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: Although N-terminal pro-B-type natriuretic peptide (NT-proBNP) has a strong relationship with incident cardiovascular disease (CVD), few studies have examined whether NT-proBNP adds to risk prediction algorithms, particularly in women. OBJECTIVES: This study sought to evaluate the relationship between NT-proBNP and incident CVD in women. METHODS: Using a prospective case-cohort within the WHI (Women's Health Initiative) observational study, we selected 1,821 incident cases of CVD (746 myocardial infarctions, 754 ischemic strokes, 160 hemorrhagic strokes, and 161 other cardiovascular [CV] deaths) and a randomly selected reference cohort of 1,992 women without CVD at baseline. RESULTS: Median levels of NT-proBNP were higher at study entry among incident cases (120.3 ng/l [interquartile range (IQR): 68.1 to 219.5 ng/l]) than among control subjects (100.4 ng/l [IQR: 59.7 to 172.6 ng/l]; p < 0.0001). Women in the highest quartile of NT-proBNP (>/=140.8 ng/l) were at 53% increased risk of CVD versus those in the lowest quartile after adjusting for traditional risk factors (1.53 [95% confidence interval (CI): 1.21 to 1.94]; p for trend <0.0001). Similar associations were observed after adjustment for Reynolds Risk Score covariables (1.53 [95% CI: 1.20 to 1.95]; p for trend <0.0001); the association remained in separate analyses of CV death (2.66 [95% CI: 1.48 to 4.81]; p for trend <0.0001), myocardial infarction (1.39 [95% CI: 1.02 to 1.88]; p for trend = 0.008), and stroke (1.60 [95% CI: 1.22 to 2.11]; p for trend <0.0001). When added to traditional risk covariables, NT-proBNP improved the c-statistic (0.765 to 0.774; p = 0.0003), categorical net reclassification (0.08; p < 0.0001), and integrated discrimination (0.0105; p < 0.0001). Similar results were observed when NT-proBNP was added to the Reynolds Risk Score. CONCLUSIONS: In this multiethnic cohort of women with numerous CV events, NT-proBNP modestly improved measures of CVD risk prediction.

OxLDL/beta2GPI complexes have been implicated in the initiation and progression of atherosclerosis and associated with disease severity and adverse outcomes. We investigate the significance of anti-oxLDL/beta2GPI antibodies and oxLDL/beta2GPI complexes in patients with arterial and idiopathic venous disease. A cohort of 61 arterial disease patients, 32 idiopathic venous disease patients, and 53 healthy controls was studied. Because statins influence oxLDL/beta2GPI, these complexes were analyzed on subjects not taking statins. Arterial and venous groups expressed higher levels of IgG anti-oxLDL/beta2GPI antibodies than controls without any other significant clinical association. OxLDL/beta2GPI complexes were significantly elevated in arterial (0.69 U/mL, P = 0.004) and venous disease (0.54 U/mL, P = 0.025) than controls (0.39 U/mL). Among arterial diseases, oxLDL/beta2GPI was 0.85 U/mL for carotid artery disease, 0.72 U/mL for peripheral artery disease, and 0.52 U/mL for abdominal aortic aneurysm. There was a significant association with male gender, age, hypertension, and history of thrombosis. Subjects with oxLDL/beta2GPI above the median (0.25 U/mL) were more likely to have arterial (OR 4.5, P = 0.004) or venous disease (OR 4.1, P = 0.008). Multivariate regression indicated that males (P = 0.021), high cholesterol (P = 0.011), and carotid disease (P = 0.023) were significant predictors of oxLDL/beta2GPI. The coexistence of oxLDL/beta2GPI in arterial and venous disease may suggest a common oxidative mechanism that independently predicts carotid artery disease.

BACKGROUND: Platelets are a major contributor to atherothrombosis and may contribute to the heightened risk of perioperative cardiovascular events. We sought to examine changes in platelet activity in subjects undergoing vascular surgery. METHODS: Platelet activity in 18 patients (median age 74, 45% female) undergoing non-emergent open vascular surgery was assessed by light transmission aggregometry in response to saline, epinephrine and adenosine-5 diphosphate (ADP), and by flow cytometric analysis of monocyte-platelet aggregation (MPA). Platelet activity was assessed preoperatively (T1), 1-hour into the operation (T2), 1-hour (T3), 24-hours (T4) and 48-hours post-operatively (T5). Data were compared using the Wilcoxon Signed Ranks Test. Continuous variables are summarized as medians and (interquartile, IQR) ranges. RESULTS: Spontaneous platelet aggregation increased transiently during the surgical period (T1-5.8% [2.4, 10.8], T2-13.5% [9.3, 26.5], T3-7.5% [3.3, 17], T4-10.0% [7.3, 16.3], T5-7.25% [4.5, 29.9], P=0.002). Similar trends in perioperative platelet activity were noted for platelet aggregation in response to epinephrine (P=0.035) and ADP (P=0.036). Using flow cytometry, we found an increase in MPA during the perioperative period (P=0.047), which was most significant between T1 and T3 (P=0.005). CONCLUSIONS: Platelet activity increases significantly during and following open vascular surgery. This data may help explain the pathophysiology of increased thrombotic risk during the perioperative period of vascular surgery.

BACKGROUND: The American Heart Association recommends targeting 7 cardiovascular (CV) health metrics to reduce morbidity and mortality. Control of these targets in patients undergoing CV intervention is uncertain. METHODS: We prospectively studied patients undergoing elective percutaneous coronary or peripheral intervention from November 2010 to May 2012. We recorded data on patient demographics, clinical characteristics, and social history. Risk factor control was categorized as ideal, intermediate, or poor according to the 7 American Heart Association-defined CV health metrics (smoking status, body mass index, physical activity, diet, cholesterol, blood pressure, and metabolic control). Linear regression model was used to evaluate the association between baseline characteristics and poor CV health. RESULTS: Among 830 consecutive patients enrolled, mean age is 67.3 +/- 10.8 years, 74.2% are male, and 62.1% are white. The adequacy of achievement of ideal CV health is suboptimal in our cohort; the mean number of ideal CV metrics is 2.15 +/- 1.06. Less than 1 in 10 (9.7%) met >/=4 ideal CV health metrics. After multivariate analysis, male sex (P = .04), nonwhite race (P = .01), prior coronary artery disease (P < .01), prior peripheral arterial disease (P < .01), and history of depression (P = .01) were significantly associated with poor CV health. CONCLUSIONS: Among patients referred for elective CV intervention, achievement of ideal CV health is poor. Elective interventions represent an opportunity to identify and target CV health for risk factor control and secondary prevention.

Biomarker testing for efficacy of therapy is an accepted way for clinicians to individualize dosing to genetic and/or environmental factors that may be influencing a treatment regimen. Aspirin is used by nearly 43 million Americans on a regular basis to reduce risks associated with various atherothrombotic diseases. Despite its widespread use, many clinicians are unaware of the link between suboptimal response to aspirin therapy and increased risk for inferior clinical outcomes in several disease states, and biomarker testing for efficacy of aspirin therapy is not performed as routinely as efficacy testing in other therapeutic areas. This article reviews the clinical and laboratory aspects of determining whole-body thromboxane production, particularly as it pertains to efficacy assessment of aspirin responsiveness.