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Preclinical carotid atherosclerosis enhances the global cardiovascular risk and increases the rate of cerebro- and cardiovascular events in a five-year follow-up
Atherosclerosis 211 (2010) 287–290
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Preclinical carotid atherosclerosis enhances the global cardiovascular risk and increases the rate of cerebro- and cardiovascular events in a five-year follow-up Salvatore Novo a,∗ , Patrizia Carità a , Egle Corrado a , Ida Muratori a , Claudio Pernice b , Rosalba Tantillo a , Giuseppina Novo a a Center for the Diagnosis of Preclinical and Multifocal Atherosclerosis and for Cardiovascular Prevention, Section of CardioAngiology, Department of Internal Medicine and Cardiovascular Diseases, University Hospital Paolo Giaccone, Palermo, Italy b Division of Geriatrics, Mazzara del Vallo Hospital, Italy
a r t i c l e
i n f o
Article history: Received 10 November 2009 Received in revised form 14 January 2010 Accepted 14 January 2010 Available online 25 January 2010 Keywords: GCVR Preclinical carotid atherosclerosis Primary prevention
a b s t r a c t Aim: To evaluate if the intima-media thickening (IMT) and asymptomatic carotid plaque (ACP), as expression of carotid preclinical atherosclerosis (pre-ATS), can provide further information on the global cardiovascular risk (GCVR). Methods: We studied 454 asymptomatic subjects, with a cluster of risk factors (RF), and evaluated the incidence of a first cardiovascular (CV) event in a five-year follow-up. The subjects at admission were subdivided in three groups of risk. Results: Events occurred in 38% of subjects at high risk, in 13% and 6% of subjects at intermediate and low risk (p < 0.003). Among evaluated parameters, carotid pre-ATS was a predictive marker of CV events (OR 2.7, 95% IC 1.4–5.1, p < 0.0024). In subjects with GCVR <20% the prevalence of events was 8% for normal carotid ultrasound findings, 13% for increased IMT and 15% for ACP. Conclusions: In primary prevention, the IMT measurement can give further information for a better stratification of GCVR. The pre-ATS of carotid arteries should be considered a strong predictor of future CV events and should suggest a more aggressive treatment of RF. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The intima-media thickness (IMT) is the distance (assessed by B-mode ultrasonography) between two vascular echogenic lines: the media-adventitia and the intima-media interface. Pignoli et al. demonstrated the correlation between this distance and the thickness of the arterial intima-media tunicae anatomo-pathologically measured [1]. In recent years, evidences supported the role of carotid IMT in recognition of the preclinical atherosclerosis (pre-ATS). The ARIC Study demonstrated that “traditional” and “nontraditional” cardiovascular (CV) risk factors (RF) correlates with increase in carotid IMT values [2]. In the GESCO-MURST-CIFTI-4 study we reported a significantly higher incidence of increased carotid IMT (32.5% vs. 14.7%), asymptomatic carotid plaques (ACP) (10.75% vs. 5.37%) and both lesions
∗ Corresponding author at: School of Cardiology, Master of Vascular Diseases, Master of Echocardiography, Center for the Diagnosis of Preclinical and Multifocal Atherosclerosis and for Cardiovascular Prevention, Section of CardioAngiology, Department of Internal Medicine and Cardiovascular Diseases, University Hospital “Paolo Giaccone”, of the University of Palermo Via del Vespro 139–90127 Palermo Italy. Tel.: +39 091 655 43 01; fax: +39 091 655.43.01. E-mail address: [email protected] (S. Novo). 0021-9150/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2010.01.019
together (47.2% vs. 16.2%) in subjects with one (or more than one) traditional RF than in subjects without RF [3]. Likewise, we recently demonstrated that pre-ATS is associated with “traditional” and some “emerging” RF [4]. There is evidence that an abnormal carotid IMT not only correlates with the presence of atherosclerotic lesions in other arteries (as marker of multifocal ATS) but it is also a negative prognostic factor [5]. The main effect of the carotid IMT evaluation would be that many subjects at intermediate global cardiovascular risk (GCVR) with the Framingham score would change into a higher class of risk [6]. Subjects with abnormal carotid IMT should be treated more aggressively than those with a normal thickness [7]. These evidences led the American Heart Association to state that “in estimating the cardiovascular risk of asymptomatic subjects aged >45 years, IMT measurement can provide additional information to the traditional RF” [8]. A recent meta-analysis [9], investigating the relationship between IMT and CV outcomes, registered an increased rate of myocardial infarction (10–15%) and stroke (13–18%) for every 0.1 mm increase in the IMT values. Therefore, the presence of carotid lesions, even if early and asymptomatic, may represent a powerful CV predictor. Currently, in Italy the algorithm arising from “Progetto Cuore” [10] can be considered the reference standard for the CV prediction.
288
S. Novo et al. / Atherosclerosis 211 (2010) 287–290
The “Istituto Superiore della Sanità” in the Progetto Cuore (whose recruitment phase started in 1998) analyzed prospective data coming from 12 Italian cohorts and developed a Chart of risk and an Individual risk score tailored for Italian population. The Chart is a simple paper-based graphical representation of various classes (I–VI) of absolute GCVR; it takes into consideration six RF [gender (man/woman), age, diabetes (yes/no), smoke (yes/no), systolic blood pressure and total cholesterol] and refers to SBP and TC as range of levels. The Individual score is a web-based electronic programme that, by using mathematical functions, provides a more precise GCVR in healthy subjects aged 35/69 years. This score evaluates two additional RF beyond the chart [HDL-cholesterol and antihypertensive drugs (yes/no)] and uses the precise levels (rather than “ranges” of levels) for cholesterolemia, age and systolic BP. The general population is then subdivided in three categories: at low (<3%), intermediate (≥3–19%) and high GCVR (≥20%) in 10 years. In primary prevention priority is focused on those at high risk. In this study we gave attention to subjects at low-intermediate risk (GCVR < 20%) who currently have poor probabilities to receive intensive treatments. The aim of our study was to determine the effects of including carotid IMT and ACP evaluation on the accuracy of CV prediction. Our intention was to investigate if a new model of risk stratification incorporating the IMT/ACP beyond the risk variables of the “Progetto Cuore” could more accurately predict the GCVR.
