Characterization of vascular lesions in pigs affected by porcine circovirus type 2-systemic disease.

Vascular lesions and their association with porcine circovirus type 2 (PCV2) were evaluated in multiple organs from 10 pigs affected with PCV2-systemic disease (PCV2-SD). Animals had vascular lesions in multiple organs, consisting of lymphohistiocytic lymphangitis and/or phlebitis, mild to severe necrotizing arteritis, and thrombosis within splenic arterioles and choroid plexus capillaries. Variable amounts of PCV2 nucleic acid detected by in situ hybridization were present within endothelial cells, tunica media myocytes, and perivascular and/or intralesional inflammatory cell infiltrates. PCV2 nucleic acid was detected within endothelial cells of both lymphatic and blood vessels without lesions in the associated tissues. Necrotizing arteritis was principally present in lymph nodes and kidney and consisted of degeneration, necrosis, and pyknosis of myocytes, often with intracytoplasmic, brightly eosinophilic inclusion bodies that were strongly positive for PCV2 nucleic acid. Segmental or circumferential fibrinoid necrosis was mainly present in vessels of the lymph node, spleen, and choroid plexus and was variably associated with PCV2 nucleic acid. Severe lymphangitis associated with strong intralesional PCV2 labeling was frequently detected within the mesenteric and mediastinal lymph nodes and the lamina propria of the ileum. In most tissues, medium and large lymphatics and/or veins often had disruption of the intima and mild mononuclear inflammatory cell infiltration that was variably associated with PCV2 nucleic acid. The present study indicates that vasculitis is a frequent finding in natural cases of PCV2-SD and that PCV2 may have a direct cytopathic effect on tunica media myocytes of small- and medium-sized arteries as well as endothelium.

Endothelial dysfunction, arterial stiffening, and intima-media thickening in large arteries from HIV-1 transgenic mice.

HIV patients on highly active antiretroviral therapy (HAART) exhibit elevated incidence of cardiovascular disease (CVD), including a higher risk of myocardial infarction and prevalence of atherosclerotic lesions, as well as increases in markers of subclinical atherosclerosis including increased carotid artery intima-media thickness (c-IMT), increased arterial stiffness, and impaired flow-mediated dilation. Both HAART and HIV-infection are independent risk factors for atherosclerosis and myocardial infarction. Studies implicate the HIV proteins tat, gp120, vpu, and nef in early on-set atherosclerosis. The objective of this study was to quantify the role of expression of HIV-1 proteins on the vascular function, biomechanics, and geometry of common carotid arteries and aortas. This study employed NL4-3Δ gag/pol transgenic mice (HIV-Tg), which contain the genetic sequence for the HIV-1 proteins env, tat, nef, rev, vif, vpr, and vpu but lacks the gag and pol genes and reports that HIV-Tg mice have impaired aortic endothelial function, increased c-IMT, and increased arterial stiffness. Further, HIV-Tg arteries show decreased elastin content, increased cathepsin K and cathepsin S activity, and increased mechanical residual stress. Thus, mice that express HIV proteins exhibit pre-clinical markers of atherosclerosis and these markers correlate with changes in markers of vascular remodeling. These findings are consistent with the hypothesis that HIV-proteins, independent of HAART treatment or HIV infection, could play a role in of the development of CVD.

Human immunodeficiency virus per se exerts atherogenic effects.

OBJECTIVE: Premature atherosclerosis in HIV-infected patients has been attributed to highly active antiretroviral therapy (HAART) and the associated metabolic complications. Whether HIV per se plays a role is an unresolved issue. The purpose of this study was to evaluate whether HIV per se exerts atherogenic effects. METHODS: We measured carotid intima-media thickness (IMT) and brachial endothelial-dependent (FMD) and endothelial-independent (NMD) vasodilation in 38 naïve untreated HIV-infected patients and 41 healthy control subjects. RESULTS: Control subjects were selected as to match the HIV patients for metabolic risk factors. Mean carotid IMT was higher in HIV patients (0.85+/-0.2mm; p<0.001) than in controls (0.63+/-0.1mm). In a stepwise multiple regression model, the changes in carotid IMT were predicted by the duration of HIV infection (p<0.001) and CD4 T-cells (p=0.035). Brachial FMD was impaired in HIV patients (8.8+/-3% versus 12.2+/-3% in controls; p<0.001). In contrast, NMD values practically overlapped in the HIV patients and controls. Analysis of the data in relation to viral load showed that FMD was significantly more impaired in the subgroup of patients with viral load values above the median (p<0.001). In addition, there was a highly significant, inverse correlation between FMD and the HIV-RNA copies (p<0.001). CONCLUSION: HIV infection causes functional and structural vascular alterations in a very early stage of the infection independent of HAART and metabolic factors. The data lend support to the viral infectious theory of atherosclerosis. Early assessment of the vascular status in HIV-infected patients is suggested.

