**3. Graft vascular disease**

Graft vascular disease in cardiac transplantation is an insidious complication, characterized by persistent perivascular inflammation and intimal hyperplasia. It was first described by Thomson, 1969, and emerges as the most important factor affecting long-term survival after transplantation [12].

Graft vascular disease and coronary atherosclerosis are atheromatous diseases with some similarities and differences in macroscopic and microscopic presentation. Both diseases are characterized by increased cell adhesion and leukocyte infiltration, similar environment and cytokine profiles, aberrant extracellular matrix, and early and prolonged accumulation of extracellular and intracellular lipids, as well as migration of smooth muscle cells, endothelial dysfunction, and abnormality in cellular apoptosis.

It represents a type of rejection in which aggression immune to the coronary endothelium occurs persistently and constitutes the main late complication, limiting the survival of the patient and the graft itself in the long term [13].

Although acute graft failure after transplantation has improved over the last two decades, the same cannot be said in the long run where achievements have been less pronounced. Graft vascular disease appears as the main complication after the first year of transplantation and lacks specific and effective therapy. The importance of this entity can be observed in the comparative analysis of the survival curves presented by the International Society for Heart and Lung Transplantation, in which patients who developed vasculopathy had a higher mortality rate than the others.13 The graft vascular disease is responsible for 17% of the deaths and can be detected as early as the first year after transplantation, reaching in the third year figures in the order of 42% by cinecoronariography and 75% by intravascular ultrasonography [13–17].

As for the receptor: age, sex, cytomegalovirus infection, diabetes mellitus, hypertension, dyslipidemia, smoking, obesity, and hyperhomocysteinemia. Among these are hyperlipidemia

Graft Vascular Disease

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http://dx.doi.org/10.5772/intechopen.79631

The first step in triggering graft vascular disease is the recognition that occurs after reperfusion of the graft, aggravated by postanoxic endothelial dysfunction. The major cytokines involved in the rejection process are interleukin-2 (IL-2), interferon-gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α). IL-2 induces proliferation and differentiation of T lymphocytes; IFN-γ activates the macrophages; and TNF-α alone is cytotoxic to the transplanted heart. In addition, TNF-α increases the expression of MHC class I molecules, whereas IFN-γ increases MHC expression of both classes I and II.In general, these cytokines may lead to chronic rejection of the graft. IFN-γ and TNF-α induce the production of vascular cell adhesion molecule 1 (VCAM-1), promoting monocyte adhesion and passage through the endothelium and, consequently, vascular graft disease. Explosive encephalic death promotes greater release of cytokines and adhesion molecules and increases the expression of class I and II antigens of the MHC system, promoting an inflammatory reaction exacerbated in the heart of the potential donor and leading to endothelial dysfunction.

The clinical diagnosis of graft vascular disease is difficult, since myocardial ischemia presents a silent course because it is a denervated heart. In the advanced stage, the disease often mani-

Coronary angiography may not express the true severity of the graft vascular disease, since the examination allows only the analysis of the internal diameter of the artery and not of the wall [29, 31–33]. It has been proposed to complement the examination with intravascular ultrasonography, which allows to detect the coronary artery wall thickness even in the initial phase of the process. However, this method is not yet widely used, it is invasive and is limited

Regarding the noninvasive methods, the dobutamine stress echocardiogram has shown advantages as a non-invasive screening test with good sensitivity to select patients with a

Among the alternative surgical methods, direct myocardial revascularization or angioplasty deserves special mention, although both present serious restrictions due to the universal distribution of inflammation in the arteries; therefore, the prognosis of the disease is bleak, and

Ultimately, effective treatment of graft vascular disease in humans is nonexistent, simply limiting the use of prophylactic measures to reduce risk factors. In this way, the treatment of this

Nanotechnology and nanoscience, ranging from 1 to 100 nanometers (nm), focus on materials of atomic size, molecular, and supramolecular, which point to the control and manipulation

terrible disease constitutes a fertile field of research but with multiple challenges.

fests with signs of heart failure, arrhythmias or even sudden death [14, 21, 30–32].

and diabetes mellitus with incidence between 50 and 80%.

to analysis only of the largest caliber arteries.

higher risk of graft vascular disease [13, 34–36].

**4. Nanotechnology and nanoscience**

few patients can benefit from retransplantation [31, 37, 38].

The "graft vascular disease" designation has received greater acceptance rather than the other ones—post-transplant atherosclerosis, chronic rejection, accelerated atherosclerosis, graft vasculopathy and others—because it expresses more appropriately the immunological phenomenon that is common to transplants of solid organs [9].

