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1. Introduction
Although the skin disease psoriasis was first recognized as a distinct disease as early as 1808 [1], its pathogenic mechanisms have eluded investigators for decades, its definition by Ferdinand von Hebra as a distinct entity dates back only to the year 1841 and estimates of its prevalence around 2-3% of the general population, and is characterized by an exaggerated proliferation of keratinocytes secondary to an activated immune system. The incidence is highest at the age of 20–39 years in males and 40–59 years in females, with an equal male-to-female ratio [2]. Psoriasis clinically manifests as raised, well defined erythematous plaques with irregular borders and silvery scales, affecting the upper and lower extremities equally, but with a predilection for the elbows, knees, scalp, and trunk. Psoriasis vulgaris or plaque psoriasis accounts for almost 90% of the dermatological presentation of the disease, but several other forms, including guttate, inverse, erythrodermal, pustular, and palmoplantar psoriasis may occur, as well as nail involvement. Psoriasis may have significant systemic involvement, which is underscored by the coexistence of various clinical disorders, including eye, cardiovascular, and intestinal problems, metabolic syndrome, and joint inflammation. It has a very high negative impact on quality of life, requires long-term treatment which usually has a high social and economic impact and is also associated with a decreased life span [3] [4].
2. Psoriasis types
Psoriasis classification
No one classification of psoriasis satisfies all the mentioned requirements. Usually, criteria are intermingled (Table 1), and subclasses are nonexclusive. Similar problems exist with the clinical classification of psoriatic arthropathy [5].
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
Morphologic aspects of elementary lesions
\n\t\t\t
Pustular, non-pustular but also plaque, nummular, guttate, gyrate, rupioid, elephantine, ostraceous, etc.
\n\t\t
\n\t\t
\n\t\t\t
Degree of inflammation
\n\t\t\t
Mainly inflammatory vs mainly hyperkeratotic
\n\t\t
\n\t\t
\n\t\t\t
Pattern distribution
\n\t\t\t
Extensory, inverse, seborrhoeic, widespread
\n\t\t
\n\t\t
\n\t\t\t
Extent
\n\t\t\t
One site (scalp, nail, etc.), many sites, generalized
\n\t\t
\n\t\t
\n\t\t\t
Time of first onset
\n\t\t\t
Early vs late onset
\n\t\t
\n\t\t
\n\t\t\t
Velocity of propagation
\n\t\t\t
Stable, unstable, eruptive
\n\t\t
\n\t
Table 1.
Features which have been considered in different classifications of psoriasis [6]
Classification criteria based on purported etiology rank higher in formalization compared with purely morphological ones.
2.1. Classifying psoriasis: The spectrum of clinical varieties
Psoriasis, a papulosquamous skin disease, has several different types, including: psoriasis vulgaris (common type), guttate psoriasis (small, drop like spots), inverse psoriasis (in the folds like of the underarms, navel, and buttocks), and pustular psoriasis (pus-filled, yellowish, small blisters). When the palms and the soles are involved, this is known as palmoplantar psoriasis.
The commonest type of psoriasis, accounting for 90% of all cases, is psoriasis vulgaris, in which papulosquamous plaques are well-delineated from surrounding normal skin. The plaques are red or salmon pink in color, covered by white or silvery scales and may be thick, thin, large or small (Figure 1). They are most active at the edge: rapidly progressing lesions may be annular, with normal skin in the centre. Plaques are usually distributed symmetrically, and occur most commonly on the extensor aspects of elbows and knees; scalp (where they rarely encroach beyond the hairline), lumbosacral region, and umbilicus. Active inflammatory psoriasis is characterized by the Koebner phenomenon, in which new lesions develop at sites of trauma or pressure [7].
2.2.1. Classification of psoriasis vulgaris according to phenotype: plaque-type psoriasis
There is also variation of features of psoriasis dependent on anatomical sites. Until the reasons for this variation are fully understood, they are proposed to be recorded as a phenotypic entity, although subsequently they may be shown to be part of a common pathogenetic mechanism. A further distinction arises according to the age of onset of plaque psoriasis [8]. Henseler and Christophers are credited with identifying two ages of onset: type I occurring at or before the age of 40 years—this accounts for approximately 75% of patients; and typeII presenting after the age of 40 years, with a distinct peak at 55–60 years [9].
As a consequence, chronic plaque psoriasis is the form of the disease entered into clinical trials and the object of the majority of investigations of genetics and pathogenesis of psoriasis. It is characterized by red, scaly, discoid lesions varying in size from 0.5 cm in diameter to large confluent areas on the trunk and limbs (Figure 1). There is a sharp line of demarcation between a plaque and clinically normal, uninvolved skin. Longitudinal studies of individual plaques have demonstrated that plaques are dynamic [10] with an active and expanding edge, sometimes to the extent that the advancing edge may become annular (Figure. 2) leaving clinically normal skin in the centre of the original plaque. The variety of plaque is characterized by well-demarcated plaques with a loosely adherent silvery-white scale, which preferentially affect the elbows, knees, lumbosacral area, intergluteal cleft, and scalp. Occasionally, pustular lesions may appear in the plaque (so-called psoriasis with pustules). Chronic plaque psoriasis is the most common variety of psoriasis, representing about 70% to 80% of psoriatic patients [11].
Figure 1.
Typical plaque of Psoriasis Vulgaris.
Figure 2.
Annular psoriasis showing clearance in centre of plaque.
Under the heading of plaque psoriasis, it is proposed to include, as subdivisions, a new, more logical nomenclature of phenotypes associated with specific anatomical sites, distribution, size and thickness of plaques [8].
2.2.3. Site-specific variants of Psoriasis Vulgaris (PV)
Site-specific variants of psoriasis vulgaris exist. Flexural (inverse) psoriasis in intertriginous sites is shiny, red, and typically devoid of scales (figure 3); sebopsoriasis, which can be confused with seborrhoeic dermatitis, has greasy scales and occurs in eyebrows, nasolabial folds, and postauricular and presternal sites. Psoriasis vulgaris will probably prove to be several closely related but phenotypically and genotypically distinct conditions [8].
Flexural/intertriginous: Inverse psoriasis (Flexural Psoriasis or Psoriasis of the Skin Folds) is usually located in the skin folds: i.e. armpits, under the breasts, skin folds around the groin and between the buttocks. It is particularly subject to irritation from rubbing and sweating because of its location in skin folds and tender areas (Figure 3). Plaques are thin, have minimal scale and a shiny (nonscaly) surface commonly accompanied by secondary fissuring and/or maceration. The major clinical manifestation of inverse psoriasis is sharply demarcated erythematous plaques, with varying degrees of infiltration, which often tend to itch and burn [12]. The most common lesions are found in inguinal, submammary, interglutaeal, umbilicus and genital folds, whereas the popliteus and axillae are rarely involved. The humidity and heat typical of these sites, together with the combination of local traumatic factors often associated with infections caused by dermatophytes and Candida albicans, together contribute to the development of psoriasis in accordance with the Koebner phenomenon. The Koebner phenomenon is an indicator of disease activity, may have a prognostic value, and is associated with early onset of psoriasis [13]. The Koebner phenomenon was first described by Heinrich Koebner (1838–1904) and refers to the fact that in people with certain skin diseases, especially psoriasis, trauma is followed by new lesions in the traumatized but otherwise normal skin, and these new lesions are clinically and histopathologically identical to those in the diseased skin [14].
Figure 3.
Flexural psoriasis, notes the relative lack of scale.
Seborrhoeic: Seborrhoeic psoriasis (‘sebopsoriasis’), so called because of its similarity in morphology and anatomical distribution to seborrhoeic dermatitis, may occur either in isolation or associated with plaque psoriasis elsewhere. Sites of involvement are the nasolabial folds (Figure 4), medial cheeks, nose, ears, eyebrows, hair line, scalp, presternal and interscapular regions. Characteristically the lesions are thin, red and well-demarcated (somewhat like intertriginous psoriasis) with variable degrees of scaling.
Figure 4.
Seborrhoeic psoriasis, nasolabial, ‘greasy’ appearance and finely scaled.
Scalp: The scalp is frequently the site of initial presentation and is the commonest anatomical site to be involved by psoriasis. Morphologies range from discrete plaques to total scalp involvement with either thick plaques or scaly nonthickened areas almost identical to seborrhoeic dermatitis. Sites of predilection include the immediate postauricular area and occiput. An important and fascinating observation is that the scalp lesions rarely extend > 2 cm beyond the hairline. Compared with psoriasis elsewhere, scalp involvement is frequently asymmetrical (Figure 5).
Figure 5.
Psoriasis of the scalp.
Palms/soles (nonpustular): Palmoplantar pustulosis, consisting of yellow-brown, sterile pustules on palms and soles, is still described in textbooks of dermatology as a subtype of psoriasis. About 25% of people with palmoplantar pustulosis also have chronic plaque psoriasis. The disease has different demographics to psoriasis vulgaris in that patients are predominantly women (9:1 female: male ratio) and either current or previous smokers (95%) and onset occurs in the 4th or 5th decades of life (Figure 6) [15].
Figure 6.
Plantar involvement by plaque psoriasis.
2.3. Guttate psoriasis
Psoriasis affects approximately 2% of the world population, and of these cases, 2% manifest as guttate psoriasis [16]. Guttate means "drop" in Latin; aka Teardrop Psoriasis, Raindrop Psoriasis or Psoriasis Exanthematic) is the second most common type of psoriasis. Guttate psoriasis (GP), an important clinical variant, most frequently occurs in adolescents and young adults. It is characterized by the sudden onset of widely dispersed small red scaly plaques mainly over the trunk and proximal limbs. The symptoms of GP are numerous small, red, drop-like spots which cover a large portion of the skin. Spots have an abundant scaling. Lesions are usually located on the trunk, arms, legs and scalp. GP can clear up without treatment or disappear and resurface in the form of plaque psoriasis. GP is especially common in children or young adults with a family history of psoriasis and follows streptococcal infection and/or acute stressful life events [17]. Guttate flares in patients with established psoriasis vulgaris (PV) are also frequently observed. These observations, taken together with investigative studies, indicate an important pathogenetic link between GP and PV [15]. GP is often associated with a preceding streptococcal throat infection or a rise in anti-streptococcal serum titer [16] [18]. Bacterial streptococcal infections (strep throat, chronic tonsillitis) or a viral respiratory infection usually precede and trigger the first signs of Guttate Psoriasis in persons predisposed to psoriasis. Herein, Dr. Loh in 2012 reports a case that suggests such an association. This 15-year-old girl presented with a case of acute guttate psoriasis shortly after the onset of mononucleosis. The structural characteristics of her eruption and her skin biopsy findings are consistent with guttate psoriasis (Figure 7).
Figure 7.
Clinical photographs of the abdomen with guttate psoriasiform papules and plaques. A,Unmagnified image. B, Image at higher unspecified magnification [19].
2.4. Pustular psoriasis: In a population survey of psoriasis, pustular lesions were reported at any time during the course of psoriasis by about 20% of patients [11]
Generalized pustular psoriasis: Patients with generalized pustular psoriasis (GPP) may have preexisting plaque psoriasis or develop it after pustular episodes. Acute episodes may be triggered in patients with plaque psoriasis by irritating topical therapy or abrupt corticosteroid withdrawal [20]. At the onset of an attack of acute GPP (von Zumbusch type) the skin becomes very red and tender. There may be fever and systemic symptoms such as anorexia and nausea. Within hours, myriads of pinhead-sized pustules appear, studding the erythematous background (Figure 8). Pustules may become confluent, producing lakes of pus. Subsequently, the pustules dry out, and the skin peels off, leaving a glazed, smooth erythematous surface on which new crops of pustules may appear [21]. GPP should be distinguished from acute generalized exanthematic pustulosis, a self-limiting febrile drug reaction usually resolving in 2 weeks after withdrawal of the suspected agent, characterized by pinpoint nonfollicular pustules on erythematous patches mainly involving folds. Single necrotic cells in the epidermis, eosinophils, and vasculitic changes in the dermis are peculiar pathologic features [22] [23].
Figure 8.
Early phase of generalized pustular psoriasis with edematous plaques and pustules.
Localized pustular psoriasis: Besides so-called psoriasis with pustules (sometimes referred to by the misleading term “localized form of generalized pustular psoriasis”), 2 main clinical varieties are reported as localized pustular psoriasis: acrodermatitis continua of Hallopeau and palmoplantar pustulosis.
Acrodermatitis continua, also known as dermatitis repens, is a rare, chronic, pustular eruption of the fingers and toes (Figure 9). Often, it begins after a localized trauma starting at the tip of a single digit [24].
