HIV infection can provoke vascular complications, although they are not presently viewed as one of its most serious manifestations [1]. HIV vascular complications are general infective vascular dis- eases [2]. Most of the cases presented in this chap- ter occurred before the advent of highly active antiretroviral therapy (HAART) and mostly in AIDS patients because the majority of pathology examinations were done during necropsy.
Vasculitis
Microcirculation lesions are well documented by biopsies of the nervous system and muscles in AIDS peripheral neuromuscular localizations. In a cohort study published before HAART, vasculitis was present in 24% of biopsy samples from 225 patients: 12 cytomegalovirus vasculitis, 19 “micro- vasculitis,” and one giant cells arteritis case [3].
Kieburtz et al. [4] described Candida albicans vas- culitis with thrombosis and a cerebral infarction due to cytomegalovirus vasculitis in AIDS patients.
Peripheral Arterial Localizations
Clinical reports and systematic necropsies of AIDS patients pointed out arterial lesions. Kieburtz et al.
[4] reported brain infarction in 20% of autopsies, Engstrom et al. [5] described 25 clinical cases.
Joshi et al. [6] described arterial lesions in kid- neys, spleen, thymus, and muscles in five children aged 1–7 years, including luminal narrowing with intima fibrosis, internal elastic lamina fragmenta- tion, and calcifications.
Husson et al. [7] in a cohort of 250 HIV-infect- ed children noted the appearance of two fusiform
cerebral aneurysms. Rautonen et al. [8] pointed out clinical and anatomic similarities with Kawasaki’s disease, which may be due to a retro- virus organism.
Capron et al. [9] described toe embolism in four HIV male patients (40–56 years old) from aortic and femoral ulcerated atherosclerotic plaques.
Kabus and Greco [10] described gross intimal aortic lesions at autopsy, resembling gelatiniform syphilitic ones in children with AIDS.
Clinical information about vasculitis and peripheral arterial disease in HIV infection is given by P. Mercié et al. in a separate chapter in this volume.
Venous Thrombosis
Some authors described deep venous thrombosis in AIDS, an unsurprising complication in severely bedridden patients. Confusion is possible between pulmonary embolisms and opportunistic pul- monary infections, according to Pulik et al. [11].
Deep venous thrombosis and related coagulation disorder in HIV infection are described in detail by L. Drouet in a separate chapter in this volume.
Coronary Artery Lesions
It was a surprise for us to discover, during post- mortem examination, many severe latent coronary artery lesions occurring in very young (23–31 years old) AIDS patients [1]. Both hospital and forensic necropsies were performed. The death causes were not linked with coronary lesions except in one of five sudden death cases without other pathology. Clinical coronary disease symp- toms were absent in all patients. The patients were
in AIDS Patients
A. Tabib, R. Loire
homosexuals or drug addicts or both. Pathological analysis used transverse sections taken every 0.5 cm along the epicardial routes of the three main coronary trunks. Sections obtained every 1 cm were fixed in Bouin’s solution, then embedded in paraffin for histopathological study, together with representative fragments of the left and right ventricular walls and interventricular septum making up the distal coronary network. Histological sections were stained with hemalum-phloxine-saf- fron and with Weigert’s resorcin-fuchsin method.
Every coronary examination of AIDS patients pointed out gross and microscopic lesions (100%), although a comparative examination of patients of the same age without AIDS showed only 14% of identical lesions.
Pathological Coronary Lesions
1. Common atherosclerotic plaques were present on the three main coronary trunks in 60% of cases, with two different patterns: either young plaques consisting in macrophages, foamy cells, and a small amount of extracellular lipid deposit (Fig. 1), or adult eccentric plaque with a lipid core surrounded by a fibrous wall con- sisting in macrophages, fibroblasts, smooth muscle cells, a few lymphocytes, elastic fibers, and collagenous fibers. Stenosis occluded 75%
or more of the lumen (Figs. 2–4). In one case, the right coronary artery was completely occluded by a massive thrombosis (Fig. 5).
2. Uncommon intimal thickening which was dif- fuse, circular, and concentric throughout the whole length of every coronary trunk affected all patients, occluding over 40% of the vascular Fig. 1.Common atherosclerotic young plaque.
Col HPS x100
Fig. 3.Adult eccentric plaque. Col HPS, x25
Fig. 4.Adult eccentric plaque. Col HPS, x25 Fig. 2.Adult eccentric plaque. Col HPS, x25
Fig. 5.Complete occlusion by fibrous organized plaque.
Col HPS, x25
Fig. 6.Intimal diffuse and circular thickness
Fig. 8.Intimal diffuse and circular thickness. Col HPS, x100
lumen. Collagenous and microelastic fibers were admixed with smooth muscle cells, macrophages, rare foam cells, and fibroblasts, without lymphocytes (Figs. 6–9).
