Cardiovascular disease is a group of disorders of the heart and blood vessels, that include coronary heart disease, cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, congenital heart disease and deep vein thrombosis and pulmonary embolism. According to WHO, an estimated 17 million people die of CVDs each year, making it the leading cause of death worldwide.
Expanding prevalence of cardiovascular disease, and increase in risk factors for future events has triggered the need to search for new approaches in order to contain the current trend (Tardif et al., 2006). Recognition of new risk factors, and novel drug targets aims to support an achievement of established goals (Tardif et al., 2006). For that reason, application of biomarkers in the development of improved cardiovascular intervention, in order to improve public health, has been greatly recognised (Tardif et al., 2006). The risk assessment based on more traditional biomarkers (blood pressure, serum cholesterol levels) supported the development of currently available preventive and therapeutic methods (Tardif et al., 2006). Nevertheless, currently available CVD risk measures can predict only 60-70 % of cardiovascular events, excluding the population of patients at intermediate risk, who are symptom free (Gonzalez et al., 2003; Vasan, 2006; De Backer, 2010). For that reason, other means of risk evaluation are being in use to identify and treat asymptomatic patients with increased risk (Vasan, 2006). Academic research institutions and private sector recognize the importance of biomarkers in order to improve public health status (Tardif et al., 2006). Yet, despite of current efforts, hardly any surrogates of cardiovascular events achieved validated position (Tardif et al., 2006).
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The regulatory bodies recognize the biomarker as "a characteristic that is objectively measured and evaluated as an indicator of normal biological process" (De Gruttola et al., 2001). Whereas, the surrogates are biomarkers "intended to substitute for a clinical end point" (De Gruttola et al., 2001; Cohn et al., 2004; Tardif et al., 2006). In other words, surrogates are considered as predictors of clinical outcome based on epidemiological, pathophysiological and therapeutic evidence (Tardif et al., 2006). The validation of surrogates is based on confirmation that the marker shows correlation with the true clinical outcome and has the ability to describe the full effect of intervention on clinical outcome (De Gruttola et al., 2001; Tardif et al., 2006). Many surrogate candidates show the relevance to clinical end point, but they fail to display the full therapeutic effect (Tardif et al., 2006). The failure of "candidate biomarker" to show "surrogate potency" originates from lacking evidence that the surrogate causes the disease; that the surrogate is involved in only one pathway in the multiple-pathway disease; that the surrogate is sensitive to investigated intervention, or that the surrogate measures an effect independent from the disease process (Tardif et al., 2006).
Initial validation of a "candidate-biomarker" aims to assess that a potential new biomarker is equally potent as "validated" surrogate. Additionally, technology used for evaluation is standardized, reproducible, adequately sensitive and specific when measured against clinical outcome (Tardif et al., 2006). "Next step" validation process involves demonstration that any changes recorded are due to undertaken intervention, and that this change independently estimates benefits. No biomarker will be stated as "validated" surrogate, unless correlation between "candidate-biomarker" and clinical outcome is reliably documented (Tardif et al., 2006). By using biomarkers in combination, better risk profiles may emerge to provide prognostic information, direct therapies to assess the efficacy of intervention (Tardif et al., 2006; Zethekius et al., 2008). Considering that cardiovascular pathophysiology is the complex issue, it may be the case that no single biomarker will ever provide ensigns on risk assessment (Tardif et al., 2006).
Current interest focuses on markers of inflammation and oxidative stress, as new "surrogate candidates" in cardiovascular disease (Tardif et al., 2006). Numerous studies have demonstrated the potential of endothelial function to identify risk of cardiovascular events, even before clinical manifestation (Celermajer, 1992; Bonetti et al., 2003; Tardif et al., 2006).
The question remaining to be answered is, whether endothelial function, or rather physiology is a good surrogate marker for the cardiovascular disease. A good starting point for this assessment would be to provide some background information on physiology of this "organ", followed by a review of currently available data on the subject.
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The vascular endothelium is considered as one of the largest "paracrine, endocrine and autocrine organ responsible for regulation of vascular tone and maintenance of vascular homeostasis" (Bonetti et al., 2003; Gonzalez et al., 2003; Feletou et al., 2006).