Palmoplantar pustulosis: is characterized by hyperkeratosis and clusters of pustules over the ventral aspects of hands and/or feet (Figure 10). Classification of palmoplantar pustulosis within the spectrum of psoriasis is controversial. The disease predominates in women (more than 70% of patients are women) and is much more strongly associated with smoking than plaque psoriasis [25]. Palomar-plantar pustulosis (PPP) generally appears between the ages of 20 and 60. PPP causes large pustules to form at the base of the thumb or on the sides of the heel. In time, the pustules turn brown and peel. The disease usually becomes much less active for a while after peeling.
Figure 9.
Acrodermatitis continua showing crops of pustular lesions at the tips of the fingers.
Figure 10.
Palmoplantar pustulosis.
2.5. Erythrodermic psoriasis
As already mentioned, plaque psoriasis is a rather stable disorder. The transition to a more extensive involvement, due to frequently unidentifiable triggering factors, is frequently marked by the onset of an inflammatory phase with predominant erythema and limited scaling associated with itching and rapidly progressing lesions. This unstable psoriasis may sometimes evolve to whole-body involvement. The erythrodermic phase is dominated by generalized erythema, loss of peculiar clinical features of psoriasis, and skin failure, that is, inability to maintain homeostatic functions [26]. Erythrodermic psoriasis characterized by severe scaling, itching, and pain that affects most of the body, erythrodermic psoriasis disrupts the body\'s chemical balance and can cause severe illness (Figure11). This particularly inflammatory form of psoriasis can be the first sign of the disease, but often develops in patients with a history of plaque psoriasis.
Figure 11.
Erythrodermic psoriasis.
2.6. Nail psoriasis
Approximately 50% of all patients with psoriasis develop characteristic nail changes as a clinical correlate of psoriatic inflammation of the nail matrix and/or nail bed. The most frequent signs of nail psoriasis are pitting and distal onycholysis [27]. Clinical manifestations range from pitting, yellowish discoloration, and paronychia, to subungual hyperkeratosis, onycholysis, and severe onychodystrophy (Figure 12) [28].
Figure 12.
Yellowish discoloration of fingernails.
2.7. Psoriatic arthritis
Psoriatic arthritis (PsA) is a chronic inflammatory joint disease occurring in 6–39 % of patients with psoriasis with a prevalence of PsA in the general population of about 0.1–0.25 % [29] [30]. Based on the several common clinical and radiological features, PsA is considered as a member of the family of spondyloarthritides [31]. This type of arthritis can be slow to develop and mild or it can develop rapidly. PsA can be a severe form of arthritis with prognosis similar to that of rheumatoid arthritis (RA) [32]. Psoriatic arthritis (PsA) is characterized by focal bone erosions mediated by osteoclasts at the bone–pannus junction. Importantly, 80% of patients with psoriatic arthritis have nail psoriasis (Figure13) [33]. Recognition of bone as an active organ that interacts with its environment is a relatively new development. In the pathogenesis of bone destruction associated with rheumatoid arthritis, the synovium is a site of active interplay between immune and bone cells. The interaction between T cells and osteoclasts is a critical issue in the field of osteoimmunology [34]. Further differentiate mechanisms of bone resorption and repair in PsA and RA and likely will uncover additional therapeutic targets [35].
Figure 13.
Psoriatic arthritis hand changes over time.
3. Pesoriasis causes
Psoriasis – Pathogenesis\n\t\t\t
Today, psoriasis is recognized as the most prevalent autoimmune disease caused by inappropriate activation of the cellular immune system. There are two main hypotheses about the process that occurs in the development of Psoriasis. The first considers psoriasis as primarily a disorder of excessive growth and reproduction of skin cells. The problem is simply seen as a fault of the epidermis and its keratinocytes and is characterized by hyperproliferation with incomplete differentiation of epidermal keratinocytes and decreased keratinocyte apoptosis. The second hypothesis sees the disease as being an immune-mediated disorder (immunosuppressant medications can clear psoriasis plaques) in which the excessive reproduction of skin cells is secondary to factors produced by the immune system. T cells become active, migrate to the dermis and trigger the release of cytokines which cause inflammation and the rapid production of skin cells. It is not known what initiates the activation of the T cells. That work initially pointed towards a major role of T lymphocytes as inducers of the disease phenotype and the pathogenic contribution of this cell type has now been tested through clinical studies of more than a dozen immune modifying biological agents in patients with psoriasis. The inflammatory cytokines such as tumor necrosis factor (TNF) are likely to play major pathogenic roles in this disease and that other types of inflammatory leucocytes may also serve key pathogenic functions. Here we will review some recent works on psoriasis that advances our overall understanding of disease pathophysiology regarding neuroendocrine immunology. The concept of Psoriasis & Supersystems considers site of recognition, skin barrier in the sympathetic nervous (beta2 adenoceptors) and immune systems.
Psoriasis & supersystems
The brain and the immune system, or the “supersystems”, a term recently coined by Tada (1997), are the two major adaptive systems of the body [36]. Although the immune system has been often regarded as autonomous, the last two to three decades provided strong evidence that the central nervous system (CNS) receives messages from the immune system and vice versa messages from the brain modulate immune functions. Thus, the brain and the immune system are involved in functionally relevant cross-talk, whose main function is to maintain homeostasis [37]. In psoriasis it seems that the most important components of these supersystems are ß2 adenoceptors and tumor necrosis factor alpha (TNFα). Recent studies show that the ß2-adrenergic receptor is specifically associated with the homeostasis of skin barrier. Ca has critical role in this function. Increasing evidences indicate that TNF may have immunosuppressive effects, since long-term exposure to TNF can directly prevent the activation of T cells. ß2-adrenergic receptor interacts with TNFα which is evaluated in below, respectively.
3.1. Skin’s barrier function
3.1.1. Homeostasis of skin barrier: Self-referential system
The skin barrier homeostatic function is a self-referential system because it is always monitoring its original function, i.e., water impermeability. This function is regulated by the peripheral function [38]. Epidermal homeostasis is understood as the maintenance of epidermal tissue structure and function by a fine tuned regulatory mechanism balancing proliferation and cell loss by desquamation and apoptosis [39]. Stem cells of the basal layer or stratum basal in the epidermis have a crucial role in maintaining tissue homeostasis by providing new cells to replace those that are constantly lost during tissue turnover or following injury [40]. cAMP and calcium influence the formation and maintenance of barrier function [41].
3.1.2. Skin: An indispensable and protective barrier
The first protective barrier is provided by the skin, our largest organ. It serves as the interface between the organism and the outside world and it serves many functions, such as the retention of body fluids, maintenance of body temperature, and protection against UV-light, chemical influxes, wounds, and the invasion of micro-organisms. The protective barrier function is performed by the keratinocytes of the epidermis, which are continuously produced by proliferating stem cells of the basal layer or stratum basal and differentiate during a 14 day journey towards the surface [42].
Stratum corneum (SC) & Ceramides (family of lipid molecules)
Epidermal barrier capacity is controlled by lipids that fill the extracellular space of the skin\'s surface layer-the stratum corneum. Lipid synthesis for skin barrier function takes place within the keratinocytes in all nucleated epidermal layers. Lipids are stored within the epidermal lamellar bodies (secretory organells) or keratinosomes, which are ultrastructurally visible at the level of the upper spinous layer and in the granular layer. In the outermost granular layer, the contents of lamellar bodies are secreted into the intercellular domains of the stratum granulosom–stratum corneum interface. Lamellar bodies mainly contain phospholipids, glucosylceramides and cholesterol as well as hydrolytic enzymes, which convert phospholipids, glucosylceramides and sphingomyelinase to free fatty acids and ceramides. Then, lamellar bodies cause in the formation of an impermeable, lipid-containing membrane that serves as a water barrier and is required for correct skin barrier function. The Stratum Corneom (SC) contains three types of lipids -- ceramides, cholesterol and free fatty acids. These lipids have different chemical compositions and different functions throughout the body. There are nine different types of ceramides in the Stratum Corneom, conveniently named ceramide 1 through ceramide 9, and they account for 40-50% of the lipids in this outermost layer. A ceramide is composed of sphingosine and a fatty acid. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer. Ceramide can actually act as a signaling molecule. The most well-known functions of ceramides as cellular signals include regulating the differentiation, proliferation, programmed cell death (PCD), and apoptosis (Type I PCD) of cells [43].The proliferation rate of keratinocytes to corneocytes is matched by the shedding of old corneocytes at the SC [44] and skin tissue maintains a steady number of SC layers regardless of age [45].
Desquamation, the process of cell shedding from the surface of the stratum corneum, balances proliferating keratinocytes that form in the stratum basale. These cells migrate through the epidermis towards the surface in a journey that takes approximately fourteen days. During cornification, the process whereby living keratinocytes are transformed into non-living corneocytes, the cell membrane is replaced by a layer of ceramides which become covalently linked to an envelope of structural proteins (the cornified envelope). This complex surrounds cells in the stratum corneum and contributes to the skin\'s barrier function [41]. SC serves as the principal barrier against the percutaneous penetration of chemicals and microbes and is capable of withstanding mechanical forces [46].
Stratum corneum (SC) & Proteases (kallikrein family of serine proteases)
Interestingly, two major proteases of stratum corneum SCCE/KLK7/hK7 and SCTE/KLK5/hK5 together can destroy three major components of the corneodesmosomes: DSC1, DSG1 and CDSN [47]. These enzymes belong to kallikrein family of serine proteases. Their expression starts in suprabasal keratinocytes where their inactive precursors undergo a processing by an unidentified trypsin-like protease [48]. In stratum corneum, these enzymes appear in the intercellular spaces suggesting their involvement in the desquamation [49]. Recent discoveries have highlighted the importance of various proteases, protease-inhibitors, and protease targets as key players in epidermal barrier function [50]. It has become clear in recent years that serine proteases have an important role in epidermal homeostasis, and the signaling cascades are gradually being identified [41].
3.1.4. Skin: Epidermal proteases
The specific differentiation program in stratified skin requires a specialized proteolytic system to detach the corneocytes from each other without causing a barrier defect. A number of different proteases have been reported to be involved in the desquamation process and to contribute to the barrier function of the skin. Based on their proteolytic domain, proteases are classified into serine, threonine, cysteine, aspertate, metallo, and glutamate proteases. Especially serine proteases (SPs) seem to be involved in epidermal permeability barrier homeostasis as it was reported that SP activity was increased after acute barrier disruption and that blockade by topical SP inhibitors accelerated barrier recovery after acute abrogation [51].
The Epidermal junction (EJ) plays a crucial role in the formation and maintenance of epithelial and endothelial barriers. The EJ is a complex basement membrane synthesised by basal keratinocytes and dermal fibroblasts. It plays a fundamental role as a mechanical support for the adhesion of the epidermis to the dermis and regulates the exchanges of metabolic products between these two compartments; besides, it serves as a support for keratinocytes migration during wound healing, and is traversed by various cell types (LC, lymphocytes...) during immunologic and inflammatory processes [52]. Basal keratinocytes are connected to adjacent cells by several types of intercellular junctions (including gap and adherens junctions), the most characteristic of which are the desmosomes. Formation of adherens junctions and desmosomes requires extracellular calcium [53].
Summary 1: Psoriasis & skin’s barrier function
Although the Psoriasis is a multifactorial disease, the studies show that disruption the homeostasis in skin’s barrier is the main factor. Several factors interfere of hemostatic establishment in skin. 1) Heterogeneous Structure (lipid/protein) of this barrier that is the main cause of hemostasis. This two compartment structures is renewed continuously and when the barrier function is damaged, it is repaired immediately. 2) Several proteases important for desquamation (skin shedding). 3) The Epidermal junction (EJ) plays a crucial role in the formation and maintenance of epithelial and endothelial barriers. Formation of adherens junctions and desmosomes requires extracellular calcium. Raising the calcium concentration in the cell culture medium from 0.05 to 1.2mM [53] stimulates keratinocytes to form strong cell-cell adhesions in vitro. 4) In epidermal keratinocytes, both extracellular and intracellular Ca++ is reported to be important to cell differentiation and proliferation.
The skin is a complex organ containing afferent and efferent neural networks, glands, blood vessels, smooth muscle elements, connective tissues and immune cells, many of which are modulated by catecholamines and glucocorticoid hormones. Glucocorticoids and catecholamines reach skin tissues as circulating hormones and catecholamines are released in skin by projections of the sympathetic nervous system. The sympathetic division of the autonomic nervous system within the skin is supplied by postganglionic fibers of the paravertebral chain ganglia. Catecholamines also are produced locally by keratinocytes [54] [55].
3.2.1. Skin’s Beta2 adrenergic receptors (β-ARs)
Beta2 adrenergic receptors were identified in keratinocytes more than 30 years ago, but their function in the epidermis continues to be elucidated [56]. The β-adrenergic (β-ARs) agonists are capable of modulating the two distinct components of keratinocyte directional migration via divergent signaling pathways: 1) migration rate via a cAMP-independent, mitogen-activated-protein-kinase-dependent pathway [57] and 2) galvanotaxis by a cAMP-dependent one. Previous data have shown that both endogenous and exogenous catecholamines act to attenuate the permeability response to various inflammatory mediators via β1- [58] and β2-adrenoceptors [59] [60] [61] [62]. Additionally, because β-adrenergic agonists and antagonists modulate both keratinocyte migration and galvanotaxis, they could be valuable tools for controlling reepithelialization and restoration of barrier function, an essential component of the wound healing process.
