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Ultrasound-assessed plaque occurrence in the carotid and femoral arteries are independent predictors of cardiovascular events in middle-aged men during 10 years of follow-up
Atherosclerosis 209 (2010) 469–473
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Ultrasound-assessed plaque occurrence in the carotid and femoral arteries are independent predictors of cardiovascular events in middle-aged men during 10 years of follow-up L. Davidsson a,b , B. Fagerberg a,b , G. Bergström a,b , C. Schmidt a,b,∗ a
Center for Cardiovascular and Metabolic research, Sahlgrenska Academy, University of Gothenburg, Sweden The Wallenberg Laboratory for Cardiovascular Research, Institution of Medicine, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at Gothenburg University, Göteborg, Sweden b
a r t i c l e
i n f o
Article history: Received 19 March 2009 Received in revised form 9 October 2009 Accepted 10 October 2009 Available online 8 November 2009 Keywords: Plaque Carotid artery Femoral artery Cardiovascular disease Ultrasound
a b s t r a c t Objectives: To examine if plaques in the carotid and femoral arteries were associated with cardiovascular events during a 10-year follow-up independently of usual risk factors for such diseases. Methods: Plaque occurrence in both carotid arteries, and in the right femoral artery were assessed at baseline by B-mode ultrasound in a population-based sample of 58-year-old men (n = 391) with no cardiovascular disease, and varying degrees of obesity and insulin sensitivity at entry. Anthropometry and blood pressure were recorded. Fasting venous blood samples were used for measurement of cardiovascular risk factors. Cardiovascular events occurring during follow-up were obtained by access to register data. Results: Systolic blood pressure, serum triglycerides and waist–hip ratio as well as baseline occurrence of carotid and femoral plaques were associated with events. Logistic multi-variate analyses showed that carotid plaques (OR 2.09, 95% CI 1.05–4.16, p = 0.037), femoral plaques (OR 1.99, 95% CI 1.01–3.91, p = 0.047) and concomitant presence of carotid, and femoral plaques (OR 2.53, 95% CI 1.23–5.21, p = 0.011) were associated with cardiovascular events independently of other risk factors. Plaques occurred in 0–3 arteries and there was a parallel increase in cardiovascular risk (p = 0.004). Conclusion: Occurrence of carotid or femoral plaques at baseline had similar predictive value for cardiovascular events. Increased plaque burden, with plaques in both carotid and femoral arteries increased the cardiovascular risk further. Hence, the results from this study indicate that ultrasound examination of both the carotid and femoral arteries was the preferred method to predict cardiovascular risk. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Most cases of atherosclerotic diseases such as ischemic stroke and myocardial infarction occur in the very large group of people considered at low or intermediate risk based upon traditional cardiovascular risk factors [1,2]. High-resolution B-mode ultrasound is a non-invasive method of examining the walls of peripheral arteries, such as the carotid and femoral arteries, and provides measures of intima-media thickness (IMT) and presence of plaques [3]. Many studies have shown that carotid artery IMT, as well as the occurrence of carotid plaques are associated with increased risk of myocardial infarction and stroke, independently of traditional
∗ Corresponding author at: Wallenberg Laboratory, Institution of Medicine, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at Gothenburg University, Göteborg S-413 45, Sweden. Tel.: +46 31 342 23 56; fax: +46 31 82 97 06. E-mail address: [email protected] (C. Schmidt). 0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.10.016
cardiovascular risk factors [4,5]. Ultrasound and autopsy studies have demonstrated that carotid atherosclerosis is associated with atherosclerosis elsewhere in the circulation and can be used as a marker of general atherosclerosis [6]. In comparison with carotid artery plaques, the association between femoral artery atherosclerosis and cardiovascular disease has received much less attention. Khoury et al. [7] showed that atherosclerotic plaques in the femoral arteries were strong predictors of CAD in a population with high prevalence of coronary artery disease and associated risk factors. Among patients who underwent coronary angiography, Lekakis et al. [8] showed that femoral artery IMT was an independent predictor of CAD. In a population with stable angina pectoris, increased femoral IMT and femoral plaques were found to predict the risk of revascularization [9]. Leng et al. [10] demonstrated that, in a general population, plaque occurrence in the femoral artery was associated with an increased prevalence of ischemic heart disease, but not stroke. We have previously reported that middle-aged men with nonstenotic plaques in the femoral artery suffer an increased risk for
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L. Davidsson et al. / Atherosclerosis 209 (2010) 469–473