Studies on endothelium physiology (or rather pathophysiology) have provided evidence on the importance of this organ in the development of atherosclerosis and its clinical consequences (Celermajer, 1992; Bonetti et al., 2003; Higashi and Yoshizumi, 2003). As shown, endothelial dysfunction is an early physiological state in cardiovascular events (Figure 1.), preceding plaque formation but also manifestation of any clinical symptoms (Celermajer, 1992).
Figure 1. Progression of atherosclerosis in cardiovascular disease (Higashi and Yoshizumi, 2003).
Physiological importance of the endothelium is achieved via secretion of various bioactive substances (with particularly important of nitric oxide), thus maintaining homeostasis of the vascular wall (normal vasomotion, inhibition of platelet aggregation, thrombus generation, maintenance of impermeability) (Table 1.) (Greenland et al., 2000; Gonzalez et al., 2003; Cohn et al., 2004; Feletou et al., 2006).
Table 1. Atheroprotective effects of the Healthy Endothelium (Bonetti et al., 2003).
The vasoactive factors include relaxing (e.g. adenosine, prostacylin (PGI 2 ), nitric oxide (NO), hydrogen peroxide (H2O2), epoxyeicosatrienoic acids (EETs), C-natriuretic peptide (CNP)) and contracting (e.g. thromboxane A 2, isoprostanes, superoxide anion, endothelin-1, angiiotensin II) mediators (Feletou et al., 2006). Moreover, endothelial cells directly communicate with smooth muscle cells via myoendothelial gap junctions (Feletou et al., 2006).
As already mentioned, nitric oxide (NO) is the main vasodilator secreted by endothelium, Additionally, NO also inhibits several proatherosclerotic signalling pathways; i.e. vascular smooth muscle cells (SMCs) migration, but also monocyte activation, adhesion and migration (Turner et al., 2008). Endothelial dysfunction results in reduction of the bioavailability of vasodilators, particularly nitric oxide (NO), as the result of interaction between released oxygen species and NO (Celermajer, 1992; Benotti et al., 2003). At the same time, an increase in endothelium-derived contracting factors, such as endothelin-1, is observed (Turner et al., 2008). This imbalance leads to the abnormalities of endothelium-dependent vasodilation; the functional characteristic of endothelial dysfunction (Bonetti et al., 2003).
Cardiovascular risk factors affect many aspects of normal functions of endothelium (Bonetti et al., 2003), via activation of a number of pro-oxidative genes in the vascular wall, resulting in production of reactive oxygen species that promote endothelial release of transcriptional and growth factors, proinflammatory cytokines, chemoattractant substances, adhesion molecules (Gonzalez et al., 2003; Cohn et al., 2004). All these determinants set the endothelium in a specific "endothelial activation" that promotes atherosclerosis (Bonetti et al., 2003).
A complex cascade of events triggers the transition from normal endothelial function to its dysfunction (Cohn et al., 2004). One of the earliest manifestations of increased vascular oxidant stress is limited availability of nitric oxide (NO) (Turner et al., 2008). The resulting functional consequences include abnormal vasomotor activity, development of a procoagulant endothelial surface, inflammation and finally plague formation (Cohn et al., 2004). The majority of conventional factors for cardiovascular disease are associated with endothelial dysfunction (Bonetti et al., 2003; Turner et al., 2008). These include hypercholesterolemia, hyperlipidemia, hypertension, diabetes and smoking (Bonetti et al., 2003 ;Cohn et al., 2004). For that reason, the extent of endothelial pathophysiology appears to be correlated with traditional factors (Cohn et al., 2004).
Interestingly, individuals with a similar risk factor profile may show significant variability of endothelial dysfunction as well (Hashimoto et al., 2003). Bonetti et al. (2003) explained this state as the result of "threshold regulation" of which activation triggers cardiovascular events (Bonetti et al., 2003). Additional risk determinants, such as infections, genetic heterogeneity, various duration of exposure to risk factors, and the number of factors involved, may further contribute to inconsistency (Hashimoto et al., 2003; Cohn et al., 2004). Furthermore, endothelial function can be modulated by factors contributing to vascular injury, as well as repair mechanisms (Cohn et al., 2004). For that reason, the concept of endothelial vasodilator function reflects the vascular health status, supporting the suggestion that this physiological determinant could be a useful diagnostic and prognostic tool (Bonetti et al., 2003; Cohn et al., 2004). Furthermore, its application, as an independent predictor of future or already existing cardiovascular events may be of use (Bonetti et al., 2003; Mazzucco et al., 2009).
