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Vascular OnlineFirst, published on February 16, 2015 as doi:10.1177/1708538115571404
Original Article
Analysis of risk factors and diseases associated with atherosclerosis in the progression of carotid artery stenosis
Vascular 0(0) 1–5 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1708538115571404 vas.sagepub.com
Nayara Cioffi Batagini1, Erasmo Sima˜o da Silva1, Carlos AV Pinto2, Pedro Puech-Lea˜o1 and Nelson de Luccia1
Abstract Objective: The objective of this study was to analyze the roles of demographic, clinical, and laboratory factors on the progression of atherosclerotic stenosis in carotid bifurcation. It was based on prospective information from records entered on a specific application form for follow-up outpatients at a tertiary university service. Methods: Consecutive symptomatic and asymptomatic patients (n ¼ 210) who had undergone more than one carotid duplex scan but no surgical intervention were selected for the analysis. The patients were divided into two groups: patients whose duplex scans did not show bilateral progression of carotid stenosis and patients with carotid stenosis progression of 70%. Clinical and demographic parameters were compared between groups. Results: Group II levels of plasma urea (51.6 27.8 mg/dl) and fibrinogen (493.2 113.3 mg/dl) were higher than the Group I levels (43.0 14.9 mg/dl and 441.3 106.7 mg/dl, respectively) with statistical significance (p urea ¼ 0.013 and p fibrinogen ¼ 0.018). Paradoxically, the mean body mass index was higher in Group I (26.4 4.6 kg/m2) than in Group II (24.6 3.9 kg/m2; p ¼ 0.02). Conclusions: Traditional risk factors for the development of atherosclerosis in a carotid bifurcation are important but not unique. Metabolic and inflammatory factors can contribute to disease progression.
Keywords Carotid stenosis, progression, atherosclerosis, risk factors
Introduction Although large trials have already shown the benefits of carotid endarterectomy associated with best medical therapy over the best medical therapy without intervention,1,2 the indication for intervention in asymptomatic patients is still controversial. In asymptomatic patients not selected for the intervention, an ultrasonographic follow-up of the degree of carotid stenosis can show its evolution. Therefore, it is appropriate to determine the causes of carotid stenosis progression. Recent surveys have shown that demographic, clinical, and laboratory-tested factors may be involved in the progression of carotid bifurcation atherosclerosis.3,4 However, the fact that atherosclerosis is initiated and progresses preferentially in bifurcations, curvatures, and ramifications suggests that hemodynamic–morphological factors are involved in this process.5,6 The objective of this study was to analyze the role of demographic, clinical, and laboratory factors on the
progression of atherosclerotic stenosis in carotid bifurcation in a sample of patients referred to a tertiary university service (Clinicas Hospital of the University of Sa˜o Paulo Medical School).
Materials and methods A retrospective study was performed over a seven-year period, from January 2002 to April 2009, of data 1 Vascular and Endovascular Divison, Department of Surgery, Clinicas Hospital of University of Sa˜o Paulo Medical School, Sa˜o Paulo, Brazil 2 Department of Radiology, Clinicas Hospital of University of Sa˜o Paulo Medical School, Sa˜o Paulo, Brazil
Corresponding author: Nayara Cioffi Batagini, Vascular and Endovascular Divison, Department of Surgery, Clinicas Hospital of University of Sa˜o Paulo Medical School, 155, Doctor Ene´as de Carvalho Aguiar Avenue, 60 andar, bloco 7, Jardim Ame´rica, Sa˜o Paulo, SP 05403-000, Brazil. Email: [email protected]
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recorded prospectively on a specific application form for outpatients being followed-up at the Vascular and Endovascular Division, Department of Surgery, University of Sa˜o Paulo Medical School. The ultrasound devices used to analyze the atheromatic plaques and the degree of carotid bifurcation stenosis were the Logic 9 (GE Healthcare, Milwaukee, WI, USA) and IU22 (Philips, Bothell, WA, USA). Linear transducers with a fundamental frequency of 5.0–10 MHz were used in the examinations. The ultrasound digital processing parameters were calibrated to the cervical carotid segment. The maximal Doppler angle used was 60 . The internal carotid artery was evaluated along its whole extracranial length, from its origin to the distal segments, with cross-sectional and longitudinal cuts. B-mode imaging was used to detect plaques, color Doppler to verify the presence of flow and to localize any stenotic sites, and power Doppler to determine the degree of stenosis from the Doppler velocities. Duplex scan carotid stenosis was classified according to the literature,7 as: 70%. The patients were divided into two groups: Group I: 160 individuals whose duplex scans did not show progression of carotid stenosis of 70%. Group II: 41 patients with carotid stenosis progression of 30 kg/m2. Peripheral arterial disease (PAD) was defined as an ankle-brachial index 0.05. For numeric or quantitative variables, the difference between the two groups was analyzed with unpaired Student’s t test, with the appropriate test power (Pw). Contingency tables (2 2 and k r) were applied to the qualitative variables, with a simple v2 test or a v2 test corrected by continuity (according to Yates).
