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M.539 Detection of Chlamydia pneumoniae in atherosclerothic tissue and investigation of serological status in patients with chronic atherosclerosis
Miscellaneous
•9•
DETECTION OF CHLAMYDIA PNEUMONIAE IN ATHEROSCLEROTHIC TISSUE AND INVESTIGATION OF SEROLOGICAL STATUS IN PATIENTS W I T H CHRONIC ATHEROSCLEROSIS
•]
Jukema
125
RELATIONSHIPS BETWEEN C-REACTIVE PROTEIN, CAROTID INTIMA-MEDIA THICKNESS AND SYSTEMATIC CORONARY RISK EVALUATION RISK ASSESSMENT SYSTEM IN MILITARY PILOTS IN SERBIA AND MONTENEGRO
S. Jankauskiene, E. Zurauskas, A. Laurinaviciene, B. Vaisnyte, E. Barkauskas, Z. Kucinskiene, A. Laurinavicius. Vilnius University
A. Jovelic, G. Radjen, Z. Hadukovic. Group oflnternal Clinics, Clinic of
Hospital Santariskiu Klinikos, National Centre of Pathology, Vilnius University Emergency Hospital, Vilnius, Lithuania
Cardiology, Clinic of Endocrinology, Military Medical Academy, Belgrade, Serbia and Montenegro
Objectives: Inflammatory factors together with classical risk factors ale important in the development of atherosclerosis. Chronic inflammation developed in at'terial wall could be like a response promoted by microol~ ganisms. Many infectious agents are investigated in order to establish thehethiopathogenetical role in the process of atherosclerosis but Chlamydia pneumoniae has the strongest implication. The potential role of this agent is being investigated in seroepidemiological, experimental, atherosclerothic tissue studies and clinical trials with antibiotics. Methods: We investigated 25 atherosclerothic at'teries (20 operating material and 5 autopsy samples) by immunohistochemical (IHC) staining for Chlamydia pneumoniae antigens and also sera fi'om the same patients were investigated by microimmunofluorescence assay (MIFA) for antibodies. Results: 15 arteries out of 25 were positive for Chlamydia pneumoniae antigens. No elevated Ig M antibodies were found. No COlrelation was found between elevated IgG antibodies and antigens founded in atheroma. The tendency that IgA antibodies ate more often elevated in the positive for antigens cases was revealed. Conclusions: Our study demonstrates that one immunohistochemical staining per one atheroma sample is not enough to find antigens in the sample, because the distribution of chlamydial antigens in atheroma is random and focal. We confirm findings of other investigators that presence of Chlamydia pneumoniae antigens in the atherosclerothic tissue is rare for persons that are seronegative for Chlamydia pneumoniae antibodies. Ig A antibodies to Chlamydia pneumoniae may be used for selection of patients that could be positive for chlamydial antigens in theh" vessels. Additional studies ale planned in order to get statistical confirmation of the results.
Purpose: To assess the cross-sectional relationship between C-reactive protein (CRP), common carotid at'tery intima-media thickness (CCAIMT) and absolute ten year risk calculated according to the Systematic Coronary Risk Evaluation (SCORE) risk assessment system in low risk population of militat'y pilots. Methods: SCORE was calculated according to risk assessment system (total cholesterol (TC)) for high risk countries. CRP levels were detmTnined by immunonephelometry (Dade Behring). The CCAIMT was measured by high-resolution B-mode ultrasonography. Bivat'iate con'elation, lineal" and stepwise multiple regression analysis were performed. Results: We studied 161 pilots (aged 23 to 50). Mean CCAIMT was 1.009-t-0.18 mm. SCORE significantly COla'elated with CCAIMT (Spearman's rho=0.264, p=0.001), CRP (Spearman's rho=0.166, p=0.036), glucose (Spearman's rho=0.161, p=0.041), but not with body mass index (BMI), waist ch'cumference (WC), triglycerides (Tg), HDL-c and Tg/HDL-c (p> 0.05). Multivat'iate regression model including SCORE, CRP, BMI, WC, Tg and glucose showed that SCORE (~=0.197, p=0.022), BMI (~=0.329, p=0.000) and Tg (~=0.285, p=0.001) were independent determinants of CCAIMT, explaining 26.9% of the variance. CRP not COla'elated with blood pressure, BMI, TC (p>0.05). In a multivat'iate lineal" regression model witch included smoking habits, age, Tg, Tg to HDL-c ratio, TC/HDL-c, WC and glucose, WC (~=0.418, p=0.000), Tg/HDL-c (~=0.775, p=0.001), and smoking habit (~=0.229, p=0.006) were independent predictors of CRP, explaining 44% of the vat'iance. Conclusions: Our results suggest cross-sectional independent COla'elations between SCORE and CCAIMT, but not between CRP and CCAIMT. CRP COla'elated with SCORE, but weakly with its individual components. This may suggest that in our low risk population according to SCORE, CRP and SCORE may reflect two sepat'ate entities of atherosclerosis and theh" potential additive value.
