The endothelium, which was initially considered to be a semipermeable barrier separating lumen from vessel wall, is now recognised as a complex endocrine organ responsible for a variety of physiological processes vital for vascular homeostasis. These include the regulation of vascular tone, luminal diameter and blood flow; haemostasis and thrombolysis; platelet and leucocyte vessel-wall interactions; the regulation of vascular permeability; and tissue growth and remodelling. The endothelium modulates arterial stiffness, which precedes overt atherosclerosis and is an independent predictor of cardiovascular events. Unsurprisingly, dysfunction of the endothelium may be considered as an early and potentially reversible step in the process of atherogenesis and numerous methods have been developed to assess endothelial status and large artery stiffness. Atherosclerosis is a top priority for translational research in cardiovascular disease.1 There is no doubt that it is too late when you encounter a young patient with acute myocardial infarction (MI) and hurry to restore perfusion of an occluded coronary artery, when this particular individual has been prone to MI for all of their life. There may even be a way to identify predisposed individuals from birth. Even though, there is a continuous debate how early is early and how late is late, it may seem logical that early diagnosing disease will yield better outcome, but on the other hand, some disease detected by sensitive technologies might actually represent subclinical disease that, if left alone, would never become clinically manifest.2
Traditional Risk Factors – Is it Too Late?
The use of traditional factors for risk stratification is well established and those patients identified are at an increased risk. The long-term follow-up of the Framingham Offspring cohort3 allowed the investigators to derive 30-year risk equations for hard and overall cardiovascular event. However, depending on this traditional risk factors, to assess individual risk might be late and, moreover, there are difficulties to control it. The European action on secondary prevention through intervention to reduce events (EUROASPIRE) survey carried out in eight European countries4 reports that despite improvements in lipid control, no significant changes in blood pressure levels or smoking were obtained and increases in obesity and diabetes were seen in patients with established coronary heart disease.
On the other hand, traditional risk factors for the development of atherosclerotic disease, which accelerate the process over time and increase the risk of having a heart attack, stroke or other arterial vascular problem are not present in 50 % of those who develop atherosclerotic problems.5 These individuals appear to have other genetic disorders or abnormal blood clotting, chronic inflammation of arteries or as yet unknown problems.
Genotyping – Is it Too Early?
The field of genetics is rapidly progressing and might play a role in detecting individuals who are susceptible to heart problems before they are even born. Genome-wide association (GWA) studies have been successful in identifying robust associations of single nucleotide polymorphisms (SNP) for coronary artery disease (CAD).6 A total of eleven chromosomal regions have been replicated and associated with MI and CAD and their functional significance has been studied. Furthermore, it has been shown that some of the manifestations of CAD, e.g. calcification, ectasia and main-stem stenosis, are more strongly inherited than others. The results of recent GWA studies for MI and CAD will aid in individual risk prediction for MI by molecular biological means. Important alleles include PCSK9, proprotein convertase subtilisin/kexin type 9, apolipoprotein E (Apo E), low-density lipoprotein receptors (LDLR) and Apo B.7
Non-invasive Imaging – Which Modality and Who Should be Screened?
Cardiovascular imaging is a source of continuous innovative evolution; the mostly used technologies are carotid ultrasound, coronary computed tomography (CT) and magnetic resonance (MR). Ultrasound methodology includes flow-mediated dilatation of the brachial artery, assessment of coronary flow reserve, carotid intima media thickness, pulse wave analysis, pulse wave velocity and stiffness assessment.