3.2.2. β-ARs signaling cascade
In skin, it has been proposed that epinephrine activates keratinocyte beta2AR to modulate calcium influx and begin the differentiation cascade crucial to the native architecture of the epidermis [54]. The beta2AR desensitizes upon repeated activation through several mechanisms, including downregulation of the number of beta2AR receptors [63] [64]. Indeed, beta2AR expression is more highly expressed at the basal layers of the epidermis and decreases in expression toward the stratum corneum [54], suggesting that epinephrine may be activating the receptor to increase intracellular calcium levels and induce differentiation.
The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. The PDE superfamily of enzymes is classified into 11 families, namely PDE1-PDE11, in mammals. PDEs have different substrate specificities. Some are cAMP-selective hydrolases (PDE4, 7 and 8); others are cGMP-selective (PDE5, 6, and 9). A phosphodiesterase type 4 inhibitor, commonly referred to as a PDE4 inhibitor, is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). It is a member of the larger family of PDE inhibitors. The PDE4 family of enzymes is the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system [65]. Since the late 1980s, PDE4 inhibitors have been under investigation as anti-inflammatory therapies against asthma and chronic obstructive pulmonary disease. Due to the broad anti-inflammatory activity of PDE4 inhibitors, their possible use in the treatment of atopic dermatitis and psoriasis was examined.
In psoriasis, keratinocytes within the psoriatic lesions demonstrate a low cAMP response to ß2-AR activation [66]. These findings point to a role for the cutaneous ß2-AR network in maintaining epidermal function and integrity. Moreover, it has also been shown that ß2-AR density in the human epidermis depends on the calcium concentration [67] [54], where undifferentiated keratinocytes express approximately 7500 AR per cell and differentiated keratinocytes express only 2500 receptors underlining an important function for the 2-AR in the differentiation process in human skin [68]. Stimulation of the beta2-AR leads to a transient increase in the keratinocyte intracellular calcium concentration [69] [70] and this likely occurs through several signaling cascades. The mean increase in intracellular calcium of psoriatic keratinocytes was significantly reduced compared with control keratinocytes when intracellular calcium stores were mobilized from endoplasmic reticulum with thapsigargin (an inhibitor of the endoplasmic reticulum Ca2+ ATPase was used to empty the Ca2+ stores from endoplasmic reticulum) [71].
It has already been established that the skin is an important peripheral neuro-endocrine-immune organ that is tightly networked to central regulatory systems. These capabilities contribute to the maintenance of peripheral homeostasis. Skin cells and skin as an organ coordinate and/or regulate not only peripheral but also global homeostasis. Activation of the sympathetic system is the most common studied in literature, but other possibilities have to be considered, like impairment of epidermal barrier function, which is already described. ß2-AR density in the human epidermis depends on the calcium concentration and calcium plays an important part in the regulation of proliferation and differentiation of keratinocytes.
3.3. Skin’s immunity function: Keratinocytes as immune sentinels
Keratinocytes can sense pathogens and mediate immune responses to discriminate between harmless commensal organisms and harmful pathogens. Keratinocytes are continuously in contact with external stimuli and have the capacity to produce several soluble mediators. Pathogen-associated molecular patterns (PAMPs) are recognized, among others, by Toll-like receptors (TLRs). Epidermal keratinocytes express several TLRs, located either on the cell surface (TLR1, TLR2, TLR4, TLR5 and TLR6) or in endosomes (TLR3 and TLR9) [72]. Keratinocytes are also an important source of chemokines and express chemokine receptors, and therefore can modulate an immune response by attracting different cell types into the skin.
3.3.1. Keratinocytes as a secretory organ of cytokines
Keratinocytes produce a wide array of cytokines, including tumor necrosis factor and interleukin 1α (IL-1α), IL-1β, and IL-6. Disruption of the permeability barrier increases the expression of these cytokines [73] [74]. Studies in mice deficient in these cytokines or their receptors have shown delays in permeability barrier recovery after acute disruption, suggesting that the increased cytokine production facilitates barrier repair [75] [76]. Cytokines are well known to stimulate lipid synthesis and metabolism, and one could anticipate that an increase in epidermal lipids induced by cytokines could facilitate lamellar body formation and permeability barrier recovery [75] [77] [78].
3.3.2. Sympathetic regulation of innate immunity
Activation of the sympathetic nervous system (noradrenergic nerves and adrenal medulla) exerts a potent anti-inflammatory action upon the innate immune system. Adaptive immune cells are known to express primarily the β2AR, while innate immune cells appear to express the β2AR, a1AR, and a2AR. In the case of adaptive immune responses, however, signals from the brain are transmitted back to the periphery, primarily via activation of the HPA and the SNS [79]. The magnitude of an adaptive immune response appears to be regulated by the release of norepinephrine within the direct vicinity of activated CD4+ T cells and B cells located within lymphoid tissue. The released norepinephrine stimulates the β2AR expressed on the immune cells to regulate the level of gene activity. The immune cell self-regulated immune response develops and progresses normally with the participation of norepinephrine to regulate the level of the response in an attempt to maintain immune homeostasis [80]. The importance of sympathetic nervous system has been studied in skin disorders. In vitiligo, there is a dysregulation of catecholamine biosynthesis with increased plasma and epidermal noradrenaline levels associated with high numbers of β2-ARs in differentiating keratinocytes and with a defective calcium uptake in both keratinocytes and melanocytes. In atopic eczema, a point mutation in the β-AR gene could alter the structure and function of the receptor, thereby leading to a low density of receptors on both keratinocytes and peripheral blood lymphocytes [81]. In psoriasis, β-ARs are downregulated, because the increased circulating levels of catecholamines have been observed in psoriatic patients [82] [83] [84] and a 10-fold increase in the expression of the Phenylethanolamine N-methyltransferase (PNMT), the epinephrine sythetic enzyme is also found in basal keratinocytes in involved psoriatic epidermis [85]. It is tempting to propose that long-term exposure to increased levels of catecholamines, in the circulation or locally derived by the keratinocytes themselves, in combination with increased desensitization of beta 2AR in individuals, may predispose to psoriasis. Cathecolamines regulate the immune system at regional, local and systemic levels via adrenergic receptors expressed on immune cells [86] and interestingly, β-AR blockers may cause this inflammatory autoimmune skin disease [87] [88].
3.3.3. Psoriasis & immune system
Psoriasis is a chronic inflammatory, immune-mediated skin disease, which affects 2%-3% of the population worldwide [89]. Psoriasis was until recently regarded as a T-cell-driven disease with presumed (auto) immune mechanisms as its primary cause [90] [91].
3.3.4. Psoriasis & the innate immune system
The innate immune system provides the first line of defense against infection by detecting the presence of invading pathogens in a non-specific manner. Cells of the innate immune system include macrophages, dendritic cell (DC), monocytes, neutrophils, mast cells, natural killer (NK), NKT cells and γδ T cells. Innate immune cells recruit additional leukocytes to the site of inflammation by releasing cytokines and chemokines. Many innate immune cells can also directly kill invading pathogens. In addition, the innate immune system plays a crucial role in the initiation and direction of the adaptive immune response. Mechanisms regulating barrier integrity and innate immune responses in the epidermis are important for the maintenance of skin immune homeostasis and the pathogenesis of inflammatory skin diseases [92].
3.3.5. Is psoriasis a result of the bidirectional communication between the nervous and immune systems?
The existence of an association between the brain and immunity has been documented. Data show that the nervous and immune systems communicate with one another to maintain immune homeostasis. Activated immune cells secrete cytokines that influence central nervous system activity, which in turn, activates output through the peripheral nervous system to regulate the level of immune cell activity and the subsequent magnitude of an immune response. One key mechanism responsible for such coordination involves the autonomic nervous system (norepinephrine), which serves as the messenger from the mind to the body for all organ systems, including the immune system [93]. The antigen-activated immune system regulates CNS activity through the release of cytokines that bind to receptors located peripherally on the vagus nerve or sympathetic nerve terminals or centrally within the CNS or at the blood-brain barrier. Subsequently, the CNS communicates back to the immune system by activating the SNS or the HPA to release the neurotransmitter norepinephrine or a corticosteroid hormone, respectively. Lymphocytes express receptors that bind norepinephrine and corticosteroids, providing a mechanism for these ligands to activate intracellular signaling pathways, which regulate the level of immune cell activity. A bidirectional communication between the nervous and immune systems is to maintain homeostasis, whether this requires an increase or decrease in immune cell activity. Also, skin-brain axis fMRI studies on patients with psoriasis have revealed that the processing of facial expressions of disgust is significantly impaired in subjects with psoriasis as compared with normal controls in that blood flow in the anterior insular cortex is reduced. This appears to be a coping mechanism [94].
Summary 3: Psoriasis & neural immunoregulation
The brain and the immune system are the two major adaptive systems of the body. During an immune response the brain and the immune system “talk to each other” and this process is essential for maintaining homeostasis. Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs. The immune cell self-regulated immune response develops and progresses normally with the participation of norepinephrine to regulate the level of the response in an attempt to maintain immune homeostasis. Cathecolamines regulate the immune system at regional, local and systemic levels via adrenergic receptors expressed on immune cells.
3.4. Psoriasis comorbidities: Overactivity of sympathetic nervous system
The more common comorbidities include psoriatic arthritis and anxiety/depression disorder [95] [96]. More recently, psoriasis has also been reported to be associated with metabolic disorders including obesity, dyslipidaemia and diabetes [97] [98]. Moreover, an increased mortality from cardiovascular disease in patients with severe psoriasis has been documented, and psoriasis may confer an independent risk of myocardial infarction especially in young patients [99].
3.4.1. Psoriasis & metabolic syndrome
Recent studies of epinephrine stimulation at the β2 adrenergic receptor reveal important potential long-term beneficial effects in the metabolic syndrome [100]. The association between psoriasis and metabolic disorders such as obesity, dyslipidemia, and type 2 diabetes has shown that severe psoriasis might be associated with increased mortality rate due to cardiovascular disorders [97] [98] [101].
3.4.2. Psoriasis & cardiovascular disease
The study by Gelfand et al. in 2006 indicated that patients with psoriasis are more likely than the general population to have diabetes, high cholesterol, and other “traditional” risk factors for heart disease [99] [102]. Recent studies suggest that psoriasis, particularly if severe, may be an independent risk factor for atherosclerosis, myocardial infarction (MI), and stroke. Mehta et al. in 2010 conducted a cohort study using the General Practice Research Database to determine if severe psoriasis patients have an increased risk of cardiovascular (CV) mortality [103].
3.4.3. Shared risk factors
The existence of shared risk factors between psoriasis and both CV and metabolic conditions has been shown in several epidemiological studies which demonstrate that the same co- morbidities are present in psoriasis patients, regardless of age or ethnicity [104] [105].
Summary 4: Conclusive remarks
This review shows that the overactivity of sympathetic nervous system occurs in Psoriasis disease. Abnormalities of β-ARs in their expression, signaling pathway, or in the generation of endogenous catecholamine agonists by keratinocytes have been implicated in the pathogenesis of cutaneous diseases such as atopic dermatitis, vitiligo and psoriasis. These studies suggest that mainly the localization of Beta2-adrenergic receptors in the epidermis and play an important part in the calcium dynamics and barrier homeostasis of epidermal keratinocytes [106].The decrease expression of beta2 adrenergic receptor mRNA in involved psoriatic epidermis shown by RT-PCR [107]. Together, these findings suggest that the downregulation of the number of beta adrenergic receptors, rather than an inherent defect in the receptor itself, is the mechanism that is responsible for the reduced beta-adrenergic responsiveness seen in psoriatic epidermis. This decreased response to endogenous agonists then results in a decrease in intracellular cAMP and thus an increase in keratinocyte proliferation. This downregulation can be about overactivity of sympathetic nervous system. Polimorphism studie show that inactivity of Beta2 adrenoceptor is the main cause in this disorder. Beta2 antagonists wreck this condition and reduction of cAMP could cause disruption in skin barrier hemostasis. Freund et al. in 2012 have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF-α, IL-2, IFN-γ, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis [108]. However, it may be that currently utilized therapies also work by modifying this signaling pathway. For example, vitamin D, currently used as a topical treatment of psoriasis, has been shown to increase the generation of cAMP in response to betaAR agonists [109] Glucocorticoids, the mainstay of topical therapy for psoriasis, increase both the expression of beta2AR in keratinocytes, and the generation of cAMP in response to agonists [110]. UVB irradiation, another mainstay in the treatment of psoriasis, has been shown to increase beta2AR-mediated cAMP accumulation [111].
