EXPERIMENTAL CARDIOVASCULAR AND LUNG RESEARCH
Evaluation of the intima-media complex in patients with systemic lupus erythematosus

Introduction



Over 90% of cases of stricture or obstruction of internal carotid arteries are caused by atherosclerosis. Atherosclerotic plaques are usually localized in the area of artery bifurcation – most often within the common carotid artery bulb and in the ostia of internal and external carotid arteries, more rarely in the proximal part of the common carotid artery. The development of ultrasound diagnostics has enabled non-invasive evaluation of atherosclerotic changes through the examination of echogenicity, the structure and some dimensions of vessels. The measurement of the intima-media thickness is of special importance in diagnosing atherosclerotic changes [1, 2].

The intima-media complex is a structure of the arterial wall from the tunica adventitia-tunica media borderline to the tunica media-vessel lumen borderline. Ultrasound examinations of the intima-media thickness (IMT) were introduced into clinical diagnostics in the 1980s. Insufficient resolution of the early ultrasound devices entailed lower precision of the measurements, and this in turn contributed to considerable divergences in the results obtained by different centers conducting the studies. As a consequence of the technical advancement of ultrasound devices, the IMT measurement was made automated and the examination itself became more significant in the diagnostic process.

According to the concept of parallel and simultaneous development of atherosclerosis [3-5] in many arterial areas, atherosclerotic processes occurring in carotid arteries are representative of analogous processes occurring in other ves-sels. Common carotid arteries are easy to be imaged by ultrasonography, and so the IMT measurement in those arteries provides a precious source of information about atherosclerotic processes progressing in arteries in the areas difficult to access for diagnosis. The increased IMT was shown to correlate with the presence of atherosclerotic changes in the coronary [6], renal [7] and lower limb [8] arteries. The IMT measurement in the carotid artery in its extracranial part can serve as an early marker of atherosclerotic changes and a risk factor for atherosclerotic organic complications [1, 2]. This very thickening of the complex triggers a long process of building the atherosclerotic plaque, whose fracturing in the future activates a cardiovascular incident. Independent studies show that there is a relation between the increased thickness of the IMT complex in the common carotid artery and the risk of both cerebral stroke and myocardial infarction [9]. These studies have also found that the increased IMT measurement in the carotid artery is accompanied by a raised susceptibility to myocardial infarction and ischemic cerebral stroke [10, 11]. The IM complex thickness is an independent risk factor for those diseases.

According to the standards established by the Polish Ultrasound Society in 2008 [12], the normal IMT value is less than 1 mm. In patients with IMT values of 1.00-1.29 mm, the thickening of the IMT complex is diagnosed, while a value of IMT higher than 1.3 mm should be treated as an indicator of diffuse atherosclerotic changes. The European Society of Arterial Hypertension (2003) recognized IMT exceeding 0.9 mm as a sign of organ damage. Moreover, there are suggestions in the literature [13] to treat IMT values higher than 1 mm as the equivalent of a coronary disease.

It is not only the absolute IMT value, but also the annual growth of this parameter, which is of great significance. A further increase of IMT by 0.1 mm increases the risk of myocardial infarction by 10-15% and that of a cerebral stroke by 13-18% [14].

Systemic lupus erythematosus (SLE) is one of the diseases a common manifestation of which is a morbid process that occupies the heart or vessels. The two-degree mortality model for patients with SLE [15] assumes that infection and nephropathy are an early cause of death, while cardiovascular incidents are late causes. It should be noted that symptomatic atherosclerosis occurs only in 6-10% of SLE patients, but the presence of subclinical atherosclerosis can be confirmed in as many as 30-40% [16, 17]. Arterial hypertension, hyperlipidemia and diabetes are additional, independent factors of atherosclerosis development in patients with SLE [17], which is why identifying patients from the cardiovascular incident risk group becomes a substantial matter.

One of the diagnostic tests of atherosclerosis development in SLE patients can be the IMT measurement in the ultrasound examination [18, 19]. This examination is noninvasive, does not require contrast media, is cheap and widely accessible, and, therefore, it allows one to identify patients from the cardiovascular risk group.

The aim of the study was to determine:

• whether there are differences in the thickness of the carotid arteries intima-media complex between the group of patients with systemic lupus erythematosus and the control group,

and

• whether these differences are a consequence of lupus or independent factors of atherosclerosis development.