Carotid Intima Media Thickness
The carotid intima media thickness (CIMT) is related to age and sex and is increased in subjects with main risk factors.8–11 In addition, it is a reliable indicator of the presence and extent of atherosclerosis in the coronary arteries12 and a common surrogate end-point in epidemiological studies13 and clinical trials14 and is a predictor of clinical cardiovascular events.15
The important question to answer is ‘who should be screened?’ CIMT is a well-established subclinical marker of atherosclerosis. It indicates early manifestation of atherosclerosis in the carotid arteries;16 the use of CIMT might be helpful in specific group of children at risk, for example obese and diabetic children. In the Bogalusa Heart Study, childhood body mass index (BMI) was one of the strongest predictors of increased adult CIMT,17 also in children with diabetes in whom endothelial function is impaired within the first decade of diabetes onset and precedes an increase in CIMT. The relative timing of these events is important in the evaluation of strategies to prevent progression of atherosclerosis and other vascular complications in this patient population.18 CIMT determines subclinical atherosclerosis, particularly in combination with dyslipidaemia and obesity.19 In the Young Finns study, BMI and systolic blood pressure (SBP) predicted increased adult CIMT.20 Moreover, higher CIMT was also found in adolescents who had been exposed to parental smoking during foetal life.21 Metabolic syndrome in the young is a real public health problem and denotes subclinical atherosclerosis and the more its components the more increased cardiovascular risk. CIMT can be used as a surrogate end-point as well to monitor response to intervention in those young adults.22 In addition to those with metabolic syndrome, CIMT is also helpful in patients with established cardiovascular disease. Data from a large randomised trial of antihypertensive therapy replicated the independent association of CIMT with cardiovascular prognosis.23 CIMT was also associated with asymptomatic myocardial ischaemia24 and can be used to monitor changes in risk factors induced by therapeutic interventions.25 In acute coronary syndromes (ACS), multiple complex coronary plaques are associated with positive carotid remodelling, suggesting that plaque vulnerability may be a systemic phenomenon.26 Greater CIMT is also associated with alterations of myocardial strain parameters reflecting reduced systolic and diastolic myocardial function. These observations indicate a relationship between subclinical atherosclerosis and incipient myocardial dysfunction in a population free of clinical heart disease.27
Arterial Wall Stiffness
Stiffening is a marker of progressive reduction of elasticity and hence of initial vascular sclerosis. It can be detected in various vessels as carotid and femoral arteries, the abdominal aorta and brachial and radial arteries, principally by means of echotracking techniques using a radiofrequency signal which determines the local systo-diastolic distension of the vessel in percentage of its diastolic lumen diameter.28–32 An index of wall stiffness can be calculated by the arterial pressure taken at the artery investigated (or approximating the brachial pressure) and artery distension. Arterial stiffness increase is associated with main risk factors and has a predictive value for coronary artery disease.28,32
This represents the capacity of one artery such as brachial or radial to dilate in response to transient increase in the endothelial nitric oxide (NO) secretion induced by hyperthermia reactive to three to five minutes ischaemia (or by ischaemia itself) provoked by a cuff inflating at an excluded distal circulation of the limb.33,34 The normal value of endothelium-dependent vasodilation induced by hyperthermia in the brachial artery approximates 10% of the baseline diameter of the artery.33 A decreased vasodilation of 3% or less was observed in the presence of cardiovascular risk factors as smoking, hypercholesterolaemia and family history of premature cardiovascular disease. Such impaired high-flow vasodilatation is pathological and reflects the endothelial dysfunction.33 This endothelial dysfunction occurs in the absence of definite atheromatous lesion and it is likely associated to intima-media thickening.
Coronary Computed Tomography
Coronary calcium can be detected using a CT scan. The sum of calcium deposit area within the whole coronary tree is transformed into a global score of calcium in the coronary tree.34 A calcium score of ≤0 can be subdivided into three grades: 0–9 is a low score, 10–99 is a moderate score and ≥100 is an elevated score.34 However, coronary calcium score must be interpreted according to the age and gender of the subject because they strongly influence the coronary calcium process.