4. Psoriasis — Medication
Psoriasis is skin disease with unknown etiology. There is no cure for psoriasis, but there are many treatments that can decrease the symptoms and appearance of the disease.
Treatment options
In general, there are three treatment options for patients with psoriasis: Phototherapy, topical and systemic. A combination of therapies is often recommended. Combining various topical, systemic and light treatments often allows lower doses of each and can result in increased effectiveness.
4.1. Topical treatment: Topical drugs
First line management of adult mild-to-moderate adult plaque psoriasis is with topical treatment, including vitamin D analogues and topical corticosteroids. Topical therapies are indicated for patients whose affected area is < 10% of the body surface area (BSA). Topical vitamin D analogues (VD) and topical steroids (TS) are both widely used topical treatments for psoriasis. Calcipotriol is a vitamin D analogue that regulates epidermal cell proliferation and differentiation, as well as production and release of pro-inflammatory cytokines. TS present a wide range of biological effects such as inhibition of the recruitment and migration of inflammatory cells, modulation of cytokine synthesis, chemokines release and regulation of DNA synthesis [112].Topical corticosteroids are available in different potencies and formulations but despite more than 40 years of experience, their use remains mostly based on individual experience. Published guidelines often specify the place of topical steroids within psoriasis treatment strategies [113] [114] [115] but not the efficacy and practical modalities of use. It should be noted that the majority of adverse events seen with topical therapies are cutaneous rather than systemic in nature and that the risk–benefit ratio for these patients is better with topical therapies than with biological [116].
4.2. Light therapy (phototherapy)
Solar ultraviolet (UV) radiation has been used since ancient times to treat various diseases. This has a scientific background in the fact that a large number of molecules (chromophores) in different layers of the skin interact with and absorb UV. These interactions may have both positive and negative biological implications. Most of the positive effects of solar radiation are mediated via ultraviolet-B (UVB) induced production of vitamin D in skin [117]. In our day’s phototherapy is a valuable option in the treatment of many psoriatic and nonpsoriatic conditions, including atopic dermatitis, sclerosing skin conditions such as morphea, scleroderma, vitiligo, and mycosis fungoides [118]. UVB radiation reaches the epidermis and the upper dermis where it is absorbed by DNA, trans-urocanic acid (trans-UCA), and cell membranes [119]. Absorption of UVB by nucleotides leads to the formation of DNA photoproducts, primarily pyrimidine dimers. UVB exposure reduces the rate of DNA synthesis. In addition, UVB radiation causes photoisomerization of trans-UCA to cis-UCA which has immunosuppressive effects. Furthermore, UV radiation can affect extranuclear molecular targets (cell surface receptors, kinases, phosphatases, and transcription factors) located in the cytoplasm and in the cell membanes [119]. Keratinocytes, circulating and cutaneous T lymphocytes, monocytes, Langerhans cell, mast cells and fibroblasts are all targeted by narrowband UVB [119]. Narrowband UVB induces also local and systemic immunosuppressive effects which may particularly contribute to the beneficial effects of this light source. UVA radiation penetrates more deeply into the skin than UVB, and reaches not only epidermis, but also dermis with blood vessels affecting dermal dendritic cells, dermal fibroblasts, endothelial cells, mast cells, and granulocytes [120]. UVA radiation is absorbed by pyridine nucleotides (NAD and NADP), riboflavins, porphyrins, pteridines, cobalamins and bilirubin [120] Porphyrins and riboflavins are photosensitizers. UVA effects are dominated by indirect DNA damage caused by reactive oxygen species such as singlet oxygen. The ability of UVA radiation to cause skin erythema is approximately 103 to 104 times lower than that of UVB. As UVA-1 is even less erythematogenic than broadband UVA much higher doses of UVA-1 can be tolerated by the patients. UVA-1 phototherapy works mainly through induction of apoptosis of skin infiltrating T cells, T-cell depletion and induction of collagenase-1 expression in human dermal fibroblast [121] [122].
Sunlight: Already several thousands of years ago sunlight (heliotherapy) was used to treat a variety of skin conditions in Egypt, Greece and Rome [123]. Ultraviolet (UV) light is a wavelength of light in a range too short for the human eye to see.
UVB phototherapy: Controlled doses of UVB light from an artificial light source may improve mild to moderate psoriasis symptoms. UVB phototherapy, also called broadband UVB, can be used to treat single patches, widespread psoriasis and psoriasis that resist topical treatments.
Narrowband UVB therapy: A newer type of psoriasis treatment, narrowband UVB therapy may be more effective than broadband UVB treatment. It\'s usually administered two or three times a week until the skin improves, then maintenance may require only weekly sessions.
Goeckerman therapy: The combination of UVB treatment and coal tar treatment is known as Goeckerman treatment. The two therapies together are more effective than either alone because coal tar makes skin more receptive to UVB light.
Photochemotherapy: Photochemotherapy involves taking a light-sensitizing medication (psoralen) before exposure to UVA light. UVA light penetrates deeper into the skin than does UVB light and psoralen makes the skin more responsive to UVA exposure.
Excimer laser: This form of light therapy, used for mild to moderate psoriasis, treats only the involved skin. A controlled beam of UVB light of a specific wavelength is directed to the psoriasis plaques to control scaling and inflammation. Healthy skin surrounding the patches isn\'t harmed.
Pulsed dye laser: Similar to the excimer laser, the pulsed dye laser uses a different form of light to destroy the tiny blood vessels that contribute to psoriasis plaques.
Systemic treatment: Oral or injected medications
Patients with moderate to severe disease generally require systemic agents (e.g. cyclosporin, methotrexate, oral retinoids, fumaric acid esters) to control their disease adequately. The severity of psoriasis traditionally has been evaluated by objective measurement of the extent of the body surface affected and consideration of the subtype of psoriasis, degree of disability, and feasibility of topical therapy [124].
Retinoids: Several systemic retinoids (derivatives of vitamin A) have been developed for the treatment of psoriasis. Systemic retinoids are known to have immunosuppressive and anti-inflammatory activity and to modulate epidermal proliferation and differentiation [125]. As mentioned previously, clinical data suggest that combination retinoid–PUVA therapy may be more effective than either treatment alone, and may minimize the toxicities associated with each modality through dose-sparing or independent chemopreventive effects [126] [127].
Methotrexate (MTX): It was introduced as a therapy for psoriasis in 1958 (Edmomudson et al., 1958). Taken orally, methotrexate helps psoriasis by decreasing the production of skin cells and suppressing inflammation. It may also slow the progression of psoriatic arthritis in some people. Methotrexate is generally well tolerated in low doses. Hepatic fibrosis typically occurs after total cumulative MTX doses of at least1.5 g. [128]. The risk of hepatotoxicity may decrease if MTX is given in short courses and rapidly discontinued after clinical improvement [129].
Cyclosporine: It was first used (inadvertently) for the treatment of psoriasis in 1979 [130]. Cyclosporine suppresses the immune system and is similar to methotrexate in effectiveness. Major toxicities associated with cyclosporin therapy include nephrotoxicity, hypertension and immunosuppression
Fumaric acid esters (FAE): Oral FAE therapy for psoriasis was first reported in 1959. Dimethylfumarate, and its metabolite monomethylfumarate, appear to be the principal active components of Fumaderm®. Treatment with dimethylfumarate and/or monomethylfumarate produces a beneficial shift towards Th2-like cytokine secretion associated with a reduction in peripheral lymphocytes (primarily T cells) [131] and inhibits the proliferation of epidermal keratinocytes in patients with psoriasis. Haematological changes, notably leucopenia, lymphopenia and eosinophilia, are frequently observed during FAE therapy [132].
Tumour necrosis factor alpha (TNFα) inhibitors: It is known that TNF alpha is elevated in both the skin and synovium of psoriatic patients and the effectiveness of its blockade by these two agents in psoriasis and Psoriatic arthritis (PsA) confirms its role in their pathogenesis. TNFi (infliximab, etanercept and adalimumab) revolutionised the treatment of autoimmune diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn\'s disease (CD) and plaque psoriasis. Anti-TNF alpha therapy has proved to have disease-reducing activity in PsA and psoriasis and appears to be well tolerated [133]. The widespread use of TNFalpha antagonists in recent years has led to the recognition of paradoxical adverse effects, defined as the onset or exacerbation of disorders that are usually improved by TNFalpha antagonists [134]. During these treatments, cutaneous adverse effects may occur like eczema, lupus, alopecia areata or psoriasis, which represents a paradoxical adverse effect.Then, therapy with TNF α inhibitors can be associated with paradoxical reactions. They are considered a class effect of these drugs, and their incidence ranges from 1 to 5%, with paradoxical psoriasis (psoriasis vulgaris, palmoplantar pustulosis, scalp psoriasis and their combinations) being most frequently reported [135].
Phosphodiestrase inhibitors: Phosphodiesterases play a pivotal role in degrading cyclic nucleotides (cGMP, cAMP), key second messengers in all cells. Particularly cAMP plays an important regulatory role in virtually all the cell types involved in the pathophysiology of allergic and inflammatory diseases including asthma and chronic obstructive pulmonary disease, but also skin diseases including atopic dermatitis and psoriasis. Of the cAMP-degrading PDEs, PDE4 is the one that has been studied most extensively in recent years. PDE4 is abundant, and is the major cAMP-degrading isoenzyme in almost all inflammatory and immune cells. In spite of varied structurallasses, highly selective PDE4 inhibitors have the same quality in suppressing several pro-inflammatory mechanisms likecytokine generation and secretion, superoxide generation, degranulation, IgE production, proliferation, histamine generation and chemotaxis [136] [137]. The PDE4 family comprises four genetically distinct subtypes (PDE4 A-D). These subtypes differ with respect to their regulatory behaviour and tissue expression patterns. The search for selective inhibitors of PDE4 as novel anti-inflammatory drugs has continued for more than 30 years and almost two decades have passed since targeting PDE4 became a focus in the development of novel therapeutics for pulmonary inflammatory diseases. The development of PDE4 inhibitors with PDE4B selectivity has been considered a promising approach because much evidence demonstrates that ablation or inhibition of PDE4B produces a broad spectrum of anti-inflammatory effects while minimizing unwanted side effects [138] [139]. Nazarian et al.’s studies in 2009 showed that AN-2728 (PDE4) is well tolerated and demonstrates significant effects on markers of efficacy, with results that were comparable to positive controls. AN-2728 appears to have good therapeutic potential, although further and larger trials are required to assess the long-term safety and characterize the broad utility of this drug [140]. Nevertheless, the impact of PDE4B-selective inhibitors on inflammatory diseases awaits further clinical trials. Several PDE4B and PDE4D selective inhibitors have been designed and synthesized, and their effects on inflammation are under investigation. Although several compounds have demonstrated therapeutic effects in diseases such as asthma, COPD, atopic dermatitis and psoriasis, none have reached the market. A persistent challenge in the development of PDE4 inhibitors has been drug-induced gastrointestinal adverse effects, such as nausea. Despite the challenges and complications that have been encountered during the development of PDE4 inhibitors, these drugs may provide a genuinely novel class of anti-inflammatory agents, and there are several compounds in development that could fulfill that promise [141]. McCann et al., in 2012 showed oral Apremilast targets PDE4 inhibitor, modulates a wide array of inflammatory mediators involved in psoriasis and psoriatic arthritis, including decreases in the expression of inducible nitric oxide synthase, TNF-α, and interleukin (IL)-23 and increases IL-10. In phase II studies of subjects with psoriasis and psoriatic arthritis, apremilast reversed features of the inflammatory pathophysiology in skin and joints and significantly reduces clinical symptoms. The use of an oral targeted PDE4 inhibitor for chronic inflammatory diseases, like psoriasis and psoriatic arthritis, represents a novel treatment approach that does not target any single mediator, but rather focuses on restoring a balance of pro-inflammatory and anti-inflammatory signals [142]. Now, several PDE4B and PDE4D selective inhibitors have been designed and synthesized, and their effects on inflammation are under investigation.