Results The median follow-up time was 32 months (interquartile range (IQR) 22–58) for Group I and 48 months (IQR 24–55) for Group II. The mean age was 68.7 8.5 years in Group I and 69.2 8.1 years in Group II (p ¼ 0.74). Group I was subdivided into exactly 50% men and 50% women, and Group II comprised 43.9% men and 56.1% women. There were no significant differences between the groups in follow-up time (p ¼ 0.57), age, or sex. There was no significant difference between the groups in the demographic variables: abdominal circumference, systemic arterial hypertension, systolic or diastolic arterial pressure, diabetes mellitus (Table 1). There were also no statistical differences when the hypertensive patients were subdivided into nonsevere (using up to two antihypertensive medications) and severe (using three or more antihypertensive medications). When the diabetic patients were similarly subdivided into treatment groups (dietary/oral hypoglycemic treatment or insulin treatment), there were no statistically significant differences between the groups (Table 2). Paradoxically, the mean BMI was higher in Group I (26.4 4.6 kg/m2) than in Group II (24.6 3.9 kg/m2; p ¼ 0.02) (Table 1) attributable to differences in weight. The prevalence of tabagism, PAD, or a family history of cardiovascular disease or stroke was statistically similar in the two groups, although there was a tendency to higher values in Group II (Table 2). There were no significant differences between the two groups in the use of acetylsalicylic acid (AAS),
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Table 1. Demographic variables.
Table 3. Prevalence of best medical therapy.
Group I A Abdominal circumference BMI Systolic arterial pressure Diastolic arterial pressure
Group II SD
A
SD
p
91.9
11.8
89.1
12.6
0.22 (ns)
26.4 148.9
4.6 25.5
24.6 146.7
3.9 26.6
0.020 (*) 0.64 (ns)
83.5
13.5
81.1
13.7
0.32 (ns)
A: average; SD: standard deviation; ns: not significant; *: statistically significant; BMI: body mass index.
Table 2. Demographic variables.
SAH
Diabetes mellitus Tabagism PAD FH of CVD FH of stroke
Yes No Nonsevere Severe Yes No Diet/OH Insulin Yes No Yes No Yes No Yes No
Group I (%)
Group II (%)
13.5 86.4 64.1 35.8 33.3 66.6 73.0 26.9 56.0 44.0 24.3 75.3 68.9 31.0 33.8 66.1
2.4 97.5 62.5 37.5 34.1 65.9 71.4 28.5 65.8 34.1 41.4 58.5 77.7 22.2 41.6 58.3
p 0.08 (ns) 0.99 (ns) 0.93 (ns) 0.83 (ns) 0.34 (ns) 0.05 (ns) 0.41 (ns) 0.51 (ns)
SAH: systemic arterial hypertension; OH: oral hypoglycemic agent; PAD: peripheral arterial disease; FH: family history; CVD: cardiovascular disease; ns: not significant.