A report from the Multi-Ethnic study of atherosclerosis (MESA) indicates that absolute calcium scores (CAC) predict CAD better than age-, gender- or ethnicity-adjusted percentiles.35 Another study including over 44,000 asymptomatic subjects confirmed the excellent prognosis associated with absent CAC, with a 10-year mortality of 1 %, whereas minimal CAC (Agatston score 1–10) doubles the risk.36 In another step forward, coronary CT angiography delineates that two features of plaque vulnerability (positive remodelling and low attenuation) were strongly associated with same-site development of acute coronary syndromes during the next two years suggestive of a lipid-rich core).37 CAC in association with CIMT are the tests for which insurance reimbursement is requested by a state bill introduced recently in Texas Legislature. This bill was called “a first legislative effort in the US” to encourage the identification of ”apparently healthy individuals who are at risk of a near-future heart attack.”38
Magnetic resonance imaging
Although its use is limited by availability and cost, MR imaging (MRI) for carotids can add valuable data for risk assessment of atherosclerosis. In a study of asymptomatic men with moderate carotid stenosis, intraplaque haemorrhage predicted cerebrovascular events within two years.39 Using molecular imaging, ultra-small super paramagnetic iron oxide particles, an MRI contrast agent that is taken up by macrophages, were used to successfully track reductions in human carotid inflammation with high-dose statin therapy.40 With regards to cardiac MRI, it is feasible to quantify coronary wall remodelling as well as plaque characterisation in asymptomatic subjects.41,42
Functional and Serum biomarkers – Is There a Role?
Functional markers of subclinical disease showed additive predictive value over conventional risk factors. Endothelial dysfunction as determined by abnormal flow-mediated vasodilatation was associated with five-year incident cardiovascular events in apparently healthy participants.43 The use of high-sensitivity CRP for prognostic stratification in apparently healthy subjects was reported to increase net re-classification improvement, particularly if restricted to the intermediate-risk subjects.44 Lipoprotein (a) is another useful marker. In a meta-analysis of 36 prospective studies, lipoprotein (a) was found to have modest independent associations with MI and stroke.45
The Current Way
Currently, preclinical diagnosis of atherosclerosis is based on the traditional risk factors; in addition, imaging markers such as carotid IMT, arterial stiffness, endothelium-dependent vasomotion, left ventricular hypertrophy and CAC are increasingly used to diagnose preclinical atherosclerosis and to assess the risk profile allowing to monitor the progression/regression of the arterial disease.46,47 Since atherosclerosis reflects the integrated effects of multiple risk factors over time, its preclinical diagnosis, pointed out by the detection and measurement of imaging markers, should include a global evaluation of the association of these markers with traditional, new and emerging ones included within the social, psychological and economical context. Biomarkers currently used in selected populations, while genotyping is a part of the future.
The Way Forward
The future may be achieved recovering the new way to look at the person (subject or preclinical patient). Currently, what seems to be really important in the preclinical diagnosis and risk assessment of atherosclerosis is the measurements of multiple factors involved and their interrelation and the integrated effects they have on subjects/patients. In the future we should look at problem paying more attention to the person (subject or preclinical patient) Hippocrates wrote that “it could not be possible to know medical practice for those who do not know who and what is man; this is what must be understood by those who shall take correctly care of men; if common man’s comprehension will be missed… also reality will be missed.” This means that a new and promising method is to look holistically at risk factors within the subject as a person, and that it is necessary to take into account that all acquired risk factors are a consequence of a bad relationship that people have, either with themselves (inside) or with the others (outside). Investigators and clinical practitioners pay great attention to the disease; a large literature exists considering cardiovascular risk factors and their potential effect on disease onset. However, at the same time, literature is stingy in considering, for example, that smoke, stress, obesity and alimentary disorders are not the cause of something but rather the effect of an incorrect and inappropriate interpretation and management of relationships that persons establish with those. This means that a different point of view should be experimented orienting the attention towards behaviour and relation and striving to understand what there is behind them that pushes to unsuitable and deleterious lifestyle. A statement from the World Health Organization (WHO) asserted that: “it is impossible to change social values and health behaviour without creating the necessary atmosphere and condition.”48 Social and economic problems provide the field, the person’s perception of themselves regarding their internal world and wishing to be themselves balanced against the external world are the main topics to be stressed in the incoming future.