Faculty Bibliography

BACKGROUND: Mechanisms for increased cardiovascular risk in HIV-1-infected adults are incompletely understood, but platelet activation and immune activation leading to a prothrombotic state have been proposed as significant contributors. Aspirin has antiplatelet and immunomodulatory properties. We explored whether 1 week of low-dose aspirin attenuates platelet activation and immune activation in HIV-1-infected and virologically suppressed adults on antiretroviral therapy. METHODS: Platelet activation and immune activation were measured in HIV-1-infected subjects virologically suppressed on antiretroviral therapy and controls before and after 1 week of low-dose aspirin. RESULTS: Compared with control subjects, HIV-1-infected subjects had increased platelet activation, as measured by spontaneous platelet aggregation and aggregation in response to adenosine diphosphate, collagen, and arachidonic acid. After aspirin therapy, percent aggregation decreased similarly in both HIV-1-infected and control subjects to all platelet agonists tested except aggregation in response to arachidonic acid, which remained elevated in the HIV-1-infected group. HIV-1-infected subjects exhibited increased markers of T-cell activation (CD38 and HLA-DR) and monocyte activation (sCD14), which decreased after 1 week of aspirin therapy. Moreover, leukocyte responses to Toll-like receptor stimulation were enhanced after 1 week of aspirin therapy. In vitro studies showed that HIV-1 plasma could activate healthy platelets, which in turn activated monocytes, implicating a direct role for activated platelets in immune activation. CONCLUSIONS: Our data demonstrate that heightened platelet activation and immune activation in treated HIV-1 disease are attenuated by 1 week of aspirin therapy. Aspirin should be further studied for its antithrombotic and immunomodulatory benefits in treated HIV-1 disease.

BACKGROUND: The precise relationship between risk factor burden and prevalence of peripheral artery disease (PAD) in different vascular territories (PAD, carotid artery stenosis [CAS], and abdominal aortic aneurysms [AAAs]) is unclear. METHODS: We investigated the association of modifiable risk factors (hypertension, hypercholesterolemia, smoking, diabetes, and sedentary lifestyle) with any and type-specific peripheral vascular disease (PVD) among 3.3 million patients in the U.S., aged 40 to 99, who underwent screening bilateral ankle brachial indices, carotid duplex ultrasound, and abdominal aortic ultrasound in the Life Line Screening program between 2004 and 2008. Multivariate logistic regression analysis was used to estimate the odds of disease in different risk factor categories. Population-attributable risk was calculated to estimate the proportion of disease that could be potentially ascribed to modifiable risk factors. RESULTS: Among 3,319,993 participants, prevalence of any PVD was 7.51% (95% confidence interval [CI], 7.50%-7.53%). PAD was present in 3.56% (95% CI, 3.54%-3.58%), CAS in 3.94% (95% CI, 3.92%-3.96%), and AAAs in 0.88% (95% CI, 0.86%-0.89%). The multivariate-adjusted prevalence with the presence of 0, 1, 2, 3, 4, and 5 modifiable risk factors was 2.76, 4.63, 7.12, 10.73, 16.00, and 22.08 (P < .0001 for trend) for any PVD; 1.18, 2.09, 3.28, 5.14, 8.32, and 12.43 (P < .0001 for trend) for PAD; 1.41, 2.36, 3.72, 5.73, 8.48, and 11.58 (P < .0001 for trend) for CAS; and 0.31, 0.54, 0.85, 1.28, 1.82, and 2.39 (P < .0001 for trend) for AAAs, respectively. These associations were similar for men and women. For every additional modifiable risk factor that was present, the multivariate-adjusted odds of having vascular disease increased significantly (any PVD [odds ratio (OR), 1.58; 95% CI, 1.58-1.59]; PAD [OR, 1.62; 95% CI, 1.62-1.63]; CAS [OR, 1.57; 95% CI, 1.56-1.57]; and AAA [OR, 1.51; 95% CI, 1.50-1.53]). CONCLUSION: This very large contemporary database demonstrates that risk factor burden is associated with an increased prevalence of PVD, and there is a graded association between the number of risk factors present and the prevalence of PAD, CAS, and AAAs.

Long sleep duration has been associated with increased risk of cardiovascular disease (CVD) and all-cause mortality. Inflammation and coagulation have been hypothesized as possible physiological pathways to explain this association, although specific biomarkers have not been studied. Using longitudinal data from 3942 postmenopausal women in the Women's Health Initiative observational study and clinical trials, we investigated whether fibrinogen, an acute-phase inflammatory protein involved in blood clotting, mediates the associations between sleep duration and coronary heart disease (CHD) and mortality among women. Fibrinogen levels were associated positively with self-reported long sleep duration (9+ h per night), CHD and all-cause mortality, even after adjustment for a range of sociodemographic characteristics, cardiovascular risk factors and comorbidities.Compared with self-reported 7-8 h per night sleep duration, self-reported long sleep duration was associated with increased odds of CHD [odds ratio (OR) = 2.05, 95% confidence interval (CI): 1.02-4.11]. Adjustment for fibrinogen levels reduced the increased odds of CHD associated with long sleep by approximately 8 percentage points (OR = 1.97, 95% CI: 0.98-3.97). A similar reduction in the OR was observed with mortality. For both outcomes there is support for partial mediation of 6-7%, suggesting that fibrinogen may be a mechanism through which long sleep duration is associated with CHD and mortality.

