bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetics of psoriatic arthritis
Authors: Winchester Robert , O’Rielly Darren D. , Rahman Proton
Published: August 2018

The psoriatic phenotype is clinically heterogeneous with psoriatic arthritis (PsA) itself being heterogeneous. Studies have consistently demonstrated that PsA has a strong genetic component and disease pathogenesis encompasses a complex interplay between genetic, immunological, and environmental factors. In this chapter, we will review the genetics of PsA including the major histocompatibility complex (MHC) region and non-MHC loci. We will detail how susceptibility genes can be grouped into barrier integrity, innate immune response, and adaptive immune response (particularly Th-17 lymphocyte signalling). We will articulate how these studies strongly support PsA as genetically different from PsV and that the genetic heterogeneity is likely attributed to different HLA susceptibility alleles within the MHC region that an individual carries. Furthermore, we will highlight new emerging technologies, in particular, next-generation sequencing, which may lead to new genetic discoveries in PsA.
Immunology and cytokine pathways
Authors: Kirkham Bruce
Published: August 2018

Psoriatic arthritis immunopathology has become the subject of intense study. These findings show differences to other forms of inflammatory arthritis in key pathways. Increased knowledge of innate immunity and the important role of IL-17/23 biology in both psoriasis and psoriatic arthritis, have led to new theories of immunopathogenesis in both conditions. Direct environmental stimuli could trigger innate immune cells resident in skin, which may then initiate a chronic adaptive immune response. The joint has fewer resident innate immune cells, but new studies show cells producing IL-17 may play key roles in immunopathology. The new information summarized here will provide important hypotheses for investigation of pathogenic pathways. Differences in non-immune cell function may also be critical mediators of response, for example, production of IL-12 or IL-23 by dendritic cells. Keratinocytes in skin and fibroblasts in joints may be critical in mediating cytokine production and effector function.
Mechanisms of bone destruction and proliferation in psoriatic arthritis
Authors: Lories Rik
Published: August 2018

Psoriatic arthritis is a chronic inflammatory joint disease that can affect both the peripheral and axial skeleton. The clinical presentation of psoriatic arthritis is very heterogeneous and different subforms have been described. Structural damage to the joint is a feared complication of psoriatic arthritis. The severity of joint inflammation and subsequent damage can range from mild to extreme. Over the last decade, insights into the molecular and cellular mechanisms that underlie the skeletal changes in psoriatic arthritis have gradually increased although translational validation of concepts using patient-derived materials still lags behind. Current treatment strategies directed against key mediators of inflammation appear to have good effects on joint destruction, but their short and long-term impact on new bone formation and ankylosis is still unclear. The identification of the role that key growth factors play in the latter process identifies new opportunities for therapeutic interventions.
Psoriasis: skin and nails
Authors: Rosen Cheryl F. , Kirby Brian
Published: August 2018

Psoriasis is seen in many patients with psoriatic arthritis. It forms part of the CASPAR criteria for establishing the diagnosis of psoriatic arthritis (PsA). The psoriasis accompanying PsA may be mild or quite severe, with a very large impact on quality of life. The presence of cutaneous disease may alter the treatment of a patient’s PsA. Psoriasis affects up to 2–3% of the population of Europe, the United States and Canada. The majority of patients have chronic plaque psoriasis (80%). Other clinical phenotypes include guttate psoriasis, erythrodermic psoriasis, inverse psoriasis, sebopsoriasis and pustular subtypes including generalized pustular psoriasis. Nail involvement is a frequent occurrence and indicate an increased risk of developing psoriatic arthritis. In this chapter, the different psoriatic phenotypes are described as well as the histology and, briefly, the pathophysiology of psoriasis. Environmental factors that can impact psoriasis are reviewed.
Peripheral arthritis
Authors: Scarpa Raffaele , Caso Francesco , Costa Luisa , Peluso Rosario , Di Minno Nicola Matteo Dario , Del Puente Antonio
Published: August 2018

Clinical presentation of peripheral arthritis in patients with psoriatic arthritis (PsA), has been described by Moll and Wright who classified it into four subsets: symmetrical polyarthritis, asymmetrical oligoarthritis, distal interphalangeal (DIP) arthritis and arthritis mutilans. In the symmetrical polyarthritis subset, the distribution of articular involvement is similar to rheumatoid arthritis and this has for many years justified the inappropriate use of the terminology ‘rheumatoid-like form’, at present completely abandoned. Oligoarthritis is characterized by asymmetrical involvement of few joints (less than four), which include scattered DIP or proximal interphalangeal (PIP) joints and/or metatarsophalangeal joints. DIP arthritis may occur with symmetrical or asymmetrical features, and it is often in strict association with onycopathy. The arthritis mutilans pattern is characterized by osteolysis of phalanx and metacarpals and it is very rare, occurring in less than 1% of patients with established form of arthritis. In 15-20% of the cases the arthritis may precede the onset of the psoriatic skin rash. Consequently, psoriatic arthritis ‘sine psoriasis’ should not be considered a rare clinical finding. In this subset articular involvement is clinically expressed, while cutaneous is apparently absent. Laboratory tests and imaging are relevant for differential diagnosis which in some presentations may represent a diagnostic challenge. The outcome of peripheral patterns of PsA patients is related not only to the spectrum of peripheral phenotypes, but also to early diagnosis, and metabolic aspects, which may affect excess in morbidity and mortality.
Enthesitis
Authors: Cañete Juan D. , Ramírez Julio
Published: August 2018