2. Methods As part of the Italian Research Project on the Cardiovascular Aging (MURST-GESCO-CIFTI-4) study, we examinated 454 asymptomatic subjects [215 men (M) and 239 women (W)] with mean age 57 ± 10 years. The 10-year mean incidence of CV disease predicted at baseline by the Progetto Cuore’s equation alone was compared to the occurrence of total CV events registered in five-year follow-up. The procedures were in agreement with the Helsinki Declaration of 1975 as revised in 1983 and were approved by the Ethic Council of our Department. The subjects were sampled from a population of 1100 subjects referring to our Center for a clinical evaluation. We excluded subjects with history of symptomatic peripheral artery disease, stable or unstable angina pectoris, previous myocardial infarction, procedures of revascularization with angioplasty or by-pass, procedures of endoarterectomy and cerebro-vascular events. We also excluded subjects younger than 45 years and older than 69 years. The adopted procedures for the sampling of population were in agreement with the manual of operations of the “Progetto MONICA” [11]. A total of 454 subjects were included. They had often (70%) a mean age >55 years. The higher prevalence of RF and GCVR in our population, than in the general population, may have been influenced by the “relative sampling”. At admission all subjects gave their informed consent and underwent medical examination, measurement of blood pressure (BP), anthropometric measurement, electrocardiogram and biochemistry tests. They also answered a questionnaire on personal and medical items. The family history was defined as the presence of CV diseases in first degree relatives earlier than 55 years for male and than 65 years for female. The BP was measured with a random-zero sphygmomanometer and was used the average of the measurements obtained in the two arms. Hypertension was considered as systolic or diastolic BP respectively ≥140 or ≥90 mm Hg or as the use of antihypertensive drugs. According to the American Diabetes Association’s guidelines, diabetes was considered as fast-
ing glucose concentrations higher than 126 mg/dL or as a therapy with oral hypoglycaemic agents or insulin [12]. The information about the smoking habit were taken from the questionnaire. The measurements of weight and height were performed using a statiometer on the wall and a balance on the floor. The “body mass index” (BMI = kg/m2 ) was calculated as the relation between weight and height. Obesity was defined as BMI ≥30 kg/m2 . A blood sample was drawn after 12 h overnight fast. Total cholesterol (TC), HDL-cholesterol (HDL-C) and TG (triglycerides) were quantified by enzymatic-colorimetric methods and the LDL-cholesterol was calculated with the Friedewald formula. The Hexokinase method was used for the glucose plasma concentration. 2.1. Evaluation of carotid IMT The measurement of the carotid IMT was performed with an Esaote Caris Plus machine and a linear probe of 7.5–10.0 MHz. As well as in other studies [1,4,13] both the arteries were studied. Using the dilatation of the bulb as anatomical reference, three segments were identified: (1) the distal 1.0 cm of common carotid proximal to the bifurcation, the carotid bifurcation itself, and the proximal 1.0 cm of the internal carotid artery. The mean value of IMT was an average of these six measurements. Values of carotid IMT ≥0.9 mm were considered abnormal and have been taken as a measure of increased risk. According to the joint European Society of Hypertension (ESH)/Europeans Society of Cardiology (ESC) guidelines [14] subjects were subdivided in three categories: “normal” [carotid IMT < 0.9 mm (n = 177)], “with increased IMT” [carotid IMT 0.9 mm and <1.5 mm (n = 164)] and “with asymptomatic carotid plaque (ACP)” [carotid IMT ≥1.5 mm (n = 113)]. 2.2. Stratification of the cardiovascular risk The 10-year individual GCVR was predicted at baseline by the electronic programme, available for free on the Progetto Cuore’s website (www. progettocuore.it). [10]. 2.3. Statistical analysis The statistical analysis was performed by StatView program. The differences between the various groups were evaluated with the Student’s unpaired t test. The prevalence of clinical variables was calculated and the differences between two groups were performed by the use of the chi-square test, or, if necessary, the chi-square test with Bonferroni correction. A value of p < 0.05 was considered as statistical significant. In a first step, a univariate analysis was performed. Second, the variables with a resulting p < 0.01 were selected to be tested using a multivariate analysis. In this model of multivariate analysis was used a stepwise logistic regression method. The variables with p < 0.05 and a predictive value (odds ratio) with a confidence interval of 95% were considered statistically significant. 3. Results 3.1. Prevalence of coronary risk factors The Table 1 reports the prevalence of RF in both men and women. A family history of CV disease was reported in 61% of subjects [(n = 279); 58% M vs. 64% W, p < 0. 0001]. The 21% was active smoker (30% M vs. 13% W, p < 0.0001). TC was 220 ± 58 mg/dL in men and 232 ± 68 mg/dL in women [p = not statistically significant (ns)]. The HDL-C was 39 ± 9 mg/dL in men and 47 ± 12 mg/dL in women (p < 0.0001). The LDL-C was 157 ± 56 mg/dL in men and 162 ± 65 mg/dL in women (p = ns). TG were 123 ± 65 mg/dL in men and 115 ± 48 mg/dL in women (p = ns). The fasting glucose plasma
S. Novo et al. / Atherosclerosis 211 (2010) 287–290
Table 3 Prevalence of preclinical atherosclerosis (IMT e ACP) in the three “category of risk”.