In summary: Managing psoriasis
Currently, there is no universal standard of care for patients with moderate to severe psoriasis, and the benefits and risks of systemic therapy must be weighed carefully for each patient to ensure optimal management of psoriasis symptoms and minimization of acute and cumulative toxicities [143]. Whether the symptoms are mild, moderate, or severe, the optimal treatment plan is the one the patient is most likely to follow. For those with localized disease, topical therapy is a suitable first choice. Phototherapy is generally the first-line treatment for patients with extensive psoriasis or disabling symptoms. When phototherapy is not feasible or is ineffective, systemic treatments with conventional oral agents or biologics are indicated [144]. Psoriasis is a common skin disorder that needs long-term management, not only because of its prevalence but also because of the profound impact it can have on quality of life.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/44173.pdf",chapterXML:"https://mts.intechopen.com/source/xml/44173.xml",downloadPdfUrl:"/chapter/pdf-download/44173",previewPdfUrl:"/chapter/pdf-preview/44173",totalDownloads:2554,totalViews:2478,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:0,dateSubmitted:"May 22nd 2012",dateReviewed:"October 29th 2012",datePrePublished:null,datePublished:"April 17th 2013",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/44173",risUrl:"/chapter/ris/44173",book:{slug:"psoriasis-types-causes-and-medication"},signatures:"F.Z. Zangeneh and F.S. Shooshtary",authors:[{id:"63574",title:"Dr.",name:"Farideh",middleName:"Zafari",surname:"Zangeneh",fullName:"Farideh Zangeneh",slug:"farideh-zangeneh",email:"zangeneh14@gmail.com",position:null,institution:{name:"Tehran University of Medical Sciences",institutionURL:null,country:{name:"Iran"}}},{id:"161653",title:"Dr.",name:"Fatemeh",middleName:null,surname:"Shooshtary",fullName:"Fatemeh Shooshtary",slug:"fatemeh-shooshtary",email:"fa.sarmast@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Psoriasis types",level:"1"},{id:"sec_2_2",title:"2.1. Classifying psoriasis: The spectrum of clinical varieties",level:"2"},{id:"sec_3_2",title:"2.2. Psoriasis vulgaris (chronic stationary psoriasis, plaque-like psoriasis)",level:"2"},{id:"sec_3_3",title:"2.2.1. Classification of psoriasis vulgaris according to phenotype: plaque-type psoriasis ",level:"3"},{id:"sec_4_3",title:"2.2.2. Plaque-type psoriasis: Chronic plaque psoriasis",level:"3"},{id:"sec_5_3",title:"2.2.3. Site-specific variants of Psoriasis Vulgaris (PV)",level:"3"},{id:"sec_7_2",title:"2.3. Guttate psoriasis",level:"2"},{id:"sec_8_2",title:"2.4. Pustular psoriasis: In a population survey of psoriasis, pustular lesions were reported at any time during the course of psoriasis by about 20% of patients [11]",level:"2"},{id:"sec_9_2",title:"2.5. Erythrodermic psoriasis",level:"2"},{id:"sec_10_2",title:"2.6. Nail psoriasis",level:"2"},{id:"sec_11_2",title:"2.7. Psoriatic arthritis ",level:"2"},{id:"sec_13",title:"3. Pesoriasis causes",level:"1"},{id:"sec_13_2",title:"3.1. Skin’s barrier function",level:"2"},{id:"sec_13_3",title:"3.1.1. Homeostasis of skin barrier: Self-referential system ",level:"3"},{id:"sec_14_3",title:"3.1.2. Skin: An indispensable and protective barrier",level:"3"},{id:"sec_15_3",title:"3.1.3. Skin: Epidermal barrier capacity (lipid/protein polymer structure)",level:"3"},{id:"sec_16_3",title:"3.1.4. Skin: Epidermal proteases ",level:"3"},{id:"sec_17_3",title:"3.1.5. Skin: Adherent junction proteins (Epidermal junction)",level:"3"},{id:"sec_19_2",title:"3.2. Skin’s sympathetic fibers: Neuroendocrin regulation",level:"2"},{id:"sec_19_3",title:"3.2.1. Skin’s Beta2 adrenergic receptors (β-ARs)",level:"3"},{id:"sec_20_3",title:"3.2.2. β-ARs signaling cascade",level:"3"},{id:"sec_21_3",title:"3.2.3. β2 adrenergic receptor (β-ARs): Phosphodiesterase",level:"3"},{id:"sec_22_3",title:"3.2.4. β2 adrenergic receptor (β-ARs): cAMP & Calcium",level:"3"},{id:"sec_24_2",title:"3.3. Skin’s immunity function: Keratinocytes as immune sentinels",level:"2"},{id:"sec_24_3",title:"3.3.1. Keratinocytes as a secretory organ of cytokines",level:"3"},{id:"sec_25_3",title:"3.3.2. Sympathetic regulation of innate immunity",level:"3"},{id:"sec_26_3",title:"3.3.3. Psoriasis & immune system ",level:"3"},{id:"sec_27_3",title:"3.3.4. Psoriasis & the innate immune system ",level:"3"},{id:"sec_28_3",title:"3.3.5. Is psoriasis a result of the bidirectional communication between the nervous and immune systems? ",level:"3"},{id:"sec_30_2",title:"3.4. Psoriasis comorbidities: Overactivity of sympathetic nervous system",level:"2"},{id:"sec_30_3",title:"3.4.1. Psoriasis & metabolic syndrome",level:"3"},{id:"sec_31_3",title:"3.4.2. Psoriasis & cardiovascular disease",level:"3"},{id:"sec_32_3",title:"3.4.3. Shared risk factors",level:"3"},{id:"sec_35",title:"4. Psoriasis — Medication",level:"1"},{id:"sec_35_2",title:"4.1. Topical treatment: Topical drugs ",level:"2"},{id:"sec_36_2",title:"4.2. Light therapy (phototherapy)",level:"2"}],chapterReferences:[{id:"B1",body:'Willan R.On Cutaneous Diseases. London: Johnson; 1808.'},{id:"B2",body:'Nestle FO, Kaplan DH, Barker J. Psoriasis. N. Engl. J. 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Dimethylfumarate is a potent inducer of apoptosis in human T cells. J Invest Dermatol 2003; 121: 1383–8.'},{id:"B132",body:'Mrowietz U, Christophers E, Altmeyer P. Treatment of severe psoriasis with fumaric acid esters: scientific background and guidelines for therapeutic use. The German Fumaric Acid Ester Consensus Conference. Br J Dermatol 1999; 141: 424–9.'},{id:"B133",body:'Tobin AM, Kirby B. TNF alpha inhibitors in the treatment of psoriasis and psoriatic arthritis. BioDrugs. 2005; 19: 47-57.'},{id:"B134",body:'Wendling D, Balblanc JC, Briançon D, Brousse A, Lohse A, Deprez P, Humbert P, Aubin F. Onset or exacerbation of cutaneous psoriasis during TNFalpha antagonist therapy. Joint Bone Spine. 2008; 75: 315-8. '},{id:"B135",body:'Puig L, Morales-Múnera CE, López-Ferrer A, Geli C. Ustekinumab Treatment of TNF Antagonist-Induced Paradoxical Psoriasis Flare in a Patient with Psoriatic Arthritis: Case Report and Review. Dermatology. 2012 Aug 10. (Epub ahead of print).'},{id:"B136",body:'Torphy TJ. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med. 1998; 157: 351-70.'},{id:"B137",body:'Houslay MD, Schafer P, Zhang KY. Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today. 2005; 10: 1503-19.'},{id:"B138",body:'Jin SLC, Richter W, Conti M. Insights into the physiological functions of PDE4 from knockout mice. In: Beavo JA, Francis SH, Houslay MD, eds. Cyclic Nucleotide Phosphodiesterases in Health and Disease Boca Raton, FL: CRC Press. 2007:323-46.'},{id:"B139",body:'Naganuma K, Omura A, Maekawara N, Saitoh M, Ohkawa N, Kubota T, Nagumo H, Kodama T, Takemura M, Ohtsuka Y, Nakamura J, Tsujita R, Kawasaki K, Yokoi H, Kawanishi M. Discovery of selective PDE4B inhibitors. Bioorg Med Chem Lett 2009; 19: 3174-6.'},{id:"B140",body:'Nazarian R, Weinberg JM. AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis. Curr Opin Investig Drugs. 2009; 10: 1236-42.'},{id:"B141",body:'Higgs G. Is PDE4 too difficult a drug target? Curr Opin Investig Drugs. 2010; 11: 495-8.'},{id:"B142",body:'McCann FE, Palfreeman AC, Andrews M, Perocheau DP, Inglis JJ, Schafer P, Feldmann M, Williams RO, Brennan FM. Apremilast, a novel PDE4 inhibitor, inhibits spontaneous production of tumour necrosis factor-alpha from human rheumatoid synovial cells and ameliorates experimental arthritis. Arthritis Res Ther. 2010; 12: R107. '},{id:"B143",body:'Naldi L, Griffiths CE. Traditional therapies in the management of moderate to severe chronic plaque psoriasis: an assessment of the benefits and risks. Br J Dermatol. 2005; 152: 597-615.'},{id:"B144",body:'Uhlenhake EE, Mehregan DA. Managing psoriasis: what\'s best for your patient? J Fam Pract. 2012; 61: 402-9, 451.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"F.Z. Zangeneh",address:"Zangeneh14@gmail.com",affiliation:'
Farideh Zafari Zangeneh, Vali-e-Asr, Reproductive Health Research Center, Imam Khomaini Hospital, Tehran University of Medical Sciences, Tehran, Iran
Farideh Zafari Zangeneh, Vali-e-Asr, Reproductive Health Research Center, Imam Khomaini Hospital, Tehran University of Medical Sciences, Tehran, Iran
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1. Introduction
Type A aortic dissection is a life threatening condition requiring emergency surgical intervention. Statistics show an incidence of approximately three cases per 100,000 per year [1, 2]. Data analysis from the International Registry of Acute Aortic Dissections (IRAD) reported a predominant male patient population and a mean age of 63 years at presentation [3]. Surgical repair for Type A Aortic dissection is challenging, the complexity proportionate to the location and extent of aortic tissue dissected, cardiac complications and end organ ischemia. The current standard surgical approach includes replacement of the aortic root (Bentall technique) or valve sparing root replacement, isolated ascending aorta replacement, and hemi or full arch replacement. Recent advances include frozen elephant trunk (FET) technique, total aortic repair, endovascular and hybrid approaches and stenting. All of these surgical approaches, including classification, clinical presentation, risk factors, diagnosis, pre-operative preparation, cannulation strategies, and cerebral protection will be discussed in this review.
2. Classification
The Stanford classification (1970) is the most commonly used system (Figure 1) [4]. It does not classify the site of tear. It is more of a clinically useful classification to guide acute management. Stanford type A involves ascending aorta proximal to innominate artery, irrespective of involvement of aortic arch or descending aorta. Stanford type B dissection involves only the thoracic aorta distal to the left subclavian artery [5]. Intimal tears originating distal to left subclavian artery but dissecting retrogradely into ascending aorta will be type A. Intimal tears starting in the aortic arch and extending into ascending aorta are type A and extending into descending aorta are type B. If the intimal tear is restricted to aortic arch, then it is type non-A non-B.
Figure 1.
Stanford and DeBakey classification.
The DeBakey type I involves ascending aorta and extends beyond the innominate artery. Type II involves only the ascending aorta. Type III involves thoracic aorta distal to left subclavian artery. It is more useful for long-term follow-up as it differentiates between proximal and distal aortic dissection extent (Figure 1) [4].
The Penn classification is a recently introduced method of classifying based on clinical presentation [6]. Class Aa—absence of branch vessel malperfusion or circulatory collapse; Class Ab—symptoms or signs of localised organ ischemia; Class Ac—circulatory collapse with or without cardiac involvement; Class Abc—combined localised and generalised ischemia.
3. Risk factors
Men form approximately 62–68% of all patients undergoing surgery [7]. The triad of hypertension (67–86% patients), smoking and atherosclerosis is an independent predictor of type A aortic dissection [8]. Data correlating the risk of aortic dissection in bicuspid aortic valve is limited and controversial. However, some centres advocate early prophylactic ascending aortic replacement in patients with aortas larger than approximately 5.0 cm in diameter or with a cross-sectional area to height ratio greater than approximately 10 cm2/m [9]. In the NORCAAD registry, 6% patients were reported to have bicuspid aortic valve [7]. The Marfan syndrome is present in around 4% of ATAAD patients in NORCAAD registry [10]. The patients typically have pear- shaped aneurysm of aortic root. Due to mutation in FBN1 gene, there is decreased strength and elasticity of elastin—rich tissue of aortic wall. Predominantly, medium and large sized arteries are involved in dissection (Table 1).
(1) Cardiovascular and life style factors
Uncontrolled hypertension
Age
Smoking
Dyslipidemia
Cocaine
Pregnancy
(2) Congenital and connective tissue
Bicuspid aortic valve
Marfan syndrome
(3) Iatrogenic
Coronary catheterisation
Arterial cannulation
Aortic cross clamping
IABP
(4) Vascular inflammation
Takayasu arteritis
(5) Trauma
Deceleration injury
Table 1.
Risk factors for acute aortic dissection.
4. Clinical presentation
TAAD patients (85%) typically present with sudden intense central chest pain (ripping or tearing) radiating to the neck, back or abdomen. [11]. ECG abnormalities (50% patients) include ST/T wave changes, conduction defects, and arrhythmias. This sometimes leads to the misdiagnosis of myocardial infarction leading to fatal mistake of giving antiplatelet therapy or thrombolysis. This delays the diagnosis and increases peri-operative bleeding complications. Aortic regurgitation (70% patients) can occur through prolapse of right or non- coronary valve cusps and detachment of commissures. Pulmonary oedema may occur through acute dilation of the left ventricle. Haemorrhagic pericardial tamponade is a very strong predictor of aortic dissection. Reduced or absent femoral pulses are seen. Neurological sequlae include syncope, stroke. Mal-perfusion of spinal cord leads to paraplegia. Acute renal failure and mesenteric ischemia are seen if the dissection involves descending thoracic and abdominal aorta [12]. Rupture of the aneurysm is immediately fatal.
