**3. Schistosomiasis mansoni infection may affect the natural history of atherogenesis**

Infections of Schistosoma mansoni, the adult worms significantly reduced atherogenesis in apolipoprotein E gene knockout (apoE(-/-)) mice. These effects occurred in tandem with a lowering of serum total cholesterol levels in both apoE(-/-) and random-bred laboratory mice and a beneficial increase in the proportion of HDL to LDL cholesterol. The serum cho‐ lesterol-lowering effect is mediated by factors released from S. mansoni eggs, while the pres‐ ence of adult worms seemed to have little or no effect. High levels of lipids, particularly triacylglycerols and cholesterol esters, present in the uninfected livers of both random-bred and apoE(-/-)mice fed a high-fat diet were not present in livers of the schistosome-infected mice[16].ApoE-deficient mice chronically exposed to the eggs of Schistosomamansoni over a period of 16 weeks showed thattotal serum cholesterol and low-density lipoprotein (LDL) were reduced in egg-exposed ApoE-deficient mice fed a diet high in cholesterol compared to unexposed controls. However, exposure to eggs has no effect on atherosclerotic lesion size or progression in these animals. Macrophages isolated from egg-exposed mice had an enhanced ability to take up LDL but not acetylated LDL (acLDL). This suggests that schisto‐ some eggs alone may alter serum lipid profiles through enhancing LDL uptake by macro‐ phages, but these changes do not ultimately affect atherosclerotic lesion development[17].

Previous studies have shown that people infected with schistosomiasis have lower levels of serum cholesterol than uninfected controls. In human beings the first manifestations of car‐ diovascular disease from atherogenesis arise at an advanced stage of atherosclerosis. How‐ ever, patients with hepatosplenic schistosomiasis mansoni have abnormal lipid peroxidation, with elevated erythrocyte-conjugated dienes implying dysfunctional cell membranes, and also imply that this may be attenuated by the redox capacity of antioxidant agents, which prevent accumulation of plasma malondialdehyde (MDA)[18]. These lipid metabolism changes affect the natural history of atherogenesis including the risk factors.

The alterations in the arterial wall occur during the subclinical period of atherogenesis, char‐ acterized by progressive thickening of the endothelium. This endocrine organ is responsible for physiological processes that are vital to vascular homeostasis[19].

When risk factors exist, endothelial thickening can be detected already in childhood, and can be predictive of cardiovascular events in adults[20]-[22]. Since the first anatomopatho‐ logical description, several articles have been published associating ultrasound measure‐ ments (intima-media thickening – the identifiable portion of the endothelium) with cardiovascular diseases[23].

The accuracy, reproducibility and rapidity of Doppler ultrasound have made this method a powerful tool for early diagnosis, as well as in the monitoring of atheroscletrotic lesions and even when evaluating results in population studies[24].

*C. pneumoniae* and *Cytomegalovirus*, while other lesions seem to be induced by humoral mechanisms, as in the case of H. pylori and chronic urinary, respiratory and oral infec‐

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85

Since atherosclerosis itself is an inflammatory disease, and given that infections induce a proatherogenic change in lipoproteins, a cycle is started that tends to aggravate the athero‐ sclerotic lesions[36].In certain instances of bacterial infections, beneficial effects can be found from the alterations in lipoprotein metabolism. The conjugation of LPS to lipoproteins pro‐

Regarding parasite infestations, complex mechanisms are triggered, since both the direct action of the parasite and immune reactions induced by its presence have been demon‐

Atherosclerosis-resistant rats developed early atherosclerotic plaques when infested with *T.cruzi*, while rats that were susceptible to atherosclerosis sustained fewer atherosclerotic le‐ sions when infested with *S. mansoni*. On the basis of those findings, it is postulated that in‐

The IMT has been study in infectious processes[39]. The attempt to identify early mark‐ ers of atherosclerosis has been the object of several studies. The ankle-arm index, which has been used since the 1970's to assess blood flow to the lower limbs, has been intro‐ duced in the armamentarium of cardiologists and atherogenesis experts as a marker of

Brachial artery distensibility, coronary flow reserve, pulse wave analysis, pulse wave veloci‐ ty and plethysmography have also been used to detect endothelial dysfunction and also

