**1. Introduction**

Vascular endothelial growth factor-A (VEGF-A) plays a key role in inducing angiogenesis. Angiogenesis is a multifunctional process of new vessels formation by gemmation or by cleavage of the already existing ones. There are the following successive stages of angiogenesis: (1) vasodilatation; (2) migration with adhesion and proliferation of endothelial cells; (3) formation of the vascular wall of a new three-layer vascular tube that develops as the circulation restores [1]. The VEGF was discovered in 1983 [2] as a factor raising vascular permeability, further evidence of a wider range of cytokine activity was obtained. There are 7 representatives of the VEGF family—VEGF-A, B, C, D, E, F, the growth factor of the placenta. The most common is VEGF-A, which is a homodimeric highly glycosylated protein with the molecular weight of 36–46 kDa. VEGF is registered in the heart, lungs, kidneys, adrenal glands, liver, spleen, stomach, and expression of the protein grows

under the pathology conditions. VEGF-A is represented by homodimeric isoforms consisting of 121, 145, 148, 165, 183, 189, 206 amino acid residues, among which the essential for the vascular system adequate development is VEGF-165 [3–6].

VEGF-A is produced by endothelial cells, smooth muscle vessels, macrophages, cardiac fibroblasts, lymphocytes, polymorphous nuclear cells, megakaryocytes, monocytes, platelets. Expression of VEGF-A depends on hypoxia, including hypoxia-induced factor, proangiogenic factors (HIF-1, EGF, PDGF, FGF, IL-1-beta), angiotensin II, endotoxin, high glucose level, IL-6, IL-8, IL-10, pH of the medium, oxygen concentration [4–6]. Its products are enhanced by aggregation of platelets, stretching of the left ventricle myocardium. VEGF is a proinflammatory cytokine, it inhibits the formation of dendritic cells, promotes the expression of monocytes, macrophages, leukocytes migration, stimulates adhesive molecules, and the activity of CD34 [7].

VEGF-A is a promoter of the collaterals formation in the ischemic myocardium, has a positive effect on revascularization through the following mechanisms: selective mitogenic effect on endothelial cells, stimulation of vascular endothelial cells expression, their proliferation, regeneration, vascular permeability increase, vasodilatation by activating NO synthase and prostacyclin, inhibition of apoptosis, matrix proteinase products. VEGF has antithrombotic properties due to the activation of serine proteases, urokinase, plasminogen activator, and the thrombolytic enzymes generation. However, VEGF induces the formation of the Willebrand factor and thrombogenesis [3, 4, 7].

In coronary artery disease (CAD), the double role of VEGF-A has been determined: under the conditions of acute or chronic myocardial ischemia, VEGF-A is a promoter of the coronary collaterals development, which promotes adequate blood circulation, oxygen saturation, cardiomyocyte loss prevention, heart remodeling improvement, and ultimately, a positive cardioprotective effect [8–11]. However, the negative component of the VEGF-A is its proatherogenic properties [12], which are implemented through the protein participation in the inflammatory infiltration of the atherosclerotic plaque, its neovascularization and destabilization. The VEGF expression promotes the process of monocytes migration with subsequent transformation into macrophages, the formation of foam cells and atherosclerotic tissues. The VEGF stimulates the matrix metalloprotease expression, which causes the extracellular matrix dissolution and the endothelium migration into a collagen gel with the endothelial tubes formation. The de novo formed vessels contribute to the plaque growth, its rupture, and destabilization of the clinical course in coronary artery disease [7, 13].

Information on changes in the VEGF-A level with stable CAD compared to the healthy group varied from its increase [14–16], to decrease [17] or lack of changes [18]. A number of studies have shown a direct correlation between the level of VEGF-A growth and the degree of damage to coronary vessels. Kucukardali et al. [16], examined the relationship in patients with proven CHD between the level of VEGF-A in blood plasma and the degree of coronary occlusion and the traditional risk factors. Groups with normal coronary angiogram (control), critical coronary injuries (with stenosis >70%) and non-critical changes (with stenosis of 40–70%) were selected. Logistic regression analysis showed that the VEGF-A level in patients with critical coronary sclerosis was significantly higher than in patients with normal coronary angiogram and non-critical stenosis. Higher levels of total cholesterol and LDL cholesterol in patients with critical stenosis were detected, VEGF-A negative correlation with hemoglobin and the positive correlation between VEGF-A and the age. No relationship was found between VEGF-A and other cardiac risk factors. The authors believe that the VEGF-A level growth in patients with coronary heart disease indicates critical coronary sclerosis [16]. Lin et al. [14], showed that the

**121**

healthy ones.