5. Diagnosis
Clinical: Constellation of findings of chest pain, diastolic murmur, blood pressure difference in both upper limbs, pulse deficit, neurological sequelae are good indicators for TAAD [13].
Chest X ray (Figure 2) shows widened mediastinum (49% patients), which is non-specific [14].
ECG may show ST-T changes especially in right coronary territory, non-specific changes of left ventricle hypertrophy, pericardial effusion
CT scan (Figure 3): the most reliable diagnostic tool for acute aortic dissection. It is available in almost every hospital and can be rapidly performed. Sensitivity and specificity is excellent [15]
Figure 2.
Chest X-ray of a patient with ATAD showing a widened mediastinum.
Figure 3.
CT-scan of a patient with TAAD.
The following information may be provided from a CT-scan:
Detection of the true and false lumen in the dissected aorta
Identification of the site of the intimal tear The extent of the dissection
Arch vessel and thoracic and abdominal branch vessel involvement
Planning the site of cannulation
Limitations of CT-scanning include not providing information about dissection entry site and functional status of the heart.
TEE is portable, less invasive and has sensitivity and specificity approximately 100% [16]. It provides information about:
The dissection flap and false lumen in ascending aorta
The entry site of tear using colour Doppler
Coronary ostial obstruction due to the dissection
Dilation of aorta and left ventricle function
Pericardial effusion and tamponade
Aortic regurgitation and anatomy of aortic root
Has a better window than TTE to visualise aortic arch and descending aorta
Pleural effusion
Limitations include difficulty in visualisation of the proximal arch due to the interposition of bronchial air [17].
6. Magnetic resonance imaging (MRI)
MRI is an accurate investigative modality for acute aortic dissection (sensitivity and specificity, 98%) [18]. It is rarely used in the setting of TAAD where most of the patients are wheeled into operating room as soon as the diagnosis is made. It may have a small role in those patients allergic to iodinated contrast agents or in patients with acute renal failure who are stable enough to undergo MRI.
7. Preoperative coronary angiography:
Its role is controversial [19]. Justification of not performing cardiac catheterisation include risk of catheter induced aortic rupture and delaying surgery where percentage mortality increases by 1 % every hour [20].
6. Surgical strategies
6.1 Preparation for surgery
Blood pressure (BP) control: One of the most important pre-requisites of successful outcome is very strict control of BP. Systolic BP should be less than 110 mmHg. It can be lowered using intravenous beta blocker (esmolol) or combined alpha & beta receptor antagonists (labetalol) or glyceryl trinitrate. Intravenous adrenaline should be used in patients presenting with cardiogenic shock and cardiac tamponade. Anaesthetic induction is also another step where BP should be tightly controlled. Commonly used medications include Fentanyl, isoflurane and glyceryl trinitrate. Peri-operatively, a target systolic blood pressure of 90–110 mmHg, mean arterial pressure of 60 mmHg, and central venous pressure of 8–12 mmHg are recommended [21].
Coagulation status: Aortic dissection activates inflammatory, coagulation and fibrinolytic pathways leading to disseminated intravascular coagulation. Consumption coagulopathy is worsened in some patients by inadvertently prescribing aspirin, clopidogrel by misdiagnosing these patients as having acute coronary syndromes. Hence, adequate amounts of packed red blood cells, platelets, fresh frozen plasma and cryoprecipiate should be kept ready for use.
2 arterial lines (both arms) should be placed to monitor differential blood pressures.
Also include a femoral arterial line to monitor distal perfusion pressures
Cerebral oxygenation monitoring by near—infrared spectroscopy
Invasive monitoring of intracranial pressure by lumbar catheter (occasionally)
For many years, it has been the cannulation site of choice [22]. Allowing rapid access, it is usually used in hemodynamically unstable patients, especially with impending cardiac tamponade and aortic rupture. It is important to mark the femoral artery before skin preparation as it may be difficult to localise it during hypotension. Common femoral artery is situated medial and inferior to the midpoint of the inguinal ligament. An oblique or vertical incision may be used for exposure [23]. An open Seldinger technique is quick and can be performed with minimal dissection. Advantages of this approach include (i) cardiopulmonary bypass is established quickly, (ii) easy to access with a closed chest, (iii) less likely to be dissected, (iv) prevents aortic rupture in patients with cardiac tamponade. Disadvantages include (i) stroke and malperfusion due to dynamic obstruction and (ii) retrograde perfusion leading to embolic complications due to atherosclerotic emboli. The femoral artery with a dissection flap is not used for cannulation.
Introduced in 1990s [24], axillary artery cannulation is gaining greater acceptance among surgeons as they switch to an antegrade perfusion strategy. It is more commonly used in hemodynamically stable patients. Infraclavicular dissection exposes the first part of axillary artery [25]. The pectoralis major muscle is split. The neurovascular bundle is situated deep in the clavipectoral fascia. The deltopectoral approach exposes the second and third parts for cannulation [26]. The axillary artery can be directly cannulated or anastomosed with end to side 8 mm vascular graft. Advantages include (i) antegrade perfusion flow and (ii) can be used for antegrade cerebral perfusion by occluding innominate artery. Disadvantages of this approach include (i) takes more time than femoral cannulation especially in obese patients and (ii) technically more difficult and risk of injury to brachial plexus nerves.
Central aortic cannulation:
Locating a site where the chances of not entering into the false lumen is the most critical part. It can be done with TEE, CT or epiaortic scanning. Cannulation can be performed with Seldinger technique or directly. Advantages include (i) CPB established quickly in unstable patients and (ii) antegrade flow. Disadvantages include (i) rupture of cannulation site and (ii) false lumen perfusion [27].
Figure 5.
Femoral artery cannulation.
Figure 6.
Axillary artery cannulation.
8. Peri-aortic dissection before Going on CPB and after cardiac arrest
An expeditious midline sternotomy should be done with SBP maintained around 100–110 mmHg. The dissected aorta is usually dilated, thinned out and blood seeping through adventitial layers (Figure 7).
Upon opening the pericardium, be prepared for free aortic rupture (Figure 8). To minimise the risk either (i) femoral arterial and venous cannula should be in place or (ii) if axillary artery cannulation is done, then the surgeon should be prepared to quickly place the two-stage cannula into right atrium.
Patient is cooled to a core temperature of 26–28°C. For hemi-arch replacement and short duration of total hypothermic circulatory arrest, 27°C temperature is optimum. If total arch replacement is planned, then the patient can be further cooled to 22–24°C.
After going on CPB, a left ventricular vent is placed to prevent left ventricular distension due to associated acute aortic regurgitation. Retrogarde cardioplegia catheter is placed to arrest the heart, as antegrade cardioplegic arrest may not be possible due to aortic regurgitation. After the cardiac arrest and upon opening the aorta, antegrade ostial cardioplegia can be administered.
If the patient is stable, innominate artery is carefully dissected and looped with a vascular loop before going on CPB. This can be occluded or clamped later to provide antegrade cerebral perfusion through the previously cannulated axillary artery.
After going on CPB, the aorta is dissected free from surrounding adhesions. When creating the plane between ascending aorta and main pulmonary artery, it is important to retain as much adventitial tissue on the aortic side.
It is important to identify right pulmonary artery and avoid injuring it, while dissecting ascending aorta.
Clamp the aorta somewhere in the mid-ascending aorta, which will be eventually resected while doing open distal anastomoses. This allows assessment of the site of the tear and of the aortic root and also minimises the total circulatory arrest time.
While excising the dissected ascending aorta, it is important to avoid injury to the main and right pulmonary artery.
While dissecting towards aortic root, left and right coronary ostia are identified and coronary buttons prepared (if aortic root replacement is planned).
Figure 7.
The dissected ascending aorta.
Figure 8.
Aortic rupture prior to establishing CPB.
9. Hypothermic circulatory cardiac arrest and cerebral protection strategies
Because of the low threshold tolerance to ischemia, brain protection is of paramount importance during aortic arch procedures. Hypothermia is an option to increase the ischemic time. However, there are limitations of hypothermia and hypothermic circulatory arrest. Protective effects of hypothermia last no more than 9 minutes at 30°, 14 minutes at 25°, 21 minutes at 2°, 31 minutes at 15° and 45 minutes at 10° [28]. Neurological deficits are seen in elderly patients subjected to hypothermic circulatory arrest exceeding 25 minutes.
Several cerebral perfusion techniques have been introduced to extend the safe period of arch repair without residual neurological deficits. Retrograde cerebral perfusion (RCP) in tandem with hypothermic circulatory arrest was introduced in 1990 by Ueda et al. [29] Because the cerebral venous sinuses have no valves, RCP was proposed to provide retrograde perfusion and cooling of central nervous system (CNS). It offered to back-flush air emboli and debris from the cerebral circulation. Neuroprotective effects were most likely related to cooling rather than true nutritive flow [30]. It was also found to provide limited benefit in patients with significant carotid stenosis and vascular anomalies (e.g. an incomplete Circle of Willis) [31].
Antegrade selective cerebral perfusion (SCP) was introduced by Jean Bachet and Daniel Guilmet in Europe [32] and by Teruhisa Kazui in Japan in 1986 [33]. This new perfusion method of “cold cerebroplegia” in combination with hypothermia significantly reduced neurologic complications. Antegrade selective perfusion can be established either by direct cannulation or by anastomosing a prosthetic graft. The options for locating such are (i) right subclavian artery, (ii) innominate artery, (iii) right common carotid artery. These may be combined with left common carotid artery cannulation to provide bilateral antegrade cerebral perfusion. Direct cannulation is limited by high risk of embolism due to plaque mobilisation from manipulation or by jet flow [34].
Axillary artery cannulation can be used to provide unilateral antegrade SCP during hypothermic arrest without manipulation of the arch vessels. This can be combined with balloon occludable perfusion catheter to left carotid artery to provide bilateral antegrade SCP. To avoid steal, an occlusive balloon catheter is inserted in left subclavian artery.
Unilateral antegrade SCP is sufficient for majority of patients with no pathology of the arch vessels and cerebral vessels. Adequate backflow from the contralateral carotid artery suggests good collateralisation. Near-infrared spectroscopy (NIRS) monitoring can also help to exclude contralateral malperfusion. Bilateral cerebral perfusion may be useful in patients with carotid artery stenosis, previous stroke or cerebrovascular anomalies (incomplete Circle of Willis). Malvindi concluded in his review that “While both unilateral and bilateral ASCP are acceptable, bilateral antegrade cerebral perfusion is safer, when the antegrade SCP time is more than 40-50 minute” [35].
Cerebral perfusion is performed at a rate of 8–12 cc/min/kg body weight, perfusion pressure of 40–60 mmHg at 23–28°C. Alpha stat pH management compared to pH stat management prevents “luxury perfusion” by marinating cerebral autoregulation decreasing the risk of embolization [35].
10. Technical aspects of surgical repair
10.1 Aortic root management
The aortic root is frequently involved with aortic valve rendered incompetent due to commissural dehiscence or annular dilation. Grade II and grade III aortic regurgitation was found in 40 and 23% patients, respectively, in German Registry for Acute Aortic Dissection type A (GERAADA) [36]. There are different surgical approaches for management of aortic root replacement—an aggressive or a more conservative approach.
According to the International Registry of Acute Dissection (IRAD), aortic root replacement compared with conservative root management is not associated with increased in-hospital mortality. In 1995 patients, 18 and 21.3% hospital mortality was found in root replacement and conservative root group respectively (OR 0.989; CI 0.710–1.379; p = 0.949). Mid-term results at 3 years showed a survival of 91.6+/1.3% and 92.5+/1.7% for conservative root management and root replacement group, respectively [37].
Indications to perform root replacement in a patient with ATAD include:
younger age
Marfan syndrome
bicuspid aortic valve
known aortic valve disease
moderate or severe aortic valve insufficiency
previous aortic valve replacement
large diameter aortic annulus, sinuses of Valsalva and ascending aorta
coronary artery involvement
aortic root as the most proximal site of dissection
Proximal reconstruction technical (Figures 9 and 10) details: After the excision of the dissected aortic root, aortic root reconstruction is done.
To take the maximum possible adventitia in the anastomoses.
Needle should enter the tissue at right angle to avoid tearing of needle holes.
Sutures should be spaced uniformly and pulled just enough tight to prevent cutting through the fragile tissue.
To avoid distortion of the aortic valve, the planar relationship between the graft and sinotubular junction should be maintained.