CVD during 6.6 years of follow-up, as compared to subjects without plaques [11]. The objectives of the study were to; examine (1) if plaques in the carotid and femoral arteries were associated with cardiovascular events during a 10-year follow-up independently of usual risk factors for such diseases; (2) if carotid plaques are superior to femoral plaques in predicting cardiovascular events; (3) if the concomitant occurrence of carotid and femoral plaques further increase the risk of future cardiovascular disease. 2. Materials and methods 2.1. Subjects and study design From a population-based sample of 818 men, all 58-year-old, a stratified and randomly selected group of men with varying degrees of obesity and insulin sensitivity (n = 391) were included in a prospective study with a mean follow-up period of 9.9 ± 1.9 years, as previously described in detail [12]. The baseline examination included history of previous or current cardiovascular disease, anthropometry, electrocardiogram (ECG), blood samples for assessment of cardiovascular risk factors, plasma insulin, and a health check-up. Exclusion criteria were cardiovascular disease, treated cardiovascular risk factors, clinical diabetes mellitus or other severe disease, treatment with cardiovascular drugs (antihypertensive, lipid-lowering, antidiabetic agents), or unwillingness to participate. Briefly, 1728 men were invited to a screening procedure, starting with a telephone interview. In the end 818 subjects were eligible for a further examination after which all participants were divided into quintiles (Q) of an insulin sensitivity score, which allowed immediate stratification for further studies. All subjects in the 1st and 5th Q and every 5th subject in Q 2–4, performed an ultrasound examination. The subjects received both written and oral information before they gave their consent to participate. The Ethics Committee at Sahlgrenska University Hospital approved the study. 2.2. Measurements The measurements have been described in detail elsewhere [12]. Established questionnaires were used to evaluate history of previous and current disease and smoking habits. Measurements of body weight, waist and hip circumference and blood pressure (5 min supine rest) were preformed. A 12-lead standard ECG was recorded, and venous blood samples were drawn after a fasting period of 10–12 h. Lipids were measured on non-frozen blood samples. 2.3. Ultrasound The visit for the ultrasound examination always took place in the morning. The examination was performed with an ultrasound scanner (Acuson 128) with a 7 MHz linear transducer with the aperture of 38 mm. An electrocardiographic signal (lead II) was simultaneously recorded to synchronize the image capture of the top of the R-wave to minimize variability during the cardiac cycle. Both carotid arteries and the right femoral artery were examined regarding IMT in the far wall of the carotid bifurcations, the common carotid and femoral artery. The carotid artery was scanned longitudinally and transversely to assess the occurrence of plaques. Similarly, the right femoral artery were scanned distal to the inguinal ligament along a section approximately 4 cm proximal and 1 cm distal to the flow divider (the site where the artery divides into the superficial and profound femoral arteries)
to assess the occurrence of plaques. Plaque was defined according to the Mannheim consensus [13], where a plaque is a focal structure encroaching into the arterial lumen of at least 0.5 mm or 50% thicker than the surrounding intima-media thickness (IMT) value, or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. 2.4. End-point registration Major cardiovascular events during 10 years of follow-up were defined as cardiovascular death or non-fatal myocardial infarction (MI), non-fatal stroke, aortic aneurysm, new angina pectoris or revascularization procedures. These diagnoses were based on ICD-10 classification and were obtained from the Centre of Epidemiology at the National Board of Health and Welfare. Only the first event occurring in each subject, and the time between the baseline examination and the first event were included in the analyses. No subjects were lost to follow-up of end-points. Eighteen subjects died from other causes than cardiovascular, of which cancer was the most common cause. 2.5. Statistical analyses Variables are described as mean and standard deviation, if nothing else is indicated. Pearson’s 2 -test was used for comparisons of nominal and ordinal variables. Mann–Whitney U was used to compare continuous variables. Kaplan–Meier curves were used to describe the association between plaque status and cardiovascular events. A logistic multiple regression was used to explore the association between cardiovascular risk factors and cardiovascular events. Statistics were analyzed using SPSS for Windows 15.0 (SPSS Inc., Chicago, IL, USA). p < 0.05 (two-sided) was considered statistically significant. 3. Results In this cohort of middle-aged men, 41 (10.5%) had a cardiovascular event during 10 years of follow-up. Only the first event was included in the analyses and out of these, 13 had myocardial infarction, 12 had stroke and 16 suffered from other cardiovascular events (aorta aneurysm, revascularization procedures). There were in total 6 men who died among these 41 cases. Subjects with any cardiovascular event were characterized by having significantly higher mean values of systolic blood pressure, serum triglycerides and waist–hip ratio, as well as a more frequent prevalence of plaques in carotid arteries and in the right femoral artery, as compared to subjects without cardiovascular events (Table 1). Table 2 shows the distribution of plaques in the carotid and femoral arteries at study entry in relation to the future incidence of cardiovascular disease. Pearson chi-square test showed that only the combination of femoral and carotid plaques were associated with increased incidence of cardiovascular events, compared with those without plaques. Further, there was a significant linear increase in cardiovascular events by increasing amount of plaque-affected arteries (Fig. 1). Logistic multi-variate analyses were then performed with cardiovascular events as dependent variable with carotid and femoral plaque occurrence entered separately as independent variables together with the risk factors that were significantly different between the groups as shown in Table 1. The analysis showed that plaque occurrence in the carotid arteries (OR 2.09, 95% CI, 1.05–4.16, p = 0.037), and femoral plaques (OR 1.99, 95% CI 1.01–3.91, p = 0.047) were the only factors to predict outcome independently of other risk factors (Tables 3 and 4). Figs. 2 and 3 presents Kaplan–Meier curves for cardiovascular events in the groups with and without plaques in the carotid and femoral