*Promising Role of Vascular Endothelial Growth Factor-A in Risk Stratification after PCI*

VEGF-A level in patients with total coronary occlusion was higher than in patients with partial stenotic injuries, indicating the compensatory role of the VEGF-A in angiogenesis. Nakajama et al. [15], in patients with marked coronary atherosclerosis, detected increased levels of VEGF-A compared to moderate stenosis or its lack thereof. Alber et al. [18], however, did not find correlations between the concentration of VEGF-A in the blood plasma, the presence, severity and extent of coronary vessels injuries. The authors drew attention to the fact that in patients treated with statins, the level of VEGF-A was lower, this trend indicates the mechanisms of

Ramos et al. [17], studied the dynamics of the VEGF-A level after PCI and its role as a predictor of major adverse cardiovascular events (MACE). Patients with ACS (STEMI, MI without ST segment elevation, unstable angina) and without ACS with stable angina pectoris were examined. The content of VEGF-A in the blood serum before PCI did not depend on the clinical form and was lower than that in the healthy group. The level of VEGF-A grew 1 month after revascularization and remained stable during 1 year of observation, reaching the control group's value. The results indicate the positive role of the VEGF-A level growth in the endothelium

Angiogenesis and the coronary collaterals formation in AMI is of particular importance as an adaptation process in response to myocardial hypoxia. An increase in collateral circulation limits myocardial ischemia, prevents the spread of necrosis, improves the function of the myocardium [8]. The ability of VEGF-A to promote the development of collateral circulation has been demonstrated on the MI experimental models in animals. The use of VEGF for therapeutic angiogenesis in AMI in experimental animals was performed by intracardiac administration of VEGF-encoding genes, use of deproteinized isoforms of DNA (pVEGF 165), adenoviral vectors (Ad VEGF 121), etc. As a result, initially, in the perinecrotic zone, in remote areas, and then in the MI zone, there was an increase in the number of functioning capillaries, their bulk surface, anastomoses, activation of capillary collateral circulation [1, 9], improvement of cardiac micro vessels regeneration, cardiac function [10], fibrosis reduction and increasing of the myocardium contractile function [11], which ultimately reflects the cardioprotective effects of VEGF-A as a result of angiogenesis

In most clinical studies, an increase in the VEGF-A level in AMI compared to healthy persons, patients with stable or unstable angina [8, 19–24] was determined. At the same time, in works by Ramos et al. [17], the level of VEGF-A in patients with CAD was lower than in healthy persons, and its differences between clinical

The analysis of the factors influencing the VEGF level growth in AMI showed the following. The classic cardiovascular risk factors (gender, age, hypertension, overweight, diabetes mellitus, smoking, hypercholesterolemia) in patients with AMI did not correlate with the VEGF-A level [8, 17, 21, 25], although the VEGF-A level in patients with H, DM, high BMI, obesity, HF without MI were different from

Comparison of the VEGF-A level in patients with AMI with single- and multivascular coronary sclerosis revealed a lack of cytokine correlation with a heart attack-dependent coronary artery [8, 21, 26], simultaneously, Wojakovski et al. [24], determined higher values of VEGF-A in the blood serum in patients with MI with multi-vessel injuries compared to those with single-vessel ones. No relationship was found between the VEGF level and the heart attack localization [8]. Results of the connection between the VEGF and the size of the myocardial injury, which were determined by the level of CK, CK-MB cardiomarkers, were ambiguous. Kranz et al. [8], Shimokawahara et al. [21] did not find any connection between

*DOI: http://dx.doi.org/10.5772/intechopen.82712*

statins' antiangiogenic effect.

and endothelial cells proliferation.

forms of coronary heart disease were not found.

regeneration.

#### *Promising Role of Vascular Endothelial Growth Factor-A in Risk Stratification after PCI DOI: http://dx.doi.org/10.5772/intechopen.82712*

VEGF-A level in patients with total coronary occlusion was higher than in patients with partial stenotic injuries, indicating the compensatory role of the VEGF-A in angiogenesis. Nakajama et al. [15], in patients with marked coronary atherosclerosis, detected increased levels of VEGF-A compared to moderate stenosis or its lack thereof. Alber et al. [18], however, did not find correlations between the concentration of VEGF-A in the blood plasma, the presence, severity and extent of coronary vessels injuries. The authors drew attention to the fact that in patients treated with statins, the level of VEGF-A was lower, this trend indicates the mechanisms of statins' antiangiogenic effect.

Ramos et al. [17], studied the dynamics of the VEGF-A level after PCI and its role as a predictor of major adverse cardiovascular events (MACE). Patients with ACS (STEMI, MI without ST segment elevation, unstable angina) and without ACS with stable angina pectoris were examined. The content of VEGF-A in the blood serum before PCI did not depend on the clinical form and was lower than that in the healthy group. The level of VEGF-A grew 1 month after revascularization and remained stable during 1 year of observation, reaching the control group's value. The results indicate the positive role of the VEGF-A level growth in the endothelium regeneration.