Table 2 highlights potential predictive value of endothelial function in cardiovascular disease.
Table 2. Prediction of future cardiovascular events by measurements of endothelial function (Cohn et al., 2004).
ABI indicates ankle-brachial index; ACS, acute coronary syndromes; BMI, body mass index; BP, blood pressure;
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CAD, coronary artery disease; CHF, congestive heart failure; IMT, intima-media thickness; MI, myocardial infarction;
NCA, normal coronary arteries; NTG, nitroglycerin; PAD, peripheral artery disease.
The standardization of methods used to assess endothelial physiology plays a crucial role in establishing the endothelial function as a surrogate for cardiovascular events (Table 3.), as validated methods used to assess endothelial physiology are essential tools for determining individuals at increased risk of cardiovascular events (Turner et al., 2008).
Table 3. Clinical application of potential surrogate functional markers for cardiovascular disease (Vasan, 2006).
(?, unknown or questionable/equivocal data; +, some evidence; ++, good evidence; +++, strong evidence).
Although no "gold standard" exists, several techniques (invasive and non-invasive) have found experimental and clinical application, providing results with a conclusive statement (Tamaki et al., 2003; Hashinoto et al., 2003). These methods involve the assessment of the vessel's diameter change or its blood flow change (Hashimoto et al., 2003; Yeboah et al., 2007).
Methods involved in assessment of endothelial function measure arterial vasodilation (coronary, brachial) after stimulation (a local infusion) with endothelium-dependent vasodilators (i.e. acetylcholine, brodykinin) (Corretti et al., 2002, Anderson, 2007). Other method involves a large conduit arteries, where an increase in shear stress is assessed, as a response to increased blood flow velocity. This consequently causes endothelial- NO-dependent vasodilation (Corretti et al., 2002; Mazzucco et al., 2009).
Brachial Flow-Mediated Dilation (FMD) is the most widely used technique, and can be detected by high-resolution ultrasound non-invasively (Bonetti et al., 2003; Hashimoto et al., 2003; Cohn et al., 2004; Anderson, 2007). The method is nitric oxide dependent, the abnormalities can be recorded at the early stage of disease development and the correlation between endothelial dysfunction and cardiovascular risk factors can be recorded (Anderson, 2007; Yeboah et al, 2007). As the improvement of brachial FMD is observed after antiatherogenic therapy, this method can be used to assess the interventional approach (e.g. statin therapy) (Anderson, 2007). Additionally, the method is inexpensive and reproducible, nevertheless prone to physiological and technical variability (Corretti et al., 2002; Anderson 2007). The establishment of endothelial function as a potentially important predictor of cardiovascular events, has driven the need for development of new, validated methods for assessing endothelial state (Mazzucco et al., 2009). FMD is mainly applied to coronary epicardial arteries, coronary resistance vessels, brachial artery and forearm resistance vessels (Corretti et al., 2002). In addition, results obtained by Mazzucco et al. (2009) have suggested the potential application of this technique in studying endothelial function in cerebral vasculature.
Moreover, the assessment of microvascular endothelial function can be also performed using Laser Doppler flowmerty/Imaging (LDF), as the technique provides the means of validation and reproducibility (Turner et al., 2008). LDF is facilitated to examine disease progression and responsiveness to treatment (Turner et al., 2008).
The employment of pulse wave analysis (PWA) combined with pharmacological induction, as the assessment method of endothelial function also has a potential to serve as a non-invasive and practical tool in large population and clinical studies including children (Ibrahim et al., 2009). Other methods for endothelial function assessment include the detection of "endothelial markers" in the blood, such as endothelin, von Wallebrand factor and PAI-1 (Hashimoto et al., 2003).