Table 1 Prevalence (%) of risk factors in the investigated population. RF
Men% (n = 215) Women% (n = 239)
289
0
1
2
3
4 (or more)
10 10
21 25
34 37
23 24
12 4
Category of risk:
Normal findings (p < 0.0001)
CIMT* (p: ns)
ACP** (<0.0001)
Low GCVR (<3%) Intermediate GCVR (≥3–19%) High GCVR (≥20%)
56% 23% 21%
33% 39% 28%
11% 38% 51%
*
concentration was 104 ± 21 mg/dL in men and 100 ± 26 mg/dL in women (p = ns). The incidence of diabetes was 21% in the whole population (24% in men vs. 16% in women with a difference statistically significant, p < 0.0001). A BP >140/90 mm Hg was observed in 53% of men and 21.7% of women. The 58.5% of men and 50% of women were regularly treated with antihypertensive drugs. The body weight ranged 82 ± 10 kg in men and 69 ± 12 kg in women. The BMI was 28.4 ± 3.7 kg/m2 in men and 30 ± 5 kg/m2 in women (p = ns). The prevalence of obesity (BMI > 30 kg/m2 ) was 26% in men and 33% in women (p < 0.0001) (Table 2). 3.2. Assessment of global cardiovascular risk The mean GCVR ranged 9.8 ± 7.7%. The population was organized in three groups: subjects at high [≥20% (n = 32)], at intermediate [≥3% and <20% (n = 321)] and at low [<3% (n = 101)] GCVR. 3.3. Evaluation of preclinical atherosclerosis We evaluated the ultrasound findings in the three groups. In subjects at high GCVR was shown a significant higher prevalence of increased IMT and/or ACP. (Table 3). The prevalence of normal ultrasound findings was higher in women than in men [49% (n = 118) vs. 25% (n = 59); p < 0.0001]. The prevalence of pre-ATS was instead higher in men than women [72%, (n = 156) vs. 51% (n = 121); p < 0.0001]. 3.4. Follow-up We evaluated (Table 4) the incidence of cardio- and cerebrovascular events in a five-year follow-up. Sudden death, CV death, non-fatal myocardial infarction, TIA (transient ischemic attack), non-fatal stroke and procedures of coronaric or peripheral revascularization with angioplasty or surgery were included as end-points. Overall events occurred in the 13% of subjects (n = 62); in more details, in the 38% of subjects at high risk and in the 13% and 6% of subjects at intermediate and low risk respectively (p < 0.003). Fatal (n = 56) and non-fatal (n = 6) events occurred in the 12% and 1% of subjects. The incidence of CV fatal events was higher in those with subclinical carotid lesions in all three groups. We reported a strong association between presence of carotid pre-ATS and rate of events.
**
CIMT: carotid intima-media thickness. ACP: asymptomatic carotid plaque.
Table 4 Prevalence of clinical events. Events (n)
Men (n = 215)
Women (n = 239)
Total
Sudden or cardiac death Non-fatal acute myocardial infarction Transient ischemic attack* Stroke Coronary revascularization Carotid revascularization Lower limb revascularization* Total events
4 6 1 3 11 3 8 36
2 3 3 6 7 3 2 26
6 9 4 9 18 6 10 62
*
The Progetto Cuore does not consider these events as main end-points.
In the group of subjects at GCVR <20%, total events occurred in the 8% of subjects with normal ultrasound findings, in the 13% (n = 14) with increased IMT and in the 15% (n = 23) with ACP (p < 0.012) (Fig. 1). Any “fatal” event occurred in subjects with normal findings, 2 CV deaths were registered in subjects with IMT and 2 in subjects with ACP. We evaluated the relationship between baseline variables and events. None of the RF was “alone” able to predict events. (Table 5). 4. Discussion The primary prevention of atherosclerotic events remains a serious public challenge. Scoring equation to stratify in healthy subjects the GCVR has been developed. Currently the GCVR can be estimated using “Charts of risk” or electronic calculators evaluating the main RF and aims to predict those at “increased risk”. Our research group recently investigated asymptomatic subjects at high risk, such as women in post-menopausal period [13], subjects with low HDL-C levels [15] or with metabolic syndrome [16] or subjects with a cluster of RF including age > 45 years and family history of CV diseases. We registered, after a five-year follow-up, a higher incidence of events in those subjects with baseline ultrasound evidences of carotid atherosclerosis. The relative risk increased in relation to the presence of IMT or ACP [13,15,16].
Table 2 Distribution of risk factors in both.
Mean age Family history of CV disease (%) Diabetes (%) Smoke (%) Hypertension (%) BMI (kg/m2 ) Obesity Glycaemia (mg/dL) Total cholesterol (mg/dL) HDL-cholesterol (mg/dL) LDL-cholesterol (mg/dL) Triglycerides (mg/dL)
Men 47%
Women 53%
p<
56 ± 9 58 24 30 58 28 ± 3 26 104 ± 21 220 ± 58 39 ± 9 157 ± 56 123 ± 65
57 ± 10 64 16 13 50 30 ± 5 33 100 ± 26 232 ± 68 47 ± 12 162 ± 65 115 ± 48
ns 0.0001 0.0001 0.0001 0.0001 ns 0.0001 ns ns 0.0001 ns ns
Fig. 1. Five-year incidence of CV events in subjects with and without carotid preclinical atherosclerosis.