Angiogenesis and the coronary collaterals formation in AMI is of particular importance as an adaptation process in response to myocardial hypoxia. An increase in collateral circulation limits myocardial ischemia, prevents the spread of necrosis, improves the function of the myocardium [8]. The ability of VEGF-A to promote the development of collateral circulation has been demonstrated on the MI experimental models in animals. The use of VEGF for therapeutic angiogenesis in AMI in experimental animals was performed by intracardiac administration of VEGF-encoding genes, use of deproteinized isoforms of DNA (pVEGF 165), adenoviral vectors (Ad VEGF 121), etc. As a result, initially, in the perinecrotic zone, in remote areas, and then in the MI zone, there was an increase in the number of functioning capillaries, their bulk surface, anastomoses, activation of capillary collateral circulation [1, 9], improvement of cardiac micro vessels regeneration, cardiac function [10], fibrosis reduction and increasing of the myocardium contractile function [11], which ultimately reflects the cardioprotective effects of VEGF-A as a result of angiogenesis and endothelial cells proliferation.

In most clinical studies, an increase in the VEGF-A level in AMI compared to healthy persons, patients with stable or unstable angina [8, 19–24] was determined. At the same time, in works by Ramos et al. [17], the level of VEGF-A in patients with CAD was lower than in healthy persons, and its differences between clinical forms of coronary heart disease were not found.

The analysis of the factors influencing the VEGF level growth in AMI showed the following. The classic cardiovascular risk factors (gender, age, hypertension, overweight, diabetes mellitus, smoking, hypercholesterolemia) in patients with AMI did not correlate with the VEGF-A level [8, 17, 21, 25], although the VEGF-A level in patients with H, DM, high BMI, obesity, HF without MI were different from healthy ones.

Comparison of the VEGF-A level in patients with AMI with single- and multivascular coronary sclerosis revealed a lack of cytokine correlation with a heart attack-dependent coronary artery [8, 21, 26], simultaneously, Wojakovski et al. [24], determined higher values of VEGF-A in the blood serum in patients with MI with multi-vessel injuries compared to those with single-vessel ones. No relationship was found between the VEGF level and the heart attack localization [8]. Results of the connection between the VEGF and the size of the myocardial injury, which were determined by the level of CK, CK-MB cardiomarkers, were ambiguous. Kranz et al. [8], Shimokawahara et al. [21] did not find any connection between

*Vascular Access Surgery - Tips and Tricks*

molecules, and the activity of CD34 [7].

factor and thrombogenesis [3, 4, 7].

artery disease [7, 13].

under the pathology conditions. VEGF-A is represented by homodimeric isoforms consisting of 121, 145, 148, 165, 183, 189, 206 amino acid residues, among which the

IL-1-beta), angiotensin II, endotoxin, high glucose level, IL-6, IL-8, IL-10, pH of the medium, oxygen concentration [4–6]. Its products are enhanced by aggregation of platelets, stretching of the left ventricle myocardium. VEGF is a proinflammatory cytokine, it inhibits the formation of dendritic cells, promotes the expression of monocytes, macrophages, leukocytes migration, stimulates adhesive

VEGF-A is a promoter of the collaterals formation in the ischemic myocardium,

In coronary artery disease (CAD), the double role of VEGF-A has been determined: under the conditions of acute or chronic myocardial ischemia, VEGF-A is a promoter of the coronary collaterals development, which promotes adequate blood circulation, oxygen saturation, cardiomyocyte loss prevention, heart remodeling improvement, and ultimately, a positive cardioprotective effect [8–11]. However, the negative component of the VEGF-A is its proatherogenic properties [12], which are implemented through the protein participation in the inflammatory infiltration of the atherosclerotic plaque, its neovascularization and destabilization. The VEGF expression promotes the process of monocytes migration with subsequent transformation into macrophages, the formation of foam cells and atherosclerotic tissues. The VEGF stimulates the matrix metalloprotease expression, which causes the extracellular matrix dissolution and the endothelium migration into a collagen gel with the endothelial tubes formation. The de novo formed vessels contribute to the plaque growth, its rupture, and destabilization of the clinical course in coronary

Information on changes in the VEGF-A level with stable CAD compared to the healthy group varied from its increase [14–16], to decrease [17] or lack of changes [18]. A number of studies have shown a direct correlation between the level of VEGF-A growth and the degree of damage to coronary vessels. Kucukardali et al. [16], examined the relationship in patients with proven CHD between the level of VEGF-A in blood plasma and the degree of coronary occlusion and the traditional risk factors. Groups with normal coronary angiogram (control), critical coronary injuries (with stenosis >70%) and non-critical changes (with stenosis of 40–70%) were selected. Logistic regression analysis showed that the VEGF-A level in patients with critical coronary sclerosis was significantly higher than in patients with normal coronary angiogram and non-critical stenosis. Higher levels of total cholesterol and LDL cholesterol in patients with critical stenosis were detected, VEGF-A negative correlation with hemoglobin and the positive correlation between VEGF-A and the age. No relationship was found between VEGF-A and other cardiac risk factors. The authors believe that the VEGF-A level growth in patients with coronary heart disease indicates critical coronary sclerosis [16]. Lin et al. [14], showed that the

has a positive effect on revascularization through the following mechanisms: selective mitogenic effect on endothelial cells, stimulation of vascular endothelial cells expression, their proliferation, regeneration, vascular permeability increase, vasodilatation by activating NO synthase and prostacyclin, inhibition of apoptosis, matrix proteinase products. VEGF has antithrombotic properties due to the activation of serine proteases, urokinase, plasminogen activator, and the thrombolytic enzymes generation. However, VEGF induces the formation of the Willebrand

VEGF-A is produced by endothelial cells, smooth muscle vessels, macrophages, cardiac fibroblasts, lymphocytes, polymorphous nuclear cells, megakaryocytes, monocytes, platelets. Expression of VEGF-A depends on hypoxia, including hypoxia-induced factor, proangiogenic factors (HIF-1, EGF, PDGF, FGF,

essential for the vascular system adequate development is VEGF-165 [3–6].