L. Davidsson et al. / Atherosclerosis 209 (2010) 469–473 Table 1 Baseline characteristics in 58-year-old men with and without cardiovascular disease (CVD) during follow-up. CVD (n = 41) BMI (kg/m2 ) Waist–hip ratio Fasting plasma glucose (mmol/L) Serum insulin (U/L) Mean blood pressure (mmHg) Systolic Diastolic Serum cholesterol (mmol/L) Total Low density lipoproteins High density lipoproteins Serum triglycerides LDL particle size Smoking, n (%) Never Current/former Cigarette years Plaques in carotid arteries, n (%) Plaques in right femoral artery, n (%)
No CVD (n = 350)
p-Value
26.1 ± 5.2 0.96 ± 0.07 6.23 ± 3.76
26.2 ± 4.3 0.94 ± 0.06 5.50 ± 1.00
0.14 0.026 0.567
9.71 ± 6.16
10.10 ± 7.15
0.44
132.9 ± 16.4 80.0 ± 9.0 5.86 ± 1.08 3.74 ± 1.17 1.24 ± 0.49 2.00 ± 1.48 26.02 ± 1.05 10 (24) 17 (41) 433 ± 700 25 (61) 24 (59)
127.5 ± 16.5 76.0 ± 9.0
471
Table 4 Multi-variate analysis of the association between cardiovascular events as dependent variable and occurrence of plaque in the femoral artery, mean systolic blood pressure, serum triglycerides and waist–hip ratio as independent variables. OR Plaques in the femoral artery Systolic blood pressure Serum triglycerides Waist–hip ratio
1.99 1.0 1.2 25.2
95% CI 1.01–3.91 0.99–1.03 0.91–1.52 0.08–7998.3
p-Value 0.047 0.25 0.22 0.27
0.031 0.051
5.83 ± 1.03 3.92 ± 0.91 1.28 ± 0.36 1.45 ± 0.92 26.42 ± 0.68
0.17 0.69 0.65 0.005 0.059
110 (31) 164 (47) 290 ± 388 133 (38)
0.75 0.73 0.008
126 (36)
0.005
Table 2 Cross-tabulation of plaque location in relation to type of cardiovascular events. Clinical event
MI, n (%) Stroke, n (%) Other CVD, n (%) All CVD *
Location of plaque No plaque (n = 140)
Carotid artery (n = 81)
Femoral artery (n = 67)
Both (n = 78)
2 (1.4) 2 (1.4) 4 (2.9) 8 (5.7)
4 (4.9) 3 (3.7) 2 (2.5) 9 (13.4)
3 (4.5) 3 (4.5) 2 (3.0) 8 (11.9)
4 (5.1) 4 (5.1) 8 (10.3) 16 (20.5)*
p = 0.01, Chi-square test for comparison with plaque in both arteries.
Fig. 2. Kaplan–Meier curves for cardiovascular events in 58-year-old men (n = 391) with and without plaques in the carotid arteries (upper) and the femoral artery (lower) followed for a mean period of 10 years.
Fig. 1. Bar chart showing the increase in cardiovascular events in relation to the number of arteries with ultrasound-ssessed plaques. Both carotid arteries and the right femoral artery were examined.
Table 3 Multi-variate analysis of the association between cardiovascular events as dependent variable and occurrence of plaque in the carotid arteries, mean systolic blood pressure, serum triglycerides and waist–hip ratio as independent variables. OR Plaques in carotid arteries Systolic blood pressure Serum triglycerides Waist–hip ratio
2.09 1.0 1.3 58.3
95% CI 1.05–4.16 0.99–1.03 0.98–1.76 0.17–19104.9
p-Value 0.037 0.48 0.067 0.17
Fig. 3. Kaplan–Meier curve for cardiovascular events in the groups with and without plaques in the both the carotid and femoral arteries followed for a mean period of 10 years.
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Table 5 Multi-variate analysis of the association between cardiovascular events as dependent variable and occurrence of plaque in the carotid and femoral arteries, mean systolic blood pressure, serum triglycerides and waist–hip ratio as independent variables.
Plaques in both the carotid and femoral arteries Systolic blood pressure Serum triglycerides Waist–hip ratio
OR
95% CI
p-Value
2.62 1.01 1.35 5.89
1.18–5.80 0.99–1.04 0.97–1.87 0.09–3045.6
0.018 0.36 0.075 0.62
arteries, and plaques in both the carotid and femoral arteries, respectively. A further, similar analysis demonstrated that the combination of plaque occurrence in the carotid and femoral arteries was independently associated with future cardiovascular events (OR 2.62, 95% CI 1.18–5.80, p = 0.018) (Table 5). 4. Discussion Our results show that occurrence of carotid or femoral plaques had similar predictive value for cardiovascular events in middleaged men during long term follow-up, independently of usual cardiovascular risk factors. Increased plaque burden, with plaques in both carotid and femoral arteries increased the cardiovascular risk further. Cardiovascular events were defined as cardiovascular death, myocardial infarction (MI), stroke, aortic aneurysm, angina pectoris or revascularization procedures. Similar numbers of MI and stroke were found during follow-up. Systolic blood pressure, serum triglycerides and waist–hip ratio were all associated with cardiovascular events, but did not reach statistical significance when analyzed in multi-variable analyses together with plaque occurrence. Consistent with our findings, there are several studies showing positive associations between plaque occurrence and CVD, although most of them have been focusing on the carotid arteries [3,14,15]. As regards femoral atherosclerosis several studies have demonstrated an association between femoral plaque occurrence and coronary artery disease in cohorts at high risk of such diseases, as described above [7–9]. Leng et al. [10] have concluded that plaque occurrence in the femoral artery was associated with an increased prevalence of ischemic heart disease, but not stroke, in an older population. In contrast, a meta-analysis showed that low ankle-brachial index is associated with increased risk of stroke [16], and our group has previously demonstrated that low ankle-brachial index is associated with plaque in the femoral artery [17]. Hence, the association between atherosclerosis in the lower extremities and cerebrovascular diseases has been clearly shown when anklearm index has been used. We