Some authors have proposed the validation criteria of surrogate markers for clinical anal‐ ysis. They established three conditions for validity: the first is that the marker should be more sensitive and more readily available than clinical conclusions, in addition to being easy to assess, preferably through noninvasive methods. Second, the causative relation‐ ship between the marker and the clinical conclusions should be established on epidemio‐ logic and pathophysiological bases, as well as clinical studies. It is a prerequisite that patients with and without vascular disease exhibit differences in the marker readings. Third, in intervention studies, expected clinical benefits (benefit assessment) should be anticipated from changes observed in the markers. This last argument implies that the development of markers is not only a matter of time/cost. Moreover, other diagnostic methods for measuring IMT such as the transesophageal echocardiogram, intravascular ultrasound and magnetic resonance imaging, in addition to being more expensive and

The Doppler ultrasound scan with an automatic calibrator becomes minimally sonographerdependent. Normal limits for IMT measurements have been established as between 0.4 mm and 1.0 mm, whereas those above 1.5 mm are interpreted as a plaque. The results are imme‐ diately ready for printout or to be saved on an HD or CD-ROM for occasional and future

fection by *S. mansoni* may produce a protective effect against atherosclerosis[38].

tects animals from hypotension, LPS-induced fever and death.

considered to be risk markers for cardiovascular disease[16].

more invasive, are not appropriate for screening[21],[41].

tions[35].

strated[37].

diffuse atherosclerosis[40].

There are already several well-established risk factors for atherosclerosis, such as hyperten‐ sion, dyslipidemia, smoking and diabetes[25]. However, there are other factors which are still controversial as to the predictive value of findings. Among those factors, bacterial (*C. pneumoniae, H. pylori*), as well as viral (herpes simplex, Epstein-Barr) and parasitic (*T.cruzi, S.mansoni*) infections[26].

Schistosomiasis, an endemic disease in several regions in the world and with high preva‐ lence in Pernambuco, Brazil, has been the target of research studies on disease prevention, clinical and surgical treatments to alleviate the effects of hypertension on the portal system, hypersplenism and child hypoevolutism[27],[28].

Important alterations have been demonstrated in the lipid profile of those who present with advanced disease[29]. Speculations are made as to whether those findings could influence the behavior of the intima-media complex. On the other hand, whether the lipid alterations in human hepatosplenic schistosomiasis mansoni (HSM) patients interfere with atherogene‐ sis has been investigated[30].

The hepatic lesions in patients with hepatsplenic schistosomiasis mansoni produce changes in the lipid profile. There is a tendency toward normalization after surgical treatment of por‐ tal hypertension[31]. Since those changes are related to the extent of the lesion to endothelial cells, Doppler ultrasound is used to assess whether those HSM influence intima-media thickness in humans[32].

The relation of lipoproteins to atherosclerosis is known[30]. However, several years passed before an insight was achieved into the association between the biochemical findings and the structural lesions found in the wall, especially in the vascular endothelium. The partici‐ pation of cells such as lymphocytes, macrophages and monocytes is decisive in the inflam‐ matory component of that disease.

Hypertension, dyslipidemia, diabetes and smoking constitute risk factors already largely as‐ sociated with atherogenesis. The interfaces of atherosclerosis with infections are very com‐ plex. This is due to the mechanisms used by the infectious agents and the different forms of response from the host organism. Infection and inflammation induce an acute phase re‐ sponse, which, in turn, leads to alterations in lipids and proteins. These changes initially protect the host from the deleterious effects of bacteria, viruses and parasites; however, if extended, they could contribute to atherogenesis[33].

Changes take place in the metabolism of total and HDL cholesterol and in their reverse transport over the course of an infection. The responses are not fully understood, but lipopo‐ lysaccharides (LPS) and cytokines are known to reduce total cholesterol serum levels and produce various effects in rodents[34].

The incidence of coronary artery disease and stroke is higher in patients with chronic infec‐ tions. Some lesions are supposedly produced by the infectious agent itself, as in the case of *C. pneumoniae* and *Cytomegalovirus*, while other lesions seem to be induced by humoral mechanisms, as in the case of H. pylori and chronic urinary, respiratory and oral infec‐ tions[35].