The Bentall procedure [38] is a fairly standard procedure. It includes anastomosing the composite graft to the aortic annulus and reimplantation of coronary arteries. Patients with type A aortic dissection usually have normal aortic valve cusps, as the pathology is usually limited to the aortic wall.
Valve sparing root replacement is a viable option in hemodynamically stable young patients. But it is technically more complex than straight aortic root replacement. It involves replacing the aortic root by composite graft without replacing the aortic valve. The native aortic root must be dissected from surrounding structures to 2 mm below the nadir of the aortic annulus. Coronary ostia are reimplanted into the graft. It is used to treat aortic regurgitation due to annular enlargement. Contraindications include significant cardiomyopathy, malperfusion, coronary artery disease, >65 years age.
Results from Emory in a 43 patients showed operative mortality of 4.7%. Freedom from aortic valve replacement was 100% and freedom from more than mild aortic regurgitation was 94% at 9 years follow-up. No aortic root reinterventions were required in this series [39].
Conservative approaches to the aortic root (CRR)—In most of the patients presenting with TAAD, the most common pathology seen is a primary intimal tear in the ascending aorta with dissection flap extending to non-coronary cusp. Left and right coronary sinuses are relatively preserved. Any aortic regurgitation is due to unhinging of one of the aortic valve commissural posts. The dissected sinus segments are preserved and supported with resuspension of the native valve commissural posts or prosthetic ascending aorta replacement. The advantages are that it preserves the native sinus tissue, coronary ostia are not reimplanted, shorter ischemic time, avoiding life-long anticoagulation [40]. The most commonly used methods to fortify the aortic wall include Teflon felt and biologic glue. University of Pennsylvania in their series of 489 patients showed freedom from reoperation with this technique of 96, 92 and 89% at 1, 10 and 15 years respectively. The operative mortality was 11% [41].
11. Ascending aorta
The entry site of the dissection tear is usually found the ascending aorta, which is at very high risk of rupture. After excising the dissected portion of ascending aorta, supracommissural ascending aorta replacement can be performed. Open distal anastomoses can be done under hypothermic circulatory arrest after releasing the cross clamp. This facilitates inspection of the aortic arch and if required, arch repair can be undertaken. Also, it is technically much easier to construct a very distal ascending aortic anastomoses. Around 5.6% patients underwent ascending aorta replacement in GERAADA survey [42]. But this procedure also allows for subsequent aneurysmal dilation of the remaining portion of the aorta [43].
12. Hemi-arch or full arch
When the aortic arch is examined during hypothermic circulatory arrest to look for intimal or re-entry tears, a decision is made whether an aortic arch replacement has to be done. The pre-operative CT aortogram helps in localising the dissection and also on deciding the placement of the aortic cross clamp. If the tear is in the ascending aorta or start of the aortic curvature, then hemi-arch replacement is required. If the dissection is extends more distally, a total aortic arch repair should be performed (Figure 11a, b).
Figure 11.
Total arch replacement. (a, b) Debranching of aortic arch vessels – innominate , carotid artery and left subclavian artery.
Indications for arch replacement include:
Pre-existing aneurysm of the arch
Primary intimal tear in distal arch or descending thoracic aorta
Secondary intimal tear in arch >10 mm
False lumen more than 22 mm
Descending thoracic aorta diameter more than 35 mm
A study of 188 patients by Kim et al. [44] showed that 5 year survival was lower in patients with total arch replacement compared to patients who had hemi-arch repair (65.8% vs. 83.2%, p = 0.013). Neurological complications were higher in total arch repair group compared to hemi-arch (56.9% vs. 24.8%, p < 0.001).There was a direct correlation between patent false lumen in aortic arch or descending aorta and re-intervention. The German registry for TAAD showed no significant difference in peri-operative outcomes between both groups [45]. This group suggested a more aggressive approach to reduce the rate of interventions.
13. Frozen elephant trunk (FET)
The immediate post-operative results have improved post type A Aortic dissection repair. However, long-term results are guarded by the need for aortic re-interventions due to residual dissection and patent false lumen extending into descending thoracic aorta [46]. The frozen elephant trunk technique involves total arch replacement and per-procedural deployment of stent through the true aortic lumen. It is more complex and takes more time. However, there is 90% chance of false lumen obliteration and reduced rates of re-intervention and improved long-term survival [47]. Uchida et al. [47] showed improved survival in the FET group at 5 years (95.3% vs. 69%, p = 0.03) and 100% thrombosis of false lumen in FET group compared to 29% patent false lumen in the non-FET group. However, both groups had similar operative mortality. Caution should be exercised that it should be done in high volume centres and by experienced suregons.as the total duration of hypothermic circulatory arrest can be dramatically increased.
14. Total aortic repair
Deployment of stent in the descending thoracic aorta has its drawbacks. Stent induced false lumen thrombosis activated inflammatory markers like metalloproteinases and proinflammatory cytokines [48], which contribute in the progression of aneurysm by destruction of the extracellular matrix in the aortic wall and neo-angiogenesis. Risk factors for the late development of aneurysm include (i) patent false lumen, (ii) helicoidal flow distal to the endoprosthesis, (iii) aortic wall shear stress gets modified.
Matalanis [49] has introduced the concept of total aortic repair to prevent the above mentioned complication. Patients presenting with TAAD and a descending thoracic aorta diameter of more than 40 mm can benefited from this approach. The repair involves a “Branch first “total aortic arch repair and surgical ascending aorta repair. Second part included endovascular treatment of descending aorta. It includes covered stent graft deployment in the proximal part of descending aorta and rupture of the intimal flap for the last part of aorta. The rupture is managed with the deployment and dilation under balloon of uncovered stent graft. With this approach, aneurysmal dilatation of the false channel is avoided by the creation of this new aortic channel. But, currently there is no long-term follow-up of this approach.
Bleeding is one of the most feared complication from a surgeon’s point of view. When blood comes in contact with subendothelial tissue of false lumen, it leads to a coagulopathy. Consumption of coagulation factors and fibrinolysis leads to disseminated intravascular coagulation. Activation and consumption of platelets also contributes to mortality [51]. Patients with pre-operative cardiac mal-perfusion was found to be associated with 30-day mortality of 33% (47). Pre-operative cerebral malperfusion is associated with three-fold increase in risk of stroke. Post-operative stroke and coma occurred in 10–15% and 3–9% patients respectively in one series [46]. Acute kidney injury may occur in 40–55% [50].
16. Long-term follow-up
Long-term post-operative survival in recent years at 5, 10 and 30 years is 84–85, 64–68, and 38%, respectively [52]. Health-related quality of life is lower compared to the general population. There is 32% incidence of depression and post-traumatic stress disorder [53]. Over 50% patients have resistant hypertension on follow-up.
As per the EACTS/ESC 2014 guidelines, a follow-up CT-scan of the aorta is recommended at 1, 6 and 12 months and annually thereafter [54]. There are no recommendations specific to the aortic valve or aortic regurgitation for follow-up. To follow general guidelines, one can perform follow-up echocardiography every 1–2 years for mild regurgitation and annually for moderate and asymptomatic severe regurgitation [55].
17. Conclusion
Type A Aortic dissection is an emergency requiring timely surgical intervention. With improved imaging techniques, an accurate diagnosis can now be made. Open surgical repair techniques have given good long-term results. Endovascular intervention is an emerging less invasive option which can be combined with a surgical approach to give excellent long-term results.
Abbreviations
TAAD
type A aortic dissection
aSCP
antegrade selective cerebral perfusion
RCP
retrograde cerebral perfusion
\n',keywords:"dissection, cerebral protection strategies, aortic root, ascending aorta, hemi arch, endovascular techniques",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/72619.pdf",chapterXML:"https://mts.intechopen.com/source/xml/72619.xml",downloadPdfUrl:"/chapter/pdf-download/72619",previewPdfUrl:"/chapter/pdf-preview/72619",totalDownloads:104,totalViews:0,totalCrossrefCites:0,dateSubmitted:"November 29th 2019",dateReviewed:"May 25th 2020",datePrePublished:"August 16th 2020",datePublished:"January 14th 2021",dateFinished:"June 26th 2020",readingETA:"0",abstract:"Type A Aortic dissection is a life-threatening emergency. It has varied clinical presentation from acute severe chest pain radiating to the back, collapse due to aortic rupture or pericardial tamponade or features of myocardial infarction, end organ or limb ischemia. The outcome is determined by the extent of the dissection, timing of presentation, comorbid factors, prompt diagnosis, adequate cerebral protection strategies, and skilled post-operative intensive care. Good immediate and mid-term results have been obtained with standard surgical techniques of aortic root, ascending aorta +/− hemi arch replacement. Endovascular techniques can be used as a hybrid procedure to provide more durable long term results.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/72619",risUrl:"/chapter/ris/72619",signatures:"Imran Khan, Prashant Joshi, Adrian W. Pick and Julian A. Smith",book:{id:"9585",title:"Advances in Complex Valvular Disease",subtitle:null,fullTitle:"Advances in Complex Valvular Disease",slug:"advances-in-complex-valvular-disease",publishedDate:"January 14th 2021",bookSignature:"Michael S. Firstenberg and Imran Khan",coverURL:"https://cdn.intechopen.com/books/images_new/9585.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"64343",title:null,name:"Michael",middleName:"S.",surname:"Firstenberg",slug:"michael-firstenberg",fullName:"Michael Firstenberg"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"282531",title:"Prof.",name:"Julian",middleName:null,surname:"Smith",fullName:"Julian Smith",slug:"julian-smith",email:"julian.smith@monash.edu",position:null,institution:null},{id:"290547",title:"Dr.",name:"Imran",middleName:null,surname:"Khan",fullName:"Imran Khan",slug:"imran-khan",email:"imran_khan261@yahoo.com",position:null,institution:{name:"Monash Medical Centre",institutionURL:null,country:{name:"Australia"}}},{id:"316654",title:"Dr.",name:"Prashant",middleName:null,surname:"Joshi",fullName:"Prashant Joshi",slug:"prashant-joshi",email:"mitwa.joshi@gmail.com",position:null,institution:null},{id:"316655",title:"Dr.",name:"Adrian",middleName:null,surname:"Pick",fullName:"Adrian Pick",slug:"adrian-pick",email:"pick.adrian@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Classification",level:"1"},{id:"sec_3",title:"3. Risk factors",level:"1"},{id:"sec_4",title:"4. Clinical presentation",level:"1"},{id:"sec_5",title:"5. Diagnosis",level:"1"},{id:"sec_6",title:"6. Surgical strategies",level:"1"},{id:"sec_6_2",title:"6.1 Preparation for surgery",level:"2"},{id:"sec_8",title:"7. Cannulation strategies",level:"1"},{id:"sec_9",title:"8. Peri-aortic dissection before Going on CPB and after cardiac arrest",level:"1"},{id:"sec_10",title:"9. Hypothermic circulatory cardiac arrest and cerebral protection strategies",level:"1"},{id:"sec_11",title:"10. Technical aspects of surgical repair",level:"1"},{id:"sec_11_2",title:"10.1 Aortic root management",level:"2"},{id:"sec_13",title:"11. Ascending aorta",level:"1"},{id:"sec_14",title:"12. Hemi-arch or full arch",level:"1"},{id:"sec_15",title:"13. Frozen elephant trunk (FET)",level:"1"},{id:"sec_16",title:"14. Total aortic repair",level:"1"},{id:"sec_17",title:"15. Complications of surgery for ATAD",level:"1"},{id:"sec_18",title:"16. Long-term follow-up",level:"1"},{id:"sec_19",title:"17. Conclusion",level:"1"},{id:"sec_22",title:"Abbreviations",level:"1"}],chapterReferences:[{id:"B1",body:'Golledge J, Eagle KA. Acute aortic dissection. Lancet. 2008;372:55-66'},{id:"B2",body:'Olsson C, Thelin S, Stahle E, Ekbon A, Granath F. Thoracic aortic aneurysm and dissection: Increasing prevalence and improved outcomes reported in a nationwide population based study of more than 14000 cases from 1987 to 2002. Circulation. 2006;114:2611-2618'},{id:"B3",body:'Mehta RH, Manfredini R, Hassan F, et al. Chronological patterns of acute aortic dissection. Circulation. 2002;106:1110-1115'},{id:"B4",body:'DeBakey ME, McCollum CH, Crawford ES, et al. Dissection and dissecting aneurysms of the aorta: Twenty year follow up of five hundred twenty seven patients treated surgically. Surgery. 