Preclinical Atherosclerosis, Global Cardiovascular Risk and Cardiovascular Events

The ATS is a slow-progressive process involving arteries with large and medium diameter. It seems to result both from an immune and inflammatory reaction and several studies have shown the endothelial reaction to various injuries as the main mechanism involved in the development of the focal atherosclerotic wall lesions. These lesions initially do not obstruct the blood flow. However, thrombotic events can occur and cause ischemia of the region supplied by the injured artery. The vulnerable plaque (eccentric, non stenotic, with a thin fibrous cap and big lipid core, rich of inflammatory and smooth muscle cells) is a particular type of lesion which can easily lead to complications.

In healthy subjects, the Risk Factors (RF) are conditions linked casually to atherosclerosis. They are related in a logarithmic way to the occurrence of CVE. The atherosclerotic RF can be divided into traditional and emerging. The traditional and “modifiable” RF include: dislipidemia, diabetes mellitus, hypertension, smoking, obesity, sedentary, stress, alcohol and diet. Diabetes mellitus is currently considered a “CHD equivalent”. The emerging RF (studied only for a few years) include: Metabolic Syndrome (MS) (that is characterized by the presence of various metabolic disorders at the same time in the same subject), biohumoral markers of systemic inflammation, microalbuminuria and LP (a).

The GCVR aims to stratify subjects without past history of CVD for their risk to develop CVE in the following ten years. The GCVR can be assessed through "risk charts” or electronic calculators that provide an individual score. The results indicate an absolute risk or a relative risk. Various countries use different systems in order to respect the different populations of reference. In particular, the Framingham equations have effectiveness in calculating CV risk in middle-aged Americans or Afro-American subjects. The "European charts" is a specific method for subjects belonging to "high risk" (the Northern Europe) or “low risk" (Mediterranean) European countries. Finally, the “Progetto Cuore” aims at estimating the risk in the Italian population. The Progetto Cuore’s equation is available for free on the website (www.cuore.iss.it.).

The “preclinical ATS” indicates that "something is beginning to change" in the vascular wall. Currently, signs of preclinical ATS can be investigated through non-invasive approaches. The US evaluation of the Intima-Media Thickness (IMT) and / or asymptomatic plaque of carotid arteries is a high sensitive and specific method. The IMT is not only the expression of ageing but also a specific sign of widespread atherosclerosis. The ankle blood pressure should be slightly higher than the upper arm pressure (Ankle-Brachial Index > 1). Measurement of an ABI < 0.9 indicates restricted flow in the ilio-femoro-popliteal arteries. Currently, the "Endothelial Dysfunction") is evaluable by the flow-mediated dilatation (FMD) in the brachial artery. An impaired FMD is related to some traditional RF. There is a significant negative correlation between FMD and IMT. Finally, the coronary calcium (independent predictor of CV death) can be estimated by computerized tomography and expressed as Coronary Calcium Score. The lipidic plaques can be distinguished from the fibrous ones and from calcium amounts through the levels of attenuation (Hounsfield units). The research of coronary lesions in patients with asymptomatic carotid plaque and in obese children with a cluster of RF could be a promising application in order to perform aggressive prevention.

The clinical symptoms of ATS are the “late” results of a slowly-progressing inflammatory process, that has began a long time before. "Preclinical ATS" is an early stage of this process and is characterized by minimal damage, potentially susceptible to correction. Furthermore, pre-clinical ATS (assessed by using multiple described approaches) involves a multifocal disease. For example, IMT is associated to the detection of endothelial dysfunction, to the coronary and peripheral atherosclerotic manifestations. The early carotid involvement (in spite of the slow development of lesions in other peripheral arteries) is probably due to the characteristics of the carotid flow. A reduced ABI is independently related to the presence of increased IMT and multifocal ATS. Then, it is a marker of both coronary and carotid ATS. The reduction of FMD is an “index of extension” of CAD (i.e.: one, two or three vessel involved) at the coronary angiography. A FMD lower or equal to 4.5% is a valid marker of CAD.

The risk of CV events in patients with preclinical ATS is higher than in the controls. The carotid asymptomatic lesions predict both cerebral and extra-cerebral events and are thus an expression of multifocal ATS. Furthermore, specific carotid levels (ACC, ACI and bifurcation) correlate to the risk of myocardial infarction and stroke. The coexistence of IMT both in the external and internal carotid arteries triggers the prevalence of CV events even higher. Last but not the least, IMT seems to predict the worse prognosis in patients with acute coronary syndrome undergoing percutaneous procedures. An ABI <0.9 and a reduced FMD are independently related in the long term with a higher risk of major CVE (myocardial infarction, unstable angina, sudden cardiac death, and revascularization). The calcium score provides an accurate estimation of ATS and is currently considered as a powerful predictor of major CVE and death in asymptomatic patients.

Several clinical trials have focused on the effectiveness of antihypertensive drugs on carotid lesions and CV outcome. In the last years, it has also been shown that statins induce a reduction in the progression rate of carotid IMT and the stabilization of the atherosclerotic plaques.

According to the Progetto Cuore, subjects with at least 2 or 3 RF are currently considered at intermediate risk. Recently, we demonstrated that the instrumental evidence of preclinical ATS (IMT/ACP) puts these patients into a higher category of risk. The consequent implications in clinical practice are very important: more aggressive pharmacological strategies could be useful, even if this recommendation is not yet unanimous. The inclusion of carotid IMT assessment in the "Progetto Cuore's" cards could provide further information for a better determination of GCVR and for a more aggressive pharmacological primary prevention.