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Table 5 Statistical analysis of the clinical and laboratory parameters evaluated for a predictive role in events. Baseline parameters
Statistical analysis Univariate analysis p<
Logistic regression OR (95% IC); p<
Male gender
0.05
Age
0.03
Diabetes mellitus
0.05
Smoke
0.01
Hypertension
0.02
Total cholesterol
0.05
2 or more risk factors*
0.005
1.1 (0.7–2.0); 0.47 1.1 (0.9–1.0); 0.278 1.2 (0.6–2.3); 0.466 0.9 (0.4–1.8); 0. 98 1.0 (0.7–2.1); 0.449 0.8 (0.5–1.5); 0.669 1.7(1.1–2.9); 0.025 2.7 (1.4–5.1); 0.0024
Presence of preclinical ATS (IMT and/or ACP) 0.0004
* 2 (or more) among the following RF: age >65, family history, hypertension, diabetes, smoke, hypercholesterolemia, low HDL-C values.
The joint ESH/ESC’s guidelines [14] suggested that it would be useful to look for evidences of preclinical organ damage in subjects with hypertension. Indeed, in prediciting the 10-year risk of total CV disease, the inclusion of the ultrasound study of cardiac or vascular involvement would change about the 50% of the hypertensive population at low-intermediate risk (with the traditional risk scoring) to a higher category of risk [17]. The research for preclinical organ damage aims at pointing out, from the same category, those subjects with a higher risk. The same guidelines also dedicated a specific section to the IMT measurement: it should be performed in subjects not only with newly diagnosis of hypertension but also with a history of antihypertensive therapy [17]. In this study, we showed that in managing asymptomatic subjects at “low-intermediate risk” the incorporation of indicators of pre-ATS could provide further information in improving their risk prediction. The carotid pre-ATS could be a marker of “additional” risk in order to better estimate the GCVR in this group of population that currently has poor probabilities to receive complete information and therapies for CV prevention. Our result shows that, the presence of carotid lesions increases the relative risk of CV events. Therefore, many subjects currently considered at intermediate risk present instead a higher GCVR and, as a consequence, could have benefits from more aggressive preventive treatments. By the way, it’s interesting to note that many subjects of our population were regularly in therapy for the correction of their RF (therapies for hypertension in the 58.5% of men and in the 50% of women, treatments for diabetes in the 15% of men and in the 9% of women). The low prognostic impact of the main RF may be due to their pharmacological correction.
5. Conclusions Ample evidences supported the role of carotid IMT in recognition of pre-ATS. An abnormal carotid IMT is a marker of multifocal ATS and a negative prognostic factor. Our study aimed at evaluating in subjects aged > 45 years and with a cluster of RF if the carotid pre-ATS can provide additional and independent information for a better GCVR stratification. The results seem to show that carotid preclinical atherosclerosis enhances the five-year evaluation of GCVR (normal 8%; IMT: 13%; ACP: 15%), with a significant predictive value. The incorporation of the ultrasound carotid study in the traditional systems of stratification could improve the CV prediction References [1] Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus media thickness of the arterial wall. A direct measurement with ultrasound imaging. Circulation 1986;74:1399–406. [2] Burke GL, Evans GW, Riley WA, et al. Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study. Stroke 1995;26:386–91. [3] Novo S, Pernice C, Barbagallo CM, et al. Advances in Vascular Pathology. In: Nicolaides AN, Novo S, editors. Influence of Risk Factors And Aging On Asymptomatic Carotid Lesions. Amsterdam: Elsevier Science, Excerpta Medica; 1997. p. 33–44. [4] Corrado E, Rizzo M, Tantillo R, et al. Markers of infection and inflammation influence the outcome of subjects with baseline asymptomatic carotid lesions in a five-year follow-up. Stroke 2006;37:482–6. [5] Romano G, Corrado E, Muratori I, et al. Carotid and peripheral atherosclerosis in subjects underwent to primary PCI and outcome associated with multifocal atherosclerosis. Int Angiol 2006;25:389–94. [6] Greenland P, Smith SC, Grundy SM. Improving coronary heart disease risk assessment in asymptomatic people. Role of traditional risk factors and noninvasive cardiovascular tests. Circulation 2001;104:1863–7. [7] Bard RL, Kalsi H, Rubenfire MD, Brook RD. Effect of carotid atherosclerosis screening on risk stratification during primary cardiovascular disease prevention. Am J Cardiol 2004;93:1030–2. [8] Greenland P, Abrams J, Aurigemma GP, et al. Prevention Conference V: Beyond secondary prevention. Identifying the high risk patient for primary prevention: non-invasive tests of atherosclerotic burden. Writing Group III. Circulation 2000;101:E16–22. [9] Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;115:459–67. [10] Giampaoli S, Palmieri L, Chiodini P, et al. La carta del rischio cardiovascolare globale. Italian Heart J 2004;5:177–85. [11] Menotti A, Giampaoli S, Verdecchia A et al. Il Progetto MONICA (Monitoraggio Malattie Cardiovascolari). Protocollo e manuale delle aree italiane. Rapporti ISTISAN, Roma, 1989; 89: 12. [12] American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997; 20: 1183–97. [13] Corrado E, Rizzo M, Muratori I, Coppola G, Novo S. Older age and markers of inflammation are strong predictors of clinical events in women with asymptomatic carotid lesions. Menopause 2008;12:240–7. [14] Mancia G, De Backer G, Dominiczak A, et al. Guideliness of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2007;28(12):1462–536. [15] Rizzo M, Corrado E, Coppola G, et al. Prediction of cardio- and cerebro-vascular events in subjects with subclinical atherosclerosis and low HDL-cholesterol. Atherosclerosis 2008;200, 389 95. [16] Novo G, Corrado E, Bellia A, et al. Markers of inflammation and prevalence of vascular disease in subjects with metabolic syndrome. Int Angiol 2007;26:312–7. [17] Cuspidi C, Ambrosioni E, Mancia G, et al. Role of echocardiography and carotid ultrasonography in stratifying risk in subjects with essential hypertension: the Assessment of Prognostic Risk Observational Survey. J Hypertens 2002;20:1307–14.
