Intima-media thickness of common and internal carotid arteries in patients with hepatosplenic schistosomiasis mansoni

Abstracts

OBJECTIVE: To evaluate the intima-media thickness (IMT) of common and internal carotid arteries in patients with hepatosplenic schistomiasis mansoni and those who underwent portal decompression surgery (splenectomy and left gastric artery ligature). Both groups were compared with a health volunteer control group, living in the same social-economic-environmental conditions. MEHTODS: An ultrasound Doppler with a 7.5 MHz probe was used. The IMT was measured in the three groups with 20 individuals each, of both gender, with ages ranging from 20 to 60 years. The mean and standard deviations of common and internal carotid arteries maxIMT, medIMT, minIMT were assessed. Risk factors: age, systemic arterial hypertension and cigarette smoking were investigated as regard to IMT measurements. RESULTS: There were no statistical differences in IMT between right and left side, and among surgical, non-surgical and control groups. The surgical treated patients and controls showed correlation to known atherosclerotic risk factors: age, hypertension and cigarette smoking. However, non-surgically treated patients did not present the same correlation. CONLCUSION: It is tempting to believe that non-operated schistosomotic patients may have "some protection" against atherogenesis in human beings; however, the data do not lend full support to this hypothesis.

Schistosomiais; Atherosclerosis; Ultrasonics

OBJETIVO: Avaliar a espessura do complexo miointimal (IMT) das carótidas comum e interna, em portadores de esquistossomose hepatoesplênica (EHE) não tratados cirurgicamente, já submetidos a cirurgia para descompressão do sistema porta por esplenectomia e ligadura da veia gástrica esquerda, e comparar com volutários de condições sócio-econômico-ambientais similares, não portadores de esquistossomose. MÉTODOS: Utilizando aparelho de ultra-som Doppler de 7,5MHz foram mensurados os IMT de três grupos de voluntários, de ambos os gêneros, com idades que variaram de 20 a 60 anos, sendo avaliados os IMT máximos, IMT médios, IMT mínimos e seus desvios-padrão, das carótidas comuns e internas e feitas as comparações entre os grupos e suas associações com fatores de risco: idade, hipertensão arterial e tabagismo. RESULTADOS: Não houve diferença significante na média dos IMT, entre os lados direito e esquerdo e nem entre os grupos. Nos pacientes tratados cirurgicamente, assim como nos indivíduos-controle confirmou-se a associação, já conhecida, com os fatores de risco para aterosclerose (idade, hipertensão arterial e tabagismo). Contudo, não se observou este comportamento nos pacientes não operados. CONCLUSÃO: A EHE sem tratamento cirúrgico parece conferir "alguma proteção" contra a aterogênese em seres humanos; todavia, os achados não dão suporte definitivo a esta hipótese.

Esquistossomose; Aterosclerose; Ultra-som

ORIGINAL ARTICLES

Intima-media thickness of common and internal carotid arteries in patients with hepatosplenic schistosomiasis mansoni

André Valença Guimarães^I; Carlos Teixeira Brandt, TCBC-PE^II; Adriana Ferraz^I

^IPhD in Surgery, Universidade Federal de Pernambuco, PE, Brazil

^IIPhD, University of Liverpool, UK

Correspondence address

ABSTRACT

OBJETIVE: To evaluate the intima-media thickness (IMT) of the common and internal carotid arteries in patients with hepatosplenic schistosomiasis mansoni and in those who underwent portal decompression surgery (splenectomy and left gastric artery ligation). Both groups were compared with a healthy volunteer control group with the same socioeconomic and environmental background.

METHODS: A 7.5-MHz Doppler ultrasound probe was used. The IMT was measured in the three groups comprising 20 individuals each, of either gender, with ages ranging from 20 to 60 years. Means and standard deviations were calculated from the maximum (maxIMT), minimum (minIMT), and average (aveIMT) IMT measurements for the common and internal carotid arteries. Risk factors age, systemic arterial hypertension and cigarette smoking were investigated with regard to the IMT measurements.

