mmol/L (>126 mg/dL). Patients who received a dyslipidemic medication or those with a history of elevated cholesterol levels were classified as dyslipidemic. Patients who had a relative with a history of coronary heart disease (CHD) were considered to have a family history of CHD. CAC Image Acquisition and Interpretation All patients had CAC imaging using electron beam tomography or multislice computed tomography. The correlation between CAC measurements derived from electron beam tomography with multislice computed tomography was high (r= 0.99; n= 100), consistent with previous reports (12, 13). Prior reports have detailed our methods for measuring CAC (3, 7, 9, 11). The CAC score was calculated using the method of Agatston and colleagues (14) and grouped as 0, 1 to 10, 11 to 99, 100 to 399, 400 to 999, and 1000 or greater (3). Follow-up Methods Long-term follow-up was undertaken in a consecutive series of 9715 patients. Survival status was obtained by querying the National Death Index, a central computerized index of death record information from the National Center for Health Statistics (15). Follow-up status was ascertained through 1 May 2014. Mean follow-up for surviving patients was 14.6 years (range, 12.9 to 16.8). During this observational period, 936 patients were confirmed as dead. Statistical Analysis The CAC subgroups with binary risk factor variables were compared by using chi-square analysis. The continuous measures with binary variables, such as age, were compared by using t tests or analyses of variance statistics, where appropriate. The primary end point of this analysis was time to all-cause mortality. Univariable and multivariable Cox proportional hazards models were used to estimate the relationship and added value of cardiac risk factors and CAC scores. Unadjusted, overall survival curves were plotted by the CAC subgroups. Hazard ratios and 95% CIs were calculated from the Cox model. Adjusted models included the CAC score and cardiac risk factor variables, including hypertension, diabetes, dyslipidemia, age, sex, and family history of CHD. The proportional hazards assumption was evaluated by assessing the constancy of the parallel plotted lines in the loglog graph and tested on the basis of Schoenfeld residuals. When we included a variable representing equipment use (electron beam tomography vs. multislice computed tomography), the prognostic models did not change. We examined the goodness of fit of the multivariable models using the HosmerLemeshow test on the basis of quantiles of risk, including the cardiac risk factor model and the combined risk factor and CAC model; both were nonsignificant (P> 0.80). The net reclassification improvement (NRI) statistic was calculated, including the percentage of deaths and survivors correctly reclassified when comparing 2 models (model 1 with available cardiac risk factor variables, including age, sex, hypertension, diabetes, dyslipidemia, cigarette smoking, and a family history of CHD, and model 2 with the cardiac risk factor variables and the CAC score) using the methods of Pencina and colleagues (16, 17). Although no specific cut points for 15-year mortality are established, we evaluated 2 sets of cut points for the NRI corresponding to 7.5% to 22.5% mortality (18, 19) and alternatively used cut points of less than 10%, 10% to 19.9%, and 20% or greater (1921). From model 1, we calculated the predicted probability of 15-year mortality and then categorized a variable on the basis of quartile measurements. The quartiles of predicted mortality were compared by cardiac risk factors using chi-square analysis. Statistical analysis was done using Stata, version 13.0 (StataCorp); SAS, version 9.2 (SAS Institute); and SPSS, version 22.0 (IBM SPSS). Role of the Funding Source This study received no external funding. Results Cardiac Risk Factors and CAC Descriptive Statistics In Table 1, the differences across cardiac risk factors were reported by quartiles of 15-year predicted mortality. Patients in the lower quartiles of predicted mortality were generally middle-aged, were less often female, and had a higher prevalence of dyslipidemia and family history of CHD. By comparison, the patients in the higher quartiles of predicted mortality were older; were more often female; and had a greater prevalence of hypertension, diabetes, and smoking. Table 1. Cardiac Risk Factor Prevalence Across Quartiles of Predicted 15-y Mortality in 9715 Asymptomatic Patients* In Table 2, we report the frequency of risk factors across the CAC subgroups. Patients with higher-risk CAC scores were more often older; were less likely to be female; and had a greater prevalence and extent of cardiac risk factors, such as hypertension, diabetes, and smoking. Table 2. Cardiac Risk Factor Prevalence Across CAC Score Subgroups* Unadjusted All-Cause Mortality Overall mortality was 3%, 6%, 9%, 14%, 21%, and 28%, respectively, for CAC subgroups with scores of 0, 1 to 10, 11 to 100, 101 to 399, 400 to 999, and 1000 or greater (P<0.001). The relative hazard for all-cause death was 1.68, 2.91, 4.52, 5.53, and 6.26, respectively (P<0.001). Within each of the estimated predicted mortality quartiles (Figure), survival worsened in a generally proportional manner in the subgroups with increasing CAC scores (P<0.001 for all 4 patient subgroups). Figure. Cumulative incidence of all-cause mortality by CAC across 15-y predicted mortality quartiles. All P values are <0.001. CAC = coronary artery calcification. In Cox models adjusting for CAD risk factors, the CAC score was highly predictive of time to all-cause mortality (P<0.001). A graded or proportional relationship between risk and CAC extent was seen at 10 and 15 years of follow-up. NRI With CAC Over and Above the CAD Risk Factors For cut points ranging from less than 7.5% to 22.5% or greater, the categorical NRI was 0.21 (95% CI, 0.16 to 0.32), with 27.9% of patients who died correctly reclassified by the model with CAC added (Table 3). However, the model with CAC incorrectly reclassified 7.4% of survivors to a higher-risk category than the model with cardiovascular risk factors alone. Use of an alternative set of cut points (<10% to 20%) resulted in a slight increase in the NRI (0.239), with 34.7% of deaths correctly reclassified but 10.8% of survivors misclassified (Table 4). Table 3. NRI for Adding CAC Score to a Model With Cardiac Risk Factors, Including Age, Sex, Hypertensi