Enthesitis is common in psoriatic arthritis (PsA) occurring in50–60% of patients in clinical trials. Outcome measures for enthesitis have been developed, but its clinical diagnosis may be challenging at sites other than the Achilles and plantar insertions. Power Doppler ultrasound is more sensitive than clinical examination in detecting inflammatory and/or structural changes in asymptomatic patients, which have an unknown significance. Magnetic resonance imaging is useful to evaluate enthesitis and the best technique for osteitis. The concept of synovial–entheseal complex highlights the functional link between the entheseal site and synovium, supporting an important role for biomechanical stress in enthesitis, which is proposed as the primary lesion in PsA. Animal models have improved our understanding of molecular pathways, particularly TNF and IL-23/IL-17 cytokines, and new successful targeted therapies have been developed to treat enthesitis. Prospective studies integrating clinical and image examination will be crucial to better define the clinical implications of enthesitis changes.
Dactylitis
Authors: Olivieri Ignazio , Scarano Enrico , D’Angelo Salvatore , Palazzi Carlo , Padula Angela
Published: August 2018

This chapter covers dactylitis, or ‘sausage-shaped’ digits. As the types of dactylitis depends on the tissues involved and the type of involvement, ‘false’ dactylitis is discussed, and the manifestation of diffuse swelling in spondyloarthritis (SpA) is differentiated from the other forms. Clinical aspects and imaging methods are described, followed by clinimetric assessment and the development of composite scores such as CPDAI and PASDAS. Finally, therapies are described.
Axial disease
Authors: Lubrano Ennio
Published: August 2018

This chapter summarizes the state of the art for axial involvement in psoriatic arthritis (axial PsA). The definition and measurement of axial PsA still remain problematic and this, in turn, could affect the best approach of recognition and treatment of this intriguing subset of the psoriatic disease. Axial PsA has been studied over the last few years looking at the difference in function and radiological findings compared mainly to Ankylosing Spondylitis (AS), trying to differentiate it from a coincidental AS with psoriasis. Moreover, an assessment on a possible Diffuse Idiopathic Skeletal Hyperostosis (DISH) in PsA patients and clinical-radiological differences to axial PsA has been evaluated. The role of potential new imaging techniques, such as MRI, in the assessment of axial PsA has been considered in this chapter. The diagnosis and treatment of axial PsA has been reported by using the data obtained from the literature.
Extra-articular, extra-skin disease
Authors: Van den Bosch Filip
Published: August 2018

Psoriatic disease is a multisystem disorder that affects skin and nails. Besides arthritis and spondylitis, involvement of other organ systems occurs in a significant proportion of patients. Within these extra-articular, extra-skin manifestations, eye and gut disease occupy an important place since they are linked in a bi-directional way: eye inflammation and bowel disease occur more frequently in patients with psoriasis and psoriatic arthritis, but there is also an increased prevalence of psoriasis in patients with uveitis or inflammatory bowel disease. In this chapter, we will focus primarily on spondyloarthritis concept-related extra-articular, extra-skin manifestations, such as uveitis, Crohn’s disease, and ulcerative colitis: prevalence, clinical presentation, and therapeutic consequences are discussed.
Co-morbidities
Authors: Haroon Muhammad
Published: August 2018

Psoriatic arthritis (PsA) is a chronic, multisystem inflammatory condition where patients are at a higher risk for a number of major systemic comorbidities including cardiovascular disease, obesity, depression, uveitis, and cancer. These comorbidities which are frequently unrecognized or undertreated contribute significantly to the morbidity and mortality associated with PsA. There is emerging data further supporting the link between inflammation and cardiovascular disease. The detection and management of PsA patients with comorbidities requires a coordinated approach which is not yet clearly defined. Meanwhile, it is important to conduct periodic comprehensive assessments in our PsA patients in order to identify and monitor comorbidities. The importance of multispecialty cooperation and multidisciplinary assessment cannot be over-stated.
Plain radiography
Authors: Tillett William , McHugh Neil
Published: August 2018