Graft vascular disease is a form of accelerated coronary vasculopathy of immune origin that has not yet been completely clarified, in which nonimmunological factors also take place. However, the most likely entrance door is the endothelial dysfunction, as it allows the aggression of the subintimal layer and stimulates the myointimal proliferation in the wall of the artery. The inflammatory process extends to the entire arterial bed and, occasionally, to the veins, sparing only the recipient's native vessels [8, 18].

In the initial phase of the lesion, there is a discrete thickness of the intima, with little hyperplastic fibrosis and an increase in extracellular matrix proteins. At this stage, the internal elastic lamina is still intact, and the involvement is limited to the proximal arteries. Subsequently, the thickness proceeds diffusely through the coronary vasculature, with the appearance of plaques of fibroadiposal tissue and gradual deposition of calcium with the future formation of isolated plaques of atheroma [19, 20]. The first intimal changes can be observed as early as the sixth month after transplantation [15, 16, 19].

In the late phase of the disease, it is observed that the thickness of the intima is diffuse, with hyperplasia and concentric fibrosis. A detailed study of the coronary arteries has shown the incorporation of lipids and focal plaques of atheromas interspersed with diffuse arteritis [19, 20]. The arteries thickness occurs by the infiltration of mononuclear inflammatory cells in response to alloimmune stimuli or by infection, and in this last situation, the participation of the cytomegalovirus deserves special attention. In a more advanced stage, the medial layer may be totally or partially replaced by fibrous tissue. Only vessels with little or no muscle layer can be spared [21–23].

The participation of acute rejection is controversial in the development of graft vascular disease [24–26]. Among the nonimmunological factors considered to be at risk for graft vascular disease, we highlight those that may compromise the integrity of the endothelium, as classified below [24–29]:

The donor risk factors encephalic death etiology, age, sex, atherosclerotic disease, and his or her clinical characteristics.

As for the receptor: age, sex, cytomegalovirus infection, diabetes mellitus, hypertension, dyslipidemia, smoking, obesity, and hyperhomocysteinemia. Among these are hyperlipidemia and diabetes mellitus with incidence between 50 and 80%.

The first step in triggering graft vascular disease is the recognition that occurs after reperfusion of the graft, aggravated by postanoxic endothelial dysfunction. The major cytokines involved in the rejection process are interleukin-2 (IL-2), interferon-gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α). IL-2 induces proliferation and differentiation of T lymphocytes; IFN-γ activates the macrophages; and TNF-α alone is cytotoxic to the transplanted heart. In addition, TNF-α increases the expression of MHC class I molecules, whereas IFN-γ increases MHC expression of both classes I and II.In general, these cytokines may lead to chronic rejection of the graft. IFN-γ and TNF-α induce the production of vascular cell adhesion molecule 1 (VCAM-1), promoting monocyte adhesion and passage through the endothelium and, consequently, vascular graft disease. Explosive encephalic death promotes greater release of cytokines and adhesion molecules and increases the expression of class I and II antigens of the MHC system, promoting an inflammatory reaction exacerbated in the heart of the potential donor and leading to endothelial dysfunction.

The clinical diagnosis of graft vascular disease is difficult, since myocardial ischemia presents a silent course because it is a denervated heart. In the advanced stage, the disease often manifests with signs of heart failure, arrhythmias or even sudden death [14, 21, 30–32].

Coronary angiography may not express the true severity of the graft vascular disease, since the examination allows only the analysis of the internal diameter of the artery and not of the wall [29, 31–33]. It has been proposed to complement the examination with intravascular ultrasonography, which allows to detect the coronary artery wall thickness even in the initial phase of the process. However, this method is not yet widely used, it is invasive and is limited to analysis only of the largest caliber arteries.

Regarding the noninvasive methods, the dobutamine stress echocardiogram has shown advantages as a non-invasive screening test with good sensitivity to select patients with a higher risk of graft vascular disease [13, 34–36].

Among the alternative surgical methods, direct myocardial revascularization or angioplasty deserves special mention, although both present serious restrictions due to the universal distribution of inflammation in the arteries; therefore, the prognosis of the disease is bleak, and few patients can benefit from retransplantation [31, 37, 38].

Ultimately, effective treatment of graft vascular disease in humans is nonexistent, simply limiting the use of prophylactic measures to reduce risk factors. In this way, the treatment of this terrible disease constitutes a fertile field of research but with multiple challenges.
