Authors: Novo S, Pace G, Toia P, Carità P, Corrado E, Novo G
Combining risk calculators such as SCORE (systematic coronary risk evaluation), recommended by the new 2012 European Guidelines on cardiovascular disease prevention in clinical practice with the study of arterial function offers added prediction of cardiovascular risk, which our study on arterial thickness and and a meta-analysis on arterial lesions have helped to support.
Background
New methods for prevention and treatment of cardiovascular diseases have improved by many measures: onset of clinical events is delayed, immediate outcome of disease is better and life expectancy has increased. Still, cardiovascular disease remains the leading cause of mortality, morbidity and deteriorated quality of life, worldwide (1). In Europe alone, over 4 million deaths are due to cardiac and vascular diseases, of which, atherosclerosis, deemed, the "silent killer" is a leading cause.Indeed, atherosclerosis is a slow, progressive process involving the intima and media tunicae of large and medium arteries resulting in a chronic disease that causes formation of focal lesions (plaques) containing lipids and fibrous tissue (2). When local occlusive thrombus overly atherosclerotic plaque, this process leads to acute cardiovascular events (3).
Subclinical atherosclerosis, or preclinical atherosclerosis, refers to the early stage of the process of atherosclerosis where, within the vascular walls, "something is starting to change": mounting evidence suggests that subclinical atherosclerosis confers an increased risk of cardiovascular disease. Thus, calculation of global cardiovascular risk is a strategy to:
- Uncover patients at risk of atherosclerosis and therefore at risk of developing cardio and cerebrovascular events: In preclinical atherosclerosis vascular damage is minimal and can usually be corrected.
- Stratify patients: In subjects without previous cardiovascular disease, reveal the development of events within the next ten years as likely to occur and that will help to decide on any corrective measures to put in place.
New 2012 ESC guidelines on cardiovascular disease prevention in clinical practice (4) recommend using risk charts such as the Systematic Coronary Risk Evaluation Project (SCORE) which offer a total individualised risk estimation using multiple traditional risk factors in adults without evidence of cardiovascular disease.
Carotid intima media thickness is a valuable tool in recognition of pre-atherosclerosis, and a recent meta-analysis confirms that early atherosclerotic lesions of carotid arteries are an independent marker of cerebro and cardiovascular events. Thus, combining SCORE with study of arterial function offers added prediction of risk to help distinguish individuals with high and low absolute risk, improve prevention efforts and help to decide on any investigational measures.
Carotid intima media thickness is a valuable tool in recognition of pre-atherosclerosis, and a recent meta-analysis confirms that early atherosclerotic lesions of carotid arteries are an independent marker of cerebro and cardiovascular events. Thus, combining SCORE with study of arterial function offers added prediction of risk to help distinguish individuals with high and low absolute risk, improve prevention efforts and help to decide on any investigational measures.
I - Risk
A) Traditional and emerging factors
As in other diseases, risk factors for atherosclerosis are conditions in healthy and asymptomatic subjects that are related statistically to the beginning of its pathological process. They include: dyslipidemia, diabetes mellitus, hypertension, smoking, overweight or obesity, inactivity or sedentary lifestyle, stress, alcoholism and low consumption of fruits and vegetables (5). These are the modifiable risk factors of atherosclerosis, meaning, the conditions potentially susceptible to correction. Traditional risk factors are modifiable, or not through healthy lifestyle and diet and/or pharmacological treatment. Non-modifiable risk factors are those that cannot be corrected, they are: older age, male gender, family history of cardiovascular disease and genetic predisposition. Added to these traditional risk factors are "emerging" risk factors of atherosclerosis, considered modifiable to a certain extent, such as high levels of triglycerides, and C-reactive proteins which are the conditions that have been identified more recently as casually related to atherosclerosis.
2) Global cardiovascular risk
Global cardiovascular risk is a new approach that has a two-fold aim. It seeks to establish 1) prognosis and 2) each risk factor's role in the atherosclerotic process. The weight attributed to each risk factor is estimated using complex mathematical algorithms built with data provided by large observational epidemiological studies.According to the 2010 American College of Cardiology Foundation, American Heart Association guidelines, global cardiovascular risk scores involving multiple (traditional) risk factors should be used in all asymptomatic adults without a clinical history of cardiovascular disease but with an increased cardiovascular risk to 1) assess the risk, 2) stratify incidence of probable events in the following ten years, and, at the least, 3) to target preventive interventions.