Psoriatic arthritis is a destructive inflammatory arthritis that can affect the peripheral and axial skeleton of patients with psoriasis. Plain radiography has formed an important part in defining psoriatic arthritis as a distinct clinical entity, from early work reporting on distinguishing features to more recent inclusion of osteoproliferation in the CASPAR classification criteria. Plain radiography is accessible, inexpensive and remains the standard measure of assessing damage in inflammatory arthritis. Originally considered a benign disease psoriatic arthritis is now recognised to be destructive and progressive, though not as aggressive as rheumatoid arthritis. Peripheral joint damage is characterised by erosions, joint space narrowing, osteoproliferation, osteolysis and ankylosis. Approximately twenty percent of patients have erosive disease at diagnosis progressing to approximately half of all patients by three years disease duration. In its most severe form, psoriatic arthritis mutilans, digits become shortened from gross bone resorption (osteolyisis) leading to severe functional impairment and disability. Spondyloarthritis may affect between 25-70% of patients with PsA. The radiographic features of Psoriatic Spondyloarthritis differ from Ankylosing Spondylitis, in that sacroiliitis is often asymmetrical and less severe, the cervical spine is frequently involved and syndesmophytes are asymmetrical and para-marginal. Overall radiographic features are less severe than ankylosing spondylitis. The natural history of both peripheral and axial radiographic damage in psoriatic arthritis in the modern era of early diagnosis, tight disease control and biologic drugs has yet to be established.
Use of ultrasound in psoriatic arthritis
Authors: Kaeley Gurjit S.
Published: August 2018

Psoriatic arthritis (PsA) is much more than just joint disease. Although previous clinical classifications have categorized by pattern of joint involvement and axial disease, imaging techniques such as MRI and ultrasound have demonstrated that not only are many more joints involved but also a wide variety of adjoining tissues. The concept of enthesitis is evolving and high resolution imaging studies are demonstrating involvement of tissues beyond just the enthesis. Many investigators have chosen to use sonographic entheseal systems designed for Spondyloarthritis in general which may not be appropriate and may lead to excess confounding by obesity. Inclusion of entheses that seem more relevant to PsA may improve the validity and specificity of the sonographic outcome tool. Nail affliction is associated with PsA, as well as enthesitis. Sonography is able to demonstrate the nail apparatus. More recent pathoanatomic findings may help explain the close link with enthesitis. Synovitis in PsA is often involved with inflammation and alteration of neighbouring structures such as the extensor tendons, palmar or plantar plates. Some investigators have proposed that inflammation in PsA may start at the entheseal sites and then spread to the joint. Dactylitis epitomizes the concept of multiple tissues involved in the digit giving rise to the clinical appearance of a uniformly swollen digit. Sonography can image many of these tissues in high resolution and offer insights into the pathophysiology of dactylitis.
MRI
Authors: McGonagle Dennis , Eshed Iris
Published: August 2018

The features of psoriatic arthritis (PsA) are disparate—from peripheral synovitis to axial inflammation, from bone destruction to bone formation or both, and nail disease. Fat suppression magnetic resonance imaging (MRI) has had a major impact on understanding PsA. MRI suggests a unifying anatomical basis for PsA with the common denominator of disease localization to entheses and adjacent bone and other sites of high biomechanical stress. MRI has also shown that entheseal changes are not uncommon in generalized osteoarthritis and occasionally in normals, making careful clinical correlation essential for imaging interpretation. MRI is useful in predicting the course of axial spondyloarthritis but there are no specific studies in axial PsA; most data comes from ankylosing spondylitis. Additionally MRI has been used for monitoring therapeutic response in PsA where good resolution of enthesitis/osteitis has been reported. Further studies are needed to define the role of MRI in measuring biological remission of PsA.
Assessment of joint and bone structure in PsA patients: Using high-resolution computed tomography
Authors: Figueiredo Camille , Schett Georg
Published: August 2018

Psoriatic arthritis (PsA) is associated with a distinct pattern of bone pathology, which influences the clinical picture of the disease. High-resolution computed tomography (CT) has contributed to understanding structural bone changes in PsA. Periarticular bone erosions in PsA are characterized by periosteal responses around the cortical break, distinguishing them from bone erosions in rheumatoid arthritis. Furthermore, a large number of enthesophytes can be found in CT studies of joints of PsA patients and in psoriasis patients without clinical arthritis. This latter observation supports the idea that articular changes start in psoriasis before joint disease commences. Moreover, enthesophytes are not influenced by methotrexate treatment and tumour necrosis factor inhibition. Finally, studies of systemic bone loss by high-resolution CT revealed significant alterations of the bone architecture in PsA but not in patients with skin disease only. In summary, CT has made valuable contributions in understanding the structural bone changes in PsA.
Diagnosis and classification criteria
Authors: Coates Laura C. , Taylor William J.
Published: August 2018

This chapter covers diagnosis and classification of psoriatic arthritis (PsA). Firstly the difference between diagnosis and classification criteria in terms of their design, function, and performance is discussed. The diagnostic clues of PsA are summarized: risk factors for development of arthritis amongst patients with psoriasis, signs, and symptoms of articular, entheseal and axial disease, and relevant investigations. Older classification criteria for PsA are discussed along with later modifications. The development of the CASPAR criteria is described and subsequent studies assessing the accuracy of the CASPAR criteria in different populations are then summarized. How PsA fits within the broader family of spondyloarthritides (SpA) and the performance of CASPAR compared to SpA criteria is outlined. Different subtypes of PsA, as well as the evolution of individual patients through subtypes over time, are described. Finally future proposals to develop the ‘stem’ of CASPAR to define ‘inflammatory articular, entheseal or axial disease’ are summarized.
Biomarkers of psoriatic arthritis outcomes
Authors: Oikonomopoulou Katerina , Chandran Vinod
Published: August 2018