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Preclinical carotid atherosclerosis enhances the global cardiovascular risk and increases the rate of cerebro- and cardiovascular events in a five-year follow-up Salvatore Novo a,∗ , Patrizia Carità a , Egle Corrado a , Ida Muratori a , Claudio Pernice b , Rosalba Tantillo a , Giuseppina Novo a a Center for the Diagnosis of Preclinical and Multifocal Atherosclerosis and for Cardiovascular Prevention, Section of CardioAngiology, Department of Internal Medicine and Cardiovascular Diseases, University Hospital Paolo Giaccone, Palermo, Italy b Division of Geriatrics, Mazzara del Vallo Hospital, Italy
a r t i c l e
i n f o
Article history: Received 10 November 2009 Received in revised form 14 January 2010 Accepted 14 January 2010 Available online 25 January 2010 Keywords: GCVR Preclinical carotid atherosclerosis Primary prevention
a b s t r a c t Aim: To evaluate if the intima-media thickening (IMT) and asymptomatic carotid plaque (ACP), as expression of carotid preclinical atherosclerosis (pre-ATS), can provide further information on the global cardiovascular risk (GCVR). Methods: We studied 454 asymptomatic subjects, with a cluster of risk factors (RF), and evaluated the incidence of a first cardiovascular (CV) event in a five-year follow-up. The subjects at admission were subdivided in three groups of risk. Results: Events occurred in 38% of subjects at high risk, in 13% and 6% of subjects at intermediate and low risk (p < 0.003). Among evaluated parameters, carotid pre-ATS was a predictive marker of CV events (OR 2.7, 95% IC 1.4–5.1, p < 0.0024). In subjects with GCVR <20% the prevalence of events was 8% for normal carotid ultrasound findings, 13% for increased IMT and 15% for ACP. Conclusions: In primary prevention, the IMT measurement can give further information for a better stratification of GCVR. The pre-ATS of carotid arteries should be considered a strong predictor of future CV events and should suggest a more aggressive treatment of RF. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The intima-media thickness (IMT) is the distance (assessed by B-mode ultrasonography) between two vascular echogenic lines: the media-adventitia and the intima-media interface. Pignoli et al. demonstrated the correlation between this distance and the thickness of the arterial intima-media tunicae anatomo-pathologically measured [1]. In recent years, evidences supported the role of carotid IMT in recognition of the preclinical atherosclerosis (pre-ATS). The ARIC Study demonstrated that “traditional” and “nontraditional” cardiovascular (CV) risk factors (RF) correlates with increase in carotid IMT values [2]. In the GESCO-MURST-CIFTI-4 study we reported a significantly higher incidence of increased carotid IMT (32.5% vs. 14.7%), asymptomatic carotid plaques (ACP) (10.75% vs. 5.37%) and both lesions
∗ Corresponding author at: School of Cardiology, Master of Vascular Diseases, Master of Echocardiography, Center for the Diagnosis of Preclinical and Multifocal Atherosclerosis and for Cardiovascular Prevention, Section of CardioAngiology, Department of Internal Medicine and Cardiovascular Diseases, University Hospital “Paolo Giaccone”, of the University of Palermo Via del Vespro 139–90127 Palermo Italy. Tel.: +39 091 655 43 01; fax: +39 091 655.43.01. E-mail address: [email protected] (S. Novo). 0021-9150/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2010.01.019
together (47.2% vs. 16.2%) in subjects with one (or more than one) traditional RF than in subjects without RF [3]. Likewise, we recently demonstrated that pre-ATS is associated with “traditional” and some “emerging” RF [4]. There is evidence that an abnormal carotid IMT not only correlates with the presence of atherosclerotic lesions in other arteries (as marker of multifocal ATS) but it is also a negative prognostic factor [5]. The main effect of the carotid IMT evaluation would be that many subjects at intermediate global cardiovascular risk (GCVR) with the Framingham score would change into a higher class of risk [6]. Subjects with abnormal carotid IMT should be treated more aggressively than those with a normal thickness [7]. These evidences led the American Heart Association to state that “in estimating the cardiovascular risk of asymptomatic subjects aged >45 years, IMT measurement can provide additional information to the traditional RF” [8]. A recent meta-analysis [9], investigating the relationship between IMT and CV outcomes, registered an increased rate of myocardial infarction (10–15%) and stroke (13–18%) for every 0.1 mm increase in the IMT values. Therefore, the presence of carotid lesions, even if early and asymptomatic, may represent a powerful CV predictor. Currently, in Italy the algorithm arising from “Progetto Cuore” [10] can be considered the reference standard for the CV prediction.
288
S. Novo et al. / Atherosclerosis 211 (2010) 287–290
The “Istituto Superiore della Sanità” in the Progetto Cuore (whose recruitment phase started in 1998) analyzed prospective data coming from 12 Italian cohorts and developed a Chart of risk and an Individual risk score tailored for Italian population. The Chart is a simple paper-based graphical representation of various classes (I–VI) of absolute GCVR; it takes into consideration six RF [gender (man/woman), age, diabetes (yes/no), smoke (yes/no), systolic blood pressure and total cholesterol] and refers to SBP and TC as range of levels. The Individual score is a web-based electronic programme that, by using mathematical functions, provides a more precise GCVR in healthy subjects aged 35/69 years. This score evaluates two additional RF beyond the chart [HDL-cholesterol and antihypertensive drugs (yes/no)] and uses the precise levels (rather than “ranges” of levels) for cholesterolemia, age and systolic BP. The general population is then subdivided in three categories: at low (<3%), intermediate (≥3–19%) and high GCVR (≥20%) in 10 years. In primary prevention priority is focused on those at high risk. In this study we gave attention to subjects at low-intermediate risk (GCVR < 20%) who currently have poor probabilities to receive intensive treatments. The aim of our study was to determine the effects of including carotid IMT and ACP evaluation on the accuracy of CV prediction. Our intention was to investigate if a new model of risk stratification incorporating the IMT/ACP beyond the risk variables of the “Progetto Cuore” could more accurately predict the GCVR.