•0•
THE ROLE OF ADAMTS-1 IN ATHEROSCLEROSIS: REMODELING OF CAROTID ARTERY, IMMUNOHISTOCHEMISTRY, AND PROTEOLYSIS OF VERSICAN
A. J nsson-Rylander, T. Nilsson, R. Fristsche-Danielson, A. Hammarstr m, M. Behmndt, J. Andersson, A. Thelin, P. Brodin, E. Hurt-Camejo, C. Lee-SCgaard. AstraZeneca, M lndal; Arexis, Gothenburg, Sweden We investigated the potential role of ADAMTS-1 (a disintegrin and metalloprotease with thrombospondin motif type I) in atherogenesis. ADAMTS-1 is expressed at the highest levels in the aorta when compat'ed to other human tissues examined. Immunolocalization studies in human aorta and coronary artery indicate that ADAMTS-1 expression is mainly seen at low levels in the medial layer, but up-regulated in the intima when plaque is present. We found that ADAMTS-1 mRNA levels ale significantly higher in proliferating/migrating cultured aortic VSMCs compared to resting/confluent cells. Using the mouse carotid at'tery flow cessation model, we show that there are differences in vessel remodeling in ADAMTS-1 transgenic/ApoE-deficient mice compat'ed to ApoE-deficiency alone, pat'ticularly a significant increase in intimal hyperplasia. We show that ADAMTS-1 can cleave both the large versican containing proteoglycan population purified fl'om cultured human aortic vascular" smooth muscle cells (VSMCs) and human tissue factor pathway inhibitor (TFPI) known to be expressed in atherosclerotic plaques. Finally, using versican peptide substrates, we show data suggesting that ADAMTS-1 cleaves versican at multiple sites. We hypothesize that ADAMTS-1 may promote atherogenesis by cleaving extracellulat" matrix proteins such as versican and promoting VSMC migration. ADAMTS-1 may also increase thrombogenecity of ruptured plaques by cleaving TFPI.
•]
LDL-C/HDL-C RATIO IN PATIENTS WITH CORONARY ARTERY DISEASE AND LOW HDL-C: THE RADAR STUDY
J. Jukema, A. Liem, P. Dunselman, J. van der Sloot, D. Lok, A. Zwinderrnan. Leids Universitair Medisch Centrum, Oosterschelde
Ziekenhuis, Amphia Ziekenhuis, Academisch Medisch Centrum, Deventer Ziekenhuis, Leiden, The Netherlands Low levels of HDL-C are a risk factor for coronary artery disease (CAD) and the LDL-C/HDL-C ratio is a powerful predictor of clinical events. RADAR is a randomised, multicentre, pat'allel-group, phase IIIb study, comparing the effect of rosuvastatin (RSV) with atorvastatin (ATV) on the LDL-C/HDL-C ratio in patients with CAD and low HDL-C levels. Following dietary lead-in, 461 patients aged 40-80 years with established atherosclerotic disease and HDL-C < 1 retool/1 were randomised to receive RSV 10 mg (n=230) o1"ATV 20 mg (n=231). Patients were forced-titrated at 6 weeks (RSV 20 rag, ATV 40 rag) and 12 weeks (RSV 40 rag, ATV 80 rag) (18 weeks' total treatment). Baseline LDL-C (mean -4- SD) was 3.6 -4- 1.2 mmol/1 (RSV) and 3.7 -41.3 retool/1 (ATV), and HDL-C, 0.8 -4- 0.1 retool/1 (RSV) and 0.8 -4- 0.1 retool/1 (ATV). RSV reduced the LDL-C/HDL-C ratio, LDL-C and TC to a significantly greater extent than ATV (table). Both treatments were well tolerated. Least squares mean change fi'ombaseline (%)
LDL-C/HDL-C LDL-C TC HDL-C
6 weeks RSV ATV l0 mg 20 mg
12 weeks RSV ATV 20 mg 40 mg
18 weeks RSV ATV 40 mg 80 mg
-47.0 a -44.0 a -37.4 d +3.9
-53.0 b -50.4 b -41.1 c +5.5
-57.3 c -55.3 d -44.7 d +4.7
-41.9 -38.4 -32.5 +4.1
-47.9 -45.1 -37.3 +3.1
ap<0.05; bp<0.01; ~p<0.00 l; dp<0.0001, VSATV at same time point
74th EAS Congress, 17-20 April 2004, Seville, Spain
-49.6 -48.1 -39.5 +2.7
•9•
DETECTION OF CHLAMYDIA PNEUMONIAE IN ATHEROSCLEROTHIC TISSUE AND INVESTIGATION OF SEROLOGICAL STATUS IN PATIENTS W I T H CHRONIC ATHEROSCLEROSIS
•]
Jukema
125
RELATIONSHIPS BETWEEN C-REACTIVE PROTEIN, CAROTID INTIMA-MEDIA THICKNESS AND SYSTEMATIC CORONARY RISK EVALUATION RISK ASSESSMENT SYSTEM IN MILITARY PILOTS IN SERBIA AND MONTENEGRO
S. Jankauskiene, E. Zurauskas, A. Laurinaviciene, B. Vaisnyte, E. Barkauskas, Z. Kucinskiene, A. Laurinavicius. Vilnius University
A. Jovelic, G. Radjen, Z. Hadukovic. Group oflnternal Clinics, Clinic of