Psoriatic arthritis is an inflammatory musculoskeletal disease that occurs in patients suffering from psoriasis. The disease manifests with symptoms affecting the skin, peripheral and axial joints, and periarticular structures. Diagnosis and management of psoriatic arthritis is challenging due to its heterogeneous presentation. However, early diagnosis and subsequent appropriate treatment reduces disease activity, prevents joint damage, and improves long-term outcome. It is hoped that biomarkers for disease progression and activity will aid in cost-effective clinical management of patients. Potential biomarkers under investigation for psoriatic arthritis are disease-related components derived from skin and articular tissues, biological fluids, such as blood and synovial fluid, and arthritis-associated cell populations. Imaging including ultrasound and MRI are also being evaluated as biomarkers for diagnosis, activity and outcome. Despite the challenge of bringing these new markers into the clinic, many of these markers hold promise for the future management of patients with psoriatic arthritis.
Domains and instruments
Authors: Cauli Alberto
Published: August 2018

In order to define and validate standardized outcome measurement tools both for therapeutic trials and for real life clinics, the need to precisely identify the relevant domains of psoriasis and psoriatic arthritis has led to the ‘rassemblement’ of experts and patients in the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). The output of intensive work, performed according to the Outcome Measures in Rheumatology (OMERACT) scientific method, has been the definition of the key domains and instruments relevant in PsA evaluation. This chapter summarizes the present approach in PsA assessment, focusing on the ‘pathophysiological manifestations’, as well as current ideas regarding future revisions. Patient-related outcome measures and composite scores will be detailed in other chapters.
Patient-reported outcome measures in psoriatic arthritis
Authors: Gossec Laure , Gudu Tania , de Wit Maarten
Published: August 2018

Psoriatic arthritis (PsA) is a chronic, potentially severe disease with an important impact on the lives of people who have this disease. The impact of PsA is wide-reaching, and both physical but also mental aspects of quality of life can be modified by this disease. Thus, the measurement of the patient’s status rests in part, on the assessment of patient-reported outcomes, i.e. questionnaires to assess different aspects of life. In the present chapter, we will discuss the impact of the disease from a qualitative point of view, and review different patient-reported questionnaires which are either specific to PsA, or generic, and which are used to assess people with PsA.
Composite scores in psoriatic arthritis
Authors: Helliwell Philip S.
Published: August 2018

Composite scores are assessment tools that combine a number of separate evaluations into one score. The composite score generally has more statistical power than the individual items, is more responsive, and has a greater effect size. A composite score allows synthesis of several elements into one score which can then, if psychometrically appropriate, allow the determination of disease activity (both low and high) cut-offs, and response criteria. The topics discussed in this chapter are the development and use of composite scores to assess disease activity in psoriatic arthritis: their history and development, use in practice, psychometric characteristics, and relative merits. Although there is no overall consensus on which measure to use, either in clinical trials or in the clinic, there appears to be agreement that remission should be the ideal target of treatment, with minimal/low disease activity a feasible alternative.
Approach to management and symptomatic (including non-pharmacologic) management of psoriatic arthritis
Authors: Felquer Laura Acosta , Soriano Enrique R.
Published: August 2018

Psoriatic arthritis (PsA) is a heterogenous disease with multiple manifestations and comorbidities, and requires a collaborative management with other specialists. The major symptoms bordering patients are pain stiffness, and swelling, but fatigue, depression, embarrassment and fear are frequent and not always assessed by treating physicians. Non-steroidal anti-inflammatory drugs and local glucocorticosteroid injections remain important treatment options that should be used, although with caution, in the appropriate patient. Since the pre-biologic era, physical therapy has been part of non-pharmacological treatment in patients with rheumatic disease. Unfortunately there is little evidence of the efficacy of rehabilitation in PsA with no study with high grade of evidence. Surgery should be reserved for advanced cases as the new paradigms in the treatment of PsA (early diagnosis and treatment, remission as an objective, and treat to target), would very probably reduce the already low number of patients that need this last treatment option. In PsA patients surgery outcomes are similar to those of surgical management of other forms of arthritis. Symptomatic and non-pharmacologic management of PsA remain as important adjuvants of PsA treatment, although with little evidence.
Synthetic DMARDs
Authors: Behrens Frank , Koehm Michaela , Parnham Michael J.
Published: August 2018