statin, angiotensin-converting enzyme inhibitor (ACEi), or beta-blockers (Table 3). There was no significant difference between the groups in the biomarkers: glycosylated hemoglobin, fasting glycemia, total cholesterol, HDL- or LDL-cholesterol, triglyceride, creatinine, C-reactive protein. However, Group II levels of plasma urea (51.6 27.8 mg/dl) and fibrinogen (493.2 113.3 mg/ dl) were higher than the Group I levels (43.0 14.9 mg/dl and 441.3 106.7 mg/dl, respectively) with statistical significance (p urea ¼ 0.013 and p fibrinogen ¼ 0.018) (Table 4).
AAS/clopidogrel Statin ACEi Beta-blocker
Group I (%)
Group II (%)
p
85.6 65.5 66.4 38.7
90.0 72.5 65.0 40.0
0.56 0.52 0.98 0.95
(ns) (ns) (ns) (ns)
AAS: acetylsalicylic acid; ACEi: angiotensin-converting enzyme inhibitor; ns: not significant.
Table 4. Biomarkers.
Glycosylated hemoglobin Fasting glycemia Total cholesterol HDL–cholesterol LDL–cholesterol Triglyceride Creatinine Urea C-Reactive protein Fibrinogen
GROUP I
GROUP II
A
SD
A
SD
p
6.7
1.3
7.0
1.6
0.45 (ns)
108.8 185.5 51.7 106.9 145.7 1.8 43.0 5.4 441.3
31.6 44.9 14.0 38.3 65.5 8.8 14.9 10.6 106.7
108.1 178.9 50.4 105.1 140.9 1.1 51.1 6.5 493.2
36.7 39.5 12.5 38.5 72.1 0.4 27.8 9.5 113.3
0.91 (ns) 0.46 (ns) 0.61 (ns) 0.79 (ns) 0.69 (ns) 0.66 (ns) 0.013 (*) 0.58 (ns) 0.018 (*)
Abbreviations: A ¼ average; SD ¼ standard deviation; (ns) ¼ not significant; (*) ¼ statistically significant; HDL ¼ high-density lipoprotein; LDL ¼ low-density lipoprotein.
Discussion Atherosclerosis is the main cause of death in developed countries. Patients with carotid diseases can keep stable for a long time or develop acute vascular events. Identifying risk factors of carotid stenosis progression and development of acute events is one of the major challenges of cardiovascular medicine. The results of this study show that, contrary to expectation, the risk factors associated with atherosclerosis, such as systemic arterial hypertension, diabetes mellitus, and dyslipidemia,4,14 were not statistically significant factors in the progression of carotid bifurcation stenosis. In contrast, the higher urea and fibrinogen levels in the group that presented with carotid stenosis progression suggest that other factors, such as metabolic factors, might be associated with this phenomenon. In this study, urea but not creatinine presented statistically significant correlation with the disease progression. The association of the deterioration of renal function and atherosclerosis has already been demonstrated in some studies. The chronic kidney
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disease was independently associated with carotid atherosclerosis in hypertensive patients.15 Another recent study demonstrated that in hypertensive patients, the thicker the carotid intima-media thickness is, the lower is the estimated glomerular filtration rate with the Cockcroft-Gault method.16 Nevertheless, the association between chronic kidney disease and carotid atherosclerosis is not very strong in healthy populations.17 The higher fibrinogen levels in Group II show that the presence of inflammatory and thrombogenic activity are factors contributing to stenosis progression. Although we found no difference in the C-reactive protein levels of the groups in this study, other recent studies have shown that high levels of this marker are related to carotid stenosis.18–21 Besides demonstrating a link between C-reactive protein, fibrinogen, and atherosclerotic diseases, the participation of other inflammatory elements, such as homocysteine and lipoprotein,22,23 in atherosclerosis progression has also been demonstrated. However, the routine use of these variables as cardiovascular risk predictors must still be analyzed. Studies of plasma biomarkers for the diagnosis and prognosis of atherosclerosis have been done during recent years. Until now, there is no unanimously accepted biomarker in clinical practice; nevertheless, recent advances are coming in the application of proteomic and metabolomics techniques to the study of atherosclerosis.24,25 Paradoxically, BMI was significantly higher in Group I than in Group II (p ¼ 0.02). Several studies have shown the paradoxical effect of obesity on atherosclerotic disease, because obesity seems to confer protection against these disorders.26,27 This unexpected relationship may be attributable to the actions of endocrine factors released from adipose tissue.27 This was not an epidemiological study because the sample patients were referred to a tertiary hospital. This causes sample bias, although they were severely affected patients who required no primary treatment. However, the clinical and ultrasonographic follow-up of these patients can provide important information that would only otherwise be available in population studies of large samples randomly surveyed or based on risk factors for atherosclerosis development in carotid bifurcation.