Material and methods



The IMT of common carotid arties was compared in two patient groups:

• The study group consisted of 25 patients, including 21 women and 4 men at the age of 29-52 years (mean age 39.8 years), suffering from systemic lupus erythematosus. The lupus diagnosis was proposed on the basis of the criteria developed by the American College of Rheumatology (updated in 1997 [20]). The mean duration of the disease at the time of taking the IMT measurement was 4 years. The accompanying diseases in this group included arterial hypertension (7 cases – grade 1 or higher according to the ESH/ESC classification), hyperlipidemia (12 cases – diagnosis: TC ≥ 5 mmol/l and/or LDL-C ≥ 3.0 mmol or TG ≥ 1.7 mmol/l), diabetes type 2 (2 cases, diagnosed according to the WHO criteria). At the time of the examination the patients did not report any diseases other than those mentioned above. The IMT measurement was performed as part of the diagnostics of the cardiovascular condition.

• The control group consisted of 25 healthy patients, including 20 women and 5 men at the age of 20-51 years (mean age 37.1 years), who underwent routine check-up examinations and in whom neither any criteria of lupus or any other disease of the connective tissue, nor any features of the metabolic syndrome, arterial hypertension, hyperlipidemia or pathologic glucose tolerance were found.

Lipid disorders, diabetes and arterial hypertension are independent atherosclerosis [21] development factors, which is why a subgroup of patients suffering only from systemic lupus erythematosus and without any accompanying diseases was selected from the study group. The subgroup included 13 patients (11 women, 2 men) at the age of 29-50 years (mean age 39.2 years).

The study was approved by the Ethics Committee of the Silesian Medical University. Written informed consent was obtained from patients of the study and the control group.

A USG Vivid 7 device with a 3.6 MHz probe was used in the study. The thickness of the intima-media complex of both common carotid arteries (LCCA, RCCA) was measured at the distance of about 1 cm from the bulb. The IMT measurement was taken at the cross section of the vessel, the innermost layers, where the focus of the device was set. The distance between the first, clearly separated bright line (vessel lumen – tunica media borderline) and the second bright line (tunica media – tunica adventitia borderline) determined the complex thickness. The measurement was made with 0.1 mm accuracy. Ten measurements were performed for each carotid artery.

For each series of measurements, the observations that did not fit into the range of mean value ± 1 × standard deviation were treated as odd values and were removed from the series. The IMT measurement for each series was the arithmetic mean of the remaining observations. The data received from the examinations were analyzed statistically. The character of random variable distribution was assessed by means of the Kolmogorov-Smirnov test. Variance cohesion in groups was determined on the basis of Levene’s test at the significance level of p = 0.05. The data obtained from the test were analyzed by the ANOVA single-factor variance analysis (with Scheffe’s post-hoc test analysis) or its non-parametric equivalent, the ANOVA Kruskal-Wallis test (in this case, the Mann-Whitney U test with the significance level of p = 0.05 was used in the post-hoc analysis for each pair of groups). Calculations were carried out by means of Statistica ver. 10.



Results



Basic descriptive statistics of the study groups are shown in Table I. The analysis of the result of the Kolmogorov-Smirnov test indicates that the distribution of the random variable differs from the normal one. In Levene’s test, the homogeneity (p = 0.3351) for the RCCA variable was proved, while for the LCCA variable there was no variance homogeneity in the groups (p = 0.068). A further analysis involved non-parametric tests (Kruskal-Wallis and MannWhitney U tests).

The performed ANOVA Kruskal-Wallis test showed a statistically significant difference of mean IMT values in the analyzed groups (for LCCA p = 0.024, for RCCA p = 0.005). The results are presented in Figure 1.

A further analysis performed with the Mann-Whitney U test indicated (Table II, Table III) that a statistically significant dif-ference of IMT values for both carotid arteries occurs between the control and the study groups (p = 0.006 for LCCA and p < 0.001 for RCCA), while there is no such relation (p = 0.86 for RCCA and p = 0.095 for LCCA) between the control group and the study group of patients suffering only from lupus (without coexisting diseases as independent factors of atherosclerosis development).



Discussion



Numerous studies show that there is a relation between an increased IMT in the common carotid artery and the risk of both cerebral stroke and myocardial infarction [1, 2, 7-11, 13, 19, 22]. It was found that the increased thickness of the intima-media complex of internal and external carotid arteries is accompanied by increased susceptibility to myocardial infarction and ischemic cerebral stroke [10, 11]. The thickness of the IMT complex is an independent risk factor of those diseases. According to the concept of parallel atherosclerosis development [3-5], early atherosclerotic changes observed in the lumen of peripheral arteries are a reflection of a generalized atherosclerotic process in other vessels. For that reason, measurement of the intima-media complex is presently a recognized evaluation method both of the initial and advanced atherosclerotic changes and also a control method of the applied pharmacotherapy efficiency. The method of IMT measurement is also used in determining the probability of the occurrence of coronary disease and evaluation of the risk of cardiovascular incidents in the general population [23]. Studies performed in numerous research centers [16, 17, 24, 25] indicate faster progression of the atherosclerotic process in people suffering from diseases of the connective tissue, including systemic lupus erythematosus. However, the results presented in this study show that such progression occurs mainly in patients with additional factors of atherosclerosis development, such as lipid disorders, diabetes or arterial hypertension.