Until recently, global risk was, together with other various indices, a class IIa of evidence, (i.e evidence obtained from at least one other type of well-designed quasi-experimental study or obtained from well-designed controlled trials without randomisation). Other examples of such indices are the ankle-brachial index: measuring the ankle-brachial index in asymptomatic subjects and in those with low-density lipoprotein or calcium or C-reactive protein levels: among patients whose cholesterol is below 130 mg/dl and without risk factors, calcium or C-reactive protein levels to select those to be initiated with statin therapy (6)
However, the new 2012 European Society of Cardiology Guidelines on cardiovascular disease prevention in clinical practice, state that total risk estimation using multiple risk factors (such as SCORE) is recommended for asymptomatic adults without evidence of CVD and has a level IC evidence,- i.e. data derived from a single randomised clinical trial or large non-randomised studies or evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective.
3) Charts
Global cardiovascular risk can be approximately estimated by using risk charts - standardised tables or graphs - or more accurately, through electronic calculators, which deliver an individual score. Resulting risk is absolute - the probable incidence of a major cardiovascular event, i.e. sudden death, non-fatal MI and stroke in the following 10 years - or relative - the ratio between the investigated subject's risk divided by the average subject's risk, among subjects with the same characteristics. (7-9).Limitation of risk charts include:
- Risk factors: only a few risk factors are included such that some may be omitted.
- Groups: considering individuals exclusively from a certain age group or gender.
- Follow-up: models of logistic regression restricted to definite follow-up periods (i.e. 10 years) with no difference made between events that occur at relative timepoints, for example at 1, 5 or 10 years.
- Assessment: charts are prospectively assessed only in a few subjects, as opposed to a broader scale of patients.
In 2003, the European Societies of Cardiology, Hypertension and Atherosclerosis jointly published guidelines for primary prevention of cardiovascular disease which gave way to the European Chart of Cardiovascular risk to evaluate the risk aimed European cohorts of subjects specifically. The algorithmic functions were built using data from longitudinal studies that investigated its populations and cultural habits, with differences made between Northern and Southern European countries on on hand or calibrated to specific countries. The guidelines were subsequently updated, by a Task Force in 2007, and lately, in 2012, where namely, a revised approach of risk in the young yielded revised risk charts.
In Italy, the Institute of Health through the “Progetto Cuore” aimed to better estimate the global cardiovasc
ular risk specific to Italian subjects: specific charts for Italy were built ad hoc from analysing Italian habits and lifestyles. With data from Italian longitudinal studies, conducted between the mid-80s and mid-90s “Progetto Cuore” built a database of the main risk factors. The aims of the project were to: estimate the impact of cardiovascular diseases in its general population through indicators such as prevalence, attack, incidence and mortality rates; evaluate the distribution of cardiovascular risk factors in representative samples of the Italian population and evaluate cardiovascular risk in the Italian population (15). Progetto Cuore investigated various cohorts, made up of both males and females from various Italian regions and reported total and specific mortality, fatal and non-fatal CV events - MI, stroke, coronary death, sudden death and revascularisation interventions for each. Later, Pende A. et al. analysed 84 Italian Caucasian subjects: 50 males and 34 females affected by elevated blood pressure and/or dyslipidemia, but never treated for these reasons. Included for study, was an integrated measure of both carotid wall thickness and presence of plaque the Carotid score. Carotid score giving 1 point (presence of plaque), 0.5 point (presence of increased intima-media thickness) and 0 points (absence of lesions): the final score was the sum of the possible lesions in 10 sites (3 at common carotid artery and at the bifurcation, 1 at internal carotid artery, and 1 at external carotid artery on both sides). A significant associationbetween certain parameters of early cardiovascular damage, of which the Carotid score, and the Progetto Cuore score was demonstrated in both sexes, thus demonstrating the validity of Projecto Cuore.
A meta-analysis of 8 population studies analysed the association between carotid intima media thickness and cerebro and cardiovascular events in a total of 37,197 subjects with a mean follow-up of 5.5 years. It showed that an increase in thickness of 0.1 mm was associated with a 15% enhanced risk of for acute myocardial infarction and an 18% enhanced risk or stroke.