Magnetic resonance angiography detection of abnormal carotid artery plaque in patients with cryptogenic stroke.

Background and Purpose— Ultrasonographic plaque echolucency has been studied as a stroke risk marker in carotid atherosclerotic disease. We performed a systematic review and meta-analysis to summarize the association between ultrasound-determined carotid plaque echolucency and future ipsilateral stroke risk. Methods— We searched the medical literature for studies evaluating the association between carotid plaque echolucency and future stroke in asymptomatic patients. We included prospective observational studies with stroke outcome ascertainment after baseline carotid plaque echolucency assessment. We performed a meta-analysis and assessed study heterogeneity and publication bias. We also performed subgroup analyses limited to patients with stenosis ≥50%, studies in which plaque echolucency was determined via subjective visual interpretation, studies with a relatively lower risk of bias, and studies published after the year 2000. Results— We analyzed data from 7 studies on 7557 subjects with a mean follow-up of 37.2 months. We found a significant positive relationship between predominantly echolucent (compared with predominantly echogenic) plaques and the risk of future ipsilateral stroke across all stenosis severities (0% to 99%; relative risk, 2.31; 95% confidence interval, 1.58–3.39; P<0.001) and in subjects with ≥50% stenosis (relative risk, 2.61; 95% confidence interval, 1.47–4.63; P=0.001). A statistically significant increased relative risk for future stroke was preserved in all additional subgroup analyses. No statistically significant heterogeneity or publication bias was present in any of the meta-analyses. Conclusions— The presence of ultrasound-determined carotid plaque echolucency provides predictive information in asymptomatic carotid artery stenosis beyond luminal stenosis. However, the magnitude of the increased risk is not sufficient on its own to iden tify patients likely to benefit from surgical revascularization.

Longitudinal change in magnetic susceptibility of new enhanced multiple sclerosis (MS) lesions measured on serial quantitative susceptibility mapping (QSM).