OBJECTIVE: This study sought to determine the relationship between vascular disease in different arterial territories and advanced age. BACKGROUND: Vascular disease in the peripheral circulation is associated with significant morbidity and mortality. There is little data to assess the prevalence of different phenotypes of vascular disease in the very elderly. METHODS: Over 3.6 million self-referred participants from 2003-2008 who completed a medical and lifestyle questionnaire in the United States were evaluated by screening ankle brachial indices <0.9 for peripheral artery disease (PAD), and ultrasound imaging for carotid artery stenosis (CAS) >50% and abdominal aortic aneurysm (AAA) >3cm. Participants were stratified by decade of life. Multivariate logistic regression analysis was used to estimate odds of disease in different age categories. RESULTS: Overall, the prevalence of PAD, CAS, and AAA, was 3.7%, 3.9%, and 0.9%, respectively. Prevalence of any vascular disease increased with age (40-50y: 2%; 51-60y: 3.5%; 61-70y: 7.1%; 71-80y: 13.0%; 81-90y: 22.3%; 91-100y: 32.5%; P<0.0001). Prevalence of disease in each vascular territory increased with age. After adjustment for sex, race/ethnicity, body mass index, family history of cardiovascular disease, smoking, diabetes, hypertension, hypercholesterolemia, and exercise, the odds of PAD (OR 2.14, 95% CI 2.12-2.15), CAS (OR 1.80, 95% CI 1.79-1.81), and AAA (OR 2.33, 95% CI 2.30-2.36]) increased with every decade of life. CONCLUSION: There is a dramatic increase in the prevalence of PAD, CAS, and AAA with advanced age. More than 20% and 30% of octo- and nonagenarians, respectively, have vascular disease in at least 1 arterial territory.

BACKGROUND: Thrombotic and bleeding complications are major concerns during orthopedic surgery. Given the frequency of orthopedic surgical procedures and the limited data in the literature, we sought to investigate the incidence and risk factors for thrombotic (myocardial necrosis and infarction) and bleeding events in patients undergoing orthopedic surgery. METHODS AND RESULTS: We performed a retrospective cohort analysis of 3,082 consecutive subjects >/=21 years of age undergoing hip, knee, or spine surgery between November 1, 2008, and December 31, 2009. Patient characteristics were ascertained using International Classification of Diseases, Ninth Revision, diagnosis coding and retrospective review of medical records, and laboratory/blood bank databases. In-hospital outcomes included myocardial necrosis (elevated troponin), major bleeding, coded myocardial infarction, and coded hemorrhage as defined by International Classification of Diseases, Ninth Revision, coding. Of the 3,082 subjects, mean age was 60.8 +/- 13.3 years, and 59% were female. Myocardial necrosis, coded myocardial infarction, major bleeding, and coded hemorrhage occurred in 179 (5.8%), 20 (0.7%), 165 (5.4%), and 26 (0.8%) subjects, respectively. Increasing age (P < .001), coronary artery disease (P < .001), cancer (P = .004), and chronic kidney disease (P = .01) were independent predictors of myocardial necrosis, whereas procedure type (P < .001), cancer (P < .001), female sex (P < .001), coronary artery disease (P < .001), and chronic obstructive pulmonary disease (P = .01) were independent predictors of major bleeding. CONCLUSION: There is a delicate balance between thrombotic and bleeding events in the perioperative period after orthopedic surgery. Perioperative risk of both thrombosis and bleeding deserves careful attention in preoperative evaluation, and future prospective studies aimed at attenuating this risk are warranted.

OBJECTIVE: Certain races are known to be at increased risk for stroke, and the prevalence of carotid artery stenosis (CAS) is thought to vary by race. The goal of this report was to study the prevalence of CAS in different races by analyzing a population of subjects who underwent vascular screening examinations. METHODS: The study data were provided by Life Line Screening. The cohort consists of self-referred individuals who paid for vascular screening tests. Subjects <40 and >100 years of age and those who reported a prior stroke or carotid artery intervention were excluded. Of the remaining 3,291,382 subjects, 3.7% did not self-identify a race. CAS was defined as stenosis in either internal carotid artery >/=50% by duplex ultrasound velocity criteria. RESULTS: The 3,291,382 subjects available for analysis consisted of Caucasian (2,845,936 [90%]), African American (97,502 [3.1%]), Hispanic (75,240 [2.4%]), Asian (60,982 [1.9%]), and Native American (87,757 [2.8%]) individuals. The prevalence of CAS was 3.4% in females and 4.2% in males (P