Complete mounts were reviewed and images were used prepared as well as lobuloalveolar development

A prior publication in a smaller subgroup from the WIHS cohort found HIV-infected participants had higher NTproBNP levels, and NT-proBNP was associated with typical risk factors for cardiac and pulmonary disease such as age, race, body mass index, company website smoking, illicit drug use, hepatitis C infection, hemoglobin, and hypertension. NT-proBNP may also be produced and secreted in response to mechanisms related to other common phenomenon in the HIV population such as increased inflammatory cytokines important in the pathogenesis of cardiomyopathy-interleukin- 1, interleukin-6, and tumor necrosis factor-α, exposure to toxins such as cocaine which has cardio-toxic effects, and lipotoxicity which can lead to metabolic and cardiac disease. Adjusting for other variables, no HIV-related variables were associated with elevated NT-proBNP, and HIV infection was not an independent predictor for elevated NTproBNP after adjusting for anemia, hepatitis C infection, and impaired kidney function, which were more common in the HIV-infected participants. Our findings of associations of NTproBNP in HIV-infected women were similar to prior work, but this is the first study, to our knowledge, to assess the association between NT-proBNP and mortality in HIV. We demonstrated that an elevated NT-proBNP was associated with increased all-cause mortality in HIV-infected participants, but was not significantly associated with mortality in the HIV-uninfected group from the same cohort and similar HIV risk factors. Elevated BNP levels are associated with increased mortality in patients with cardiac and pulmonary diseases, and NT-proBNP was also a marker of mortality and cardiovascular events in a community sample, the Framingham Offspring Study. The participants in our study were much younger than the Framingham Offspring study suggesting that HIV-infected individuals may have an accelerated risk of NT-proBNP-related pathology. The younger age may also explain why we did not see a significant association between elevated NT-proBNP and mortality in the HIV-uninfected participants. NT-proBNP was not associated with degree of immunosuppression and its relationship with mortality was seen in both the early and late HAART periods. Baseline CD4 count and plasma HIV RNA level were not associated with NT-proBNP in either the early HAART period, when few participants were on effective HAART or virally-suppressed, or in the late HAART period, when most were on successful HAART. These findings contrast with prior studies of biomarkers associated with mortality in HIV. For example, biomarkers of inflammation and coagulation such as CRP, IL-6, and D-dimer were often associated with greater viral levels or lower CD4 counts; however, NT-proBNP, a protein derived from cardiac myocytes, was not associated with these traditional HIV markers. Lack of association with traditional HIV markers may indicate that a mechanism independent of severity of HIV disease is involved in the association between elevated NT-proBNP levels and mortality. The underlying cause of the relationship between mortality in HIV infection and elevated NT-proBNP is unclear. Several studies in HIV have shown elevated BNP is associated with cardiac dysfunction, and because inflammation, cocaine use, and metabolic disease can be other mechanisms leading to increased NT-proBNP and are common in HIV-infected persons, NT-proBNP may be a surrogate risk marker of ongoing cardiac damage from chronic inflammation, illicit drug use, or metabolic disease in the HIV-population. We assessed the cause of death in relationship to elevated NT-proBNP level to see if the association was related to cardiac disease specifically, but very few causes of death were clinically attributed to cardiac cause in the early and late HAART periods. This study and others have also found that hepatitis C infection and anemia are independently associated with elevated NT-proBNP, and renal disease is known to affect NT-proBNP levels. We excluded persons with reduced renal function and used the calculated creatinine clearance in modeling to eliminate potential confounding from significant renal disease that would alter NT-proBNP level and mortality; however, there may be residual confounding from these factors that could explain the association we find between NT-proBNP level and mortality. Further study in a prospective manner may be necessary to determine exactly how NT-proBNP links HIV infection and mortality. As NT-proBNP is significantly associated with mortality risk and is a readily available and inexpensive test, it may be a useful marker to determine elevated risk of death in the HIVinfected population.

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