The accuracy, reproducibility and rapidity of Doppler ultrasound have made this method a powerful tool for early diagnosis, as well as in the monitoring of atheroscletrotic lesions and

There are already several well-established risk factors for atherosclerosis, such as hyperten‐ sion, dyslipidemia, smoking and diabetes[25]. However, there are other factors which are still controversial as to the predictive value of findings. Among those factors, bacterial (*C. pneumoniae, H. pylori*), as well as viral (herpes simplex, Epstein-Barr) and parasitic (*T.cruzi,*

Schistosomiasis, an endemic disease in several regions in the world and with high preva‐ lence in Pernambuco, Brazil, has been the target of research studies on disease prevention, clinical and surgical treatments to alleviate the effects of hypertension on the portal system,

Important alterations have been demonstrated in the lipid profile of those who present with advanced disease[29]. Speculations are made as to whether those findings could influence the behavior of the intima-media complex. On the other hand, whether the lipid alterations in human hepatosplenic schistosomiasis mansoni (HSM) patients interfere with atherogene‐

The hepatic lesions in patients with hepatsplenic schistosomiasis mansoni produce changes in the lipid profile. There is a tendency toward normalization after surgical treatment of por‐ tal hypertension[31]. Since those changes are related to the extent of the lesion to endothelial cells, Doppler ultrasound is used to assess whether those HSM influence intima-media

The relation of lipoproteins to atherosclerosis is known[30]. However, several years passed before an insight was achieved into the association between the biochemical findings and the structural lesions found in the wall, especially in the vascular endothelium. The partici‐ pation of cells such as lymphocytes, macrophages and monocytes is decisive in the inflam‐

Hypertension, dyslipidemia, diabetes and smoking constitute risk factors already largely as‐ sociated with atherogenesis. The interfaces of atherosclerosis with infections are very com‐ plex. This is due to the mechanisms used by the infectious agents and the different forms of response from the host organism. Infection and inflammation induce an acute phase re‐ sponse, which, in turn, leads to alterations in lipids and proteins. These changes initially protect the host from the deleterious effects of bacteria, viruses and parasites; however, if

Changes take place in the metabolism of total and HDL cholesterol and in their reverse transport over the course of an infection. The responses are not fully understood, but lipopo‐ lysaccharides (LPS) and cytokines are known to reduce total cholesterol serum levels and

The incidence of coronary artery disease and stroke is higher in patients with chronic infec‐ tions. Some lesions are supposedly produced by the infectious agent itself, as in the case of

even when evaluating results in population studies[24].

hypersplenism and child hypoevolutism[27],[28].

*S.mansoni*) infections[26].

84 Current Trends in Atherogenesis

sis has been investigated[30].

thickness in humans[32].

matory component of that disease.

produce various effects in rodents[34].

extended, they could contribute to atherogenesis[33].

Since atherosclerosis itself is an inflammatory disease, and given that infections induce a proatherogenic change in lipoproteins, a cycle is started that tends to aggravate the athero‐ sclerotic lesions[36].In certain instances of bacterial infections, beneficial effects can be found from the alterations in lipoprotein metabolism. The conjugation of LPS to lipoproteins pro‐ tects animals from hypotension, LPS-induced fever and death.

Regarding parasite infestations, complex mechanisms are triggered, since both the direct action of the parasite and immune reactions induced by its presence have been demon‐ strated[37].

Atherosclerosis-resistant rats developed early atherosclerotic plaques when infested with *T.cruzi*, while rats that were susceptible to atherosclerosis sustained fewer atherosclerotic le‐ sions when infested with *S. mansoni*. On the basis of those findings, it is postulated that in‐ fection by *S. mansoni* may produce a protective effect against atherosclerosis[38].

The IMT has been study in infectious processes[39]. The attempt to identify early mark‐ ers of atherosclerosis has been the object of several studies. The ankle-arm index, which has been used since the 1970's to assess blood flow to the lower limbs, has been intro‐ duced in the armamentarium of cardiologists and atherogenesis experts as a marker of diffuse atherosclerosis[40].

Brachial artery distensibility, coronary flow reserve, pulse wave analysis, pulse wave veloci‐ ty and plethysmography have also been used to detect endothelial dysfunction and also considered to be risk markers for cardiovascular disease[16].

Some authors have proposed the validation criteria of surrogate markers for clinical anal‐ ysis. They established three conditions for validity: the first is that the marker should be more sensitive and more readily available than clinical conclusions, in addition to being easy to assess, preferably through noninvasive methods. Second, the causative relation‐ ship between the marker and the clinical conclusions should be established on epidemio‐ logic and pathophysiological bases, as well as clinical studies. It is a prerequisite that patients with and without vascular disease exhibit differences in the marker readings. Third, in intervention studies, expected clinical benefits (benefit assessment) should be anticipated from changes observed in the markers. This last argument implies that the development of markers is not only a matter of time/cost. Moreover, other diagnostic methods for measuring IMT such as the transesophageal echocardiogram, intravascular ultrasound and magnetic resonance imaging, in addition to being more expensive and more invasive, are not appropriate for screening[21],[41].

