Detailed clinical history is essential. Information regarding diet, exercise, previous cardiac events, smoking, marital status, stress, sleep apnea and general complaints are decisive. In a multinational study [4] of 14,000 patients with suspected of CAD subjected to coronary computed tomographic angiography, typical angina was associated with highest prevalence of ≥50 % stenosis, compared to other categories, but the prevalence was lower than predicted by previous guidelines. The highest prevalence were in older male patients with typical angina.

Family history of premature heart disease among sibilings is an independent RF. The risk of CHD in siblings of victims of premature CHD is approximately 50 % higher for men and less for women [5]. In comparison with a population without family history, the risk of dying from CHD is 5.2 times higher compared to those with positive family history.

In the General Cardiovascular Risk Profile (GCRP) of the MESA study a CAC > 300 was considered high risk [6]. In that study Scheuner et al demonstrated that when family history was added to GCRP it permitted reclassification into low, intermediate and high risk of having CAC >300. Furthermore, in a case–control study of MI patients without established CAD, a detailed family history predicted primary ventricular fibrillation (VF); 43.1 % had histories of parents with familial sudden death versus 25.1 % of controls [7].

A recent review analyzed health-behavior changes when a strong CAD family history was present. That information, by itself, was not sufficient to promote personal health-related changes [8]. In contrast, 99 % of the individuals diagnosed with Familial Hypercholesteromia by DNA testing adhered to the proposed treatment [9]. Hence, perception of cardiovascular risk by single polymorphism was deemed more reliable to those individuals.

Hypertension is one of the major modifiable RF for CVD. In the Prospective Studies Trialists’ Collaboration [10] an increment of 20 mmHg in SBP or 10 mmHg in DBP, in middle-aged and elderly persons, increased by twofold the risk of CHD and stroke mortality [10]. Children with prehypertension associated to overweight, obesity and positive family history had increased risk by about twofold 11]. In the CARDIA study [12], FRS predicted hypertension risk in young individuals. Adiposity measures and ethnicity were related in the prediction of hypertension risk observed in the TOPS study [11]. Although African-Americans showed no influence of adiposity in their hypertension risk, among Caucasian greater adiposity in the neck and waist led to increased risk in 30 % to 56 %, respectively. Even in lean or overweighted elderly, increased abdominal adiposity was strongly associated to higher hypertension risk when compared with control without central obesity [13].

In the Strong Heart Study [14], in American Indians, the positive association among age, obesity and ethnicity to hypertension development was confirmed. In that study, microalbuminuria and macroalbuminuria elevated the risk to hypertension in 3.47 and 1.72 times, respectively; therefore albuminuria was considered a relevant risk factor for hypertension.

A meta-analysis of observational studies involving more than 1 million individuals without prior histories of stroke or heart disease carried out by the Prospective Studies Trialists’ Collaboration [10] demonstrated that death from CAD and stroke increases continuously and linearly from SBP levels as low as 115 mmHg systolic and 75 mmHg DBP.

Metabolic Syndrome (MS) consists in the presence of 3 of 5 factors: abdominal obesity, elevated triglyceride, reduced HDL-c, elevated blood pressure, elevated plasma fasting glucose or diabetes [15]. Patients with MS are twice as likely to develop CVD in the next 5–10 years compared with no MS. Type 2 diabetes increases risk by about fivefold [16].

Lipids-high LDL and triglycerides and low HDL are traditional RF [17]. We also demonstrated that an elevated triglyderides/HDL ratio is associated with premature CAD [17]. However, 15–20 % of patients with acute cardiac events had no major RFs. Hence, more than 20 new biomarkers have been proposed. Among those, inflammatory markers such as high-sensitivity C-Reactive Protein (hsCRP), have been especially considered in acute and chronic situations as well. The role of hsCRP was emphasized in The JUPITER study [18] which included individuals with low to normal LDL-C who were at increased CV risk as identified by elevated hsCRP above 2 mg/L and who did not require statin treatment based on current guidelines. In the group treated with Rosuvastatin, 20 mg/day, 44 % reduction in the primary endpoint of major cardiovascular events and a 20 % in total mortality in the statins group versus placebo were noted (p < 0.00001).

