Prof. Giovanni Amoroso
Prof. Salvatore Novo,
The presence of preclinical atherosclerosis increases global cardiovascular risk - preclinical atherosclerosis can be considered an emerging determinant in assessing global cardiovascular risk. Independent markers of multifocal atherosclerosis -directly associated with an increased risk of CV events- are intima-media thickness, reduced ankle-brachial pressure index and impaired flow-mediated dilatation. Risk factors for atherosclerosis alone aren’t accurate enough in predicting cardiovascular disease in adults with no history of atherosclerosis disease. Multidetector computed tomography may be a useful non-invasive technique to detect silent coronary artery disease in patients with peripheral preclinical atherosclerosis.
Single or multiple risk factors increase Cardiovascular risk (CV risk) in an exponential manner. The presence of one or more risk factors for atherosclerosis (ATS) is associated with the development of cardiovascular disease (CVD). A specific condition is defined as risk factor when it is possible, on the basis of a strong statistical association, to relate it to the incidence of new cases of disease and if it is clinically demonstrated that new disease cases can be reduced by correcting the same risk factor. In the same subject, single or multiple RF increase CV risk in an exponential manner rather than in additive one.
Beyond traditional risk factors such as age, gender, family history of cardiovascular disease (CVD), hypertension, hypercholesterolemia, diabetes and smoking, other important conditions are emerging risk factors such as fibrinogen, hs-CRP and other markers of inflammation, the metabolic syndrome (MS), hyperhomocysteinemia, a burden of previous infections, and instrumental markers of preclinical atherosclerosis (ATS).
By using data of large population studies the concept of “Global Cardiovascular Risk” (GCVR) was defined and it was rapidly applied in clinical practice with the elaboration of risk charts, through the development of algorithms for primary prevention of CVD based on the simultaneous analysis of a few main risk factors (age, gender, diabetes, smoking, systolic blood pressure values and total cholesterol). The algorithm’s reliability derives from equations and mathematic models opportunely elaborated for it. GCVR calculation is a simple and objective method for identifying patients with CV risk <20% in 10 years for which diet and life style changes are indicated and those with CV >20% in 10 years for which a pharmacological treatment is mandatory.
Today, numerous risk charts are used in various countries: they are different for both specific types of risk factors or the number of risk factors considered and type of population on which statistic analysis are made, so that it becomes possible and easy to realise an extremely specific GCVR stratification capable to consider different cultures and lifestyles (Framingham, Euroscore, and “Progetto Cuore” chart in Italy). A few years ago the NECP-ATP III Guidelines introduced “high CV risk” individuals, referring to subjects with evidence of coronary heart disease or subjects with the presence of “equivalent status” (Diabetes, Atherosclerotic Obstructive Peripheral Arteriopathy, Carotid Stenosis >50% or Stroke or Abdominal Aortic Aneurism history) (1).
The ATS process can be defined as a progressive structural remodelling of the vessel wall towards definitive plaque formation and possible related complications. According to new data, the disease begins as an endothelium functional disorder capable of determining a loss of vascular homeostasis and related functional reserve that initially can become clinically evident only in conditions in which it needs to increase tissue metabolic requirements (Effort Angina, Transient Ischemic Attack, Intermittent Claudication) while, after more time, they can become symptomatic at rest because even basal perfusion is impaired (Acute Coronary Syndrome, Stroke, Critical Leg Ischemia, CV death).
Functional disorder and initial structural wall changes characterise a precocious disease phase and identify a “Preclinical ATS” condition that, for it's own definition, doesn’t slow a corresponding cluster of clinical sings. The identification of specific markers related to this precocious phase of ATS is very useful to introduce a new strategy of primary prevention in clinical practice. Preclinical markers of ATS are related to the presence of risk factors for ATS, to multifocal ATS and to the severity of coronary stenosis evaluated both by IVUS (p < 0.0001) or angiographically (p= 0.03) (2).