2) Subclinical atherosclerosis
On our end, we examined 454 asymptomatic subjects (215 males and 239 females), mean age 57 ± 10 years with a cluster of risk factors, over a five-year follow-up period evaluating the incidence of cardiovascular events. It resulted that events occurred in 38% of subjects at high risk, in 13% and 6% of subjects at intermediate and low risk (p < 0.003). Carotid pre-atherosclerosis was among the evaluated parameters, a predictive marker of cardiovascular events (OR 2.7, 95% IC 1.4–5.1, p < 0.0024). In subjects with global cardiovascular risk < 20% according to the charts of “Italian Progetto Cuore” for subjects with normal carotid ultrasound finding at baseline the prevalence of events was 8%, 13% for subjects with increased IMT and 15% for subjects with ACP (including two deaths). We concluded that carotid intima media thickness is a valuable tool in recognition of pre-atherosclerosis, and our results are in line with a recent meta-analysis confirming that early atherosclerotic lesions of carotid arteries are an independent marker of cerebro and cardiovascular events (17, 18).
Moreover, the Heart Attack Prevention and Education (SHAPE) guidelines recommend noninvasive screening in all asymptomatic men 45-75 years of age and asymptomatic women 55-75 years of age (except those defined as at very low risk) in view of detecting and treating those with subclinical atherosclerosis (19).
3) Improved evaluation of risk
In the Atherosclerosis Risk In Communities study, Nambi et al. found that intima-media thickening and asymptomatic carotid plaque presence improved prediction of coronary heart disease risk. Adding this parameter to the risk prediction model of Framingham, reclassified over 10% of individuals into the higher risk category beyond traditional risk factors.
The study is especially significant in that investigators put forward that small, nonstenotic carotid plaque might be a different phenotype than atherosclerosis, which would carry an important contribution to vascular risk beyond carotid intima media thickening. Plaque presence was defined if two of the following three criteria were met: carotid intima media thickening of 1.5 mm, abnormal wall shape and abnormal wall texture. Thus, investigators concluded that adding plaque and carotid intima media thickening to traditional risk factors improves risk prediction beyond the Framingham chart (20).
Regarding subclinical organ damage, the study of Sehestedt, analysed 1,968 subjects without cardiovascular disease and not receiving treatment. It showed that, beyond Systemic Coronary Risk Evaluation (SCORE), the estimate of subclinical organ damage predicts cardiovascular death, and the combination of both subclinical organ damage and SCORE may improve risk prediction. Risk of cardio Progetto Cuore vascular death was, independently of SCORE, associated with atherosclerotic plaques in the carotid arteries [hazard ratio 2.5 (1.6-4.0)].
Moreover analysing subjects with a SCORE between 1 and 5% (moderate risk), together with the evaluation of subclinical atherosclerosis, increased test sensitivity from 72 to 89% (P= 0.006), but reduced specificity from 75 to 57% (P< 0.002) and positive predictive value from 11 to 8% (P= 0.07) (21).
4) Avoidance of misclassification
Identification of preclinical alterations in arterial function and structure, such as carotid intima-media thickness, stiffness or wave reflection, may refine cardiovascular risk stratification and decrease the chances of misclassification of cardiovascular risk. They are relatively expensive and noninvasive tests, performing by arterial ultrasonography and tonometry, useful to supplement - not to replace - the standard risk assessment algorithms, hence to identify candidates for aggressive therapy, especially in the intermediate-risk group (22,23).
In our experience, which we covered before in a previous edition of the e-journal of Cardiology Practice, the incidence of CV events, in a ten year follow-up, is enhanced in patients with subclinical-ATS, including an increase of 56% and 7% rates (respectively non-fatal and fatal events) in that people considered as low-intermediate risk according to the “Italian Progetto Cuore” Risk Chart (24). Increased IMT or asymptomatic carotid plaque predicts CV events improving the risk stratification of asymptomatic patients aged greater than 45 years, with a cluster of risk factors (4). Carotid intima-media thickness is increasingly used as a surrogate marker for atherosclerosis.