1982;92(6):1118-1134'},{id:"B5",body:'Nienaber CA, Clough RE. Management of acute aortic dissection. Lancet. 2015;385(9970):800-811'},{id:"B6",body:'Augoustides JG, Szeto WY, Desai ND, et al. Classification of acute type A dissection: Focus on clinical presentation and extent. European Journal of Cardiothoracic Surgery. 2011;39(4):519-522'},{id:"B7",body:'Geirsson A, Aklsson A, Franco-Cereceda A, et al. The Nordic consortium for acute type A aortic dissection (NORCAAD): Objectives and design. Scandinavian Cardiovascular Journal. 2016;50(5-6):334-340'},{id:"B8",body:'Landenhed M, Engstrom G, Gottsater A, et al. Risk profiles for aortic dissection and ruptured or surgically treated aneurysms: A prospective cohort study. Journal of the American Heart Association. 2015;4(1):e-1513'},{id:"B9",body:'Wojnarski CM, Svenson LG, Roselli EE, et al. Aortic dissection in patients with bicuspid aortic valve—Associated aneurysms. The Annals of Thoracic Surgery. 2015 Nov;100(5):1666-1674'},{id:"B10",body:'Geirsson A, Shioda K, Olsson C, et al. Differential outcomes of open and clamp-on distal anastomoses techniques in acute type A aortic dissection. The Journal of Thoracic and Cardiovascular Surgery. 2019;157:1750-1758'},{id:"B11",body:'Elsayed RS, Cohen RG, Fleischman F, et al. Acute type A aortic dissection. Cardiology Clinics. 2017;35(3):331-345'},{id:"B12",body:'Czerny H, Schoenhoff F, Etz C, et al. The impact of pre-operative malperfusion on outcome in acute type A aortic dissection: Results from the GERAADA registry. Journal of the American College of Cardiology. 2015;65(24):2628-2635'},{id:"B13",body:'Rogers AM, Hermann LK, Booher AM, Nienebar CA, Williams DM, Kazerooni EA, et al. Sensitivity of the aortic dissection risk score, a novel guideline based tool for identification of acute aortic dissection at initial presentation: Results from the international registry of acute aortic dissection. Circulation. 2011;123:2213-2218'},{id:"B14",body:'Hagan PG, Ninebar CA, Isselbacher EM, Bruckman D, Karavite DJ, Russman PL, et al. The international registry of acute aortic dissection (IRAD): New insights into an old disease. JAMA. 2000;283:897-903'},{id:"B15",body:'Rogers IS, Banerji D, Siegel EL, et al. Usefulness of comprehensive cardiothoracic computed tomography in the evaluation of acute undifferentiated chest discomfort in the emergency department (CAPTURE). The American Journal of Cardiology. 2011;107(5):643-650'},{id:"B16",body:'Meredith EL, Masani ND. Echocardiography in the emergency assessment of acute aortic syndromes. European Journal of Echocardiography. 2009;10(1):131-139'},{id:"B17",body:'Nienehar CA, Clough RE, Sakalikhson N, et al. Aortic dissection. Nature Reviews. Disease Primers. 2016;2:16071'},{id:"B18",body:'Rylski B. Endovascular repair of acute type A aortic dissection. We have the rechnology but where is the courage? Interactive Cardiovascular and Thoracic Surgery. 2017;25:501-502'},{id:"B19",body:'Creswell LL, Kouchoukos NT, Cox JL, Rosenbloom M. Coronary artery disease in patients with type A aortic dissection. The Annals of Thoracic Surgery. 1995;59:585-590'},{id:"B20",body:'Erbel R, Alfonso F, Boileau C, Dirsch O, Eber B, Haverick A, et al. Diagnosis and management of aortic dissection. European Heart Journal. 2001;22:1642-1681'},{id:"B21",body:'Carl M, Alms A, Braun J, Dougas A, Erl J, Goetz A, et al. S3 guidelines for intensive care in cardiac surgery patients: hemodynamic monitoring and cardiocirculatory system. German Medical Science. 2010;8:Doc 12'},{id:"B22",body:'Tsiouris A, Elkinavy S, Ziganshin BA, Elefteriades JA. Open Seldinger guided femoral artery cannulation technique for thoracic aortic surgery. The Annals of Thoracic Surgery. 2016;101:2231-2235'},{id:"B23",body:'Valentine RJ, Wind G. Anatomic Exposures in Vascular Surgery. Philadelphia: Lippincott Wlliams and Williams; 2003'},{id:"B24",body:'Ogino H, Sasaki H, Minatoya K, Matsuda H, Tauaka H, Watannki H, et al. Evolving arch surgery using integrated antegrade selective cerebral perfusion: Impact of axillary artery perfusion. Journal of Thoracic and Cadiovascualr Surgery. 2008;136:641-648'},{id:"B25",body:'Sabik JF, Lytle BW, McCartht PM, Cosgrove DM. Axillary artery: An alternative site of arterial cannulation for patients with extensive aortic and peripheral vascular disease. The Journal of Thoracic and Cardiovascular Surgery. 1995;109:885-890'},{id:"B26",body:'Pasic M, Schubel J, Buer M, Yankah C, Kuppe M, et al. Cannulation of right axillary artery for surgery of acute type A aortic dissection. European Journal of Cardio-Thoracic Surgery. 2003;24:231-235'},{id:"B27",body:'Sabashnikov A, Heinen S, Deppe AC, Zeriouh M, Weymann A, et al. Axillary or aortic cannulation for aortic repair in patients with stanford a dissection? The Annals of Thoracic Surgery. 2016;102(3):787-794'},{id:"B28",body:'McCullough JN, Zhang N, Reich DL, et al. Cerebral metabolic suppression during hypothermic circulatory arrest in humans. The Annals of Thoracic Surgery. 1999;67:1895-1899'},{id:"B29",body:'Ueda Y. A reappraisal of retrograde cerebral perfusion. Annals of Cardiothoracic Surgery. 2013;2(3):316-325. DOI: 10.3978/j.issn.2225-319X.2013.01.02'},{id:"B30",body:'Reich DL, Uysal S, Ergin MA, et al. Retrograde cerebral perfusion during thoracic aortic surgery and late neuropsychological dysfunction. European Journal of Cardio-Thoracic Surgery. 2001;19:594-600'},{id:"B31",body:'Liebeskind DS. Collateral circulation. Stroke. 2003;34:2279-2284'},{id:"B32",body:'Bachet J, Guilnet D, Goudot B, Delentdecker P, Brodaty D, et al. Antegrade cerebral perfusion with cold blood: A 13 year experience. The Annals of Thoracic Surgery. 1999;67(6):1874-1878'},{id:"B33",body:'Kazui T. Total arch replacement with separated graft technique and selective antegrade cerebral perfusion. Annals of Cardiothoracic Surgery. 2013;2(3):353-357'},{id:"B34",body:'Griepp RB. Cerebral protection during aortic arch surgery. The Journal of Thoracic and Cardiovascular Surgery. 2001;121:425-427'},{id:"B35",body:'Malvindi PG, Scrascia G, Vitale N. Is unilateral antegrade cerebral perfusion equivalent to bilateral cerebral perfusion for patients undergoing arch surgery? Interactive Cradiovascualr and Thoracic Surgery. 2008;7:891-897'},{id:"B36",body:'Kruger T, Weigang E, Hoffmann I, Blettner M, Aebert H, GERAADA INVESTIGATORS. Cerebral protection during surgery for acute aortic dissection type A: Results of the German registry for acute aortic dissection type A (GERAADA). European Journal of Cardio-Thoracic Surgery. 2011;40:435-440'},{id:"B37",body:'Di Eusanio M, Trimarchi S, Peterson MD, et al. Root replacement surgery versus more conservative management during type A acute aortic dissection repair. The Annals of Thoracic Surgery. 2014;98:2078-2084'},{id:"B38",body:'Varrica A, Satriano A, de Vincentiis C, Biondi A, Trimarchi S, et al. Bentall operation in 375 patients: Long-term results and predictors of death. The Journal of Heart Valve Disease. 2014 Jan;23(1):127-134'},{id:"B39",body:'Leshnower BG, Myung RJ, McPherson L, et al. Midterm results of David V valve sparing aortic root replacement in acute type A aortic dissection. Annals of Thoarcic Surgery. 2015;99:795-800'},{id:"B40",body:'Park KH, Lim C, Choi JH, et al. Midterm change of descending aortic false lumen after repair of acute type A dissection. The Annals of Thoracic Surgery. 2009;87:103-108'},{id:"B41",body:'Rylski B, Bavaria JE, Milewski RK, et al. Long term results of neomedia sinus valsalva repair in 489 patients with type A aortic dissection. Annals of Thoarcic Surgery. 2014;98:582-588'},{id:"B42",body:'Kruger T, Weigang E, Hoffman I, Blettner M, Aebert H, GERAADA INVESTIGATORS. Cerebral protection during surgery for acute aortic dissection type A: Results of the German registry for acute aortic dissection type A (GERAADA). Circulation. 2011;124:434-443'},{id:"B43",body:'Halstead JC, Meier M, Etz C, Spielvogel D, Bodian C, Wurm M, et al. The fate of the distal aorta after repair of acute type A aortic dissection. The Journal of Thoracic and Cardiovascular Surgery. 2007;133:127-135'},{id:"B44",body:'Kim JB, Chung CH, Moon DH, et al. Total arch repair versus hemiarch repair in the management of acute DeBakey type I aortic dissection. European Journal of Cardio-Thoracic Surgery. 2011;40:881-887'},{id:"B45",body:'Weigang E, Conzelmann L, Kallenbach K, et al. German registry for acute aortic dissection type a (GERAADA)-lessons learned from the registry. The Thoracic and Cardiovascular Surgeon. 2010;58:154-158'},{id:"B46",body:'Kazui T, Yamashita K, Washiyama N, et al. Impact of an aggressive surgical approach on surgical outcome in type A aortic dissection. The Annals of Thoracic Surgery. 2002;74:S1844-S1847'},{id:"B47",body:'Uchida N, Shibamura H, Katyama A, et al. Operative strategy for acute type a aortic dissection: Ascending aortic or Hemiarch versus Total arch replacement with frozen elephant trunk. The Annals of Thoracic Surgery. 2009;87:773-777'},{id:"B48",body:'Cifani N, Proietta M, Tritapepe L, Die Gioia C, Ferri L, Taurino M, et al. Stanford—A acute aortic dissection, inflammation and metalloproteinases: A review. Annals of Medicine. 2015;45:441-446'},{id:"B49",body:'Matalanis G, Ips S. A new paradigm in the management of acute type A aortic dissection: Total aortic repair. The Journal of Thoracic and Cardiovascular Surgery. 2019;157(1):3-11'},{id:"B50",body:'Zindovic I, Gudbjartsson T, Ahlsson A, et al. Malperfusion in acute type A aortic dissection: An update from the Nordic Consortium for acute type A aortic dissection. The Journal of Thoracic and Cardiovascular Surgery. 2019;157:1324.e6-1336.e6'},{id:"B51",body:'Cate JW, Timers H, Becker AE. Coagulopathy in ruptured or dissecting aortic aneurysms. The American Journal of Medicine. 1975;59(2):171-176'},{id:"B52",body:'Pan E, Kyoto V, Savunen T, et al. Earrly and late outcomes after open ascending aortic surgery: 47 year experience in a single centre. Heart and Vessels. 2018;33(4):427-433'},{id:"B53",body:'Endlich M, Hamiko M, Gestrich C, et al. Long term outcome and quality of life in aortic type A dissection survivors. The Journal of Thoracic and Cardiovascular Surgery. 2016;64:91-99'},{id:"B54",body:'Hiratzka LF, Bakris GL, Beckman JA, et al. ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Journal of the American College of Cardiology. 2010, 2010;55(14):e27-e129'},{id:"B55",body:'Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS guidelines for the management of valvular heart disease. European Heart Journal. 2017;38(36):2739-2791'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Imran Khan",address:"imran_khan261@yahoo.com",affiliation:'
Department of Cardiothoracic Surgery, Royal North Shore Hospital, Australia
Department of Cardiothoracic Surgery, Monash Medical Centre, Australia
'},{corresp:null,contributorFullName:"Adrian W. Pick",address:null,affiliation:'
Department of Cardiothoracic Surgery, Monash Medical Centre, Australia
'},{corresp:null,contributorFullName:"Julian A. Smith",address:null,affiliation:'
Department of Cardiothoracic Surgery, Monash Medical Centre, Australia
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As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 118,000 international scientists and researchers.
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The Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
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OAPF Publishing Options
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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Personal contact and support throughout the publishing process from your dedicated Author Service Manager
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Assurance that your manuscript meets the highest publishing standards
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To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at oapf@intechopen.com for further details or assistance.
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Added Value of Publishing with IntechOpen
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Choosing to publish with IntechOpen ensures the following benefits:
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Indexing and listing across major repositories, see details ...
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Long-term archiving
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Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
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Dissemination and Promotion
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Benefits of Publishing with IntechOpen
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Proven world leader in Open Access book publishing with over 10 years experience
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+4,800 OA books published
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Most competitive prices in the market
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Fully compliant with OA funding requirements
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Optimized processes, enabling publication between 8 and 12 months
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Personal support during every step of the publication process
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+146,150 citations in Web of Science databases
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Currently strongest OA platform with over 130 million downloads
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