Conclusion The analysis of a sample of patients referred to a tertiary vascular surgery service showed that traditional risk factors for the development of atherosclerosis in a carotid bifurcation are important but not unique. High plasma fibrinogen and urea are significantly
associated with this progression. These results indicate the need to control these factors in this group of patients to avoid disease progression. Conflict of interest None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995; 273: 1421–1428. 2. Halliday A, Harrison M, Hayter E, et al. Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. 10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): a multicentre randomised trial. Lancet 2010; 376: 1074–1084. 3. de Weerd M, Greving JP, Hedblad B, et al. Prediction of asymptomatic carotid artery stenosis in the general population: identification of high-risk groups. Stroke 2014; 45: 2366–2371. 4. Mathiesen EB, Joakimsen O and Bønaa KH. Prevalence of and risk factors associated with carotid artery stenosis: the Tromsø Study. Cerebrovasc Dis 2001; 12: 44–51. 5. Martin D, Zaman A, Hacker J, et al. Analysis of haemodynamic factors involved in carotid atherosclerosis using computational fluid dynamics. Br J Radiol 2009; 82: S33–S38. 6. Lee SW, Antiga L, Spence JD, et al. Geometry of the carotid bifurcation predicts its exposure to disturbed flow. Stroke 2008; 39: 2341–2347. 7. Grant EG, Benson CB, Moneta GL, et al. Carotid artery stenosis: gray-scale and Doppler US diagnosis—Society of Radiologists in Ultrasound Consensus Conference. Radiology 2003; 229: 340–346. 8. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement: Executive Summary. Crit Pathw Cardiol 2005; 4: 198–203. 9. Alberti KG, Zimmet P, Shaw J; IDF Epidemiology Task Force Consensus Group. The metabolic syndrome—a new worldwide definition. Lancet 2005; 366: 1059–1062. 10. Jerrard-Dunne P, Markus HS, Steckel DA, et al. Early carotid atherosclerosis and family history of vascular disease: specific effects on arterial sites have implications for genetic studies. Arterioscler Thromb Vasc Biol 2003; 23: 302–306. 11. Hirsch AT, Haskal ZJ, Hertzer NR, et al. Circulation 2006; 113: e463–e654. (American Association for Vascular Surgery; Society for Vascular Surgery; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine and Biology; Society of Interventional Radiology; ACC/AHA Task Force on
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Practice Guidelines Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease; American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; Vascular Disease Foundation. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation Circulation 2006; 113: e463–e654. Lijmer JG, Hunink MG, van den Dungen JJ, et al. ROC analysis of noninvasive tests for peripheral arterial disease. Ultrasound Med Biol 1996; 22: 391–398. Timaran CH, McKinsey JF, Schneider PA, et al. Reporting standards for carotid interventions from the Society for Vascular Surgery. J Vasc Surg 2011; 53: 1679–1695. Dua A, Patel B, Kuy S, et al. Asymptomatic 50% to 75% internal carotid artery stenosis in 288 patients: risk factors for disease progression and ipsilateral neurological symptoms. Perspect Vasc Surg Endovasc Ther 2012; 24: 165–170. Ohara T, Kokubo Y, Toyoda K, et al. Impact of chronic kidney disease on carotid atherosclerosis according to blood pressure category: the Suita study. Stroke 2013; 44: 3537–3539. Yang P, Yuan H, Weng C, et al. Carotid intima-media thickness and estimated glomerular filtration rate in
