Faculty Bibliography

INTRODUCTION: There is epidemiological evidence that metal contaminants may play a role in the development of atherosclerosis and its complications. Moreover, a recent clinical trial of a metal chelator had a surprisingly positive result in reducing cardiovascular events in a secondary prevention population, strengthening the link between metal exposure and cardiovascular disease (CVD). This is, therefore, an opportune moment to review evidence that exposure to metal pollutants, such as arsenic, lead, cadmium, and mercury, is a significant risk factor for CVD. METHODS: We reviewed the English-speaking medical literature to assess and present the epidemiological evidence that 4 metals having no role in the human body (xenobiotic), mercury, lead, cadmium, and arsenic, have epidemiologic and mechanistic links to atherosclerosis and CVD. Moreover, we briefly review how the results of the Trial to Assess Chelation Therapy (TACT) strengthen the link between atherosclerosis and xenobiotic metal contamination in humans. CONCLUSIONS: There is strong evidence that xenobiotic metal contamination is linked to atherosclerotic disease and is a modifiable risk factor.

BACKGROUND: Troponin elevation is a risk factor for mortality in patients with non-ST-segment-elevation acute coronary syndromes. However, the prognosis of patients with troponin elevation and nonobstructive coronary artery disease (CAD) is unknown. Our objective was therefore to evaluate the impact of nonobstructive CAD in patients with non-ST-segment-elevation acute coronary syndromes and troponin elevation enrolled in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. METHODS AND RESULTS: In the ACUITY trial, 3-vessel quantitative coronary angiography was performed in a formal substudy of 6921 patients presenting with non-ST-segment-elevation acute coronary syndromes. Patients with elevated admission troponin levels were stratified by the presence or absence of obstructive CAD (any lesion with quantitative diameter stenosis >50%). Propensity score matching was performed to adjust for baseline characteristics. Of 2442 patients with elevated troponin, 197 (8.8%) had nonobstructive CAD. Maximum diameter stenosis was 87.4 (73.2, 100.0) versus 22.6 (19.2, 25.7; P<0.0001) in patients with versus without obstructive CAD, respectively. Propensity matching yielded 117 patients with nonobstructive CAD and 331 patients with obstructive CAD, with no significant baseline differences between groups. In the matched cohort, overall 1-year mortality was significantly higher in patients with nonobstructive CAD (5.2% versus 1.6%; hazard ratio [95% confidence interval]=3.44 [1.05, 11.28]; P=0.04), driven by greater noncardiac mortality. Conversely, recurrent myocardial infarction and unplanned revascularization rates were significantly higher in patients with obstructive CAD. CONCLUSIONS: Patients with non-ST-segment-elevation acute coronary syndromes and elevated troponin levels but without obstructive CAD, while having low rates of subsequent myocardial infarction and unplanned revascularization, are still at considerable risk for 1-year mortality from noncardiac causes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00093158.

Background: Patients with moderate or severe ischemia have a heightened risk for myocardial infarction and cardiovascular death. Geographic variation in the proportion of stress myocardial perfusion imaging (MPI) and echocardiography (echo) with at least moderate ischemia is unknown. Methods: De-identified monthly MPI and stress echo screening logs from sites participating in the NHLBI-funded ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) Trial were reviewed for site-specific number of studies with site-interpreted moderate or severe ischemia. Data are reported as site-weighted medians (interquartile range [IQR]). Results: 97 sites contributed 448 months totaling 46,530 studies. Of 34,463 MPI and 12,067 stress echo studies, 1,308 (3.9% [IQR: 1.2, 8.0]) and 466 (3.2% [IQR: 0.0, 10.0]), respectively, had at least moderate ischemia (P=0.74). Median age was 66 years (IQR: 59, 73); 29.5% were female. Regional variation in study proportion with at least moderate ischemia was observed for both MPI and stress echo (P<0.001 for both, Table) and age (P<0.001), but not for sex (P=0.22). Compared to outside-US, US studies were less likely to have at least moderate ischemia (P<0.001). Conclusions: Regional variations exist in the proportion of stress imaging studies with moderate or severe ischemia. Moderate or severe ischemia was lowest among US studies, suggesting inter-country variability in the clinical assessment of ischemia. (Figure Presented)