**120**

VEGF-A and CK; Hojo et al. [20], Ogawa et al. [22], showed a positive correlation between VEGF-A and CK-MB and suggested an association between the prevalence of MI and the increase in the VEGF-A formation.

Several studies were devoted to the dynamics of VEGF-A in the acute phase of the MI and the subsequent post-infarction prognosis. The VEGF-A level in AMI after PCI peaked on the 7th–14th days [8, 20, 21, 27, 28] and returned to the norm for 6 months [28]. According to experimental data, administering of VEGF 124 before the coronary artery occlusion was accompanied by a pronounced activation of the angiogenesis process, collateral circulation in the perinecrotic zone and the distant regions of myocardium on the 7th day of the experiment [1]. It is possible to assume that a peak increase in the VEGF-A level for 7–10 days of AMI corresponds to the beginning of active angiogenesis. Mechanisms of VEGF-A endogenous expression activation in AMI are associated with response to hypoxia and acute myocardial ischemia and are implemented at the molecular level. A number of studies have provided additional information on the pathogenesis of VEGF-A expression enhancement in AMI. Thus, according to Hojo et al. [20], in patients with AMI, VEGF-A level was determined in the blood serum and in mononuclear cells of peripheral blood. Its blood serum levels peaked at the 14th day of AMI and correlated positively with the CK. There was a slight difference in the VEGF-A level in mononuclear cells: it was maximally elevated on the 7th day of AMI, did not correlate with CK, its reliably higher values were determined in patients with LVEF—≥40% compared to the VEGF group <40%. The authors believe that peripheral blood mononuclear cells are an important source of VEGF-A, and if they are mononuclear cells that infiltrate myocardium injured by infarction, VEGF-A, locally formed by mononuclear cells, promotes endothelial proliferation, the formation of microvessels, recovery of the damaged endothelium, healing of the infarcted myocardium, performing an important role in improving systolic function after MI [20].

Kranz et al. [8], observed a significant increase in the level of VEGF-A in the blood of AMI patients, which was maximally expressed on the 7th–10th days and reached the baseline value for 6 months, with unstable angina, the cytokine value did not reliably differ from the control. The absence of VEGF-A level differences in the blood serum and coronary sinus was detected unexpectedly, i.e. the infracted myocardium is not the main source of VEGF-A in the blood stream. The authors found a reliable growth in the number of platelets in the dynamics of MI. Platelets are an important source of VEGF-A, and the cytokine level growth in AMI can be explained by an increase in the number of platelets, and their aggregation enhancement, which leads to the secretion of growth factors from alpha granules.

Korybalska et al. [23], determined a significant increase in the level of VEGF-A in the blood serum of STEMI patients compared to healthy individuals. The number of platelets did not differ between patients with STEMI and healthy persons, however, in patients with STEMI, a direct reliable correlation between VEGF-A and platelets was found. The cytokine concentration increased immediately after retrosternal pain onset in patients with occlusive thrombi, which corresponded to the 3–4° by the TIMI scale. The authors believe that the VEGF-A level growth in patients with STEMI occurs not only due to ischemia and hypoxia of the myocardium, but can also be formed from activated platelets and characterize patients with increased intracoronary thrombosis [23].

Wojakovski et al. [24], studied the correlation between the levels of the VEGF, pro- and anti-inflammatory markers, traditional risk factors, the status of systolic function of the lungs, and the marker of inflammation—high sensitive CRP (hsCRP) in patients with AMI and stable angina. The authors found that the level of VEGF-A in patients with AMI was reliably higher than in those with stable angina, in AMI patients with a multi-vessel injury it was higher than in those with

**123**

*Promising Role of Vascular Endothelial Growth Factor-A in Risk Stratification after PCI*

bilization, its level increase may have a negative prognostic value.