A number of studies, mainly experimental and clinical, have demonstrated the superiority of endothelial dysfunction to clinical risk factors in all cardiovascular events (Mazzucoo et al., 2009). Schachinger et al. (2000) and Suwaidi et al., (2000) observed an association between reduction in acetylcholine-mediated endothelium-dependent vasodilation, or coronary blood flow and cardiovascular events among patients with mild coronary disease. Heitzer et al. (2001), based on results from follow up period of patients with mild coronary disease, also observed an increase in cardiovascular events among patients with compromised acetylcholine- and nitroprusside-mediated endothelium-dependent vasodilation. Although conclusive results have been obtained from patients with recognized cardiovascular risk factors, unfortunately the same cannot be stated for individuals without established risk factors (Shimbo et al., 2007).
The recent data obtained by Yeboah et al. (2007) from CHS study of 2792 adults, also confirmed the associated of peripheral artery endothelial dysfunction and cardiovascular events, "making it one of the strongest pieces of evidence to date to support this claim" (Anderson, 2007).
Up to date, Yeboah et al. (2007), obtained significantly important results bringing a new sign on endothelial function and its predictive prospective as a surrogate of cardiovascular events. Results obtained from population-based cohort study of older adults (72-98 of age) enabled Yeboah and colleagues (2007) to make the final conclusion that brachial FMD, measuring endothelial dysfunction can be considered as an independent predictor of cardiovascular events. At the same time, Yeboah et al. (2007) concluded that brachial FMD contributed insignificantly to the prognostic accuracy of "standard" risk factor score, but could supplement the assessment with additional prognostic information.
A biomarker characterized by accuracy and reproducibility obtained via standardized assessment will represent a "validated" value for a clinical outcome (Vasan, 2006). Additional factors, such as acceptability by patients, an ease of interpretation and high specificity of results, will make a potential marker a strong candidate for surrogate (Vasan, 2006). Furthermore, the application of any new "predictor" should be clearly specified; that is whether it is for screening, diagnosis or assessing the intervention outcome, as their determinants highly influence the properties of biomarker (Vasan , 2006).
Cardiovascular disease is characterized by a very long, rather asymptomatic phase starting at childhood (lipid deposits in the intima of systemic arteries) and progressing through a preclinical stage, finally manifesting itself at middle age (Celermajer, 1992; Gonzalez et al., 2003; Deanfield et al., 2007; Feletou et al., 2006). The manifestation of endothelial pathophysiology is considered as an early process in the pathogenesis of atherosclerosis (Yeboah et al., 2007). The role of endothelial function in cardiovascular events has become the focus of intense investigation (Anderson, 2007).
The importance of endothelial function relates to antiatherogenic role of this "big secretary organ" (Anderson, 2007). But at the same time to exploit the functional properties of endothelial cells, it is essential to translate the information obtained from a basic science to clinical application, and to give it a strong reference in interventional assessment (Anderson, 2007).
Abnormalities of endothelium-dependent vasodilation represent a characteristic feature of developing atherosclerosis and correspond with future cardiovascular risk (Celermajer, 1992; Gonzalez et al., 2003; Anderson, 2007). Thus, measurement of endothelial function could potentially find its application in risk assessment and improvement in therapeutic outcome (Benotti et al., 2003; Gonzalez et al., 2003). For endothelial function to become fully validated surrogate, standardization of techniques used for assessment is required. Furthermore, large scale epidemiological and clinical research studies are needed in order to assess the correlation between endothelial function and cardiovascular risk factors as a predictor of undertaken intervention; such as screening, diagnosis, prognosis and therapy monitoring (Vasan, 2006). As mentioned, brachial FMD in the main method used to assess endothelial function, although other techniques become to emerge as a potential. Currently, endothelial function measurement lacks significant reproducibility and is influenced by many variables. The validation of endothelial function as a surrogate marker of cardiovascular events will not become fully accomplished, unless more precise, less invasive, and broadly acceptable methods are in use. "Next generation" of methods should make measurements more acceptable by large group of individuals, including children, making research studies more applicable to the population as the whole.
In summary, endothelial function measurement shows independent predictive potential for cardiovascular events, but to explore the thesis with reference to larger population group, additional studies on symptoms free and factor free individuals are required to answer more remaining questions.