Background and Purpose— Silent brain infarction (SBI) on magnetic resonance imaging has been proposed as a subclinical risk marker for future symptomatic stroke. We performed a systematic review and meta-analysis to summarize the association between magnetic resonance imaging–defined SBI and future stroke risk. Methods— We searched the medical literature to identify cohort studies involving adults with SBI detected by magnetic resonance imaging who were subsequently followed up for incident clinically defined stroke. Study data and quality assessment were recorded in duplicate with disagreements in data extraction resolved by a third reader. Strength association between magnetic resonance imaging–detected SBI and future symptomatic stroke was measured by an hazard ratio. Results— The meta-analysis included 13 studies (14 764 subjects) with a mean follow-up ranging from 25.7 to 174 months. SBI predicted the occurrence of stroke with a random effects crude relative risk of 2.94 (95% confidence interval, 2.24–3.86, P<0.001; Q=39.65, P<0.001). In the 8 studies of 10 427 subjects providing hazard ratio adjusted for cardiovascular risk factors, SBI was an independent predictor of incident stroke (hazard ratio, 2.08 [95% confidence interval, 1.69–2.56; P<0.001]; Q=8.99; P=0.25). In a subgroup analysis pooling 9483 stroke-free individuals from large population-based studies, SBI was present in ≈18% of participants and remained a strong predictor of future stroke (hazard ratio, 2.06 [95% confidence interval, 1.64–2.59]; P<0.01). Conclusions— SBI is present in ≈1 in 5 stroke-free older adults and is associated with a 2-fold increased risk of future stroke. Future studies of in-depth stroke risk evaluations and intensive prevention measures are warranted in patients with clinically unrecognized radiologically evident brain infarctions.

Correlation Between Aeroallergen Levels and New Diagnosis of Eosinophilic Esophagitis in New York City.

Background Magnetic resonance imaging of carotid plaque can aid in stroke risk stratification in patients with carotid stenosis. However, the prevalence of complicated carotid plaque in patients with cryptogenic stroke is uncertain, especially as assessed by plaque imaging techniques routinely included in acute stroke magnetic resonance imaging protocols. We assessed whether the magnetic resonance angiography–defined presence of intraplaque high-intensity signal (IHIS), a marker of intraplaque hemorrhage, is associated with ipsilateral cryptogenic stroke. Methods and Results Cryptogenic stroke patients with magnetic resonance imaging evidence of unilateral anterior circulation infarction and without hemodynamically significant (≥50%) stenosis of the cervical carotid artery were identified from a prospective stroke registry at a tertiary-care hospital. High-risk plaque was assessed by evaluating for IHIS on routine magnetic resonance angiography source images using a validated technique. To compare the presence of IHIS on the ipsilateral versus contralateral side within individual patients, we used McNemar’s test for correlated proportions. A total of 54 carotid arteries in 27 unique patients were included. A total of 6 patients (22.2%) had IHIS-positive nonstenosing carotid plaque ipsilateral to the side of ischemic stroke compared to 0 patients who had IHIS-positive carotid plaques contralateral to the side of stroke (P=0.01). Stroke severity measures, diagnostic evaluations, and prevalence of vascular risk factors were not different between the IHIS-positive and IHIS-negative groups. Conclusions Our findings suggest that a proportion of strokes classified as cryptogenic may be mechanistically related to complicated, nonhemodynamically significant cervical carotid artery plaque that can easily be detected by routine magnetic resonance imaging/magnetic resonance angiography acute stroke protocols.

CT Angiographic Features of Symptom-Producing Plaque in Moderate-Grade Carotid Artery Stenosis

To measure the longitudinal change in multiple sclerosis (MS) lesion susceptibility using quantitative susceptibility mapping (QSM).

Prognostic Utility of Coronary Artery Calcium Scoring in Active Smokers: A 15-Year Follow-Up Study

Objective: The relation between food allergies and eosinophilic esophagitis (EoE) is well established. Aeroallergens may also contribute to the development of EoE; however, there are limited data to support or refute this hypothesis. The objectives of this pilot study were to determine whether there is a seasonal variation in the onset of symptoms and/or diagnosis of EoE and whether these variations correlate with a specific pollen concentration within New York City. Methods: We performed a retrospective chart review to identify all pediatric patients at New York Presbyterian Weill Cornell Medical Center diagnosed with EoE between 2002 and 2012. Sixty-six patients were identified and 28 were excluded. Cases were classified by both date of initial symptoms and date of histologic diagnosis. Pollen counts from a certified New York City counting station and the percentage of EoE cases were collated monthly and seasonally and compared. Results: There was a seasonal variation in onset of symptoms and diagnosis of EoE, with the highest number of patients reporting onset of symptoms of EoE in July to September, and those being diagnosed with EoE in October to December. There was a seasonal correlation between peak levels of grass pollen and peak onset of EoE symptoms, which were both highest in July to September. The diagnosis of EoE peaked one season later. Conclusions: The study findings suggest that there is a correlation between specific aeroallergens and both the onset of symptoms and time of diagnosis of patients with EoE.