Systolic blood pressure (SBP) often varies between clinic visits within individuals, which can affect estimation of cardiovascular disease (CVD) risk. We analyzed data from participants with two clinic visits separated by a median of 17 days in the Third National Health and Nutrition Examination Survey (n = 808). Ten-year CVD risk was calculated with SBP obtained at each visit using the Pooled Cohort Equations. The mean age of participants was 46.1 years, and 47.3% were male. The median SBP difference between the two visits was -1 mm Hg (1st to 99th percentiles: -23 to 32 mm Hg). The median estimated 10-year CVD risk was 2.5% and 2.4% at the first and second visit, respectively (1st to 99th percentiles -5.2% to +7.1%). Meaningful risk reclassification (ie, across the guideline recommended 7.5% threshold for statin initiation) occurred in 12 (11.3%) of 106 participants whose estimated CVD risk was between 5% and 10%, but only in two (0.3%) of 702 participants who had a 10-year estimated CVD risk of <5% or >10%. SBP variability can affect CVD risk estimation, and can influence statin eligibility for individuals with an estimated 10-year CVD risk between 5% and 10%.

Although the incidence of and mortality after ST-segment elevation myocardial infarction (STEMI) is decreasing, time trends in anatomical location of STEMI and associated short-term prognosis have not been examined in a population-based community study. We determined 22-year trends in age- and race-adjusted gender-specific incidences and 28-day case fatality of hospitalized STEMI by anatomic infarct location among a stratified random sample of 35- to 74-year-old residents of 4 communities in the Atherosclerosis Risk in Communities study. STEMI infarct location was assessed by 12-lead electrocardiograms from the hospital record and was coded as anterior, inferior, lateral, and multilocation STEMIs using the Minnesota code. From 1987 to 2008, a total of 4,845 patients had an incident STEMI; 37.2% were inferior STEMI, 32.8% were anterior, 16.8% occurred in multiple infarct locations, and 13.2% were lateral STEMI. For inferior, anterior, and lateral STEMIs in both men and women, significant decreases were observed in the age-adjusted annual incidence and the associated 28-day case fatality. In contrast, for STEMI in multiple infarct locations, neither the annual incidence nor the 28-day case fatality changed over time. The age- and race-adjusted annual incidence and associated 28-day case fatality of STEMI in anterior, inferior, and lateral infarct locations decreased during 22 years of surveillance; however, no decrease was observed for STEMI in multiple infarct locations. In conclusion, our findings suggest that there is room for improvement in the care of patients with multilocation STEMI.

BACKGROUND: Risk stratification of atrial fibrillation patients with a congestive heart failure (C), hypertension (H), age >/= 75 (A), diabetes (D), stroke or transient ischemic attack (TIA) (S2) (CHADS2) score of <2 remains imprecise, particularly in women. Our objectives were to validate the CHADS2 and congestive heart failure (C), hypertension (H), age >/= 75 (A2), diabetes (D), stroke, TIA or prior thromboembolic disease (S2)- vascular disease (V), age 65-74 (A), female gender (S) (CHA2DS2-VASc) stroke risk scores in a healthy cohort of American women with atrial fibrillation and to determine whether CHA2DS2-VASc further risk-stratifies individuals with a CHADS2 score of <2. METHODS: We identified a cohort of 5981 women with atrial fibrillation not on warfarin at baseline (mean age 65.9 +/- 7.2 years) enrolled in the Women's Health Initiative and followed for a median of 11.8 years. Univariate and multivariate proportional hazards analyses were used to examine these 2 risk scores, with main outcome measures being annualized event rates of ischemic stroke or transient ischemic attack stratified by risk score. RESULTS: Annualized stroke/transient ischemic attack rates ranged from 0.36% to 2.43% with increasing CHADS2 score (0-4+) (hazard ratio [HR] 1.57; 95% confidence interval [CI], 1.45-1.71 for each 1-point increase) and 0.20%-2.02% with increasing CHA2DS2-VASc score (1-6+) (HR 1.50; 95% CI, 1.41-1.60 for each 1-point increase). CHA2DS2-VASc had a higher c statistic than CHADS2: 0.67 (95% CI, 0.65-0.69) versus 0.65 (95% CI, 0.62-0.67), P <.01. For CHADS2 scores <2, stroke risk almost doubled with every additional CHA2DS2-VASc point. CONCLUSIONS: Although both CHADS2, and CHA2DS2-VASc are predictive of stroke risk in postmenopausal women with atrial fibrillation, CHA2DS2-VASc further risk-stratifies patients with a CHADS2 score <2.