2. Methods As part of the Italian Research Project on the Cardiovascular Aging (MURST-GESCO-CIFTI-4) study, we examinated 454 asymptomatic subjects [215 men (M) and 239 women (W)] with mean age 57 ± 10 years. The 10-year mean incidence of CV disease predicted at baseline by the Progetto Cuore’s equation alone was compared to the occurrence of total CV events registered in five-year follow-up. The procedures were in agreement with the Helsinki Declaration of 1975 as revised in 1983 and were approved by the Ethic Council of our Department. The subjects were sampled from a population of 1100 subjects referring to our Center for a clinical evaluation. We excluded subjects with history of symptomatic peripheral artery disease, stable or unstable angina pectoris, previous myocardial infarction, procedures of revascularization with angioplasty or by-pass, procedures of endoarterectomy and cerebro-vascular events. We also excluded subjects younger than 45 years and older than 69 years. The adopted procedures for the sampling of population were in agreement with the manual of operations of the “Progetto MONICA” [11]. A total of 454 subjects were included. They had often (70%) a mean age >55 years. The higher prevalence of RF and GCVR in our population, than in the general population, may have been influenced by the “relative sampling”. At admission all subjects gave their informed consent and underwent medical examination, measurement of blood pressure (BP), anthropometric measurement, electrocardiogram and biochemistry tests. They also answered a questionnaire on personal and medical items. The family history was defined as the presence of CV diseases in first degree relatives earlier than 55 years for male and than 65 years for female. The BP was measured with a random-zero sphygmomanometer and was used the average of the measurements obtained in the two arms. Hypertension was considered as systolic or diastolic BP respectively ≥140 or ≥90 mm Hg or as the use of antihypertensive drugs. According to the American Diabetes Association’s guidelines, diabetes was considered as fast-
ing glucose concentrations higher than 126 mg/dL or as a therapy with oral hypoglycaemic agents or insulin [12]. The information about the smoking habit were taken from the questionnaire. The measurements of weight and height were performed using a statiometer on the wall and a balance on the floor. The “body mass index” (BMI = kg/m2 ) was calculated as the relation between weight and height. Obesity was defined as BMI ≥30 kg/m2 . A blood sample was drawn after 12 h overnight fast. Total cholesterol (TC), HDL-cholesterol (HDL-C) and TG (triglycerides) were quantified by enzymatic-colorimetric methods and the LDL-cholesterol was calculated with the Friedewald formula. The Hexokinase method was used for the glucose plasma concentration. 2.1. Evaluation of carotid IMT The measurement of the carotid IMT was performed with an Esaote Caris Plus machine and a linear probe of 7.5–10.0 MHz. As well as in other studies [1,4,13] both the arteries were studied. Using the dilatation of the bulb as anatomical reference, three segments were identified: (1) the distal 1.0 cm of common carotid proximal to the bifurcation, the carotid bifurcation itself, and the proximal 1.0 cm of the internal carotid artery. The mean value of IMT was an average of these six measurements. Values of carotid IMT ≥0.9 mm were considered abnormal and have been taken as a measure of increased risk. According to the joint European Society of Hypertension (ESH)/Europeans Society of Cardiology (ESC) guidelines [14] subjects were subdivided in three categories: “normal” [carotid IMT < 0.9 mm (n = 177)], “with increased IMT” [carotid IMT 0.9 mm and <1.5 mm (n = 164)] and “with asymptomatic carotid plaque (ACP)” [carotid IMT ≥1.5 mm (n = 113)]. 2.2. Stratification of the cardiovascular risk The 10-year individual GCVR was predicted at baseline by the electronic programme, available for free on the Progetto Cuore’s website (www. progettocuore.it). [10]. 2.3. Statistical analysis The statistical analysis was performed by StatView program. The differences between the various groups were evaluated with the Student’s unpaired t test. The prevalence of clinical variables was calculated and the differences between two groups were performed by the use of the chi-square test, or, if necessary, the chi-square test with Bonferroni correction. A value of p < 0.05 was considered as statistical significant. In a first step, a univariate analysis was performed. Second, the variables with a resulting p < 0.01 were selected to be tested using a multivariate analysis. In this model of multivariate analysis was used a stepwise logistic regression method. The variables with p < 0.05 and a predictive value (odds ratio) with a confidence interval of 95% were considered statistically significant. 3. Results 3.1. Prevalence of coronary risk factors The Table 1 reports the prevalence of RF in both men and women. A family history of CV disease was reported in 61% of subjects [(n = 279); 58% M vs. 64% W, p < 0. 0001]. The 21% was active smoker (30% M vs. 13% W, p < 0.0001). TC was 220 ± 58 mg/dL in men and 232 ± 68 mg/dL in women [p = not statistically significant (ns)]. The HDL-C was 39 ± 9 mg/dL in men and 47 ± 12 mg/dL in women (p < 0.0001). The LDL-C was 157 ± 56 mg/dL in men and 162 ± 65 mg/dL in women (p = ns). TG were 123 ± 65 mg/dL in men and 115 ± 48 mg/dL in women (p = ns). The fasting glucose plasma
S. Novo et al. / Atherosclerosis 211 (2010) 287–290
Table 3 Prevalence of preclinical atherosclerosis (IMT e ACP) in the three “category of risk”.