Detection of Symptomatic Carotid Plaque Using Source Data from MR and CT Angiography: A Correlative Study

BACKGROUND AND PURPOSE: Emerging evidence indicates that plaque imaging can improve stroke risk stratification in patients with carotid artery atherosclerosis. We studied the association between soft and hard (calcified) plaque thickness measurements on CTA and symptomatic disease status (ipsilateral stroke or TIA) in patients with moderate-grade carotid artery stenosis. MATERIALS AND METHODS: We measured soft-plaque and hard-plaque thickness on CTA axial source images in each carotid artery plaque in subjects with NASCET 50%–69% ICA stenosis. We used logistic regression and receiver operating characteristic analyses to assess the strength of the association between thickness measurements and prior stroke or TIA. RESULTS: Twenty of 72 vessels studied (27.7%) had ischemic symptoms ipsilateral to the side of moderate-grade carotid stenosis. Each 1-mm increase in soft plaque resulted in a 3.7 times greater odds of a prior ipsilateral ischemic event (95% CI, 1.9–7.2). Conversely, for each 1-mm increase in hard plaque, the odds of being symptomatic decreased by approximately 80% (OR, 0.22; 95% CI, 0.10%–0.48%). Receiver operating characteristic analysis showed an area under the curve of 0.88 by using soft-plaque thickness measurements to discriminate between asymptomatic and symptomatic plaques. Sensitivity and specificity were optimized by using a maximum soft-plaque thickness of 2.2 mm, which provided a sensitivity of 85% and a specificity of 83%. CONCLUSIONS: Simple CTA plaque-thickness measurements might differentiate symptomatic and asymptomatic moderate-grade carotid artery plaque. With further prospective validation, CTA plaque measures could function as an easily implementable tool for risk stratification in carotid artery disease.

Diagnostic accuracy of intracellular uptake rates calculated using dynamic Gd-EOB-DTPA-enhanced MRI for hepatic fibrosis stage