BACKGROUND: Although higher visit-to-visit variability (VVV) of blood pressure (BP) is associated with increased cardiovascular disease risk, the physiological basis for VVV of BP is incompletely understood. METHODS: We examined the associations of aortic distensibility (assessed by magnetic resonance imaging) and artery elasticity indices (determined by radial artery pulse contour analysis) with VVV of BP in 2,640 and 4,560 participants, respectively, from the Multi-Ethnic Study of Atherosclerosis. Arterial measures were obtained at exam 1. BP readings were taken at exam 1 and at 3 follow-up visits at 18-month intervals (exams 2, 3, and 4). VVV was defined as the SD about each participant's mean systolic BP (SBP) across visits. RESULTS: The mean SDs of SBP were inversely associated with aortic distensibility: 7.7, 9.9, 10.9, and 13.2mm Hg for quartiles 4, 3, 2, and 1 of aortic distensibility, respectively (P trend < 0.001). This association remained significant after adjustment for demographics, cardiovascular risk factors, mean SBP, and antihypertensive medication use (P trend < 0.01). In a fully adjusted model, lower quartiles of large artery and small artery elasticity (LAE and SAE) indices were also associated with higher mean SD of SBP (P trend = 0.02 for LAE; P trend < 0.001 for SAE). CONCLUSIONS: In this multiethnic cohort, functional alterations of central and peripheral arteries were associated with greater long-term VVV of SBP.

IMPORTANCE Controversy remains about whether depression can be successfully managed after acute coronary syndrome (ACS) and the costs and benefits of doing so. OBJECTIVE To determine the effects of providing post-ACS depression care on depressive symptoms and health care costs. DESIGN Multicenter randomized controlled trial. SETTING Patients were recruited from 2 private and 5 academic ambulatory centers across the United States. PARTICIPANTS A total of 150 patients with elevated depressive symptoms (Beck Depression Inventory [BDI] score >/=10) 2 to 6 months after an ACS, recruited between March 18, 2010, and January 9, 2012. INTERVENTIONS Patients were randomized to 6 months of centralized depression care (patient preference for problem-solving treatment given via telephone or the Internet, pharmacotherapy, both, or neither), stepped every 6 to 8 weeks (active treatment group; n = 73), or to locally determined depression care after physician notification about the patient's depressive symptoms (usual care group; n = 77). MAIN OUTCOME MEASURES Change in depressive symptoms during 6 months and total health care costs. RESULTS Depressive symptoms decreased significantly more in the active treatment group than in the usual care group (differential change between groups, -3.5 BDI points; 95% CI, -6.1 to -0.7; P = .01). Although mental health care estimated costs were higher for active treatment than for usual care, overall health care estimated costs were not significantly different (difference adjusting for confounding, -$325; 95% CI, -$2639 to $1989; P = .78). CONCLUSIONS For patients with post-ACS depression, active treatment had a substantial beneficial effect on depressive symptoms. This kind of depression care is feasible, effective, and may be cost-neutral within 6 months; therefore, it should be tested in a large phase 3 pragmatic trial. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01032018.