An important component in raising the VEGF-A level, angiogenesis enhancing, cardiac blood flow, myocardial perfusion, oxygen transport, and the entry of energy substrates into cardiomyocytes is its effect on the structural and functional parameters of the myocardium, followed by adaptive or dysadaptive remodeling. Moreover, the VEGF-A expression and its receptors in cardiac fibroblasts and non-endothelial cells with properties of fibroblasts that perform tissue growth and regeneration assumes cytokine involvement in the process of myocardial remodeling in the ischemia and necrosis zones [29]. With experimental MI in rats, administration of VEGF-A-165 and VEGF-B-167 into the myocardium reduced myocardial fibrosis and improved its contractile function, viability, and remodeling of the left ventricle [11]. Administration of anti-P-selectin-conjugated liposomes containing the VEGF to experimental MI rats was accompanied by a 37% reduction in collagen deposition in the myocardium, a significant improvement in the pressure of the LV filling, with a significant improvement in the cardiac function 4 weeks after the MI: LV EDD reduction, growth of the fractional shortening, at the same time, the number of anatomical and perfused vessels increased [10, 30, 31]. Injection of the collagen-bound VEGF domain resulted in the infarction area reduction, improvement of the processes of LV remodeling within 3 months, and 12 months later, in the MI zone, mature vasculature and myocardium-like tissues were

observed. Thus, the protection of cardiomyocytes from apoptosis and involvement

The results of clinical studies on the correlation between VEGF-A and postinfarction remodeling are ambiguous. Thus, in the AMI patients, the indices of LV volumes, determined by ventriculography on the 14th day of AMI, were increased in the group with a high peak VEGF-A value compared to the low VEGF-A value group, the peak of the VEGF-A plasma level positively correlated with LV EDV and LV ESV. These differences were absent in the chronic phase of MI. The authors believe that endogenous VEGF-A plays an important role in the dilatation of LV in patients with AMI [21]. Soeki et al. [33], referred patients, in whom 3 months after

remodeling; the authors did not find changes in the VEGF level between patients with and without remodeling. However, patients with AMI and improvement of systolic function, compared to patients without such improvement, had higher VEGF-A levels in mononuclear cells of the peripheral blood; the authors believe that

, to the group with

of precursor cells in the infarction zone occurred [32].

the AMI an increase in the EDV-index was more than 5 ml/m<sup>2</sup>

mono-vascular injury, in group with EF <40% and Killip III–IV class in comparison with EF >40% and Killip I–II class, with a duration of pain syndrome >6 h compared to that of <6 h. Acute myocardial ischemia was associated with a reduction in the level of anti-inflammatory cytokine IL-10. Although the authors did not find correlation between VEGF-A and IL-10, they believe that changes of these cytokines concentration will help identify persons with high cardiovascular risk. The level of hsCRP, a marker, the importance of which was proven in inflammation, had a negative correlation with anti-inflammatory cytokine IL-10 and a positive one with VEGF-A, which indicates the VEGF-A participation in the immune response to AMI. Eržen et al. [28], determined a reliable increase in the level of the VEGF in patients with MI, on average 20.5 months ago, compared to the control, a reliable positive correlation between the VEGF level and the pro-inflammatory IL-6 and IL-8 molecules, lack of correlation between VEGF and the atherosclerotic injury parameters, although dilatation of the right shoulder artery and the intima-media thickness of the common carotid artery in the examined patients were significantly weakened. The authors believe that the VEGF-A increase in the stable phase after the past MI is a part of inflammatory activity, since VEGF-A in these patients stimulates neovascularization, inflammation of the plaque and promotes its desta-

*DOI: http://dx.doi.org/10.5772/intechopen.82712*

#### *Promising Role of Vascular Endothelial Growth Factor-A in Risk Stratification after PCI DOI: http://dx.doi.org/10.5772/intechopen.82712*

mono-vascular injury, in group with EF <40% and Killip III–IV class in comparison with EF >40% and Killip I–II class, with a duration of pain syndrome >6 h compared to that of <6 h. Acute myocardial ischemia was associated with a reduction in the level of anti-inflammatory cytokine IL-10. Although the authors did not find correlation between VEGF-A and IL-10, they believe that changes of these cytokines concentration will help identify persons with high cardiovascular risk. The level of hsCRP, a marker, the importance of which was proven in inflammation, had a negative correlation with anti-inflammatory cytokine IL-10 and a positive one with VEGF-A, which indicates the VEGF-A participation in the immune response to AMI.

Eržen et al. [28], determined a reliable increase in the level of the VEGF in patients with MI, on average 20.5 months ago, compared to the control, a reliable positive correlation between the VEGF level and the pro-inflammatory IL-6 and IL-8 molecules, lack of correlation between VEGF and the atherosclerotic injury parameters, although dilatation of the right shoulder artery and the intima-media thickness of the common carotid artery in the examined patients were significantly weakened. The authors believe that the VEGF-A increase in the stable phase after the past MI is a part of inflammatory activity, since VEGF-A in these patients stimulates neovascularization, inflammation of the plaque and promotes its destabilization, its level increase may have a negative prognostic value.