Hospital Santariskiu Klinikos, National Centre of Pathology, Vilnius University Emergency Hospital, Vilnius, Lithuania
Cardiology, Clinic of Endocrinology, Military Medical Academy, Belgrade, Serbia and Montenegro
Objectives: Inflammatory factors together with classical risk factors ale important in the development of atherosclerosis. Chronic inflammation developed in at'terial wall could be like a response promoted by microol~ ganisms. Many infectious agents are investigated in order to establish thehethiopathogenetical role in the process of atherosclerosis but Chlamydia pneumoniae has the strongest implication. The potential role of this agent is being investigated in seroepidemiological, experimental, atherosclerothic tissue studies and clinical trials with antibiotics. Methods: We investigated 25 atherosclerothic at'teries (20 operating material and 5 autopsy samples) by immunohistochemical (IHC) staining for Chlamydia pneumoniae antigens and also sera fi'om the same patients were investigated by microimmunofluorescence assay (MIFA) for antibodies. Results: 15 arteries out of 25 were positive for Chlamydia pneumoniae antigens. No elevated Ig M antibodies were found. No COlrelation was found between elevated IgG antibodies and antigens founded in atheroma. The tendency that IgA antibodies ate more often elevated in the positive for antigens cases was revealed. Conclusions: Our study demonstrates that one immunohistochemical staining per one atheroma sample is not enough to find antigens in the sample, because the distribution of chlamydial antigens in atheroma is random and focal. We confirm findings of other investigators that presence of Chlamydia pneumoniae antigens in the atherosclerothic tissue is rare for persons that are seronegative for Chlamydia pneumoniae antibodies. Ig A antibodies to Chlamydia pneumoniae may be used for selection of patients that could be positive for chlamydial antigens in theh" vessels. Additional studies ale planned in order to get statistical confirmation of the results.
Purpose: To assess the cross-sectional relationship between C-reactive protein (CRP), common carotid at'tery intima-media thickness (CCAIMT) and absolute ten year risk calculated according to the Systematic Coronary Risk Evaluation (SCORE) risk assessment system in low risk population of militat'y pilots. Methods: SCORE was calculated according to risk assessment system (total cholesterol (TC)) for high risk countries. CRP levels were detmTnined by immunonephelometry (Dade Behring). The CCAIMT was measured by high-resolution B-mode ultrasonography. Bivat'iate con'elation, lineal" and stepwise multiple regression analysis were performed. Results: We studied 161 pilots (aged 23 to 50). Mean CCAIMT was 1.009-t-0.18 mm. SCORE significantly COla'elated with CCAIMT (Spearman's rho=0.264, p=0.001), CRP (Spearman's rho=0.166, p=0.036), glucose (Spearman's rho=0.161, p=0.041), but not with body mass index (BMI), waist ch'cumference (WC), triglycerides (Tg), HDL-c and Tg/HDL-c (p> 0.05). Multivat'iate regression model including SCORE, CRP, BMI, WC, Tg and glucose showed that SCORE (~=0.197, p=0.022), BMI (~=0.329, p=0.000) and Tg (~=0.285, p=0.001) were independent determinants of CCAIMT, explaining 26.9% of the variance. CRP not COla'elated with blood pressure, BMI, TC (p>0.05). In a multivat'iate lineal" regression model witch included smoking habits, age, Tg, Tg to HDL-c ratio, TC/HDL-c, WC and glucose, WC (~=0.418, p=0.000), Tg/HDL-c (~=0.775, p=0.001), and smoking habit (~=0.229, p=0.006) were independent predictors of CRP, explaining 44% of the vat'iance. Conclusions: Our results suggest cross-sectional independent COla'elations between SCORE and CCAIMT, but not between CRP and CCAIMT. CRP COla'elated with SCORE, but weakly with its individual components. This may suggest that in our low risk population according to SCORE, CRP and SCORE may reflect two sepat'ate entities of atherosclerosis and theh" potential additive value.