3. Unusual and original lesions consisting in pro- liferation of smooth muscle cells mixed with
Fig. 7.Intimal diffuse and circular thickness. Col HPS, x25
Fig.9.Intimal diffuse and circular thickness with foamy cells.
Col HPS, x100
numerous packed elastic fibers, which formed mamillated endoluminal protrusions resem- bling vegetations, were present in 40% of cases (Figs. 10–12).
The distal coronary network of intramural arterioles was also the site of a diffuse concentric
Fig. 10.Mamillated endoluminal protrusion. Col HPS, x25
Fig.12.Mamillated endoluminal protrusion. Col Weigert, x25
Fig. 13.Distal coronary network. Col HPS, x25
Fig. 14.Distal coronary network. Col HPS, x100
Fig. 15.Distal coronary network. Col HPS, x100 intimal wall thickening occluding more than 80%
of the lumen in 25% of cases (Figs. 13–15).
Immunohistochemical data allowed true iden- tification of smooth muscle cells (alpha-actin and
vimentin expression) as the main elements of dif- fuse intimal layer thickening. The expression of tumor necrosis factor-alpha (TNF-α) and inter- leukin-1alpha (IL-1α) in these cells was signifi- cantly greater than in smooth muscle cells of the underlying media. Fibrocytes and fibroblasts were scarcely disseminated on the periphery of athero- sclerotic plaques, mixed with smooth muscle cells and some lymphocytes. CD68 expression identi- fied macrophages, proving also TNF-α and IL-1 expression. Factor VIII expression appeared on endothelial cells.
Coronary lesions in AIDS patients have some of the characteristics of common atherosclerosis, such as eccentric fibro-lipidic plaques. But they also present similarities with coronary lesions fol- Fig. 11.Mamillated endoluminal protrusion. Col HPS, x100
lowing heart transplantation (so-called chronic rejection), such as diffuse concentric intimal thickening occurring in coronary trucks and in the distal network [12].
Pathogenetic Hypotheses
Three possibilities can explain HIV-associated vascular alterations: (1) direct cellular infection by HIV (macrophages, smooth muscle cells, endothe- lial cells), (2) blood coagulation alterations, and (3) cellular infection by opportunistic elements [13]. Every change must naturally be mediated by numerous cytokines and adhesion molecules:
today it is often possible only to demonstrate the presence or absence of these mediators, which is an indirect method that cannot indicate if cells are a source or target (or both) of the mediators.
1. Direct cellular infection by HIV. This phenome- non is demonstrated for macrophages, which is the first cellular target of the virus along with CD4 lymphocytes. It has not been demonstrated in vitro for endothelial cells, but some modifica- tions are perhaps due to this alteration: von Wil- lebrand’s factor VIII, soluble thrombomodulin, E-selectin, and CD4 molecule increase [14].
These modifications involve endothelium pro- perties: antigen presentation – IL-1, TNF-a secre- tion – and IL-2 production by T cells, which secondarily involve basal membrane degrada- tion via Tat protein [15, 16]. Morphogenetic modifications of intimal intercellular matrix facilitate the penetration of lymphocytes and macrophages that are the target cells for HIV infection and replication. Infected macrophages would initiate medial smooth muscle activation and proliferation [17]. Endothelial cells seem to be heterogeneous, with discontinuous cells of sinusoid capillary cells displaying a different behavior [18].
2. Hypercoagulability has been demonstrated in AIDS: von Willebrand’s factor and tissular plas- minogen activator increase, while there is a decrease in beta-2 microglobulin, S protein- free plasmatic fraction (protein C cofactor), and second heparin-cofactor (thrombin
inhibitor). Other possible thrombogenic fac- tors can be demonstrated: antiphospholipid antibodies (70% of AIDS cases) and lipoprotein LP(a) increase (common epitope for HIV and blood platelets), whereas hypertriglyceridemia and apolipoprotein AII decrease [19, 20].
3. Opportunistic infections demonstrate vascular tropism [21]. Viral cytolysis and endothelial necrosis favor the parietal adhesion of macrophages, an early known atherosclerotic stage. Cytomegalovirus alters endothelial cells as well as smooth muscle medial cells leading to multiplication, phenotype transformation with collagen and microelastic element synthe- sis and foam cells formation.
Experimental pathology studies in Macacus monkeys demonstrate a diffuse arteriopathy pres- ent in 25% of the population after simian immun- odeficiency virus (SIV) infection, without a proven responsibility for either SIV or opportunistic infection [22].
Conclusion
Numerous hypotheses exist to explain AIDS vascu- lar disorders. It is likely that the frequency of coro- nary lesions is high and underestimated because little attention is given during autopsy to coronary examination. Benditt’s monoclonal origin of vas- cular lesions [23], depending on a viral cause, could provide a physiopathological answer.
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