Today, Preclinical ATS identification is possible through the use of different methods: carotid ultrasound study which identifies specific wall transformations such as increased Intima-Media Thickness (IMT) or Asymptomatic Carotid Plaque (ACP), Ankle Brachial pressure Index (ABI) measurement, evaluation of endothelial dysfunction by Flow-Mediated Vasodilation (FMD) and Multidetector Computed Tomography of coronary arteries (MDCT).
Definition Echocolordoppler duplex scanning evaluation of the carotid wall is a non invasive, low cost, and highly reproducible procedure even if, like most parts of the echographic analysis, it is strongly operator dependent. The Doppler mode permits the visualisation of vessels and an evaluation of flow disturbance that helps to quantify stenosis severity. It measures the IMT and size and number of atheromatous plaques.
Interpreting readings According to the ESC/ESH 2007 Guidelines on the Management of Arterial Hypertension, normal IMT is the distance between the media-adventitia interface and the intima-media interface; - it is normal if it is :
Increased IMT (or ACP) is related to the presence ATS risk factors, to their number, intensity or duration (3, 4); it is statistically associated to endothelial dysfunction (5).
IMT is a very useful tool There is a remarkable correlation between every Framingham risk score and IMT (p=0,005) (6). Recent studies demonstrated an existing relation between IMT increase and coronary stenosis (p=0,001) asserting that it can be used as a highly safe marker of multifocal ATS and advanced disease (7). Also demonstrated, is the usefulness of carotid ultrasound examination to improve the ability of stress testing to predict coronary artery disease: in doubt test patients, IMT or ACP increase probability to estimate stenosis higher than 50 per cent (8). IMT is a potent and independent predictor of future cerebro- and cardiovascular events (Myocardial Infarction and Stroke), as several studies demonstrated (the Finnish, the ARIC, the Rotterdam, the CHS study and so on) (9-12). IMT seems to be associated with a two or more fold risk of acute coronary events. Evidence of ACP is associated to a 4 fold increased risk while hemodynamically significant stenosis increase coronary risk about 6 times compared to one of an individual without atherosclerotic vascular involvement. The ACSRS Study clearly showed the relation between asymptomatic ACP stenosis and cerebral events providing new risk stratification approach (13).
Normally, ankle systolic arterial pressure (posterior or anterior tibial artery) is just a little higher than brachial pressure measurements so that their ratio always is > 1.0. This parameter is called the Ankle-Brachial pressure Index (ABI) and can reflect altered pressure values if the arterial system is impaired from ATS; when it is reduced < 0.90 in literature it is accepted that a patient is suffering from asymptomatic PAD (14). It is a very simple and non expensive parameter and can also be evaluated by general practitioners. Several population trials evidence an important correlation between decreased ABI, carotid or coronary ATS and future cardiac or cerebrovascular events as demonstrated in different studies (HOPE, Edinburgh, CAPRIE and getABI studies) (15-18). In this latter German study involving 6880 patients with a mean age of 72 years, with a follow-up of five years, normal subjects showed a mortality rate of 9.5%, patients with ABI < 0.9, a mortality of 19.2% and patients with symptomatic PAD, a mortality rate of 24.1% (18).
Impaired endothelial function is the first step in ATS. Acetylcholine (Ach) is an important vasodilatation stimulus, when vascular homeostasis is preserved, since it causes endothelial release of Nitric Oxide (NO), which is a strong dilatation agent. When Ach infusion determines vasoconstriction, it means that endothelial dysfunction is present. Recently, a new, non-invasive technique was introduced, to evaluate brachial artery flow-mediated dilatation (FMD). The evaluation through a US assessment of brachial artery in basal condition and after 5 minutes of occlusion (250 mm Hg) determined a reactive hyperaemia and therefore, FMD. A low FMD is a marker of multifocal ATS and of the extension of the disease. Indeed, this is demonstrated by the fact that a progressive FMD reduction occurs when the number of coronary arteries involved and CV events increase (19, 20).