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hypertensive patients. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2014; 39: 465–470. Kokubo Y. Carotid atherosclerosis in kidney disease. Contrib Nephrol 2013; 179: 35–41. Fabris F, Zanocchi M, Bo M, et al. Carotid plaque, aging, and risk factors. A study of 457 subjects. Stroke 1994; 25: 1133–1140. Mullenix PS, Steele SR, Martin MJ, et al. C-reactive protein level and traditional vascular risk factors in the prediction of carotid stenosis. Arch Surg 2007; 142: 1066–1071. Lombardo A, Biasucci LM, Lanza GA, et al. Inflammation as a possible link between coronary and carotid plaque instability. Circulation 2004; 109: 3158–3163. Hackam DG and Anand SS. Emerging risk factors for atherosclerotic vascular disease: a critical review of the evidence. JAMA 2003; 290: 932–940. Larsson PT, Hallerstam S, Rosfors S, et al. Circulating markers of inflammation are related to carotid artery atherosclerosis. Int Angiol 2005; 24: 43–51. Davenport DL, Xenos ES, Hosokawa P, et al. The influence of body mass index obesity status on vascular surgery 30-day morbidity and mortality. J Vasc Surg 2009; 49: 140–147. Teul J, Rupe´rez FJ, Garcia A, et al. Improving metabolite knowledge in stable atherosclerosis patients by association and correlation of GC-MS and 1H NMR fingerprints. J Proteome Res 2009; 8: 5580–5589. Martinez-Pinna R, Barbas C, Blanco-Colio LM, et al. Proteomic and metabolomic profiles in atherothrombotic vascular disease. Curr Atheroscler Rep 2010; 12: 202–208. van Kuijk JP, Flu WJ, Galal W, et al. The influence of polyvascular disease on the obesity paradox in vascular surgery patients. J Vasc Surg 2011; 53: 399–406. Jackson RS, Black JH 3rd, Lum YW, et al. Class I obesity is paradoxically associated with decreased risk of postoperative stroke after carotid endarterectomy. J Vasc Surg 2012; 55: 1306–1312.
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Vascular OnlineFirst, published on February 16, 2015 as doi:10.1177/1708538115571404
Original Article
Analysis of risk factors and diseases associated with atherosclerosis in the progression of carotid artery stenosis
Vascular 0(0) 1–5 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1708538115571404 vas.sagepub.com
Nayara Cioffi Batagini1, Erasmo Sima˜o da Silva1, Carlos AV Pinto2, Pedro Puech-Lea˜o1 and Nelson de Luccia1
Abstract Objective: The objective of this study was to analyze the roles of demographic, clinical, and laboratory factors on the progression of atherosclerotic stenosis in carotid bifurcation. It was based on prospective information from records entered on a specific application form for follow-up outpatients at a tertiary university service. Methods: Consecutive symptomatic and asymptomatic patients (n ¼ 210) who had undergone more than one carotid duplex scan but no surgical intervention were selected for the analysis. The patients were divided into two groups: patients whose duplex scans did not show bilateral progression of carotid stenosis and patients with carotid stenosis progression of 70%. Clinical and demographic parameters were compared between groups. Results: Group II levels of plasma urea (51.6 27.8 mg/dl) and fibrinogen (493.2 113.3 mg/dl) were higher than the Group I levels (43.0 14.9 mg/dl and 441.3 106.7 mg/dl, respectively) with statistical significance (p urea ¼ 0.013 and p fibrinogen ¼ 0.018). Paradoxically, the mean body mass index was higher in Group I (26.4 4.6 kg/m2) than in Group II (24.6 3.9 kg/m2; p ¼ 0.02). Conclusions: Traditional risk factors for the development of atherosclerosis in a carotid bifurcation are important but not unique. Metabolic and inflammatory factors can contribute to disease progression.