An important component in raising the VEGF-A level, angiogenesis enhancing, cardiac blood flow, myocardial perfusion, oxygen transport, and the entry of energy substrates into cardiomyocytes is its effect on the structural and functional parameters of the myocardium, followed by adaptive or dysadaptive remodeling. Moreover, the VEGF-A expression and its receptors in cardiac fibroblasts and non-endothelial cells with properties of fibroblasts that perform tissue growth and regeneration assumes cytokine involvement in the process of myocardial remodeling in the ischemia and necrosis zones [29]. With experimental MI in rats, administration of VEGF-A-165 and VEGF-B-167 into the myocardium reduced myocardial fibrosis and improved its contractile function, viability, and remodeling of the left ventricle [11]. Administration of anti-P-selectin-conjugated liposomes containing the VEGF to experimental MI rats was accompanied by a 37% reduction in collagen deposition in the myocardium, a significant improvement in the pressure of the LV filling, with a significant improvement in the cardiac function 4 weeks after the MI: LV EDD reduction, growth of the fractional shortening, at the same time, the number of anatomical and perfused vessels increased [10, 30, 31]. Injection of the collagen-bound VEGF domain resulted in the infarction area reduction, improvement of the processes of LV remodeling within 3 months, and 12 months later, in the MI zone, mature vasculature and myocardium-like tissues were observed. Thus, the protection of cardiomyocytes from apoptosis and involvement of precursor cells in the infarction zone occurred [32].

The results of clinical studies on the correlation between VEGF-A and postinfarction remodeling are ambiguous. Thus, in the AMI patients, the indices of LV volumes, determined by ventriculography on the 14th day of AMI, were increased in the group with a high peak VEGF-A value compared to the low VEGF-A value group, the peak of the VEGF-A plasma level positively correlated with LV EDV and LV ESV. These differences were absent in the chronic phase of MI. The authors believe that endogenous VEGF-A plays an important role in the dilatation of LV in patients with AMI [21]. Soeki et al. [33], referred patients, in whom 3 months after the AMI an increase in the EDV-index was more than 5 ml/m<sup>2</sup> , to the group with remodeling; the authors did not find changes in the VEGF level between patients with and without remodeling. However, patients with AMI and improvement of systolic function, compared to patients without such improvement, had higher VEGF-A levels in mononuclear cells of the peripheral blood; the authors believe that

*Vascular Access Surgery - Tips and Tricks*

of MI and the increase in the VEGF-A formation.

important role in improving systolic function after MI [20].

increased intracoronary thrombosis [23].

Kranz et al. [8], observed a significant increase in the level of VEGF-A in the blood of AMI patients, which was maximally expressed on the 7th–10th days and reached the baseline value for 6 months, with unstable angina, the cytokine value did not reliably differ from the control. The absence of VEGF-A level differences in the blood serum and coronary sinus was detected unexpectedly, i.e. the infracted myocardium is not the main source of VEGF-A in the blood stream. The authors found a reliable growth in the number of platelets in the dynamics of MI. Platelets are an important source of VEGF-A, and the cytokine level growth in AMI can be explained by an increase in the number of platelets, and their aggregation enhance-

Korybalska et al. [23], determined a significant increase in the level of VEGF-A in the blood serum of STEMI patients compared to healthy individuals. The number of platelets did not differ between patients with STEMI and healthy persons, however, in patients with STEMI, a direct reliable correlation between VEGF-A and platelets was found. The cytokine concentration increased immediately after retrosternal pain onset in patients with occlusive thrombi, which corresponded to the 3–4° by the TIMI scale. The authors believe that the VEGF-A level growth in patients with STEMI occurs not only due to ischemia and hypoxia of the myocardium, but can also be formed from activated platelets and characterize patients with

Wojakovski et al. [24], studied the correlation between the levels of the VEGF, pro- and anti-inflammatory markers, traditional risk factors, the status of systolic function of the lungs, and the marker of inflammation—high sensitive CRP (hsCRP) in patients with AMI and stable angina. The authors found that the level of VEGF-A in patients with AMI was reliably higher than in those with stable angina, in AMI patients with a multi-vessel injury it was higher than in those with

ment, which leads to the secretion of growth factors from alpha granules.

VEGF-A and CK; Hojo et al. [20], Ogawa et al. [22], showed a positive correlation between VEGF-A and CK-MB and suggested an association between the prevalence

Several studies were devoted to the dynamics of VEGF-A in the acute phase of the MI and the subsequent post-infarction prognosis. The VEGF-A level in AMI after PCI peaked on the 7th–14th days [8, 20, 21, 27, 28] and returned to the norm for 6 months [28]. According to experimental data, administering of VEGF 124 before the coronary artery occlusion was accompanied by a pronounced activation of the angiogenesis process, collateral circulation in the perinecrotic zone and the distant regions of myocardium on the 7th day of the experiment [1]. It is possible to assume that a peak increase in the VEGF-A level for 7–10 days of AMI corresponds to the beginning of active angiogenesis. Mechanisms of VEGF-A endogenous expression activation in AMI are associated with response to hypoxia and acute myocardial ischemia and are implemented at the molecular level. A number of studies have provided additional information on the pathogenesis of VEGF-A expression enhancement in AMI. Thus, according to Hojo et al. [20], in patients with AMI, VEGF-A level was determined in the blood serum and in mononuclear cells of peripheral blood. Its blood serum levels peaked at the 14th day of AMI and correlated positively with the CK. There was a slight difference in the VEGF-A level in mononuclear cells: it was maximally elevated on the 7th day of AMI, did not correlate with CK, its reliably higher values were determined in patients with LVEF—≥40% compared to the VEGF group <40%. The authors believe that peripheral blood mononuclear cells are an important source of VEGF-A, and if they are mononuclear cells that infiltrate myocardium injured by infarction, VEGF-A, locally formed by mononuclear cells, promotes endothelial proliferation, the formation of microvessels, recovery of the damaged endothelium, healing of the infarcted myocardium, performing an