Today CV stratification methods can use also Coronary Multidetector Computed Tomography (MDCT). Coronary Computed Tomography offers possibility to study the morphology of coronary vessels, including both lumen and wall characteristics (21-23). This technique is useful not only for the non invasive control of patients underwent PTCA or coronary by pass but also for the demonstration of asymptomatic coronary artery disease (CAD) in patients with preclinical ATS and stress test not conclusive (stress testing, echostress, perfusional SPECT stress myocardial scintigraphy). In fact, a finding of not significant coronary lesions may be useful for a more aggressive correction of CV RF, using also statins with a target LDL-C of < 100 (or 70) mg and so to avoid future AMI and Stroke.
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.
1. Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R, Dallongeville J, De Backer G, Ebrahim S, Gjelsvik B, Herrmann-Lingen C, Hoes A, Humphries S, Knapton M, Perk J, Priori SG, Pyorala K, Reiner Z, Ruilope L, Sans-Menendez S, Scholte Op Reimer W, Weissberg P, Wood D, Yarnell J, Zamorano JL; Other experts who contributed to parts of the guidelines:, Walma E, Fitzgerald T, Cooney MT, Dudina A; European Society of Cardiology (ESC) Committee for Practice Guidelines (CPG):, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Funck-Brentano C, Filippatos G, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL; Document reviewers:, Hellemans I, Altiner A, Bonora E, Durrington PN, Fagard R, Giampaoli S, Hemingway H, Hakansson J, Kjeldsen SE, Larsen ML, Mancia G, Manolis AJ, Orth-Gomer K, Pedersen T, Rayner M, Ryden L, Sammut M, Schneiderman N, Stalenhoef AF, Tokgözoglu L, Wiklund O, Zampelas A. European guidelines on cardiovascular disease prevention in clinical practice: executive summary of the Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (Constituted by representatives of nine societies and by invited experts). Eur Heart J. 2007; 28: 2375-414. 2. Amato M, Montorsi P, Rafani A, Oldani E, Galli S, Ravagnani PM, Tremoli E and Baldassarre D. Carotid intima-media thickness by B-mode ultrasound as surrogate of coronary atherosclerosis: correlation with quantitative coronary angiography and coronary intravascular ultrasound findings. European Heart Journal 2007 28(17):2094-2101. 3. Novo S, Pernice C, Barbagallo C M, Tantillo R, Caruso R, Longo B. Influence of risk factors and aging on asymptomatic carotid lesions. In: Advances in Vascular Pathology 1997, A. N. Nicolaides and S. Novo (Eds.), Elsevier Science, Excerpta Medica, Amsterdam, 1997, pp. 33-44. 4. Corrado E, Bonura F., Tantillo R, Muratori I, Rizzo M, Vitale G, Mansueto S, Novo S. Markers of infection and inflammation influence the outcome of patients with baseline asymptomatic carotid lesions in a 5 years follow-up. Stroke 2006; 37: 482-6. 5. Corrado E, Muratori I, Tantillo R, Contorno F, Coppola G, Strano A, Novo S. Relationship between endothelial dysfunction, intima media thickness and cardiovascular risk factors in asymptomatic subjects. Int Angiol. 2005; 24:52-8. 6. Touboul PJ, Vicaut E, Labreuche J, Belliard JP, Cohen S, Kownator S, Portal JJ, Pithois-Merli I, Amarenco P and PARC study participating physicians. Correlation between the Framingham risk score and intima media thickness: the Paroi Artérielle et Risque Cardio-vasculaire (PARC) study. Atherosclerosis 2007; 192:363-9. 