Coronary artery calcium (CAC) is a frequent finding in smokers, and it is a marker of accelerated atherosclerosis in this population.1 Prior research has demonstrated a higher rate of five to ten year estimated all-cause mortality in smokers with CAC as compared to smokers without CAC.2,3 However, previous studies have produced limited insight regarding the long-term efficacy of CAC for risk stratification in smokers. This study therefore sought to examine the association between smoking, CAC, and all-cause mortality over a 15-year period. The study population was a cohort of 4,143 consecutive asymptomatic patients aged 55 and older (mean 63.2±6.6 years, range 55–99) without known coronary artery disease (CAD) who had been referred by their physician for CAC testing between 1991 and 2004. All study participants completed a baseline questionnaire of demographic characteristics and baseline cardiovascular risk factors. Cigarette smoking was considered present if a subject was an active smoker at the time of CAC scanning. CAC measurement was performed by electron beam computed tomography (EBCT) at three different centers in the United States using standard methods as previously described.3 Each calcified lesion was scored using the method developed by Agatston et al.4 All individuals provided informed consent for a pre-test interview, CAC testing, and follow-up. The study received approval from the appropriate Human Investigations Committee and conforms to the 1975 Declaration of Helsinki. The primary endpoint was all-cause mortality. Individuals masked to baseline data ascertained mortality status using the Social Security Death Index with 100% mortality ascertainment among study participants. For statistical analyses, the chi-square test was employed for comparison of categorical variables. Between-group comparisons for continuous variables were computed using an independent samples t-test or Mann-Whitney U test as appropriate. A Kaplan-Meier survival curve with log-rank test compared survival rates for smokers versus nonsmokers, according to the presence and severity of CAC. Cox proportional hazard regression reporting hazard ratios (HR) with 95% confidence intervals (95% CI) were used to estimate all-cause mortality adjusting for age, sex, diabetes, hypertension, dyslipidemia, and family history of premature CAD. All Cox models were stratified according to smoking status as well as the presence or absence (Model 1) or severity (Model 2) of CAC. As there was no significant interaction effect between sex and CAC, analyses stratified by sex were not performed. Assumption of proportional hazards was evaluated using Schoenfeld residuals. Statistical analyses were performed using SAS version 9.3 software (SAS Institute Inc., Cary, NC). A two-tailed p-value <0.05 was considered statistically significant. The patients were followed on average for 14.5 years (interquartile range 13.5–15.3). At the time of CAC assessment, 39% were self-reported active smokers. Of 553 deaths that occurred, 270 (16.6%) and 283 (11.3%) were smokers and nonsmokers at the time of CAC scan, respectively. Smokers were more prone to a family history of premature CAD (70.7% vs 65.3%, p<0.001) and diabetes (10.4% vs 8.5%, p=0.04) as compared with nonsmokers (Table 1). Smokers had higher median CAC scores (19 vs 3, interquartile range 0–195, p<0.001) and increased CAC severity (p<0.001 for trend), while nonsmokers were more likely to have a CAC of 0 than smokers (47.8 vs. 38.7%, p<0.001). Table 1 Clinical Characteristics of Subjects Irrespective of smoking status, higher CAC severity was associated with heightened mortality risk over the course of this study (p<0.001 by log-rank) (Figure). In multivariable Cox hazard regression models, smokers with a CAC of zero had a nearly two-fold (HR 1.73, 95% CI = 1.20–2.50, p=0.003) increased risk of mortality (Table 2, Model 1). In the presence of any CAC, the adjusted risk of mortality was more than three-fold (HR 3.07, 95% CI = 2.32–4.07, p<0.001) higher in nonsmokers, while the adjusted risk of mortality was almost five-fold (HR 4.67, 95% CI = 3.52–6.20, p<0.001) higher among smokers. Similar findings were observed in patients without additional cardiac risk factors (e.g. hypertension, diabetes, dyslipidemia, family history of premature CAD). In both smokers and nonsmokers, the adjusted risk of death appeared to increase incrementally according to the severity of CAC (Table 2, Model 2). Figure Cumulative survival among non-smokers and smokers stratified by CAC score Table 2 Risk of all-cause death among non-smokers and smokers according to the presence and severity of coronary artery calcium Overall, we found that across nearly 15 years of follow-up, the presence of CAC remained strongly predictive of all-cause mortality in this cohort of older smokers, even in the absence of other cardiac risk factors. Our findings are consistent with prior studies of shorter duration demonstrating increased mortality in smokers with CAC.2,3 Furthermore, in contrast to the general population for which the absence of CAC (CAC=0) is associated with an excellent prognosis,5 in our study smokers with a CAC=0 remained at an elevated risk of death. As such, for smokers a CAC=0 should not be considered a “negative risk factor.”3 Our study was limited by its observational design. Prior smoking history and smoking intensity as measured by pack years were not obtained. Data were unavailable regarding cause-specific mortality, cardiovascular events, post-test changes in risk factors, downstream pharmacological therapy or smoking cessation. Future long-term prospective cohort studies are needed to address these limitations. However, this is the largest cohort of consecutive patients undergoing CAC screening for which outcome data are available. Our findings are timely in that many smokers aged 55–80 are poised to undergo annual lung cancer screening by low dose computed tomography (CT).6–8 There is a high correlation between CAC discovered by CT and ECG-gated CAC screening protocols.9 This study proposes a potential benefit in highlighting the presence of any CAC detected by CT, rather than considering it as an “incidental” finding. While further research regarding CAC in lung cancer screening cohorts is clearly needed, our findings indicate that smokers with CAC detected by CT are at elevated risk and warrant early and aggressive cardiac risk factor reduction.