**122**

VEGF-A, which is formed in mononuclear cells infiltrating the infarcted myocardium, plays an important role in angiogenesis, re-endothelialization, restoration of the LV systolic function after the AMI [20]. Devaux et al. [19], determined the LV remodeling according to the EDV dynamics in the period between the patient's hospitalization and 6 months after the MI; the first group consisted of patients with ΔEDV, which did not undergo significant changes or was decreasing; group 2 included patients whose ΔEDV was increasing. The level of VEGF-B was 69% higher in patients with ΔEDV ≤ 0 than in patients with ΔEDV > 0. The authors believe that the low level of VEGF-B in blood with AMI is associated with a high risk of LV remodeling and is its predictor.

In accordance with the spectrum of the VEGF biological cardiovascular effects, a number of studies are devoted to the role of cytokine for the long-term prognosis in patients with MI. The contradictory results were obtained. Thus, Heeschen et al. [34], determined the level of VEGF-A in plasma of 1090 patients with ACS 8.7 h after the onset of the event. The frequency of major cardiovascular complications during the 6 months of observation was high in patients with the initially increased VEGF-A level. But other studies have obtained evidence that it is the decrease in the VEGF-A level which is an independent prognostic factor of recurrent cardiovascular events in other studies. Thus, Niu et al. [25], determined the VEGF-A level on the 7th day after MI, groups with low and high (less than or greater than 190 ng/ml) median VEGF-A levels. Repeated examinations were carried out every 2 months during the year; MACE, which included cardiovascular death, heart failure, severe arrhythmias, cardiogenic shock and post-infarction angina, were recorded. Within 6 months, the MACE frequency in the VEGF-A high-level group was significantly lower than in the low-cytokine group. Accordingly, the VEGF-A concentration in the group of patients without MACE was significantly higher than that in the MACE group.

Multivariant regression analysis showed that the decrease of the VEGF-A level is an independent MACE risk factor, its high value on the 7th day after AMI determines a positive long-term prognosis. Matsudaira et al. [27], examined 879 patients with AMI after successful PCI within the framework of a prospective, multicenter NAMIS study (Nagoya Acute Myocardial Infarction Study). According to VEGF-A level terciles, which was determined on the 7th day of AMI, 3 groups were formed, in which within 6 months of observation the major unfavorable cardiac and cerebral events were determined: cardiac death, repeated ACS, hospitalization for heart failure, strokes. Compared to the "medium" tercile, patients with the "low" tercile had a much higher risk of MACE. The authors believe that the low of VEGF-A level on the 7th day after AMI is associated with a significant increase in the MACE risk for 6 months.

Unlike the previous authors, Ramos et al. [17], determined that the level of VEGF-A in patients with AMI was lower than that of healthy individuals at admission, it was getting increased within 1 month term and remained steadily increased up to 1 year of observation. But in this study, it was shown that a decrease in the VEGF-A level < 40.8 pg./ml contributed to an increased risk of MACE for 5 years. The obtained results indicated the positive role of VEGF-A in the cardiovascular circulation restoration and confirmed its prognostic importance. In studies of Teplyakov et al. [35], the degree of ischemic genesis cardiac failure progression, most of the examined were postinfarction patients, there was a decrease in the VEGF-A level, and the initial low VEGF-A level characterized the unfavorable CHF course.

It is known that psychological stress is involved in the development and progression of cardiovascular disease. Thus, in an INTERHEART study performed in 52 world countries, anxiety and depression ranked third among the MI risk factors [36]. In Surtees et al. [37], within the 8.5 years period of observation, patients with a

**125**

*Promising Role of Vascular Endothelial Growth Factor-A in Risk Stratification after PCI*

"major" depression were by 2.7 times more likely to die from the coronary heart disease. Findings from this large prospective cohort study suggest that increased psychological distress is associated with elevated stroke risk. Episodic major depressive disorder was not associated with incident stroke in this study. Doering et al. [38], demonstrated that the presence of anxiety and depression was the predictor of the overall death-rate in patients with coronary artery disease. Versteeg et al. [39], showed that depression was independently associated with an increased risk of the overall death-rate for 5 years in patients with coronary artery disease. In the study by Beach et al. [40], the high level of depression by the Patient Health Questionaire-9 (PHQ-9) was reliably associated with re-hospitalization after 6 months in patients with acute coronary syndrome, heart failure, or arrhythmia. Mechanisms to be associated with anxiety-depressive disorders (ADD) and cardiovascular diseases are complex and take into account both behavioral and physiological factors: smoking, lifestyle underactivity, obesity, as well as increased platelet aggregation, arterial pressure, reduced insulin sensitivity and disordered