RESULTS: There were no statistical differences in IMT between right and left side arteries, and between the surgical, non-surgical and control groups. The surgical patients and the controls showed a correlation with known atherosclerotic risk factors: age, hypertension and cigarette smoking. However, non-surgically treated patients did not present the same correlation.

CONCLUSION: It is tempting to believe that non-operated schistosomal patients may have "some protection" against atherogenesis; however, the data do not lend full support to that hypothesis.

Keywords: Schistosomiasis. Atherosclerosis. Ultrasound.

INTRODUCTION

The first manifestations of cardiovascular disease arise at an advanced stage of atherosclerosis. However, alterations in the arterial wall occur during the subclinical period, characterized by progressive thickening of the endothelium. This endocrine organ is responsible for physiological processes that are vital to vascular homeostasis¹.

When risk factors exist, endothelial thickening can be detected already in childhood, and can be predictive of cardiovascular events in adults^2-4. Since the first anatomopathological description, several articles have been published associating ultrasound measurements (intima-media thickening – the identifiable portion of the endothelium) with cardiovascular diseases⁵.

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 studies⁶.

There are already several well-established risk factors for atherosclerosis, such as hypertension, dyslipidemia, smoking and diabetes⁷. 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) infections⁸.

Schistosomiasis, an endemic disease in several regions in the world and with high prevalence 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 hypoevolutism^9,10 .

Important alterations have been demonstrated in the lipid profile of those who present with advanced disease¹¹. Speculations are made as to whether those findings could influence the behavior of the intima-media complex. No report exists in the literature with respect to the measurement of carotid intima-media thickness as a predictor of degenerative arterial disease in patients with the hepatosplenic form of schistosomiasis, which justifies the present investigation. On the other hand, whether the lipid alterations in human hepatosplenic schistosomiasis mansoni patients interfere with atherogenesis was not investigated.

The objective of this investigation was to evaluate the thickness of the intima-media complex of the common and internal carotid arteries of hepatosplenic schistosomiasis mansoni (HSM) patients through color Doppler ultrasound.

METHODS

This case-control study was conducted at the Pediatric General Surgery and the Gastroenterology Services of the UFPE and at the Vascular Ultrasonography Service of the Centro Diagnóstico José Rocha de Sá in Recife, PE, Brazil.

The sample was composed of three groups of individuals of either gender, with ages ranging from 20 to 60 years, randomly recruited from the Pediatric General Surgery and the Gastroenterology outpatient clinics of the UFPE.

Group I (HSM) – 6 men and 14 women, all with positive clinical history and laboratory tests for hepatosplenic schistosomiasis mansoni, non-operated. With regard to schooling, most (16) patients in this group only had some primary school, and only two patients had finished secondary school. The mean age was 44 years; mean weight, 59 kg; mean height was 1.58 m, and mean BMI, 24. In this group, there were no diabetic patients; three patients were hypertensive, and three were current smokers.

Group II (HSM-OP) – 7 men and 13 women with positive clinical history and laboratory tests for hepatosplenic schistosomiasis mansoni, who had already undergone total splenectomy, left gastric vein ligation and sclerotherapy of esophageal varices after bleeding recurrence. As for schooling, most (16 patients) only had some primary school, and only two patients had concluded secondary school. The mean age was 38 years; mean weight, 59 kg; mean height was 1.56 m, and BMI, 24. There were no diabetic patients in this group; eight patients were hypertensive, and three were smokers.

Group III (Control) – healthy volunteers, 4 men and 16 women, free of HSM, matched for age group, socioeconomic and environmental background. With regard to schooling, seven subjects had secondary education and three had finished primary school. The remainder only had some primary education. The mean age was 37 years; mean weight, 67 kg; mean height, 1.58 m, and mean BMI was 27. In this group, there were no diabetics either; four individuals were hypertensive, three had dyslipidemia and one was a smoker.

All indivíduals or patients who had had hepatitis or were regular users of alcohol were excluded from the study.

The ultrasound examinations of the carotid intima-media complex were conducted with a portable GE Vivid I MFG 2006, Convex, 8L-RS, Linear (4-10 MHz) ultrasound scanner. By this technique, two parallel echogenic lines separated by an anechoic space can be seen on the arterial wall. Those lines are generated by the interfaces blood-intima and media-adventitia. The distance between those two lines produces a reliable index of the intima-media thickening (IMT)⁴.