Synthetic disease modifying anti-rheumatic drugs (sDMARDs) are first line systemic treatment options for management of active psoriatic arthritis (PsA). Most of the compounds are used based on evidence from clinical trials in rheumatoid arthritis and from experience in routine care. Methotrexate is often recommended as the first choice within among sDMARDs, despite controversial or missing evidence of efficacy, according to experience over many years. Leflunomide, sulfasalazine, and cyclosporin are additional established options to treat PsA. The recently approved PDE4 inhibitor, apremilast, has broad evidence of efficacy. All these drugs have different strengths and weaknesses and varying levels of evidence for treatment of PsA. Therefore, the best treatment choice must be based on the different individual manifestations of the disease and comorbid conditions. In this chapter, the evidence levels for the different clinical symptoms are listed and suggestions for a hierarchical order of choice are given, adapted to likely clinical scenarios.
Biologic DMARDs (TNF inhibitors)
Authors: Boyd Tristan , Kavanaugh Arthur
Published: August 2018

Tumor necrosis factor-α‎ inhibitors (TNFi) can effectively treat all domains of disease in patients with psoriatic arthritis (PsA). They have been shown to be effective and also generally safe and well tolerated in numerous clinical trials. This chapter reviews clinical trial evidence for the efficacy and safety of TNFi in PsA and highlights evidence-based treatment recommendations for their use. Emerging treatment strategies involving the use of TNFi in the management of PsA are also discussed.
Biologic treatments for psoriatic arthritis apart from TNF inhibition
Authors: Mease Philip
Published: August 2018

Psoriatic arthritis (PsA) is an immunologically mediated inflammatory disease characterized by arthritis, enthesitis, dactylitis, spondylitis, and psoriasis. Prior to the introduction of targeted biologic medications, such as TNF inhibitors, the ability to control disease activity was limited, with only modest effects noted with traditional oral medications such as methotrexate and sulfasalazine. The introduction of TNF inhibitors substantially changed the outlook of PsA patients, yielding significant response in all relevant clinical domains and demonstrating the ability to inhibit progressive structural damage of joints. However, not all patients responded to these agents and many patients displayed initial response which waned over time, partly due to immunogenicity (development of antibodies which blocked full therapeutic effect of the biologic protein), or because of tolerability and side effect issues. Thus, it has been important to develop new medicines which target other key cytokines and immunologic pathways. Several medicines with a different mechanism of action have been approved or are in development for the treatment of PsA. Ustekinumab inhibits both IL12 and IL23 and thus is felt to work in both the TH1 and TH7 pathways of inflammation. The oral medicine apremilast inhibits phosphodiesterase 4, thus modulating the cyclic AMP pathway in immunologic cells, yielding an anti-inflammatory effect. Both of these medicines have been approved for the treatment of PsA as well as psoriasis. An emerging group of therapies, the IL17 inhibitors, has demonstrated significant effectiveness in psoriasis and PsA and one of these, Secukinumab, has been approved for psoriasis, PsA, and AS. Other medicines in development include the co-stimulatory blockade agent, abatacept, oral Janus Kinase (JAK) inhibitors, and an emerging group of therapies which inhibit IL23. As modulators of immune cell function, these agents have the potential to increase risk for infection, as well as other side effects. These must be discussed with the patient and considered when determining overall risk benefit analysis regarding their use. The emergence of medicines with a different mechanism of action than TNF inhibition has broadened and strengthened our ability to effectively treat PsA.
Treatment algorithm and treat to target
Authors: Coates Laura C. , Kavanaugh Arthur , Ritchlin Christopher T.
Published: August 2018

This chapter covers the evidence for treatment algorithms and treatment to target in PsA. Evidence for treatment algorithms including step up vs step down approaches to prescribing and early vs delayed treatment is discussed. EULAR recommendations for treating to target in SpA are outlined with a summary of the level of evidence available at that time. Key outcome measures that could be utilized as targets in PsA are reviewed with discussion of their merits and deficiencies. A detailed description of the first treat to target study in PsA is presented: the TICOPA study. The impact of comorbidities on treatment decisions is discussed, both related SpA conditions such as uveitis and inflammatory bowel disease, and non-SpA comorbidities such as the metabolic syndrome and liver disease. Finally, suggestions for translation into clinical practice are outlined, highlighting the need for multi-speciality collaborative working, full assessment of disease activity and subsequent optimal treatment.
Recent progress in psoriatic arthritis and areas for further research
Authors: Fitzgerald Oliver , Gladman Dafna
Published: August 2018

This chapter will summarize the most important areas of recent progress related to psoriatic arthritis (PsA) as illustrated in the previous chapters. Not all areas of progress will be mentioned but we will endeavour to point out the pivotal developments which have changed the ways by which we diagnose, assess, and treat this complex disease. We will then highlight the key questions which are the focus of ongoing research and in which, in turn, will likely result in further changes to both our understanding of the disease PsA and how it is managed.
Relevance of developmental studies for clinicians
Authors: Basso Cristina , Henderson Deborah J. , de la Pompa José Luis , Kelly Robert G. , Pérez-Pomares José Maria , Sedmera David , van den Hoff Maurice
Published: August 2018

In this short chapter we outline the rationale of this textbook.
An evolutionary perspective on the origin of the cardiovascular system of vertebrates
Authors: Oostra Roelof-Jan , Jensen Bjarke , Moorman Antoon F.M.
Published: August 2018

