Faculty Bibliography

Dual antiplatelet therapy is the cornerstone in the management of patients with acute coronary syndromes (ACS). Ticagrelor, an oral, direct, reversibly binding, P2Y12 receptor antagonist, is approved for the prevention of atherothrombotic events in adult patients with ACS. In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor was associated with significant reductions in cardiovascular events, cardiovascular mortality, and all-cause mortality compared with clopidogrel. A subanalysis of PLATO trial data identified a geographic region interaction (p = 0.045), indicating reduced efficacy of ticagrelor versus clopidogrel in North American patients. This effect could be due to chance, but may be explained by an interaction of ticagrelor with high aspirin doses, which are commonly used in the United States. In patients taking low-dose maintenance aspirin, ticagrelor was more effective than clopidogrel in decreasing cardiovascular events regardless of the geographic region. A proposed hypothetical mechanism for the interaction between ticagrelor and higher aspirin dose is linked to the level of P2Y12 inhibition and the potential prothrombotic effects of high-dose aspirin through the suppression of prostacyclin. A review of data regarding aspirin use for secondary prevention of events in ACS demonstrated that low aspirin doses (75 to 160 mg/day) are consistently favored for short- and long-term use because of the lack of a dose-response relationship between increasing aspirin dose and improved efficacy, and a higher incidence of gastrointestinal bleeding with increasing aspirin dose. The use of low aspirin doses reflects good clinical practice and is encouraged in current guidelines.

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.

OBJECTIVES: This study sought to perform a systematic review and meta-analysis to understand the role of stress cardiac magnetic resonance imaging (CMR) in assessing cardiovascular prognosis in patients with known or suspected coronary artery disease (CAD). BACKGROUND: Although stress CMR is excellent for the diagnosis of obstructive CAD, the prognostic value of stress CMR has been less well described. METHODS: PubMed, Cochrane CENTRAL, and metaRegister of Controlled Trials were searched for stress CMR studies with >6 months of prognostic data. Primary endpoints were cardiovascular death, myocardial infarction (MI), and a composite outcome of cardiovascular death or MI during follow-up. Summary effect estimates were generated with random-effects modeling, and annualized event rates were assessed. RESULTS: Nineteen studies (14 vasodilator, 4 dobutamine, and 1 that used both) involved a total of 11,636 patients with a mean follow-up of 32 months. Patients had a mean age of 63 +/- 12 years, 63% were male, and 26% had previous MI; mean left ventricular ejection fraction was 61 +/- 12%; and late gadolinium enhancement was present in 29% and ischemia in 32%. Patients with ischemia had a higher incidence of MI (odds ratio [OR]: 7.7; p < 0.0001), cardiovascular death (OR: 7.0; p < 0.0001), and the combined endpoint (OR: 6.5; p < 0.0001) compared with those with a negative study. The combined outcome annualized events rates were 4.9% for a positive versus 0.8% for a negative stress CMR (p < 0.0001), 2.8% versus 0.3% for cardiovascular death (p < 0.0001), and 2.6% versus 0.4% for MI (p < 0.0005). The presence of late gadolinium enhancement was also significantly associated with a worse prognosis. CONCLUSIONS: A negative stress CMR study is associated with very low risk of cardiovascular death and MI. Stress CMR has excellent prognostic characteristics and may help guide risk stratification of patients with known or suspected CAD.

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.

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.