Table 1 Prevalence (%) of risk factors in the investigated population. RF
Men% (n = 215) Women% (n = 239)
289
0
1
2
3
4 (or more)
10 10
21 25
34 37
23 24
12 4
Category of risk:
Normal findings (p < 0.0001)
CIMT* (p: ns)
ACP** (<0.0001)
Low GCVR (<3%) Intermediate GCVR (≥3–19%) High GCVR (≥20%)
56% 23% 21%
33% 39% 28%
11% 38% 51%
*
concentration was 104 ± 21 mg/dL in men and 100 ± 26 mg/dL in women (p = ns). The incidence of diabetes was 21% in the whole population (24% in men vs. 16% in women with a difference statistically significant, p < 0.0001). A BP >140/90 mm Hg was observed in 53% of men and 21.7% of women. The 58.5% of men and 50% of women were regularly treated with antihypertensive drugs. The body weight ranged 82 ± 10 kg in men and 69 ± 12 kg in women. The BMI was 28.4 ± 3.7 kg/m2 in men and 30 ± 5 kg/m2 in women (p = ns). The prevalence of obesity (BMI > 30 kg/m2 ) was 26% in men and 33% in women (p < 0.0001) (Table 2). 3.2. Assessment of global cardiovascular risk The mean GCVR ranged 9.8 ± 7.7%. The population was organized in three groups: subjects at high [≥20% (n = 32)], at intermediate [≥3% and <20% (n = 321)] and at low [<3% (n = 101)] GCVR. 3.3. Evaluation of preclinical atherosclerosis We evaluated the ultrasound findings in the three groups. In subjects at high GCVR was shown a significant higher prevalence of increased IMT and/or ACP. (Table 3). The prevalence of normal ultrasound findings was higher in women than in men [49% (n = 118) vs. 25% (n = 59); p < 0.0001]. The prevalence of pre-ATS was instead higher in men than women [72%, (n = 156) vs. 51% (n = 121); p < 0.0001]. 3.4. Follow-up We evaluated (Table 4) the incidence of cardio- and cerebrovascular events in a five-year follow-up. Sudden death, CV death, non-fatal myocardial infarction, TIA (transient ischemic attack), non-fatal stroke and procedures of coronaric or peripheral revascularization with angioplasty or surgery were included as end-points. Overall events occurred in the 13% of subjects (n = 62); in more details, in the 38% of subjects at high risk and in the 13% and 6% of subjects at intermediate and low risk respectively (p < 0.003). Fatal (n = 56) and non-fatal (n = 6) events occurred in the 12% and 1% of subjects. The incidence of CV fatal events was higher in those with subclinical carotid lesions in all three groups. We reported a strong association between presence of carotid pre-ATS and rate of events.
**
CIMT: carotid intima-media thickness. ACP: asymptomatic carotid plaque.
Table 4 Prevalence of clinical events. Events (n)
Men (n = 215)
Women (n = 239)
Total
Sudden or cardiac death Non-fatal acute myocardial infarction Transient ischemic attack* Stroke Coronary revascularization Carotid revascularization Lower limb revascularization* Total events
4 6 1 3 11 3 8 36
2 3 3 6 7 3 2 26
6 9 4 9 18 6 10 62
*
The Progetto Cuore does not consider these events as main end-points.
In the group of subjects at GCVR <20%, total events occurred in the 8% of subjects with normal ultrasound findings, in the 13% (n = 14) with increased IMT and in the 15% (n = 23) with ACP (p < 0.012) (Fig. 1). Any “fatal” event occurred in subjects with normal findings, 2 CV deaths were registered in subjects with IMT and 2 in subjects with ACP. We evaluated the relationship between baseline variables and events. None of the RF was “alone” able to predict events. (Table 5). 4. Discussion The primary prevention of atherosclerotic events remains a serious public challenge. Scoring equation to stratify in healthy subjects the GCVR has been developed. Currently the GCVR can be estimated using “Charts of risk” or electronic calculators evaluating the main RF and aims to predict those at “increased risk”. Our research group recently investigated asymptomatic subjects at high risk, such as women in post-menopausal period [13], subjects with low HDL-C levels [15] or with metabolic syndrome [16] or subjects with a cluster of RF including age > 45 years and family history of CV diseases. We registered, after a five-year follow-up, a higher incidence of events in those subjects with baseline ultrasound evidences of carotid atherosclerosis. The relative risk increased in relation to the presence of IMT or ACP [13,15,16].
Table 2 Distribution of risk factors in both.
Mean age Family history of CV disease (%) Diabetes (%) Smoke (%) Hypertension (%) BMI (kg/m2 ) Obesity Glycaemia (mg/dL) Total cholesterol (mg/dL) HDL-cholesterol (mg/dL) LDL-cholesterol (mg/dL) Triglycerides (mg/dL)
Men 47%
Women 53%
p<
56 ± 9 58 24 30 58 28 ± 3 26 104 ± 21 220 ± 58 39 ± 9 157 ± 56 123 ± 65
57 ± 10 64 16 13 50 30 ± 5 33 100 ± 26 232 ± 68 47 ± 12 162 ± 65 115 ± 48
ns 0.0001 0.0001 0.0001 0.0001 ns 0.0001 ns ns 0.0001 ns ns
Fig. 1. Five-year incidence of CV events in subjects with and without carotid preclinical atherosclerosis.
290
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Table 5 Statistical analysis of the clinical and laboratory parameters evaluated for a predictive role in events. Baseline parameters
Statistical analysis Univariate analysis p<
Logistic regression OR (95% IC); p<
Male gender
0.05
Age
0.03
Diabetes mellitus
0.05
Smoke
0.01
Hypertension
0.02
Total cholesterol
0.05
2 or more risk factors*
0.005
1.1 (0.7–2.0); 0.47 1.1 (0.9–1.0); 0.278 1.2 (0.6–2.3); 0.466 0.9 (0.4–1.8); 0. 98 1.0 (0.7–2.1); 0.449 0.8 (0.5–1.5); 0.669 1.7(1.1–2.9); 0.025 2.7 (1.4–5.1); 0.0024
Presence of preclinical ATS (IMT and/or ACP) 0.0004
* 2 (or more) among the following RF: age >65, family history, hypertension, diabetes, smoke, hypercholesterolemia, low HDL-C values.