have previously shown that in our study-population, femoral plaque occurrence and plaque size were associated with CVD, during 6.6 years of follow-up [11]. The rational for the present study was to examine if the occurrence of plaques in the carotid and femoral arteries provided different information on cardiovascular risk during a more extended follow-up period. We found that the presence of either femoral or carotid plaques had similar risk for future cardiovascular disease. After adjustment for covariates, concomitant plaques in the carotid and femoral arteries showed an OR of 2.6 (95% CI 1.18–5.80) for future cardiovascular events. An alternative analysis showed that among subjects with plaques at baseline in the carotid, or femoral arteries, or in both these arteries 13.4%, 11.9%, and 20.5%, respectively developed cardiovascular disease. Only subjects with both carotid and femoral plaques differed from those without plaques in future risk. In addition, the number of arteries with plaques at baseline increased from 0 to 3 with a parallel increase in cardiovascular risk. These data give support
to a previous study indicating that the total plaque burden in the carotid and femoral arteries is important [18]. The present study has some limitations. First, our study was small and did not allow a closer study of risk prediction separately in cases with cerebrovascular and coronary artery disease. The original sample size calculation was performed with the aim to show the association between insulin resistance and atherosclerosis. Secondly, the present study only included 58-year-old men and therefore it may not be possible to generalize the findings also to females. There are studies indicating that atherosclerosis accelerates more rapidly in women than in men after the age of 50 years [19]. Further, we only examined the right femoral artery and therefore we cannot comment on the occurrence of plaques in the left femoral artery. The reason for only examining only the right femoral artery originates from a reproducibility study of measurement of IMT [20]. In that study we showed that if recordings and measurements were performed on the carotid arteries bilaterally, it was possible to reduce the inter-observer variability significantly. This beneficial effect was not observed for the femoral artery. As a result from our variability study and in order not to prolong the duration of the examinations for the patients we decided to examine the carotid arteries bilaterally and examine only the right femoral artery. A larger study, with more extensive ultrasound examinations of both legs would have increased the precision of the study. If anything, the results may have underestimated the importance of femoral plaque occurrence by the routine of examining only the right femoral artery. An attempt to evaluate the effect of inter-current treatment during follow-up on outcome was made by inclusion of results from a re-examination that was performed 3 years after the baseline examination. However, this attempt was hampered by a relatively high drop-out rate at the 3-year re-examination. Still, the finding, that the occurrence of plaques in the carotid and femoral arteries in apparently healthy middle-aged men predicts future cardiovascular disease during 10 years, without consideration of risk factor development and treatment during this period of time, is valuable. The information on clinical events was based on register data. Apart from the fact that no case was lost to follow-up, it has been shown that the diagnostic accuracy of national registers in Sweden is good [21]. To summarize, ultrasound-assessed plaque occurrence in the carotid and femoral arteries, were both predictors of cardiovascular events in middle-aged men during 10 years of follow-up, independently of traditional risk factors. Plaques in both arterial territories indicated even higher cardiovascular risk. Hence, the results from this study indicate that ultrasound examination of both the carotid and femoral arteries was the preferred method to predict cardiovascular risk in this. Conflict of interest No conflict of interest to declare. Acknowledgements Grants from the Swedish Foundation for Strategic Research Swedish Heart-Lung Foundation, the Swedish Medical Research Council (12270, 10880), King Gustav V and Queen Viktoria Foundation, Astra Zeneca, Mölndal, Sweden supported this work. References [1] Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). J Am Med Assoc 1986;256:2823–8.
L. Davidsson et al. / Atherosclerosis 209 (2010) 469–473 [2] MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765–74. [3] Stein JH, Korcarz CE, Hurst RT. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid IntimaMedia Thickness Task Force (vol 21, pg 93, 2008). J Am Soc Echocardiogr 2008;21:376–1376. [4] O’Leary DH, Polak JF. Intima-media thickness: a tool for atherosclerosis imaging and event prediction. Am J Cardiol 2002;90:18L–21L. [5] Ebrahim S, Papacosta O, Whincup P, et al. Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 1999;30:841–50. [6] Joakimsen O, Bonaa KH, Stensland-Bugge E, et al. Age and sex differences in the distribution and ultrasound morphology of carotid atherosclerosis: the Tromso Study. Arterioscler Thromb Vasc Biol 1999;19:3007–13. [7] Khoury Z, Schwartz R, Gottlieb S, et al. Relation of coronary artery disease to atherosclerotic disease in the aorta, carotid, and femoral arteries evaluated by ultrasound. Am J Cardiol 1997;80:1429–33. [8] Lekakis JP, Papamichael CM, Cimponeriu AT, et al. Atherosclerotic changes of extracoronary arteries are associated with the extent of coronary atherosclerosis. Am J Cardiol 2000;85:949–52. [9] Held C, Hjemdahl P, Eriksson SV, et al. Prognostic implications of intima-media thickness and plaques in the carotid and femoral arteries in patients with stable angina pectoris. Eur Heart J 2001;22:62–72. [10] Leng GC, Papacosta O, Whincup P, et al. Femoral atherosclerosis in an older British population: prevalence and risk factors. Atherosclerosis 2000;152:167–74. [11] Schmidt C, Fagerberg B, Hulthe J. Non-stenotic echolucent ultrasound-assessed femoral artery plaques are predictive for future cardiovascular events in middle-aged men. Atherosclerosis 2005;181:125–30. [12] Bokemark L, Wikstrand J, Wedel H, et al. Insulin, insulin propeptides and intima-media thickness in the carotid artery in 58-year-old clinically healthy