7. Kablak-Ziembicka A. Relationship between carotid intima-media thickness, atherosclerosis risk factors and angiography findings in patients with coronary artery disease. Acta Cardiol. 2002; 57: 40-1. 8. Kanwar M, Rosman HS et al. Usefulness of Carotid ultrasound to improve the ability of stress testing to predict coronary artery disease. Am J Cardiol 2007; 99: 1196-200. 9. Salonen JT. Ultrasonographically assessed carotid morphology and the risk of coronary heart disease. Arterioscl Thromb 1991; 11: 1245-49. 10. Chambless LE. Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol 2000; 151: 478-87. 11. Bots ML. Tissue plasminogen activator and risk of myocardial infarction. The Rotterdam Study. Circulation 1997; 96: 1432-37. 12. O’Leary DH. Carotid artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. NEJM 1999; 340: 14-22. 13. Nicolaides A. N., Kakkos S. K., Griffin M., Sabetai M., Dhanjil S., Tegos T., Thomas D. J., Giannoukas A., Geroulakos G., Georgiou N., Francis S., Ioannidou E., Dorè C. J. for the Asymptomatic Carotid Stenosis and Risk of Stroke (ACSRS) Study Group (Novo S. et al.). Severity of asymptomatic carotid stenosis and risk of ipsilateral hemispheric ischemic events: results from the ACSRS Study. Eur J Vasc Endovasc Surg 2005; 30: 275-284. 14. Hirsh AT, Hiatt WR et al., PARTNERS Study - Peripheral Arterial Disease Detection, Awareness, and Treatment in Primary Care. JAMA 2001; 286: 1317-24. 15. Ostergren JB, Sleight P, Dagenais G et al. Impact of ramipril in patients with evidence of clinical or subclinical peripheral arterial disease. Eur Heart J. 2004; 25: 17-24. 16. Dormandy JA, Creager MA. Ankle: arm blood pressure index as a predictor of atherothrombotic events: evidence from CAPRIE (Abstract). Cerebrovasc Dis 1999; 9 (Suppl 1): 1-128. 17. Fowkes FG, Housley E, Cawood EH, Macintyre CC, Ruckley CV, Prescott RJ. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol. 1991; 20: 384-92. 18. Diehm C, Lange S, Darius H, Pittrow D, von Stritzky B, Tepohl G, Haberl RL, Allenberg JR, Dasch B, Trampisch HJ. Association of low ankle brachial index with high mortality in primary care. Eur Heart J. 2006; 27: 1743-9. 19. Corrado E, Rizzo M, Muratori I, Carella M, Coppola G, Novo S. Endothelial dysfunction and carotid lesions are strong predictors of clinical events in patients with early stages of atherosclerosis: a 24 months follow-up study. Coronary Heart Disease, in press. 20. Landmesser U, Hornig B, Drexler H. Endothelium Function: A Critical Determinant in Atherosclerosis. Circulation. 2004; 109 (suppl. II): II-27-II-33. 21. Runza G, Rizzo M, Evola S, Alaimo V, Novo G, Corrado E, Evola G, Palazzolo G, Triolo OF, Gennaro F, Hoffmann E, Midiri M, Novo S. Forty-slice multidetector computed tomography for non-invasive diagnostic approach to coronary artery disease. Ital Cardiol 2007; 8: 508-18. 22. Novo G, Runza G, Evola S, Triolo OF, Alaimo V, Rizzo M, La Fata A, Palazzolo G, Sutera F, Andolina G, Hoffmann E, Novo S, Midiri M. Usefulness of coronary angiography performed by multidetector computed tomography (MDTC) to control aorto-coronary by-pass. GIC 2007, in press 23. Dewey M, Hamm B. CT Coronary Angiography: Examination Technique, Clinical Results, and Outlook on Future Developments]. Rofo 2007; 179: 246-60.
Novo S, Amoroso G, Novo G Chair of Cardiovascular Disease, post-graduate School of Cardiology, II Level Master of Vascular Disease and Division of Cardiology, University Hospital “P. Giaccone” of the University of Palermo – Italy Email: firstname.lastname@example.org
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