The statistical analysis of results, due to the lack of normal distribution of the random variable in the study groups, used non-parametric tests, i.e. the ANOVA KruskalWallis and Mann-Whitney U tests [26, 27]. These tests can be used for measurable and ordinal data, the distribution of which does not comply with Student t-test assumptions. In the case of measurable data, the null hypothesis is based on the lack of significant differences between arithmetic means. It is assessed [28] that the strength of the MannWhitney U test is about 95% of that of the Student t-test. In the present study, the test strength in the pair of study-control groups was 0.89, while in the control-subgroup pair it was 0.53. It is assumed [26] that a satisfactory test strength is over 0.75, and so the results of the comparison between the control group and the subgroup should be treated cautiously.

The results of the studies show that the intima-media complex thickness among the patients with systemic lupus erythematosus is statistically bigger than among the healthy subjects of the same age. The mean IMT value for the study group was from 0.2 mm (LCCA) to 0.3 mm (RCCA) higher than for the control group. There were some people in both groups who had minimal values (0.4 mm) and maximal values (1.3 mm), yet the number of people with a thickened intima-media complex (IMT equal to or higher than 1.0 mm) was considerably higher in the study group. These explicit tendencies did not occur between the control group and the subgroup suffering only from lupus. In this case, the difference was only 0.15 mm. Following the criteria of the Polish Ultrasound Society [12], only 4% of cases of the IMT value in the whole study group were understood as indicating the presence of diffused atherosclerotic changes, while as many as 72% of cases had a justified diagnosis of thickened intima-media complex. The important fact is that not a single case was diagnosed in the group suffering only from lupus, where the IMT > 1.3 mm, while the number of cases with a thickened complex was almost two times smaller and amounted to 41%. These observations confirm the results obtained by other research centers, which proved fast progression of the atherosclerotic process among people suffering from systemic diseases of the connective tissue, including lupus [16, 17, 24]. However, they also indicate that the dynamics of this process depend on additional, coexisting factors, such as hyperlipidemia, arterial hypertension or diabetes.

Systemic lupus erythematosus is a chronic autoimmunological disease occupying numerous tissues and organs. This disease can develop at any age, but the incidence peak falls at the age of 20 to 40 years. Clinical experience suggests that the inflammatory process develops in the cardiovascular system in a high percentage of patients suffering from SLE (up to 60%). It was proved [25] that it can involve the pericardium, myocardium, endocardium, valves and coronary and peripheral vessels. Early vessel atherosclerosis, occurring even in pediatric patients, is a complication common for systemic diseases of the connective tissue. The IMT examination should become a fundamental one for all patients with diagnosed diseases of the connective tissue and should be performed regularly in order to prevent the unfavorable con-sequence of developing atherosclerosis [29]. The doctor also should recommend to this group a lifestyle that will prevent the occurrence of other factors of atherosclerotic changes.



Conclusions



The group of patients with SLE was found to have increased thickness of the intima-media complex in comparison with the population of healthy subjects. Moreover, the unfavorable influence of independent factors of atherosclerosis development on the increase of the IMT value in patients with lupus was observed. This observation suggests faster progression of the atherosclerotic process in this group of patients.

The measurement of IMT enables observation of progression of atherosclerosis in asymptomatic patients. It provides priceless time, during which a proper treatment can be administered and a long-term observation can be carried out. The fact that IMT measurement is cheap, repeatable and easy to perform is of great importance, which is why we believe that it should be used more widely as a non-invasive screening test in atherosclerosis diagnostics and monitoring.



Funding



This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.



Disclosure



The authors report no conflicts of interest.



References



1. Davis PH, Dawson JD, Riley WA, Lauer RM. Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine Study. Circulation 2001; 104: 2815-2819.

2. Touboul PJ, Labreuche J, Vicaut E, Amarenco P, GENIC Investigators. Carotid intima-media thickness, plaques, and Framingham risk score as independent deter-minants of stroke risk. Stroke 2005; 36: 1741-1745.

3. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999; 340: 115-126.

4. Dembinska-Kiec A. Miażdżyca naczyń: Choroba niedokrwienna serca. Giec L (red.). Wydawnictwo Lekarskie PZWL, Warszawa 1996.