The origin of the cardiovascular system of vertebrates is inferred from comparisons of basal chordates but must also encompass bewildering discrepancies. Basal chordates like lancelets (cephalochordates) have a vascular pattern similar to that of a vertebrate embryo, but without a recognizable heart or myocardium. Instead, the ‘venous’ part of their circulation contains contractile vessels, located upstream and downstream of the liver. Tunicates (urochordates) have a tubular heart containing cardiomyocytes and enclosed by a pericardium. Their circulation is open and the dominant pacemaker activity can be at either end of the heart tube, causing blood flow to reverse periodically. Recent molecular investigations have proved that urochordates rather than cephalochordates are the closest living relatives of vertebrates. This implies that the cardiovascular peculiarities of lancelets may be primitive ancestral qualities and that the original building plan of the vertebrate circulation featured a post-hepatic as well as a pre-hepatic cardiac pump.
From epiblast to mesoderm: elaboration of a fate map for cardiovascular progenitors
Authors: Lopez-Sanchez Carmen , Garcia-Lopez Virginio , Schoenwolf Gary C. , Garcia-Martinez Virginio
Published: August 2018

The origin and migration of cardiovascular progenitors have been identified using multiple cell fate mapping techniques monitoring marked epiblast cells through time at carefully defined stages of early gastrulation. These studies have revealed that ordered groups of cells from the epiblast move into the anterior region of the primitive streak, and then migrate anterior laterally to define the first heart field in the mesodermal layer. Subsequently, the right and left components of the first heart field fuse into a single straight heart at the embryonic midline. Additional cells derived from the second heart field are added to the cardiac tube and contribute to further heart development. Heterotopic and heterochronic transplantation studies have revealed that cardiac precursor cells are plastic and do not form a specific subpopulation of the cardiac mesoderm. Specification of the heart fields occurs after ingression of precardiac cells through the primitive streak.
Cardiac fields and myocardial cell lineages
Authors: De Bono Christopher , Théveniau-Ruissy Magali , Kelly Robert G.
Published: August 2018

We focus on the origin of myocardial cells in the first and second heart fields in splanchnic mesoderm in the early embryo. Genetic lineage tracing using Cre recombinase activated conditional reporter genes has made a major contribution to our understanding of cardiac progenitor cells and will be discussed together with other experimental approaches to analysing cell lineages at the clonal level. Interactions between myocardial, epicardial and endocardial lineages are essential for coordinated function and homeostasis of the normal heart. Perturbation of heart field development and myocardial lineage contributions to the heart through developmental or acquired pathologies results in and modulates the progression of cardiac disease. Understanding the origin of myocardial lineages during embryonic development and how they converge to generate an integrated heart is thus a major biomedical objective. Furthermore, reactivation of developmental programmes is likely to be of major importance in strategies aimed at repair of the damaged heart.
Transcriptional regulation of early cardiovascular development
Authors: Fulcoli F. Gabriella , Baldini Antonio
Published: August 2018

The two major cardiac cell lineages of the vertebrate heart, the first and second cardiac fields (FHF and SHF), have different developmental ontogeny and thus different transcription programs. Most remarkably, the fate of cardiac progenitors (CPs) of the FHF is restricted to cardiomyocyte differentiation. In contrast, SHF CPs, which are specified independently, are maintained in a multipotent state for a relatively longer developmental time and can differentiate into multiple cell types. The identity of the transcription factors and regulatory elements involved in progenitor cell programming and fate are only now beginning to emerge. Apparent inconsistencies between studies based on tissue culture and in vivo embryonic studies confirm that the ontogeny of cardiac progenitors is strongly driven or affected by regionalization, and thus by the signals that they receive in different regions. This chapter summarizes current knowledge about transcription factors and mechanisms driving CP ontogeny, with special focus on SHF development.
The developmental origin of myocardium at the venous pole of the heart
Authors: van Wijk Bram , Barnett Phil , van den Hoff Maurice J.B.
Published: August 2018

The focus of this chapter is an evaluation of the developmental origin of the myocardial component of the venous pole. The venous pole has a complex morphological architecture, reflecting its embryological and evolutionary development from several component parts. We describe the developmental changes observed in the architecture of the inflow of the heart and the large vessels that drain into the venous pole. As the formation of the proepicardium and the epicardial-derived cells are intimately connected to the forming inflow, this topic will also be covered. We compare the development of the inflow in chicken, mouse, and human. We then review the results obtained using the two-component genetic mouse system Cre-LoxP with respect to the myocardial components added to the forming cardiac inflow. These data are discussed within the now discriminated first, second, and third heart fields.
Cardiac growth I: Cardiomyocyte proliferation
Authors: Meilhac Sigolène M.
Published: August 2018