The examinees were evaluated in the supine position with the head elevated at 15 degrees and turned away from the ultrasound probe. The common carotids were scanned at a distance of 1 to 3 cm proximally to the bifurcations, and the internal carotids, in their first 2 cm. All measurements were made in real time through the images obtained longitudinally with the automatic calibrator of the equipment. Twelve measurements were obtained for each individual, totaling 720 measurements. The mean time of each procedure was 15 to 20 minutes.

The presence of an atherosclerotic plaque was defined as irregular, localized thickening of at least 1.5 mm. Luminal diameter was defined as the mean of the distances measured between the most prominent portion of line I of the artery near wall and line I of the far wall, at the end of diastole in three cardiac cycles. The arterial wall opposite to the probe (far wall) was chosen for the assessments as it is less subject to interference during image capture.

The results for the qualitative variables were expressed as frequencies. The results for the quantitative variables were expressed as means and standard deviations. The statistical tests used were Pearson's chi-square or Fisher's Exact test (when the conditions for applying the former were not fulfilled). The tests F (ANOVA) or Kruskal-Wallis, Student's t-test or Wilcoxon Signed Ranks Test and Mann-Whitney were used for inferential statistics. The hypothesis of normality was tested by the Kolmogorov-Smirnov test and the hypothesis of equality of variances was tested through Levene's F test. The margin of error or significance level in the statistical tests was 5.0%.

The study was approved by the Human Research Ethics Committee of the Centro de Ciências da Saúde, UFPE. The participants provided written informed consent. For those under 18 years of age, the parents signed the informed consent document authorizing their participation in the study.

RESULTS

None of the 60 patients had diabetes, and the most frequent associated disease was arterial hypertension, with 40.0% in the operated group, 20.0% in the control group and 15.0% in the non-operated group. Smoking was found in 15.0% of the patients in the operated group, 15.0% in the non-operated, and one (5.0%) patient in the control group; no significant difference was established across groups for any of these variables (p >0.05) (Table 1).

Table 2 shows the means and standard deviations for the measurements of maximum, minimum and average IMT (maxIMT, minIMT and aveIMT, respectively) for the common carotids according to side and group. No significant difference was found across groups for the right and left sides, nor between sides for any of the groups. No statistical difference was found for the analyzed measures: maximum, minimum and average IMT in the common carotid (p >0.05).

It is worth noting that the means for maxIMT, minIMT and aveIMT values showed higher correlations in the group of non-operated patients than in the control group. The greatest difference between groups in relation to the means for maxIMT was 0.09 mm in the right side (RCC–maximum) (0.81 mm for the non-operated group vs 0.72 mm in the control group ). With respect to the means for minIMT measurements, the greatest difference was 0.09 mm in the left side (LCC–minimum), again between the non-operated and control groups (0.53 mm vs 0.44 mm respectively). The greatest difference in aveIMT means was 0.09 mm in the right side common carotid (RCC-average), between the non-operated and control groups (0.66 mm vs 0.57 mm respectively).

The means for the right side measurements were equal to, or a little higher than those for the left side, and the greatest differences were 0.06 mm in the control group for maxIMT (0.81 mm vs 0.75 mm, respectively); 0.01 mm in the operated and control groups for minIMT; and 0.03 mm in the non-operated group for the aveIMT (0.66 mm vs 0.63 mm respectively) (Table 2).

Regarding the frequencies of common carotid IMT measurements with values above 1.5 mm (plaque): one plaque was found in the measurement of maxIMT and one plaque when measuring aveIMT in the operated group (Table 3).

No significant differences were observed across groups for the right and left sides, nor between sides for any of the groups. No statistically significant differences occurred (p >0.05) in any of the analyzed measurements for the internal carotid.