The joint ESH/ESC’s guidelines [14] suggested that it would be useful to look for evidences of preclinical organ damage in subjects with hypertension. Indeed, in prediciting the 10-year risk of total CV disease, the inclusion of the ultrasound study of cardiac or vascular involvement would change about the 50% of the hypertensive population at low-intermediate risk (with the traditional risk scoring) to a higher category of risk [17]. The research for preclinical organ damage aims at pointing out, from the same category, those subjects with a higher risk. The same guidelines also dedicated a specific section to the IMT measurement: it should be performed in subjects not only with newly diagnosis of hypertension but also with a history of antihypertensive therapy [17]. In this study, we showed that in managing asymptomatic subjects at “low-intermediate risk” the incorporation of indicators of pre-ATS could provide further information in improving their risk prediction. The carotid pre-ATS could be a marker of “additional” risk in order to better estimate the GCVR in this group of population that currently has poor probabilities to receive complete information and therapies for CV prevention. Our result shows that, the presence of carotid lesions increases the relative risk of CV events. Therefore, many subjects currently considered at intermediate risk present instead a higher GCVR and, as a consequence, could have benefits from more aggressive preventive treatments. By the way, it’s interesting to note that many subjects of our population were regularly in therapy for the correction of their RF (therapies for hypertension in the 58.5% of men and in the 50% of women, treatments for diabetes in the 15% of men and in the 9% of women). The low prognostic impact of the main RF may be due to their pharmacological correction.
5. Conclusions Ample evidences supported the role of carotid IMT in recognition of pre-ATS. An abnormal carotid IMT is a marker of multifocal ATS and a negative prognostic factor. Our study aimed at evaluating in subjects aged > 45 years and with a cluster of RF if the carotid pre-ATS can provide additional and independent information for a better GCVR stratification. The results seem to show that carotid preclinical atherosclerosis enhances the five-year evaluation of GCVR (normal 8%; IMT: 13%; ACP: 15%), with a significant predictive value. The incorporation of the ultrasound carotid study in the traditional systems of stratification could improve the CV prediction References [1] Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus media thickness of the arterial wall. A direct measurement with ultrasound imaging. Circulation 1986;74:1399–406. [2] Burke GL, Evans GW, Riley WA, et al. Arterial wall thickness is associated with prevalent cardiovascular disease in middle-aged adults. The Atherosclerosis Risk in Communities (ARIC) Study. Stroke 1995;26:386–91. [3] Novo S, Pernice C, Barbagallo CM, et al. Advances in Vascular Pathology. In: Nicolaides AN, Novo S, editors. Influence of Risk Factors And Aging On Asymptomatic Carotid Lesions. Amsterdam: Elsevier Science, Excerpta Medica; 1997. p. 33–44. [4] Corrado E, Rizzo M, Tantillo R, et al. Markers of infection and inflammation influence the outcome of subjects with baseline asymptomatic carotid lesions in a five-year follow-up. Stroke 2006;37:482–6. [5] Romano G, Corrado E, Muratori I, et al. Carotid and peripheral atherosclerosis in subjects underwent to primary PCI and outcome associated with multifocal atherosclerosis. Int Angiol 2006;25:389–94. [6] Greenland P, Smith SC, Grundy SM. Improving coronary heart disease risk assessment in asymptomatic people. Role of traditional risk factors and noninvasive cardiovascular tests. Circulation 2001;104:1863–7. [7] Bard RL, Kalsi H, Rubenfire MD, Brook RD. Effect of carotid atherosclerosis screening on risk stratification during primary cardiovascular disease prevention. Am J Cardiol 2004;93:1030–2. [8] Greenland P, Abrams J, Aurigemma GP, et al. Prevention Conference V: Beyond secondary prevention. Identifying the high risk patient for primary prevention: non-invasive tests of atherosclerotic burden. Writing Group III. Circulation 2000;101:E16–22. [9] Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;115:459–67. [10] Giampaoli S, Palmieri L, Chiodini P, et al. La carta del rischio cardiovascolare globale. Italian Heart J 2004;5:177–85. [11] Menotti A, Giampaoli S, Verdecchia A et al. Il Progetto MONICA (Monitoraggio Malattie Cardiovascolari). Protocollo e manuale delle aree italiane. Rapporti ISTISAN, Roma, 1989; 89: 12. [12] American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997; 20: 1183–97. [13] Corrado E, Rizzo M, Muratori I, Coppola G, Novo S. Older age and markers of inflammation are strong predictors of clinical events in women with asymptomatic carotid lesions. Menopause 2008;12:240–7. [14] Mancia G, De Backer G, Dominiczak A, et al. Guideliness of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2007;28(12):1462–536. [15] Rizzo M, Corrado E, Coppola G, et al. Prediction of cardio- and cerebro-vascular events in subjects with subclinical atherosclerosis and low HDL-cholesterol. Atherosclerosis 2008;200, 389 95. [16] Novo G, Corrado E, Bellia A, et al. Markers of inflammation and prevalence of vascular disease in subjects with metabolic syndrome. Int Angiol 2007;26:312–7. [17] Cuspidi C, Ambrosioni E, Mancia G, et al. Role of echocardiography and carotid ultrasonography in stratifying risk in subjects with essential hypertension: the Assessment of Prognostic Risk Observational Survey. J Hypertens 2002;20:1307–14.