In recent years, the evidence base for participation of VEGF-A in the cerebrovascular disease pathogenesis, including ADD, is growing. VEGF-A is known to be involved in such processes in the central nervous system as the ontogenetic development of the

An increase in the VEGF-A level in patients with major depression was observed

[44–48]; the correlation between depression and VEGF-A is confirmed by the fact that cytokine stimulates neurogenesis caused by antidepressants [49, 50]. In patients with coronary heart disease, higher levels of VEGF-A, CRP, IL-6 gene expression and cortisol level reduction were detected, indicating an increase in

It should be noted that in these works, patients with major depression were somatically healthy, or patients with coronary artery disease were with a stable course. However, in acute experimental ischemia, psychological stress was associated with a decrease in the VEGF-A and its signaling molecules (P44/P42, MAPK, Akt) expression, violation of neurovascularization at the macro- and microvascular levels, which the authors associate with the oxidative stress activation in the isch-

The aim of our research was investigation of association between VEGF-A level in STEMI patients with TIMI III and development of repeated coronary events and adverse remodeling within 6-month follow-up and determination of the factors

Sixty-two patients with STEMI, 51 (82.3%) male and 11 (17.7%) female, at the average age (58.63 ± 8.90) years with acute STEMI during 2–12 h of symptoms onset

nervous system, which includes the processes of migration, differentiation, synaptogenesis, myelination, neuroprotection, stimulation of neurogenesis in adulthood, post-ischemic restoration of cerebral and vessel tissues, stimulation of memory formation mechanisms. VEGF-A participates in all phases of neuro-and angiogenesis: formation of blood vessels de-novo from mesenchymal stem cells, formation of new capillaries, expansion of arteriolar anastomoses, and also demonstrates direct neurotrophic and neuroprotective properties. Thus, the role of VEGF in the pathogenesis of cerebrovascular pathology, including anxiety-depressive

disorders, is to combine angiotropic and neurotropic activity [43].

*DOI: http://dx.doi.org/10.5772/intechopen.82712*

endothelial function [41, 42].

immune-mediated activity [51].

influencing this relationship.

**2. Material and methods**

emic tissue [52].

**2.1 Patients**

#### *Promising Role of Vascular Endothelial Growth Factor-A in Risk Stratification after PCI DOI: http://dx.doi.org/10.5772/intechopen.82712*

"major" depression were by 2.7 times more likely to die from the coronary heart disease. Findings from this large prospective cohort study suggest that increased psychological distress is associated with elevated stroke risk. Episodic major depressive disorder was not associated with incident stroke in this study. Doering et al. [38], demonstrated that the presence of anxiety and depression was the predictor of the overall death-rate in patients with coronary artery disease. Versteeg et al. [39], showed that depression was independently associated with an increased risk of the overall death-rate for 5 years in patients with coronary artery disease. In the study by Beach et al. [40], the high level of depression by the Patient Health Questionaire-9 (PHQ-9) was reliably associated with re-hospitalization after 6 months in patients with acute coronary syndrome, heart failure, or arrhythmia.

Mechanisms to be associated with anxiety-depressive disorders (ADD) and cardiovascular diseases are complex and take into account both behavioral and physiological factors: smoking, lifestyle underactivity, obesity, as well as increased platelet aggregation, arterial pressure, reduced insulin sensitivity and disordered endothelial function [41, 42].

In recent years, the evidence base for participation of VEGF-A in the cerebrovascular disease pathogenesis, including ADD, is growing. VEGF-A is known to be involved in such processes in the central nervous system as the ontogenetic development of the nervous system, which includes the processes of migration, differentiation, synaptogenesis, myelination, neuroprotection, stimulation of neurogenesis in adulthood, post-ischemic restoration of cerebral and vessel tissues, stimulation of memory formation mechanisms. VEGF-A participates in all phases of neuro-and angiogenesis: formation of blood vessels de-novo from mesenchymal stem cells, formation of new capillaries, expansion of arteriolar anastomoses, and also demonstrates direct neurotrophic and neuroprotective properties. Thus, the role of VEGF in the pathogenesis of cerebrovascular pathology, including anxiety-depressive disorders, is to combine angiotropic and neurotropic activity [43].

An increase in the VEGF-A level in patients with major depression was observed [44–48]; the correlation between depression and VEGF-A is confirmed by the fact that cytokine stimulates neurogenesis caused by antidepressants [49, 50]. In patients with coronary heart disease, higher levels of VEGF-A, CRP, IL-6 gene expression and cortisol level reduction were detected, indicating an increase in immune-mediated activity [51].

It should be noted that in these works, patients with major depression were somatically healthy, or patients with coronary artery disease were with a stable course. However, in acute experimental ischemia, psychological stress was associated with a decrease in the VEGF-A and its signaling molecules (P44/P42, MAPK, Akt) expression, violation of neurovascularization at the macro- and microvascular levels, which the authors associate with the oxidative stress activation in the ischemic tissue [52].

The aim of our research was investigation of association between VEGF-A level in STEMI patients with TIMI III and development of repeated coronary events and adverse remodeling within 6-month follow-up and determination of the factors influencing this relationship.