Yet, hsCRP has not been adopted uniformly in guidelines. That is due to the fact that its power to predict absolute risk is low and it is a nonspecific marker, being extremely high in other systemic infections or vessel injuries due to trauma.

Increments in several cytokines plasma concentrations, such as Interleukin-6 (IL-6) have been correlated with plaque instabilization [19]. The TNF and CD40/ families, are linked to immunemodulation and trombogenicity. Although their participation in plaque instability is indisputable, lack of specificity makes them inappropriate for routine use in clinical practice. The same occurs with endothelial markers, the family of ICAM (inter-cellular adhesion molecule) and VCAM (vascular cell adhesion molecule), E-selectin, PAI-I (plasminogen activator inhibitor) and others [20].

Results of the SIESTA study [21] suggest that the association of NT-proBNP and fibrinogen could be a marker to predict acute events. Fibrinogen besides hsCRP, higher plasma PAI-1 and serum aldosterone had also a strong correlation in MS development [15].

Another extensively studied biomarker is Liprotein-associated phospholipase A2 (Lp-PLA) [2], a proinflammatory enzyme that degrades phospholipids into low density liprotein cholesterol (LDL-C). The WOSCOPS [22] and ARIC [23] studies demonstrated an association of Lp-PLA2 and CHD. Recently, 66 healthy individuals and 111 patients with stable angina and at least one vessel with >50 % stenosis were classified according to the number of affected vessels: no disease, 1, 2, or 3 vessels disease. Except for lower age in the control group, smoking, hypertension and diabetes were similar in all participants. Mieloperoxidase, hsCRP and Lp-PLA2 also were analyzed. Lp-PLA 2 was elevated in all individuals and positively correlated with RF but not with the number of vessels disease; hsCRP was increased in all coronary patients, independently of RF or the affected vessels. There was no significance difference in mieloperoxidase between the groups [20]. Oxidation biomarkers [24] such as oxidized phospholipids in plasma also have been shown to correlate with risk of peripheral arterial disease.

Genetic biomarkers are of great interest. Atherosclerosis is a typical polygenic disease. Indeed CAD is determined by multiple genes, each one with modest influence. The first genetic variant for CAD, 9p21, was identified in 2007. Since then the CARDIoGRAMplusCAD Consortium [25] confirmed the association of 36 genetic variants with CAD in sample size of 190,000 participants, in independent populations. Most of the SNPs (single nucleotide polymorphisms) mediate their risk independent of conventional RF. Yet 10 of the variants act through cholesterol, hypertension and ABO. Furthermore, most SNPs signaling risk variant are found in non-coding protein regions. Despite considerable efforts, genetic prediction remains elusive, and have not yet been incorporated in the guidelines. Emotional and social RFs are also recognized. CAD has been related to five specific psychological factors: anxiety, depression, character traits and personality, social isolation and chronic life stress [26]. For instance, different forms of stresses may affect the cardiovascular system through direct stimulation of neuroendocrine pathways or indirectly by unhealthy behaviors: diet, smoking, lack of exercise, and excessive drinking (Fig. 2). In the Whitehall II Study [26] work stress was associated with poor diet (eating less fruits and vegetables), less physical activity, metabolic syndrome, lower heart rate variability, and elevated morning cortisol, Greater reports of work stress were associated with higher risk of CVD, i.e., fatal events, MI and definite angina. The InterHeart Study [27] also documented the role of social/emotional factors upon MI incidence.

Ultrasonic measurements of carotid intima-media thickness (CIMT) is widely used to detect atherosclerosis. A meta-analyses [28] of 37,197 subjects, adjusted for age and sex, showed that a difference of 0.1 mm in CIMT increases the risk of future of MI by 10–15 %, and the stroke risk increases by 13–18 % [28]. In the large multicenter European Carotid Intima Media Thickness and IMPROVE studies [29] confirmed the positive correlation between increased risk and increased CIMT. Finally, a stronger relation with the prediction of stroke and IMCT was evidenced in numerous studies (Rotterdam, Malmo Diet and Cancer, ARIC, Cardiovascular Health Study). The presence of a plaque confers special risk. Easiness to perform, great availability and low costs are characteristics that make this technique attractive.