5. Libby P. Current concepts of pathogenesis of the acute coronary syndromes. Circulation 2001; 104: 365-372.

6. Horita Y, Tadaokoro M, Taura K, Mishima Y, Miyazaki M, Kohno S, Kawano Y. Relationship between carotid artery intima-media thickness and arteriosclerotic renal artery stenosis in type 2 diabetes with hypertension. Kidney Blood Press Res 2002; 25: 255-259.

7. Kablak-Ziembicka A, Tracz W, Przewlocki T, Pieniazek P, Sokolowski A, Konieczynska M. Association of increased carotid intima media thickness with the extent of coronary artery disease. Heart 2004; 90: 1286-1290.

8. Dijk JM, van der Graaf Y, Bots ML, Grobbee DE, Algra A. Carotid intima media thickness and the risk of new vascular events in patients with manifest atherosclerotic disease: the SMART study. Eur Heart J 2006; 27: 1971-1978.

9. Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction. The Rotterdam Study. Circulation 1997; 96: 1432-1437.

10. del Sol IA, Bots ML, Grobbee DE, Hofman A, Witteman JC. Carotid intima-media thickness AT different sites: relation to incident myocardial infarction. The Rot-terdam Study. Eur Heart J 2002; 23: 934-940.

11. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK. Carotid-artery intima media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999; 340: 14-22.

12. Jakubowski W. Standardy badań USG Polskiego Towarzystwa Ultrasonograficznego. Roztoczańska Szkoła Ultrasonografii. Warszawa, Zamość 2008.

13. Kunicka K, Bieniaszewski L. Ocena ultrasonograficzna tętnic domózgowych. Choroby Serca i Naczyń. Tom 2. Via Medica, Gdańsk 2010.

14. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007; 115: 459-467.

15. Urowitz MB, Bookman AAM, Koehler BE, Gordon DA, Smythe HA, Ogryzlo MA. The bimodal mortality pattern of SLE. Am J Med 1976; 60: 221-225.

16. Urowitz MB, Gladman DD. Accelerated atheroma in lupus – background. Lupus 2000; 9: 161-165.

17. Hallegua DS, Wallace DJ. How accelerated atherosclerosis in SLE has changed our management of the disorder. Lupus 2000; 9: 228-231.

18. Kullo IJ, Malik AR. Arterial ultrasonography and tonometry as adjuncts to cardiovascular risk stratification. J Am Coll Cardiol 2007; 49: 1413-1426.

19. Stein JH, Fraizer MC, Aeschlimann SE, Nelson-Worel J, McBride PE, Douglas PS. Vascular age: integrating carotid intima-media thickness measurements with global coronary risk assessment. Clin Cardiol 2004; 27: 388-392.

20. American College of Rheumatology. 1997 Update of the 1982 American College of Rheumatology revised criteria for classification of systemic lupus erythemato-sus. Available at: http://tinyurl.com/1997SLEcriteria. Accessed March 15, 2012.

21. Heiss G, Sharrett AR, Barnes R, Chambless LE, Szklo M, Alzola C. Carotid atherosclerosis measured by B-mode ultrasound in populations: association with cardio-vascular risk factors In the ARIC study. Am J Epidemiol 1991; 134: 250-256.

22. Bots ML, den Rijuter HM. Should we indeed measure carotid intima-media thickness for improving prediction of cardiovascular events after IMPROVE? J Am Coll Cardiol 2012; 60: 1500-1502.

23. Salonen R, Salonen JT. Determinants of carotid intima media thickness: population based ultrasonography study in eastern Finnish men. J Intern Med 1991; 229: 225-231.

24. Drzewoski J. Toczeń rumieniowaty układowy przyczyną przedwczesnej miażdżycy u kobiet. Kardiol Pol 2008; 66: 1200-1201.

25. Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA, Jansen-McWilliams L, D’Agostino RB, Kuller LH. Age-specific incidence rates of myocardial infarction and angina in women with systemic lapus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997; 145: 408-415.

26. Stanisz A. Biostatystyka. Wydawnictwo Uniwersytetu Jagiellońskiego, Kraków 2005.

27. Petrie A, Sabin C. Statystyka medyczna w zarysie. Wydawnictwo Lekarskie PZWL, Warszawa 2006.

28. Stansz A. Podstawy statystyki dla prowadzących badania naukowe. Testy nieparametryczne. Medycyna Praktyczna 2009; 9.

29. Tyrell PN, Beyene I, Feldman BM, McCrindle BW, Silverman ED, Bradley TJ. Rheumatic disease and carotid intima-media thickness: a systematic review and me-ta-analysis. Arterioscler Thromb Vasc Biol 2010; 30: 1014-1026.