It is worth noting that, with the exception of the minIMT measurements in the operated group, the right side means were higher than those for the left side; the greatest differences between sides occurred with the non-operated group: 0.12 for maxIMT measurements (0.90 mm vs 0.78 mm); 0.07 for minIMT measurements (0.56 mm vs 0.49 mm), and 0.09 for the measurement of aveIMT in the non-operated group (0.73 mm vs 0.64 mm) (Table 4).

Across groups, the greatest difference in relation to the means for maxIMT was 0.06 mm in the left side (LIC-maximum) (0.84 mm in the operated group vs 0.78 mm in the non-operated group). For minIMT means, the greatest difference was 0.08 mm in the right side (RIC-minimum) between the non-operated and the operated group (0.56 mm and 0.48 mm, respectively). For the aveIMT measurements, the greatest difference was 0.07 mm in the right side (RIC) between the operated group and each of the other groups (0.73 mm in the operated group vs 0.66 mm in the other two groups).

Table 5 shows the frequencies of the IMT measurements for the internal carotid with plaque (values above 1.5 mm). Two plaques were identified in the right side in the operated group; one plaque was also found in the left side when measuring maxIMT; another plaque in the right side and one in the left side in the aveIMT measurements.

In table 6 the values are shown for the correlation between age and each one of the maxIMT measurements for the common carotid and internal carotid by group. All correlations were found to be positive, indicating that maxIMT measurements tend to increase with age; for the non-operated group, that correlation was statistically significant.

The correlations with maximum RCC in the operated group and with maximum LCC in the control group were not significant; the greater correlation with age was 0.650 in the control group with maximum RIC (Table 6).

Table 7 shows that the means for maxIMT measurements in the common carotid were higher among the hypertensive than the non-hypertensive patients in all groups.

With the exception of the non-operated group, the means for the measurements of maxIMT in the internal carotid were higher among hypertensive subjects than among those who were non-hypertensive.

Significant differences were recorded for maximum LCC in the non-operated group; with the exception of maximum LIC in the group of operated patients; for maximum RCC and maximum LIC in the control group (Table 7).

Table 8 shows the means for the measurements of maxIMT in the common carotid and the internal carotid, which were correspondently higher among patients presenting with some risk factor (hypertension, dyslipidemia and smoking) than among those who had no risk factors, across groups. However, significant differences were only recorded for maximum RCC in the operated group and maximum LCC and LIC in the control group.

The association between the increase in IMT means and risk factors (age, arterial hypertension and smoking) tended to occur with individuals in the control group and those who were hepatosplenic schistosomiasis mansoni patients already clinically and surgically treated.

The non-surgical patients did not show that association, which suggests that hepatosplenic schistosomiasis may have a "protective effect" on the atherogenesis phenomenon in humans.

DISCUSSION

The decision to study the severe form of schistosomiasis mansoni was based on information showing that hepatic lesions produced at that stage change the lipid profile, and that there is a tendency toward normalization after surgical treatment of portal hypertension^9,12. Since those changes are related to the extent of the lesion to endothelial cells, Doppler ultrasound can be used to assess whether those HSM influence intima-media thickness in humans.

The relation of lipoproteins to atherosclerosis is known¹³. 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 participation of cells such as lymphocytes, macrophages and monocytes is decisive in the inflammatory component of that disease.

Hypertension, dyslipidemia, diabetes and smoking constitute risk factors already largely associated with atherogenesis.

The interfaces of atherosclerosis with infections are very complex. 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 response, 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 atherogenesis¹⁴.

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 lipopolysaccharides (LPS) and cytokines are known to reduce total cholesterol serum levels and produce various effects in rodents¹⁵.

The incidence of coronary artery disease and stroke is higher in patients with chronic infections. 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 infections^16,17.

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 atherosclerotic lesions¹⁸.

In certain instances of bacterial infections, beneficial effects can be found from the alterations in lipoprotein metabolism. The conjugation of LPS to lipoproteins protects 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 demonstrated¹⁹.

Atherosclerosis-resistant rats developed early atherosclerotic plaques when infested with T.cruzi, while rats that were susceptible to atherosclerosis sustained fewer atherosclerotic lesions when infested with S. mansoni. On the basis of those findings, it is postulated that infection by S. mansoni may produce a protective effect against atherosclerosis²⁰.