The Doppler ultrasound scan with an automatic calibrator becomes minimally sonographerdependent. Normal limits for IMT measurements have been established as between 0.4 mm and 1.0 mm, whereas those above 1.5 mm are interpreted as a plaque. The results are imme‐ diately ready for printout or to be saved on an HD or CD-ROM for occasional and future comparisons. Questions that might be raised concerning loss of sensitivity with this type of equipment have already been addressed in a comparison with conventional machines[42].

consequence of HIV itself that activates the endothelial directly or indirectly through

Atherogenesis: Diseases that May Affect the Natural History "Schistosomiasis and HIV Infection"

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87

There is evidence that both pathophysiological HIV to antiretroviral therapy may affect the profile lipídico[58],[59], insulina resistance[60],[61] and the response of vasodilatação[62]. The increased mortality in individuals with HIV due to cardiovascular events in young pa‐ tients, often without classic risk factors for atherosclerosis, is cause for concern and the sub‐

Antiretroviral therapy is associated with pro-atherogenic metabolic abnormalities such as metabolic syndrome, type II diabetes, abnormal distribution of body fat, these conditions al‐ so associated with arterial disease coronariana[63],[64]. Some studies suggest that class of drugs known as protease inhibitors (PI) can be associated with premature atherosclerosis and cardiovascular events, vasculares[47]. It is not clear, but what is the real contribution of

The measurement of intima-media complex (IMT) by ultrasonography (USG) is a nonin‐ vasive marker of early atherosclerosis and may reflect the increased overall cardiovascu‐ lar risk and is associated with increased risk of acute myocardial infarction (AMI) and /

The IMT can be used as a predictor of atherosclerotic disease in coronary arteries independ‐ ently of classical risk factors: age, sex, smoking, hypertension, dyslipidemia, diabetes and family history of coronary artery disease (CAD). IMTcan be consideredas a markerfor the

The study using IMT has been performed in patients with acquired immunodeficiency syn‐ drome (AIDS) in the investigation of risk factors for atherosclerosis as an early marker, but

In AIDS patients the automatic measurement of MIC performed in right and left common carotid, with software determining produces the following measures: average, maximum and minimum (Figure 1). In this same place three manual measurements can be performed. Thus, it is possible to calculate the arithmetic mean of the measure in manual right and left common carotid and the maximum and minimum extent (Figure 2). In the right and left in‐ ternal carotid it can be performed as manual. The gold standard can be represented by the mean of automatic measurements from the right common carotid (RCA) and left common carotid (LCA)[73],[74]. We have measured population of 50 years AIDS patients, the MIC was considered thickened if > 0.8 mm[75] was considered the presence of a thickening dem‐

The ankle-brachial index (ABI) is a simple, noninvasive, high predictive value for peripheral artery disease and has significant association with risk of cardiovascular mortality. It is a good method to be safe, reproducible, low cost, outpatient use and validated in the general population. Early diagnosis of atherosclerosis identifies people at high risk for cardiovascu‐

lar events and thus provides effective treatment and control of factors risco[55].

production of citocinas[57].

ject of new studies[44],[46].

or AVC[65]-[67].

ART in HIV and increased risk of cardiovascular disease.

evaluation ofatherosclerosissubclínica[68]-[70].

there are few studies prospectivos[71],[72].

onstrated plate when WCC > 1.5mm[73],[76].

The carotid artery ensures easy access to the examiner; for its anatomy, as it is a superfi‐ cial artery and follows a more or less straight path along the cervical segment, in addi‐ tion to being a vessel with abundant elastic fibers that respond promptly to hemodynamic "stress"[23].

A study with populations at difference ages showed that IMT increases at a rate of [IMTmm = 0.009 x age+0.35], i.e., it is a biological phenomenon that can be quantified[30].

The means for IMT values of common and internal carotids are higher among patients with some risk factor (hypertension, age and smoking). This pattern occurs in normal subjects and patients with hepatosplenic schistosomiasis mansoni clinical and surgical treated, but this phenomenon is not observed in these patients without any treatment[43]. These find‐ ings lend support to the hypothesis that hepatosplenic schistosomiasis mansoni may be a protective factor against atherogenesis[30].