Keywords Carotid stenosis, progression, atherosclerosis, risk factors
Introduction Although large trials have already shown the benefits of carotid endarterectomy associated with best medical therapy over the best medical therapy without intervention,1,2 the indication for intervention in asymptomatic patients is still controversial. In asymptomatic patients not selected for the intervention, an ultrasonographic follow-up of the degree of carotid stenosis can show its evolution. Therefore, it is appropriate to determine the causes of carotid stenosis progression. Recent surveys have shown that demographic, clinical, and laboratory-tested factors may be involved in the progression of carotid bifurcation atherosclerosis.3,4 However, the fact that atherosclerosis is initiated and progresses preferentially in bifurcations, curvatures, and ramifications suggests that hemodynamic–morphological factors are involved in this process.5,6 The objective of this study was to analyze the role of demographic, clinical, and laboratory factors on the
progression of atherosclerotic stenosis in carotid bifurcation in a sample of patients referred to a tertiary university service (Clinicas Hospital of the University of Sa˜o Paulo Medical School).
Materials and methods A retrospective study was performed over a seven-year period, from January 2002 to April 2009, of data 1 Vascular and Endovascular Divison, Department of Surgery, Clinicas Hospital of University of Sa˜o Paulo Medical School, Sa˜o Paulo, Brazil 2 Department of Radiology, Clinicas Hospital of University of Sa˜o Paulo Medical School, Sa˜o Paulo, Brazil
Corresponding author: Nayara Cioffi Batagini, Vascular and Endovascular Divison, Department of Surgery, Clinicas Hospital of University of Sa˜o Paulo Medical School, 155, Doctor Ene´as de Carvalho Aguiar Avenue, 60 andar, bloco 7, Jardim Ame´rica, Sa˜o Paulo, SP 05403-000, Brazil. Email: [email protected]
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recorded prospectively on a specific application form for outpatients being followed-up at the Vascular and Endovascular Division, Department of Surgery, University of Sa˜o Paulo Medical School. The ultrasound devices used to analyze the atheromatic plaques and the degree of carotid bifurcation stenosis were the Logic 9 (GE Healthcare, Milwaukee, WI, USA) and IU22 (Philips, Bothell, WA, USA). Linear transducers with a fundamental frequency of 5.0–10 MHz were used in the examinations. The ultrasound digital processing parameters were calibrated to the cervical carotid segment. The maximal Doppler angle used was 60 . The internal carotid artery was evaluated along its whole extracranial length, from its origin to the distal segments, with cross-sectional and longitudinal cuts. B-mode imaging was used to detect plaques, color Doppler to verify the presence of flow and to localize any stenotic sites, and power Doppler to determine the degree of stenosis from the Doppler velocities. Duplex scan carotid stenosis was classified according to the literature,7 as: 70%. The patients were divided into two groups: Group I: 160 individuals whose duplex scans did not show progression of carotid stenosis of 70%. Group II: 41 patients with carotid stenosis progression of 30 kg/m2. Peripheral arterial disease (PAD) was defined as an ankle-brachial index 0.05. For numeric or quantitative variables, the difference between the two groups was analyzed with unpaired Student’s t test, with the appropriate test power (Pw). Contingency tables (2 2 and k r) were applied to the qualitative variables, with a simple v2 test or a v2 test corrected by continuity (according to Yates).