Efficient contraction of the heart depends on the size and oriented architecture of the myocardium. This is severely compromised by myocardial infarction or in cardiomyopathies. Deciphering the mechanisms underlying heart growth has attracted much attention over the past decade, after the demonstration that the mammalian heart has some potential to regenerate, thus raising hopes that heart repair may become a reality. The mechanisms of cardiac growth during development have been well studied in the mouse model, taking advantage of sophisticated genetic engineering and new tools for tracking cell lineages and behaviour. We discuss the current view of the intrinsic regulation of cardiomyocyte behaviour, as well as how it is modulated by interplay with other cardiac cell types or with the environment. Such fundamental knowledge is important for understanding the origin of congenital heart defects and for the development of novel strategies of heart repair.
Cardiac growth II: Cardiomyocyte polarization
Authors: Zaffran Stéphane
Published: August 2018

During vertebrate embryogenesis, the planar cell polarity (PCP) signalling pathway is responsible for cell movements essential for convergent extension during gastrulation, neural tube closure, neural crest cell migration, and heart morphogenesis. In the heart, the non-canonical Wnt/PCP pathway regulates cell polarity, cell shape, and cell dynamics during formation of the cardiac crescent and deployment of second heart field cardiac progenitors to the poles of the heart tube. PCP signalling is also essential for the establishment of left–right patterning in the early embryo. This chapter reviews our current understanding of PCP signalling in heart morphogenesis and how it affects the pathogenesis of congenital heart diseases.
Defining cardiac domains from the inside: NOTCH in endocardial–myocardial interactions
Authors: D’Amato Gaetano , Luxán Guillermo , de la Pompa José Luis
Published: August 2018

In this chapter we illustrate the signalling interactions of the endocardium with the other cardiac tissues to coordinate cardiac development. First, we describe the developmental origins of the endocardium. Then we focus on the Notch pathway because of its unique signalling activity in the endocardium, and briefly describe the elements of this signalling mechanism and the key cardiogenic processes that require endocardial Notch signalling: patterning of the early embryonic endocardium into prospective territories for valves and ventricular chambers, early valve formation, ventricular trabeculation, and compaction. Finally, we discuss how Notch dysfunction in the endocardium results in cardiac structural malformations that can lead to congenital heart disease.
Origin and diversity of cardiac fibroblasts: developmental substrates of adult cardiac fibrosis
Authors: Ruiz-Villalba Adrián , Frangogiannis Nikolaos , Pérez-Pomares José Maria
Published: August 2018

Cardiac connective tissues are primarily formed by cardiac fibroblasts (CF) of diverse embryonic origins. Whereas CF specific roles in cardiac morphogenesis remain under-researched, their involvement in adult cardiac fibrosis is clinically relevant. Cardiac fibrosis is a common element of several chronic cardiac conditions characterized by the loss of ventricular wall mechanical function, ultimately driving to heart failure. In the ischaemic heart early reparative fibrosis evidences the very restricted regenerative potential of the myocardium. In non-ischaemic diseases fibrosis is activated by unknown signals. We summarize current knowledge on the origin of CFs and their developmental roles, and discuss the differential disease-dependent response of different CF subpopulations to various pathological stimuli. We also describe the characteristic cell-cell and cell-matrix interactions that determine the fibrotic remodelling of the myocardium. We analyse experimental models for the study of cardiac fibrosis, and suggest future directions in the search for new markers and therapeutic targets.
Building the cardiovascular system: the acquisition of a functional form
Authors: Sedmera David , Thompson Robert P.
Published: August 2018

In this chapter we discuss key aspects of heart morphogenesis, namely the formation of the cardiac conduction system, coronary vascularization, and septation. We discuss functional studies and their contribution to our understanding of normal and abnormal development. Finally, we provide some explanations for particular shapes of the left ventricle in different species, reasoning that it is due to combination of physical constrains and functional optimization.
Blood vessel differentiation and growth
Authors: Benedito Rui , Siekmann Arndt F.
Published: August 2018

A variety of diseases are related to or dependent on the vascular system. Several lines of evidence show that adequate manipulation of the vascular function in disease requires targeting and interfering with the same molecular pathways and cellular processes that act to form vessels during embryo or organ development. Therefore an understanding of the mechanisms that regulate vascular development in this non-pathological context is of major importance, since it may lead to better ways of treating vascular-related pathologies. This chapter covers the most significant cellular and molecular mechanisms involved in the origin, life, and death of the endothelial cellwhich is involved in several important developmental and pathological processes. Most of the mechanisms described were identified in animal model systems. However, owing to the high evolutionary conservation of these, they are likely be very similar to those occurring in humans and in disease.
From cushions to leaflets: morphogenesis of cardiac atrioventricular valves
Authors: MacGrogan Donal , Pérez-Pomares José Maria , Chaudhry Bill , de la Pompa José Luis , Henderson Deborah J.
Published: August 2018