•0•
THE ROLE OF ADAMTS-1 IN ATHEROSCLEROSIS: REMODELING OF CAROTID ARTERY, IMMUNOHISTOCHEMISTRY, AND PROTEOLYSIS OF VERSICAN
A. J nsson-Rylander, T. Nilsson, R. Fristsche-Danielson, A. Hammarstr m, M. Behmndt, J. Andersson, A. Thelin, P. Brodin, E. Hurt-Camejo, C. Lee-SCgaard. AstraZeneca, M lndal; Arexis, Gothenburg, Sweden We investigated the potential role of ADAMTS-1 (a disintegrin and metalloprotease with thrombospondin motif type I) in atherogenesis. ADAMTS-1 is expressed at the highest levels in the aorta when compat'ed to other human tissues examined. Immunolocalization studies in human aorta and coronary artery indicate that ADAMTS-1 expression is mainly seen at low levels in the medial layer, but up-regulated in the intima when plaque is present. We found that ADAMTS-1 mRNA levels ale significantly higher in proliferating/migrating cultured aortic VSMCs compared to resting/confluent cells. Using the mouse carotid at'tery flow cessation model, we show that there are differences in vessel remodeling in ADAMTS-1 transgenic/ApoE-deficient mice compat'ed to ApoE-deficiency alone, pat'ticularly a significant increase in intimal hyperplasia. We show that ADAMTS-1 can cleave both the large versican containing proteoglycan population purified fl'om cultured human aortic vascular" smooth muscle cells (VSMCs) and human tissue factor pathway inhibitor (TFPI) known to be expressed in atherosclerotic plaques. Finally, using versican peptide substrates, we show data suggesting that ADAMTS-1 cleaves versican at multiple sites. We hypothesize that ADAMTS-1 may promote atherogenesis by cleaving extracellulat" matrix proteins such as versican and promoting VSMC migration. ADAMTS-1 may also increase thrombogenecity of ruptured plaques by cleaving TFPI.
•]
LDL-C/HDL-C RATIO IN PATIENTS WITH CORONARY ARTERY DISEASE AND LOW HDL-C: THE RADAR STUDY
J. Jukema, A. Liem, P. Dunselman, J. van der Sloot, D. Lok, A. Zwinderrnan. Leids Universitair Medisch Centrum, Oosterschelde
Ziekenhuis, Amphia Ziekenhuis, Academisch Medisch Centrum, Deventer Ziekenhuis, Leiden, The Netherlands Low levels of HDL-C are a risk factor for coronary artery disease (CAD) and the LDL-C/HDL-C ratio is a powerful predictor of clinical events. RADAR is a randomised, multicentre, pat'allel-group, phase IIIb study, comparing the effect of rosuvastatin (RSV) with atorvastatin (ATV) on the LDL-C/HDL-C ratio in patients with CAD and low HDL-C levels. Following dietary lead-in, 461 patients aged 40-80 years with established atherosclerotic disease and HDL-C < 1 retool/1 were randomised to receive RSV 10 mg (n=230) o1"ATV 20 mg (n=231). Patients were forced-titrated at 6 weeks (RSV 20 rag, ATV 40 rag) and 12 weeks (RSV 40 rag, ATV 80 rag) (18 weeks' total treatment). Baseline LDL-C (mean -4- SD) was 3.6 -4- 1.2 mmol/1 (RSV) and 3.7 -41.3 retool/1 (ATV), and HDL-C, 0.8 -4- 0.1 retool/1 (RSV) and 0.8 -4- 0.1 retool/1 (ATV). RSV reduced the LDL-C/HDL-C ratio, LDL-C and TC to a significantly greater extent than ATV (table). Both treatments were well tolerated. Least squares mean change fi'ombaseline (%)
LDL-C/HDL-C LDL-C TC HDL-C
6 weeks RSV ATV l0 mg 20 mg
12 weeks RSV ATV 20 mg 40 mg
18 weeks RSV ATV 40 mg 80 mg
-47.0 a -44.0 a -37.4 d +3.9
-53.0 b -50.4 b -41.1 c +5.5
-57.3 c -55.3 d -44.7 d +4.7
-41.9 -38.4 -32.5 +4.1
-47.9 -45.1 -37.3 +3.1
ap<0.05; bp<0.01; ~p<0.00 l; dp<0.0001, VSATV at same time point
74th EAS Congress, 17-20 April 2004, Seville, Spain
-49.6 -48.1 -39.5 +2.7