Relation of subepicardial adipose tissue to carotid intima-media thickness in patients with human immunodeficiency virus.

Patients infected with human immunodeficiency virus (HIV) are at increased risk for subclinical atherosclerosis. Whether increased cardiac adiposity may be related to HIV subclinical atherosclerosis is still unexplored. The objective of this study was to evaluate whether echocardiographically determined subepicardial adipose tissue, an index of cardiac adiposity, is related to carotid intima-media thickness (IMT), an index of subclinical atherosclerosis, in HIV-infected patients receiving highly active antiretroviral therapy. Echocardiographic epicardial fat thickness and ultrasonographic IMT were measured in 103 consecutive HIV-infected Caucasian subjects receiving highly active antiretroviral therapy. Echocardiographic subepicardial adipose tissue showed an excellent correlation with IMT (r = 0.92, p <0.01). Multiple regression analysis showed that IMT was best predicted by epicardial fat thickness (r(2) = 0.81, p <0.01). In conclusion, this study suggests, for the first time, that epicardial adipose tissue, an index of cardiac adiposity, may be significantly related to subclinical atherosclerosis in HIV-infected patients.

Carotid intima-media thickness in HIV-infected individuals: relationship of premature atherosclerosis to neuropsychological deficits?

BACKGROUND: Intima-media thickness (IMT) measured by extracranial duplex sonography is a surrogate marker for atherosclerosis. It is well known that IMT is greater in HIV patients than in age-matched healthy controls due to HIV- induced endothelial damage and metabolic side-effects of antiretroviral therapy. However, it remains unclear whether atherosclerosis has an additional impact on cognitive function in HIV patients. Therefore, the objective of this study was to investigate the correlation between IMT and neuropsychological deficits in HIV patients. METHODS: 47 HIV patients and 40 age-matched healthy controls were examined by extracranial ultrasound 2 and 3 cm before the flow divider to evaluate differences in IMT. Possible neuropsychological deficits in HIV patients were assessed using a battery of 10 neuropsychological tests. Results of neuropsychological tests and markers of disease severity were correlated with IMT in HIV patients. RESULTS: IMT was significantly greater in patients than in healthy controls (p < 0.001). However, none of the neuropsychological tests correlated significantly with IMT measurements in HIV patients. There was only a weak correlation between deficits in attention and IMT in HIV patients (r = 0.44; p = 0.005), which was non-significant after correction for multiple comparisons. Markers of disease severity (CD4 cell count, HIV load in plasma, duration of HIV disease) did not correlate with IMT either. CONCLUSION: IMT was greater in HIV patients compared to age-matched controls but it appears that premature atherosclerosis has no additional impact on the evolution of neuropsychological deficits in HIV patients. IMT did not correlate with the severity of immunodeficiency.

Inhibition of rat vascular smooth muscle cell proliferation in vitro and in vivo by recombinant replication-competent herpes simplex virus.

BACKGROUND AND PURPOSE: The proliferation of vascular smooth muscle cells (VSMCs) is a common feature associated with vascular proliferative disorders such as atherosclerosis and restenosis after balloon angioplasty. We examined the antiproliferative effects of recombinant replication-competent herpes simplex virus (HSV), hrR3, to proliferative VSMCs both in vitro and in vivo. METHODS: Early passages of Sprague-Dawley rat VSMCs were infected with hrR3 at a low multiplicity of infection (0.01 to 1.0) to examine the in vitro cytotoxic activity of this recombinant HSV to VSMCs in a proliferative state. Sprague-Dawley rats underwent balloon dilatation injury of the left carotid artery to induce neointimal formation. The injured carotid arteries were infected with hrR3 five days after balloon injury. Two weeks after injury, the left carotid arteries were fixed, and the areas of the neointimal and medial layers were analyzed microscopically. Because the reporter Escherichia coli lacZ gene in hrR3 is expressed only in infected cells in which the virus is actively replicating, virus replication was confirmed by X-gal staining. RESULTS: A morphometric analysis revealed that there were significant differences in the intima/media ratio between the HSV-treated group and mock-infected group (0. 354+/-0.068 and 1.08+/-0.055, respectively). In the histological study (X-gal staining), positive X-gal staining was observed chiefly in the VSMCs in the medial layer just beneath the internal elastic lamina, indicating active viral replication. CONCLUSIONS: Virus-mediated cytocidal therapy using recombinant HSV vector is a promising modality for the treatment of the restenosis after balloon angioplasty.