At the looping stage of heart development, tissue patterning of myocardium and endocardium at the atrioventricular (AV) junction defines a morphogenic field competent to form valves that initially appear as protrusions of proteoglycan-rich extracellular matrix (ECM) called endocardial cushions (ECs) which are cellularized by an endocardial-mesenchymal transition (EMT). Cellular proliferation results in fusion of the major AV mesenchymal cushions and AV septation, whereas smaller cushions receive a supply from epicardially derived cells. These various sources of mesenchyme precursors give rise to most of the valve structures, leaflets, annuli, and supporting tension apparatus. During valve leaflet maturation, the ECM matrix accumulates collagen and elastin and assembles into a thin flexible fibrous structure, which is remarkably tough. Valve development is regulated by the cross-talk between developmental signalling pathways. Pathogenic mutations in a subset of developmentally important genes have been linked to valve disease, suggesting that developmental defects may underlie valve disease in adulthood.
Development of the arterial valves
Authors: Henderson Deborah J. , Chaudhry Bill , de la Pompa José Luis
Published: August 2018

The arterial valves guarding the entrances to the aorta and pulmonary trunk have many similarities to the mitral and tricuspid valves in the atrioventricular region of the heart. Despite these similarities, there are significant differences in the formation and structure of the arterial and atrioventricular valves. The most fundamental of these relate to the lineage origins of the cells forming the primitive cushions. Although the fate of the different lineages remains unclear, each makes a permanent contribution to the mature valve. Arterial valve formation is intrinsically linked to cushion formation and outflow tract septation; therefore abnormalities in these processes have a profound impact on development of the valve leaflets. In this chapter we highlight the main differences in the development and structure of the arterial valves, compared with the atrioventricular valves, show how abnormalities in these developmental processes can result in arterial valve anomalies, and discuss controversies within the literature.
The role of the neural crest in cardiac development
Authors: Dyer Laura A. , Kirby Margaret L.
Published: August 2018

The cardiac neural crest (CNC) plays pivotal roles in numerous steps of cardiac development. Every aspect of the CNC cell’s lifespan is highly orchestrated, from its induction in the dorsal neural tube to its migration to its differentiation at its final destination. During migration, CNC cells are affected by their environment and simultaneously modulate the extra-cellular milieu through which they migrate. In the pharyngeal arches, CNC cells repattern the originally symmetrical arch arteries, producing the great arteries. Because the cardiac neural crest is essential for many aspects of heart development, it is unsurprising that human CNC-related syndromes have severe phenotypes. This chapter describes how CNC cells are formed and contribute to their final destinations. Essential signalling pathways are presented in the context of CNC development, and CNC-related syndromes are included to highlight this population’s broad importance during development.
The multiple functions of the proepicardial/epicardial cell lineage in heart development
Authors: Dettman Robert , Guadix Juan Antonio , Cano Elena , Carmona Rita , Muñoz-Chápuli Ramón
Published: August 2018

The epicardium is the outer cell layer of the vertebrate heart. In recent years, both the embryonic and adult epicardium have revealed unsuspected peculiarities and functions, which are essential for cardiac development. In this chapter we review the current literature on the epicardium, and describe its evolutionary origin, the mechanisms leading to the induction of its extracardiac progenitor tissue, the proepicardium, and the way in which the proepicardium is transferred to the heart to form the epicardium. We also describe the epicardial epithelial–mesenchymal transition from which mesenchymal cells originate, and the developmental fate of these cells, which contribute to the vascular, interstitial, valvular, and adipose tissue. Finally, we review the molecular interactions established between the epicardium and the myocardium, which are key for myocardial development and can also play a role in cardiac homeostasis. This chapter highlights how the epicardium has become a major protagonist in cardiac biology.
The genetics of congenital heart disease
Authors: Bentham James R.
Published: August 2018

Congenital heart disease (CHD) is defined as a structural cardiac malformation resulting from an abnormality of development; 8% of CHD is inherited in a Mendelian fashion and 12% results from chromosomal imbalance. Recurrence risk and new research suggest that even the remaining 80% of patients without an identifiable familial or syndromic basis for disease may have an identifiable genetic cause. The potential to understand these mechanisms is increasing with the advent of new sequencing techniques which have identified multiple or single rare variants and/or copy number variants clustering in cardiac developmental genes as well as common variants that may also contribute to disease, for example by altering metabolic pathways. Work in model organisms such as mouse and zebrafish has been pivotal in identifying CHD candidate genes. Future challenges involve translating the discoveries made in mouse models to human CHD genetics and manipulating potentially protective pathways to prevent disease.
Arterial wall remodelling in congenital heart disease
Authors: Prapa Matina , Ho S. Yen
Published: August 2018

The thoracic aorta is the second most common site of aneurysm formation after the abdominal aorta. Thoracic aortic aneurysms (TAAs) often result from medial wall degeneration secondary to genetic aberrations. Over recent decades, unprecedented research in the field of connective tissue disease has led to identification of key molecular pathways involved in TAA formation. Prolonged survival of congenital heart disease patients following successful reparative surgery has also led to increased incidence of TAA in this context with extensive investigations of underlying mechanisms. This chapter summarizes breakthrough discoveries in congenital arterial wall remodelling and discusses their potential clinical applications.