Elevated osteoprotegerin is associated with abnormal ankle brachial indices in patients infected with HIV: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Patients infected with HIV have an increased risk for accelerated atherosclerosis. Elevated levels of osteoprotegerin, an inflammatory cytokine receptor, have been associated with a high incidence of cardiovascular disease (including peripheral arterial disease, or PAD), acute coronary syndrome, and cardiovascular mortality. The objective of this study was to determine whether PAD is prevalent in an HIV-infected population, and to identify an association with HIV-specific and traditional cardiovascular risk factors, as well as levels of osteoprotegerin.</p> <p>Methods</p> <p>One hundred and two patients infected with HIV were recruited in a cross-sectional study. To identify the prevalence of PAD, ankle-brachial indices (ABIs) were measured. Four standard ABI categories were utilized: ≤ 0.90 (definite PAD); 0.91-0.99 (borderline); 1.00-1.30 (normal); and >1.30 (high). Medical history and laboratory measurements were obtained to determine possible risk factors associated with PAD in HIV-infected patients.</p> <p>Results</p> <p>The prevalence of PAD (ABI ≤ 0.90) in a young HIV-infected population (mean age: 48 years) was 11%. Traditional cardiovascular risk factors, including advanced age and previous cardiovascular history, as well as elevated C-reactive protein levels, were associated with PAD. Compared with patients with normal ABIs, patients with high ABIs had significantly elevated levels of osteoprotegerin [1428.9 (713.1) pg/ml vs. 3088.6 (3565.9) pg/ml, respectively, p = 0.03].</p> <p>Conclusions</p> <p>There is a high prevalence of PAD in young HIV-infected patients. A number of traditional cardiovascular risk factors and increased osteoprotegerin concentrations are associated with abnormal ABIs. Thus, early screening and aggressive medical management for PAD may be warranted in HIV-infected patients.</p

Clinical relevance of endpoints in clinical trials for acid sphingomyelinase deficiency enzyme replacement therapy

Background: Acid sphingomyelinase deficiency (ASMD) also known as Niemann-Pick disease, is a rare lysosomal storage disorder with a diverse disease spectrum that includes slowly progressive, chronic visceral (type B) and neurovisceral forms (intermediate type A/B), in addition to infantile, rapidly progressive fatal neurovisceral disease (type A). Purpose and methods: We review the published evidence on the relevance of splenomegaly and reduced lung diffusion capacity to the clinical burden of chronic forms of ASMD. Targeted literature searches were conducted to identify relevant ASMD and non-ASMD studies for associations between diffusing capacity of the lungs for carbon monoxide (DLCO) and splenomegaly, with clinical parameters and outcome measures. Results: Respiratory disease and organomegaly are primary and independent contributors to mortality, disease burden, and morbidity for patients with chronic ASMD. The degree of splenomegaly correlates with short stature, atherogenic lipid profile, and degree of abnormality of hematologic parameters, and thus may be considered a surrogate marker for bleeding risk, abnormal lipid profiles and possibly, liver fibrosis. Progressive lung disease is a prevalent clinical feature of chronic ASMD, contributing to a decreased quality of life (QoL) and an increased disease burden. In addition, respiratory-related complications are a major cause of mortality in ASMD. Conclusions: The reviewed evidence from ASMD natural history and observational studies supports the use of lung function and spleen volume as clinically meaningful endpoints in ASMD trials that translate into important measures of disease burden for patients

Association of HIV viral load with monocyte chemoattractant protein-1 and atherosclerosis burden measured by magnetic resonance imaging