Since there was no report in the literature on carotid IMT of schistosomiasis patients as an imaging study to evaluate the impact of that disease on the behavior of atherogenesis, it was decided to undertake the present study. This decision was based on research work involving the study of IMT in other infectious processes²¹. Since the differences between the means of IMT measurements found in the groups were very small, sample size showed too small for significant differences to be observed. Despite these limitations, the present findings were in line with the literature regarding the risk factors already known.

The age range of 20-60 years was chosen with the purpose of avoiding very young participants, in whom atherogenesis was not yet manifest, as well as elderly individuals, for whom atherosclerotic phenomena were predictable events.

Although there was a prevalence of the female gender, that factor was not statistically significant. The mean age ranged between 36 and 44 years and was also homogeneous across groups. The BMI, slightly higher in the control group, showed no significant difference.

By excluding hepatitis and alcoholic patients, two important confusing variables were circumvented, since those entities interfere directly with liver function. Diabetes, another disease that accelerates atherogenesis, was not observed in any of the subjects.

The attempt to identify early markers 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 introduced in the armamentarium of cardiologists and atherogenesis experts as a marker of diffuse atherosclerosis²².

Brachial artery distensibility, coronary flow reserve, pulse wave analysis, pulse wave velocity and plethysmography have also been used to detect endothelial dysfunction and also considered to be risk markers for cardiovascular disease¹.

The choice for Doppler ultrasound for the assessment of intima-media thickening was based on evidence from other authors regarding the sensitivity, reproducibility and reliability of that tool, especially its great predictive power for cardiovascular events, in particular cerebrovascular accidents and acute myocardial infarction.

Some authors have proposed the validation criteria of surrogate markers for clinical analysis. 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 relationship between the marker and the clinical conclusions should be established on epidemiologic 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^{4, 22}.

The Doppler ultrasound scan with an automatic calibrator becomes minimally sonographer-dependent. 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 immediately 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 machines²³.

The choice for the carotid artery was made in view of its topographic characteristics, which ensure easy access to the examiner; also, for its anatomy, as it is a superficial artery and follows a more or less straight path along the cervical segment, in addition to being a vessel with abundant elastic fibers that respond promptly to hemodynamic "stress"⁶.

A study with populations at difference ages showed that IMT would increase at an average rate of [IMTmm = 0.009 x age+0.35], i.e., it is a biological phenomenon that can be objectively quantified²⁴.

Despite the fact that the present study included three hypertensive patients and three smokers in the non-operated group; eight hypertensive patients and three smokers in the operated group; four hypertensive and three dyslipidemic patients, and a smoker in the control group, there were no statistically significant differences between them. Thus, the sample was deemed homogeneous for those risk factors.

No significant difference was observed in the IMT measurements of the common carotids with respect to the sides (right and left), nor across groups for the maxIMT, aveIMT and minIMT parameters

Regarding Tables 3 and 5, that seven measurements of IMT >1.5 mm were found in two patients of the non-operated group and none in the operated or control groups.

With regard to age, a greater correlation was found between that variable and IMT means in the operated and control groups than in the non-operated group (in which Pearson's correlation was very low). Hypertension was also more associated with the increase in IMT means in the non-operated and control group patients.

Although there were no significant differences, the means for IMT values of common and internal carotids were found to be correspondently higher among patients with some risk factor (hypertension, age and smoking), especially in the operated and control groups, but that behavior was not observed in the non-operated group.

CONCLUSIONS

The evaluation of the intima-media complex of the carotid arteries in hepatosplenic schistosomiasis mansoni patients through Doppler ultrasonography warrants the conclusion that the carotid intima-media thickening found in surgically-treated patients, as well as in control subjects, confirmed an association with atherosclerosis risk factors (age, arterial hypertension and smoking). However, the same was not observed in non-operated patients, which suggests that hepatosplenic schistosomiasis mansoni without surgical treatment may confer a "protective effect" against atherogenesis in humans.

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Publication Dates

• Publication in this collection
  09 Nov 2009
• Date of issue
  Aug 2009

History

• Received
  07 Nov 2008
• Accepted
  17 Jan 2009