As shown in the study of Roksana et al, assessing subclinical atherosclerosis (especially trough intima media thickness) in multiple arterial sites may yield a better estimate of disease risk than Framingham risk score alone. Its use relies on its ability to predict future clinical cardiovascular end points, allowing appropriate early management in those patients with subclinical atherosclerosis (25).
The evidence for arterial stiffness, assessed as carotid distensibility or aortic pulse wave velocity, as an indicator for risk of cardiovascular disease, is restricted to subjects with either hypertension or end-stage renal disease or based on small studies in renal transplant patients and elderly.
ConclusionII - Carotid intima-media thickness
According to several prospective studies, analysis of arterial function and structure provides added prognostic information compared to conventional risk factors alone. It allows:- Screening for subclinical disease
- Distinguishing those with high and those with low absolute risk of cardiovascular disease
- Implementing efforts for prevention prior to a devastating cardiovascular event
- Investigating possible reasons for increased arterial thickening, such as an occult underlying insulin-resistant condition or residual lipid risk markers.
1) Screening in low and intermediate risk individuals
Screening should be carried out especially in low-risk individuals with a family history of premature cardiovascular disease or those with any of the National Cholesterol Education Program risk factors which are : current cigarette smoking, hypertension - systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg and/or pharmacological treatment -, HDL cholesterol level <1 .04=".04" age="age" and="and" any="any" attack="attack" br="br" cardiovascular="cardiovascular" disease="disease" family="family" first-degree="first-degree" heart="heart" history="history" in="in" l="l" men="men" mmol="mmol" nbsp="nbsp" of="of" premature="premature" relative="relative" women.="women." years="years">Measured by B-mode ultrasound, in large-scale population studies carotid intima media thickness is a relatively simple and inexpensive noninvasive technique which can be performed repeatedly without adverse effects on patients. It is associated with CVD and is an independent predictor of stroke and myocardial infarction. In asymptomatic adults at intermediate risk, it is an especially valuable indicator of subclinical atherosclerosis and hence, of cardiovascular risk (16), providing a graded measure of vascular damage. Technical approach and operator training, as well experience performing the test, must be carefully followed to achieve high quality results.A meta-analysis of 8 population studies analysed the association between carotid intima media thickness and cerebro and cardiovascular events in a total of 37,197 subjects with a mean follow-up of 5.5 years. It showed that an increase in thickness of 0.1 mm was associated with a 15% enhanced risk of for acute myocardial infarction and an 18% enhanced risk or stroke.
2) Subclinical atherosclerosis
On our end, we examined 454 asymptomatic subjects (215 males and 239 females), mean age 57 ± 10 years with a cluster of risk factors, over a five-year follow-up period evaluating the incidence of cardiovascular events. It resulted that events occurred in 38% of subjects at high risk, in 13% and 6% of subjects at intermediate and low risk (p < 0.003). Carotid pre-atherosclerosis was among the evaluated parameters, a predictive marker of cardiovascular events (OR 2.7, 95% IC 1.4–5.1, p < 0.0024). In subjects with global cardiovascular risk < 20% according to the charts of “Italian Progetto Cuore” for subjects with normal carotid ultrasound finding at baseline the prevalence of events was 8%, 13% for subjects with increased IMT and 15% for subjects with ACP (including two deaths). We concluded that carotid intima media thickness is a valuable tool in recognition of pre-atherosclerosis, and our results are in line with a recent meta-analysis confirming that early atherosclerotic lesions of carotid arteries are an independent marker of cerebro and cardiovascular events (17, 18).
Moreover, the Heart Attack Prevention and Education (SHAPE) guidelines recommend noninvasive screening in all asymptomatic men 45-75 years of age and asymptomatic women 55-75 years of age (except those defined as at very low risk) in view of detecting and treating those with subclinical atherosclerosis (19).
3) Improved evaluation of risk
In the Atherosclerosis Risk In Communities study, Nambi et al. found that intima-media thickening and asymptomatic carotid plaque presence improved prediction of coronary heart disease risk. Adding this parameter to the risk prediction model of Framingham, reclassified over 10% of individuals into the higher risk category beyond traditional risk factors.