Results The median follow-up time was 32 months (interquartile range (IQR) 22–58) for Group I and 48 months (IQR 24–55) for Group II. The mean age was 68.7 8.5 years in Group I and 69.2 8.1 years in Group II (p ¼ 0.74). Group I was subdivided into exactly 50% men and 50% women, and Group II comprised 43.9% men and 56.1% women. There were no significant differences between the groups in follow-up time (p ¼ 0.57), age, or sex. There was no significant difference between the groups in the demographic variables: abdominal circumference, systemic arterial hypertension, systolic or diastolic arterial pressure, diabetes mellitus (Table 1). There were also no statistical differences when the hypertensive patients were subdivided into nonsevere (using up to two antihypertensive medications) and severe (using three or more antihypertensive medications). When the diabetic patients were similarly subdivided into treatment groups (dietary/oral hypoglycemic treatment or insulin treatment), there were no statistically significant differences between the groups (Table 2). Paradoxically, the mean BMI was higher in Group I (26.4 4.6 kg/m2) than in Group II (24.6 3.9 kg/m2; p ¼ 0.02) (Table 1) attributable to differences in weight. The prevalence of tabagism, PAD, or a family history of cardiovascular disease or stroke was statistically similar in the two groups, although there was a tendency to higher values in Group II (Table 2). There were no significant differences between the two groups in the use of acetylsalicylic acid (AAS),
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Table 1. Demographic variables.
Table 3. Prevalence of best medical therapy.
Group I A Abdominal circumference BMI Systolic arterial pressure Diastolic arterial pressure
Group II SD
A
SD
p
91.9
11.8
89.1
12.6
0.22 (ns)
26.4 148.9
4.6 25.5
24.6 146.7
3.9 26.6
0.020 (*) 0.64 (ns)
83.5
13.5
81.1
13.7
0.32 (ns)
A: average; SD: standard deviation; ns: not significant; *: statistically significant; BMI: body mass index.
Table 2. Demographic variables.
SAH
Diabetes mellitus Tabagism PAD FH of CVD FH of stroke
Yes No Nonsevere Severe Yes No Diet/OH Insulin Yes No Yes No Yes No Yes No
Group I (%)
Group II (%)
13.5 86.4 64.1 35.8 33.3 66.6 73.0 26.9 56.0 44.0 24.3 75.3 68.9 31.0 33.8 66.1
2.4 97.5 62.5 37.5 34.1 65.9 71.4 28.5 65.8 34.1 41.4 58.5 77.7 22.2 41.6 58.3
p 0.08 (ns) 0.99 (ns) 0.93 (ns) 0.83 (ns) 0.34 (ns) 0.05 (ns) 0.41 (ns) 0.51 (ns)
SAH: systemic arterial hypertension; OH: oral hypoglycemic agent; PAD: peripheral arterial disease; FH: family history; CVD: cardiovascular disease; ns: not significant.
statin, angiotensin-converting enzyme inhibitor (ACEi), or beta-blockers (Table 3). There was no significant difference between the groups in the biomarkers: glycosylated hemoglobin, fasting glycemia, total cholesterol, HDL- or LDL-cholesterol, triglyceride, creatinine, C-reactive protein. However, Group II levels of plasma urea (51.6 27.8 mg/dl) and fibrinogen (493.2 113.3 mg/ dl) were higher than the Group I levels (43.0 14.9 mg/dl and 441.3 106.7 mg/dl, respectively) with statistical significance (p urea ¼ 0.013 and p fibrinogen ¼ 0.018) (Table 4).
AAS/clopidogrel Statin ACEi Beta-blocker
Group I (%)
Group II (%)
p
85.6 65.5 66.4 38.7
90.0 72.5 65.0 40.0
0.56 0.52 0.98 0.95
(ns) (ns) (ns) (ns)
AAS: acetylsalicylic acid; ACEi: angiotensin-converting enzyme inhibitor; ns: not significant.
Table 4. Biomarkers.