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men. The Atherosclerosis and Insulin Resistance study (AIR). Diab Med 2002;19:144–51. Touboul PJ, Hennerici MG, Meairs S, et al. Mannheim carotid intima-media thickness consensus (2004–2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis 2007;23:75–80. Komorovsky R, Desideri A, Coscarelli S, et al. Prognostic implications of sonographic characteristics of carotid plaques in patients with acute coronary syndromes. Heart 2005;91:819–20. Prabhakaran S, Singh R, Zhou X, et al. Presence of calcified carotid plaque predicts vascular events: the Northern Manhattan Study. Atherosclerosis 2007;195:e197–201. Doobay AV, Anand SS. Sensitivity and specificity of the ankle-brachial index to predict future cardiovascular outcomes: a systematic review. Arterioscler Thromb Vasc Biol 2005;25:1463–9. Suurkula M, Fagerberg B, Wendelhag I, et al. Atherosclerotic disease in the femoral artery in hypertensive patients at high cardiovascular risk. The value of ultrasonographic assessment of intima-media thickness and plaque occurrence. Risk Intervention Study (RIS) Group. Arterioscler Thromb Vasc Biol 1996;16:971–7. Lamina C, Meisinger C, Heid IM, et al. Association of ankle-brachial index and plaques in the carotid and femoral arteries with cardiovascular events and total mortality in a population-based study with 13 years of follow-up. Eur Heart J 2006;27:2580–7. Holdsworth RJ, McCollum PT, Bryce JS, et al. Symptoms, stenosis and carotid plaque morphology. Is plaque morphology relevant? Eur J Vasc Endovasc Surg 1995;9:80–5. Schmidt C, Wendelhag I. How can the variability in ultrasound measurement of intima-media thickness be reduced? Studies of interobserver variability in carotid and femoral arteries. Clin Physiol 1999;19:45–55. Rosen M, Alfredsson L, Hammar N, et al. Attack rate, mortality and case fatality for acute myocardial infarction in Sweden during 1987–95. Results from the national AMI register in Sweden. J Intern Med 2000;248:159–64.
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Ultrasound-assessed plaque occurrence in the carotid and femoral arteries are independent predictors of cardiovascular events in middle-aged men during 10 years of follow-up L. Davidsson a,b , B. Fagerberg a,b , G. Bergström a,b , C. Schmidt a,b,∗ a
Center for Cardiovascular and Metabolic research, Sahlgrenska Academy, University of Gothenburg, Sweden The Wallenberg Laboratory for Cardiovascular Research, Institution of Medicine, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at Gothenburg University, Göteborg, Sweden b
a r t i c l e
i n f o
Article history: Received 19 March 2009 Received in revised form 9 October 2009 Accepted 10 October 2009 Available online 8 November 2009 Keywords: Plaque Carotid artery Femoral artery Cardiovascular disease Ultrasound
a b s t r a c t Objectives: To examine if plaques in the carotid and femoral arteries were associated with cardiovascular events during a 10-year follow-up independently of usual risk factors for such diseases. Methods: Plaque occurrence in both carotid arteries, and in the right femoral artery were assessed at baseline by B-mode ultrasound in a population-based sample of 58-year-old men (n = 391) with no cardiovascular disease, and varying degrees of obesity and insulin sensitivity at entry. Anthropometry and blood pressure were recorded. Fasting venous blood samples were used for measurement of cardiovascular risk factors. Cardiovascular events occurring during follow-up were obtained by access to register data. Results: Systolic blood pressure, serum triglycerides and waist–hip ratio as well as baseline occurrence of carotid and femoral plaques were associated with events. Logistic multi-variate analyses showed that carotid plaques (OR 2.09, 95% CI 1.05–4.16, p = 0.037), femoral plaques (OR 1.99, 95% CI 1.01–3.91, p = 0.047) and concomitant presence of carotid, and femoral plaques (OR 2.53, 95% CI 1.23–5.21, p = 0.011) were associated with cardiovascular events independently of other risk factors. Plaques occurred in 0–3 arteries and there was a parallel increase in cardiovascular risk (p = 0.004). Conclusion: Occurrence of carotid or femoral plaques at baseline had similar predictive value for cardiovascular events. Increased plaque burden, with plaques in both carotid and femoral arteries increased the cardiovascular risk further. Hence, the results from this study indicate that ultrasound examination of both the carotid and femoral arteries was the preferred method to predict cardiovascular risk. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Most cases of atherosclerotic diseases such as ischemic stroke and myocardial infarction occur in the very large group of people considered at low or intermediate risk based upon traditional cardiovascular risk factors [1,2]. High-resolution B-mode ultrasound is a non-invasive method of examining the walls of peripheral arteries, such as the carotid and femoral arteries, and provides measures of intima-media thickness (IMT) and presence of plaques [3]. Many studies have shown that carotid artery IMT, as well as the occurrence of carotid plaques are associated with increased risk of myocardial infarction and stroke, independently of traditional