BACKGROUND: HIV-infected individuals may be at increased risk for atherosclerosis. Although this is partially attributable to metabolic factors, HIV-associated inflammation may play a role. OBJECTIVE: To investigate associations of HIV disease with serum monocyte chemoattractant protein-1/chemokine (C-C motif) ligand 2 (MCP-1/CCL2) levels and atherosclerosis burden. DESIGN: A cross-sectional analysis. METHODS: : Serum MCP-1/CCL2, fasting lipids, and glucose tolerance were measured in 98 HIV-infected and 79 demographically similar uninfected adults. Eighty-four participants had MRI of the carotid arteries and thoracic aorta to measure atherosclerosis burden. Multivariate analyses were performed using linear regression. RESULTS: Mean MCP-1/CCL2 levels did not differ between HIV-infected and uninfected participants (P = 0.65). Among HIV-infected participants, after adjusting for age, BMI, and cigarette smoking, HIV-1 viral load was positively associated with MCP-1/CCL2 (P = 0.02). Multivariate analyses adjusting for sex, low-density lipoprotein cholesterol, total cholesterol:high-density lipoprotein cholesterol ratio, cigarette smoking, MCP-1/CCL2, and protease inhibitor use found that HIV infection was associated with greater mean thoracic aorta vessel wall area (VWA, P < 0.01) and vessel wall thickness (VWT, P = 0.03), but not with carotid artery parameters. Compared with being uninfected, having detectable HIV-1 viremia was associated with greater mean thoracic aorta VWA (P < 0.01) and VWT (P = 0.03), whereas being HIV-infected with undetectable viral load was associated with greater thoracic aorta VWA (P = 0.02) but not VWT (P = 0.15). There was an independent positive association of MCP-1/CCL2 with thoracic aorta VWA (P = 0.01) and VWT (P = 0.01). CONCLUSION: HIV-1 viral burden is associated with higher serum levels of MCP-1/CCL2 and with atherosclerosis burden, as assessed by thoracic aorta VWA and VWT

Protein Kinase A, Ca2+/Calmodulin-Dependent Kinase II, and Calcineurin Regulate the Intracellular Trafficking of Myopodin between the Z-Disc and the Nucleus of Cardiac Myocytes▿

Spatial and temporal resolution of intracellular signaling can be achieved by compartmentalizing transduction units. Myopodin is a dual-compartment, actin-bundling protein that shuttles between the nucleus and the Z-disc of myocytes in a differentiation- and stress-dependent fashion. Importin α binding and nuclear import of myopodin are regulated by serine/threonine phosphorylation-dependent binding of myopodin to 14-3-3. Here we show that in the heart myopodin forms a Z-disc signaling complex with α-actinin, calcineurin, Ca2+/calmodulin-dependent kinase II (CaMKII), muscle-specific A-kinase anchoring protein, and myomegalin. Phosphorylation of myopodin by protein kinase A (PKA) or CaMKII mediates 14-3-3 binding and nuclear import in myoblasts. Dephosphorylation of myopodin by calcineurin abrogates 14-3-3β binding. Activation of PKA or inhibition of calcineurin in adult cardiac myocytes releases myopodin from the Z-disc and induces its nuclear import. The identification of myopodin as a direct target of PKA, CaMKII, and calcineurin defines a novel intracellular signaling pathway whereby changes in Z-disc dynamics may translate into compartmentalized signal transduction in the heart

HIV envelope gp120 activates human arterial smooth muscle cells

There have been increasing reports of acute coronary thrombotic events in patients with HIV. Although these clinical events have been attributed primarily to dyslipidemia associated with protease inhibitor therapy, autopsy studies in children with HIV suggest the presence of an underlying arteriopathy. This study demonstrates that the HIV envelope protein, gp120, activates human arterial smooth muscle cells to express tissue factor, the initiator of the coagulation cascade. The induction of tissue factor by gp120 is mediated by two biologically relevant coreceptors for HIV infection, CXCR4 and CCR5, and is also dependent on the presence of functional CD4. Induction of tissue factor by gp120 requires activation of mitogen-activating protein kinases, activation of protein kinase C, and generation of reactive oxygen species, signaling pathways that have protean effects on smooth muscle cell physiology. The activation of smooth muscle cells by gp120 may play an important role in the vascular, thrombotic, and inflammatory responses to HIV infection