Glycosylated hemoglobin Fasting glycemia Total cholesterol HDL–cholesterol LDL–cholesterol Triglyceride Creatinine Urea C-Reactive protein Fibrinogen
GROUP I
GROUP II
A
SD
A
SD
p
6.7
1.3
7.0
1.6
0.45 (ns)
108.8 185.5 51.7 106.9 145.7 1.8 43.0 5.4 441.3
31.6 44.9 14.0 38.3 65.5 8.8 14.9 10.6 106.7
108.1 178.9 50.4 105.1 140.9 1.1 51.1 6.5 493.2
36.7 39.5 12.5 38.5 72.1 0.4 27.8 9.5 113.3
0.91 (ns) 0.46 (ns) 0.61 (ns) 0.79 (ns) 0.69 (ns) 0.66 (ns) 0.013 (*) 0.58 (ns) 0.018 (*)
Abbreviations: A ¼ average; SD ¼ standard deviation; (ns) ¼ not significant; (*) ¼ statistically significant; HDL ¼ high-density lipoprotein; LDL ¼ low-density lipoprotein.
Discussion Atherosclerosis is the main cause of death in developed countries. Patients with carotid diseases can keep stable for a long time or develop acute vascular events. Identifying risk factors of carotid stenosis progression and development of acute events is one of the major challenges of cardiovascular medicine. The results of this study show that, contrary to expectation, the risk factors associated with atherosclerosis, such as systemic arterial hypertension, diabetes mellitus, and dyslipidemia,4,14 were not statistically significant factors in the progression of carotid bifurcation stenosis. In contrast, the higher urea and fibrinogen levels in the group that presented with carotid stenosis progression suggest that other factors, such as metabolic factors, might be associated with this phenomenon. In this study, urea but not creatinine presented statistically significant correlation with the disease progression. The association of the deterioration of renal function and atherosclerosis has already been demonstrated in some studies. The chronic kidney
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disease was independently associated with carotid atherosclerosis in hypertensive patients.15 Another recent study demonstrated that in hypertensive patients, the thicker the carotid intima-media thickness is, the lower is the estimated glomerular filtration rate with the Cockcroft-Gault method.16 Nevertheless, the association between chronic kidney disease and carotid atherosclerosis is not very strong in healthy populations.17 The higher fibrinogen levels in Group II show that the presence of inflammatory and thrombogenic activity are factors contributing to stenosis progression. Although we found no difference in the C-reactive protein levels of the groups in this study, other recent studies have shown that high levels of this marker are related to carotid stenosis.18–21 Besides demonstrating a link between C-reactive protein, fibrinogen, and atherosclerotic diseases, the participation of other inflammatory elements, such as homocysteine and lipoprotein,22,23 in atherosclerosis progression has also been demonstrated. However, the routine use of these variables as cardiovascular risk predictors must still be analyzed. Studies of plasma biomarkers for the diagnosis and prognosis of atherosclerosis have been done during recent years. Until now, there is no unanimously accepted biomarker in clinical practice; nevertheless, recent advances are coming in the application of proteomic and metabolomics techniques to the study of atherosclerosis.24,25 Paradoxically, BMI was significantly higher in Group I than in Group II (p ¼ 0.02). Several studies have shown the paradoxical effect of obesity on atherosclerotic disease, because obesity seems to confer protection against these disorders.26,27 This unexpected relationship may be attributable to the actions of endocrine factors released from adipose tissue.27 This was not an epidemiological study because the sample patients were referred to a tertiary hospital. This causes sample bias, although they were severely affected patients who required no primary treatment. However, the clinical and ultrasonographic follow-up of these patients can provide important information that would only otherwise be available in population studies of large samples randomly surveyed or based on risk factors for atherosclerosis development in carotid bifurcation.
Conclusion The analysis of a sample of patients referred to a tertiary vascular surgery service showed that traditional risk factors for the development of atherosclerosis in a carotid bifurcation are important but not unique. High plasma fibrinogen and urea are significantly
associated with this progression. These results indicate the need to control these factors in this group of patients to avoid disease progression. Conflict of interest None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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