∗ Corresponding author at: Wallenberg Laboratory, Institution of Medicine, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at Gothenburg University, Göteborg S-413 45, Sweden. Tel.: +46 31 342 23 56; fax: +46 31 82 97 06. E-mail address: [email protected] (C. Schmidt). 0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.10.016
cardiovascular risk factors [4,5]. Ultrasound and autopsy studies have demonstrated that carotid atherosclerosis is associated with atherosclerosis elsewhere in the circulation and can be used as a marker of general atherosclerosis [6]. In comparison with carotid artery plaques, the association between femoral artery atherosclerosis and cardiovascular disease has received much less attention. Khoury et al. [7] showed that atherosclerotic plaques in the femoral arteries were strong predictors of CAD in a population with high prevalence of coronary artery disease and associated risk factors. Among patients who underwent coronary angiography, Lekakis et al. [8] showed that femoral artery IMT was an independent predictor of CAD. In a population with stable angina pectoris, increased femoral IMT and femoral plaques were found to predict the risk of revascularization [9]. Leng et al. [10] demonstrated that, in a general population, plaque occurrence in the femoral artery was associated with an increased prevalence of ischemic heart disease, but not stroke. We have previously reported that middle-aged men with nonstenotic plaques in the femoral artery suffer an increased risk for
470
L. Davidsson et al. / Atherosclerosis 209 (2010) 469–473
CVD during 6.6 years of follow-up, as compared to subjects without plaques [11]. The objectives of the study were to; examine (1) if plaques in the carotid and femoral arteries were associated with cardiovascular events during a 10-year follow-up independently of usual risk factors for such diseases; (2) if carotid plaques are superior to femoral plaques in predicting cardiovascular events; (3) if the concomitant occurrence of carotid and femoral plaques further increase the risk of future cardiovascular disease. 2. Materials and methods 2.1. Subjects and study design From a population-based sample of 818 men, all 58-year-old, a stratified and randomly selected group of men with varying degrees of obesity and insulin sensitivity (n = 391) were included in a prospective study with a mean follow-up period of 9.9 ± 1.9 years, as previously described in detail [12]. The baseline examination included history of previous or current cardiovascular disease, anthropometry, electrocardiogram (ECG), blood samples for assessment of cardiovascular risk factors, plasma insulin, and a health check-up. Exclusion criteria were cardiovascular disease, treated cardiovascular risk factors, clinical diabetes mellitus or other severe disease, treatment with cardiovascular drugs (antihypertensive, lipid-lowering, antidiabetic agents), or unwillingness to participate. Briefly, 1728 men were invited to a screening procedure, starting with a telephone interview. In the end 818 subjects were eligible for a further examination after which all participants were divided into quintiles (Q) of an insulin sensitivity score, which allowed immediate stratification for further studies. All subjects in the 1st and 5th Q and every 5th subject in Q 2–4, performed an ultrasound examination. The subjects received both written and oral information before they gave their consent to participate. The Ethics Committee at Sahlgrenska University Hospital approved the study. 2.2. Measurements The measurements have been described in detail elsewhere [12]. Established questionnaires were used to evaluate history of previous and current disease and smoking habits. Measurements of body weight, waist and hip circumference and blood pressure (5 min supine rest) were preformed. A 12-lead standard ECG was recorded, and venous blood samples were drawn after a fasting period of 10–12 h. Lipids were measured on non-frozen blood samples. 2.3. Ultrasound The visit for the ultrasound examination always took place in the morning. The examination was performed with an ultrasound scanner (Acuson 128) with a 7 MHz linear transducer with the aperture of 38 mm. An electrocardiographic signal (lead II) was simultaneously recorded to synchronize the image capture of the top of the R-wave to minimize variability during the cardiac cycle. Both carotid arteries and the right femoral artery were examined regarding IMT in the far wall of the carotid bifurcations, the common carotid and femoral artery. The carotid artery was scanned longitudinally and transversely to assess the occurrence of plaques. Similarly, the right femoral artery were scanned distal to the inguinal ligament along a section approximately 4 cm proximal and 1 cm distal to the flow divider (the site where the artery divides into the superficial and profound femoral arteries)
to assess the occurrence of plaques. Plaque was defined according to the Mannheim consensus [13], where a plaque is a focal structure encroaching into the arterial lumen of at least 0.5 mm or 50% thicker than the surrounding intima-media thickness (IMT) value, or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. 2.4. End-point registration Major cardiovascular events during 10 years of follow-up were defined as cardiovascular death or non-fatal myocardial infarction (MI), non-fatal stroke, aortic aneurysm, new angina pectoris or revascularization procedures. These diagnoses were based on ICD-10 classification and were obtained from the Centre of Epidemiology at the National Board of Health and Welfare. Only the first event occurring in each subject, and the time between the baseline examination and the first event were included in the analyses. No subjects were lost to follow-up of end-points. Eighteen subjects died from other causes than cardiovascular, of which cancer was the most common cause. 