The study is especially significant in that investigators put forward that small, nonstenotic carotid plaque might be a different phenotype than atherosclerosis, which would carry an important contribution to vascular risk beyond carotid intima media thickening. Plaque presence was defined if two of the following three criteria were met: carotid intima media thickening of 1.5 mm, abnormal wall shape and abnormal wall texture. Thus, investigators concluded that adding plaque and carotid intima media thickening to traditional risk factors improves risk prediction beyond the Framingham chart (20).
Regarding subclinical organ damage, the study of Sehestedt, analysed 1,968 subjects without cardiovascular disease and not receiving treatment. It showed that, beyond Systemic Coronary Risk Evaluation (SCORE), the estimate of subclinical organ damage predicts cardiovascular death, and the combination of both subclinical organ damage and SCORE may improve risk prediction. Risk of cardio Progetto Cuore vascular death was, independently of SCORE, associated with atherosclerotic plaques in the carotid arteries [hazard ratio 2.5 (1.6-4.0)].
Moreover analysing subjects with a SCORE between 1 and 5% (moderate risk), together with the evaluation of subclinical atherosclerosis, increased test sensitivity from 72 to 89% (P= 0.006), but reduced specificity from 75 to 57% (P< 0.002) and positive predictive value from 11 to 8% (P= 0.07) (21).
4) Avoidance of misclassification
Identification of preclinical alterations in arterial function and structure, such as carotid intima-media thickness, stiffness or wave reflection, may refine cardiovascular risk stratification and decrease the chances of misclassification of cardiovascular risk. They are relatively expensive and noninvasive tests, performing by arterial ultrasonography and tonometry, useful to supplement - not to replace - the standard risk assessment algorithms, hence to identify candidates for aggressive therapy, especially in the intermediate-risk group (22,23).
In our experience, which we covered before in a previous edition of the e-journal of Cardiology Practice, the incidence of CV events, in a ten year follow-up, is enhanced in patients with subclinical-ATS, including an increase of 56% and 7% rates (respectively non-fatal and fatal events) in that people considered as low-intermediate risk according to the “Italian Progetto Cuore” Risk Chart (24). Increased IMT or asymptomatic carotid plaque predicts CV events improving the risk stratification of asymptomatic patients aged greater than 45 years, with a cluster of risk factors (4). Carotid intima-media thickness is increasingly used as a surrogate marker for atherosclerosis.
As shown in the study of Roksana et al, assessing subclinical atherosclerosis (especially trough intima media thickness) in multiple arterial sites may yield a better estimate of disease risk than Framingham risk score alone. Its use relies on its ability to predict future clinical cardiovascular end points, allowing appropriate early management in those patients with subclinical atherosclerosis (25).
The evidence for arterial stiffness, assessed as carotid distensibility or aortic pulse wave velocity, as an indicator for risk of cardiovascular disease, is restricted to subjects with either hypertension or end-stage renal disease or based on small studies in renal transplant patients and elderly.
The new ESC 2012 guidelines on cardiovascular disease prevention in clinical practice recommend using SCORE in adults without evidence of cardiovascular disease. On the other hand, our experience shows that carotid intima media thickness is a valuable tool in recognition of pre-atherosclerosis, and a recent meta-analysis confirms that early atherosclerotic lesions of carotid arteries are an independent marker of cerebro and cardiovascular events. Thus, combining SCORE with study of arterial function can help to distinguish individuals with high and low absolute risk, improve prevention efforts and help decide on investigational measures.
Notes to editor
Novo S. S, MD, FESC, FACC
Via Del Vespro, 129
90139 – Palermo - Italy
Phone: - fax +39-091-6554301
Chair of Cardiovascular Diseases, Centre for the Early Diagnosis of Preclinical and Multifocal Atherosclerosis and for Secondary Prevention, University of Palermo, Division of Cardiology, University Hospital "Paolo Giaccone", Department of Internal Medicine, Cardiovascular Disease, Palermo, Italy.
Authors' disclosures: None declared.
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Via Del Vespro, 129
90139 – Palermo - Italy
Phone: - fax +39-091-6554301
Chair of Cardiovascular Diseases, Centre for the Early Diagnosis of Preclinical and Multifocal Atherosclerosis and for Secondary Prevention, University of Palermo, Division of Cardiology, University Hospital "Paolo Giaccone", Department of Internal Medicine, Cardiovascular Disease, Palermo, Italy.
Authors' disclosures: None declared.
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The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
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