2.5. Statistical analyses Variables are described as mean and standard deviation, if nothing else is indicated. Pearson’s 2 -test was used for comparisons of nominal and ordinal variables. Mann–Whitney U was used to compare continuous variables. Kaplan–Meier curves were used to describe the association between plaque status and cardiovascular events. A logistic multiple regression was used to explore the association between cardiovascular risk factors and cardiovascular events. Statistics were analyzed using SPSS for Windows 15.0 (SPSS Inc., Chicago, IL, USA). p < 0.05 (two-sided) was considered statistically significant. 3. Results In this cohort of middle-aged men, 41 (10.5%) had a cardiovascular event during 10 years of follow-up. Only the first event was included in the analyses and out of these, 13 had myocardial infarction, 12 had stroke and 16 suffered from other cardiovascular events (aorta aneurysm, revascularization procedures). There were in total 6 men who died among these 41 cases. Subjects with any cardiovascular event were characterized by having significantly higher mean values of systolic blood pressure, serum triglycerides and waist–hip ratio, as well as a more frequent prevalence of plaques in carotid arteries and in the right femoral artery, as compared to subjects without cardiovascular events (Table 1). Table 2 shows the distribution of plaques in the carotid and femoral arteries at study entry in relation to the future incidence of cardiovascular disease. Pearson chi-square test showed that only the combination of femoral and carotid plaques were associated with increased incidence of cardiovascular events, compared with those without plaques. Further, there was a significant linear increase in cardiovascular events by increasing amount of plaque-affected arteries (Fig. 1). Logistic multi-variate analyses were then performed with cardiovascular events as dependent variable with carotid and femoral plaque occurrence entered separately as independent variables together with the risk factors that were significantly different between the groups as shown in Table 1. The analysis showed that plaque occurrence in the carotid arteries (OR 2.09, 95% CI, 1.05–4.16, p = 0.037), and femoral plaques (OR 1.99, 95% CI 1.01–3.91, p = 0.047) were the only factors to predict outcome independently of other risk factors (Tables 3 and 4). Figs. 2 and 3 presents Kaplan–Meier curves for cardiovascular events in the groups with and without plaques in the carotid and femoral
L. Davidsson et al. / Atherosclerosis 209 (2010) 469–473 Table 1 Baseline characteristics in 58-year-old men with and without cardiovascular disease (CVD) during follow-up. CVD (n = 41) BMI (kg/m2 ) Waist–hip ratio Fasting plasma glucose (mmol/L) Serum insulin (U/L) Mean blood pressure (mmHg) Systolic Diastolic Serum cholesterol (mmol/L) Total Low density lipoproteins High density lipoproteins Serum triglycerides LDL particle size Smoking, n (%) Never Current/former Cigarette years Plaques in carotid arteries, n (%) Plaques in right femoral artery, n (%)
No CVD (n = 350)
p-Value
26.1 ± 5.2 0.96 ± 0.07 6.23 ± 3.76
26.2 ± 4.3 0.94 ± 0.06 5.50 ± 1.00
0.14 0.026 0.567
9.71 ± 6.16
10.10 ± 7.15
0.44
132.9 ± 16.4 80.0 ± 9.0 5.86 ± 1.08 3.74 ± 1.17 1.24 ± 0.49 2.00 ± 1.48 26.02 ± 1.05 10 (24) 17 (41) 433 ± 700 25 (61) 24 (59)
127.5 ± 16.5 76.0 ± 9.0
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Table 4 Multi-variate analysis of the association between cardiovascular events as dependent variable and occurrence of plaque in the femoral artery, mean systolic blood pressure, serum triglycerides and waist–hip ratio as independent variables. OR Plaques in the femoral artery Systolic blood pressure Serum triglycerides Waist–hip ratio
1.99 1.0 1.2 25.2
95% CI 1.01–3.91 0.99–1.03 0.91–1.52 0.08–7998.3
p-Value 0.047 0.25 0.22 0.27
0.031 0.051
5.83 ± 1.03 3.92 ± 0.91 1.28 ± 0.36 1.45 ± 0.92 26.42 ± 0.68
0.17 0.69 0.65 0.005 0.059
110 (31) 164 (47) 290 ± 388 133 (38)
0.75 0.73 0.008
126 (36)
0.005
Table 2 Cross-tabulation of plaque location in relation to type of cardiovascular events. Clinical event
MI, n (%) Stroke, n (%) Other CVD, n (%) All CVD *
Location of plaque No plaque (n = 140)
Carotid artery (n = 81)
Femoral artery (n = 67)
Both (n = 78)
2 (1.4) 2 (1.4) 4 (2.9) 8 (5.7)
4 (4.9) 3 (3.7) 2 (2.5) 9 (13.4)
3 (4.5) 3 (4.5) 2 (3.0) 8 (11.9)
4 (5.1) 4 (5.1) 8 (10.3) 16 (20.5)*
p = 0.01, Chi-square test for comparison with plaque in both arteries.
Fig. 2. Kaplan–Meier curves for cardiovascular events in 58-year-old men (n = 391) with and without plaques in the carotid arteries (upper) and the femoral artery (lower) followed for a mean period of 10 years.
Fig. 1. Bar chart showing the increase in cardiovascular events in relation to the number of arteries with ultrasound-ssessed plaques. Both carotid arteries and the right femoral artery were examined.
Table 3 Multi-variate analysis of the association between cardiovascular events as dependent variable and occurrence of plaque in the carotid arteries, mean systolic blood pressure, serum triglycerides and waist–hip ratio as independent variables. OR Plaques in carotid arteries Systolic blood pressure Serum triglycerides Waist–hip ratio
2.09 1.0 1.3 58.3
95% CI 1.05–4.16 0.99–1.03 0.98–1.76 0.17–19104.9
p-Value 0.037 0.48 0.067 0.17
Fig. 3. Kaplan–Meier curve for cardiovascular events in the groups with and without plaques in the both the carotid and femoral arteries followed for a mean period of 10 years.
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Table 5 Multi-variate analysis of the association between cardiovascular events as dependent variable and occurrence of plaque in the carotid and femoral arteries, mean systolic blood pressure, serum triglycerides and waist–hip ratio as independent variables.
Plaques in both the carotid and femoral arteries Systolic blood pressure Serum triglycerides Waist–hip ratio
OR
95% CI
p-Value
2.62 1.01 1.35 5.89
1.18–5.80 0.99–1.04 0.97–1.87 0.09–3045.6
0.018 0.36 0.075 0.62
arteries, and plaques in both the carotid and femoral arteries, respectively. A further, similar analysis demonstrated that the combination of plaque occurrence in the carotid and femoral arteries was independently associated with future cardiovascular events (OR 2.62, 95% CI 1.18–5.80, p = 0.018) (Table 5). 4. Discussion Our results show that occurrence of carotid or femoral plaques had similar predictive value for cardiovascular events in middleaged men during long term follow-up, independently of usual cardiovascular risk factors. Increased plaque burden, with plaques in both carotid and femoral arteries increased the cardiovascular risk further. Cardiovascular events were defined as cardiovascular death, myocardial infarction (MI), stroke, aortic aneurysm, angina pectoris or revascularization procedures. Similar numbers of MI and stroke were found during follow-up. Systolic blood pressure, serum triglycerides and waist–hip ratio were all associated with cardiovascular events, but did not reach statistical significance when analyzed in multi-variable analyses together with plaque occurrence. Consistent with our findings, there are several studies showing positive associations between plaque occurrence and CVD, although most of them have been focusing on the carotid arteries [3,14,15]. As regards femoral atherosclerosis several studies have demonstrated an association between femoral plaque occurrence and coronary artery disease in cohorts at high risk of such diseases, as described above [7–9]. Leng et al. [10] have concluded that plaque occurrence in the femoral artery was associated with an increased prevalence of ischemic heart disease, but not stroke, in an older population. In contrast, a meta-analysis showed that low ankle-brachial index is associated with increased risk of stroke [16], and our group has previously demonstrated that low ankle-brachial index is associated with plaque in the femoral artery [17]. Hence, the association between atherosclerosis in the lower extremities and cerebrovascular diseases has been clearly shown when anklearm index has been used. We have previously shown that in our study-population, femoral plaque occurrence and plaque size were associated with CVD, during 6.6 years of follow-up [11]. The rational for the present study was to examine if the occurrence of plaques in the carotid and femoral arteries provided different information on cardiovascular risk during a more extended follow-up period. We found that the presence of either femoral or carotid plaques had similar risk for future cardiovascular disease. After adjustment for covariates, concomitant plaques in the carotid and femoral arteries showed an OR of 2.6 (95% CI 1.18–5.80) for future cardiovascular events. An alternative analysis showed that among subjects with plaques at baseline in the carotid, or femoral arteries, or in both these arteries 13.4%, 11.9%, and 20.5%, respectively developed cardiovascular disease. Only subjects with both carotid and femoral plaques differed from those without plaques in future risk. In addition, the number of arteries with plaques at baseline increased from 0 to 3 with a parallel increase in cardiovascular risk. These data give support
to a previous study indicating that the total plaque burden in the carotid and femoral arteries is important [18]. The present study has some limitations. First, our study was small and did not allow a closer study of risk prediction separately in cases with cerebrovascular and coronary artery disease. The original sample size calculation was performed with the aim to show the association between insulin resistance and atherosclerosis. Secondly, the present study only included 58-year-old men and therefore it may not be possible to generalize the findings also to females. There are studies indicating that atherosclerosis accelerates more rapidly in women than in men after the age of 50 years [19]. Further, we only examined the right femoral artery and therefore we cannot comment on the occurrence of plaques in the left femoral artery. The reason for only examining only the right femoral artery originates from a reproducibility study of measurement of IMT [20]. In that study we showed that if recordings and measurements were performed on the carotid arteries bilaterally, it was possible to reduce the inter-observer variability significantly. This beneficial effect was not observed for the femoral artery. As a result from our variability study and in order not to prolong the duration of the examinations for the patients we decided to examine the carotid arteries bilaterally and examine only the right femoral artery. A larger study, with more extensive ultrasound examinations of both legs would have increased the precision of the study. If anything, the results may have underestimated the importance of femoral plaque occurrence by the routine of examining only the right femoral artery. An attempt to evaluate the effect of inter-current treatment during follow-up on outcome was made by inclusion of results from a re-examination that was performed 3 years after the baseline examination. However, this attempt was hampered by a relatively high drop-out rate at the 3-year re-examination. Still, the finding, that the occurrence of plaques in the carotid and femoral arteries in apparently healthy middle-aged men predicts future cardiovascular disease during 10 years, without consideration of risk factor development and treatment during this period of time, is valuable. The information on clinical events was based on register data. Apart from the fact that no case was lost to follow-up, it has been shown that the diagnostic accuracy of national registers in Sweden is good [21]. To summarize, ultrasound-assessed plaque occurrence in the carotid and femoral arteries, were both predictors of cardiovascular events in middle-aged men during 10 years of follow-up, independently of traditional risk factors. Plaques in both arterial territories indicated even higher cardiovascular risk. Hence, the results from this study indicate that ultrasound examination of both the carotid and femoral arteries was the preferred method to predict cardiovascular risk in this. Conflict of interest No conflict of interest to declare. Acknowledgements Grants from the Swedish Foundation for Strategic Research Swedish Heart-Lung Foundation, the Swedish Medical Research Council (12270, 10880), King Gustav V and Queen Viktoria Foundation, Astra Zeneca, Mölndal, Sweden supported this work. References [1] Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). J Am Med Assoc 1986;256:2823–8.
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