bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.
Coronary anomalies
Authors: Basso Cristina , Perèz-Pomares José Maria , Thiene Gaetano , Houyel Lucile 
Published: August 2018

Abstract
Coronary artery anomalies occur either in isolation or in the context of congenital heart defects (CHD). Isolated coronary artery anomalies include anomalies of connection to the pulmonary artery or to the aorta, anomalies of the intrinsic coronary arterial anatomy including anomalous orifices, and anomalies of myocardial/coronary arterial interaction including myocardial bridges and fistulae. Such defects are of major significance in clinical cardiology and cardiac surgery because of their association with myocardial ischaemia and sudden death. Coronary anomalies associated with CHD can result from three types of developmental perturbation: (1) anomalous epicardial course (in congenitally corrected transposition of the great arteries and L-looped ventricles), (2) anomalous communication with a high-pressure ventricular cavity (pulmonary atresia with intact ventricular septum and hypoplastic left heart syndrome), or (3) anomalous connection to the aorta. Outflow tract defects represents 30–40% of CHD, and their main characteristic is great artery defects influencing coronary arterial anatomy.
Myocardial non-compaction
Authors: Sheppard Mary N. 
Published: August 2018

Abstract
Isolated left ventricular non-compaction is a controversial entity which has only been reported in the past 30 years. It is becoming more frequently diagnosed due to the use of echocardiography and MRI. It can present in fetal life, infancy, childhood, and adult life. Clinically, the patient can present with cardiac arrhythmias, cardiac failure, systemic emboli due to thrombosis within the ventricles, and sudden death. It can be a genetic entity associated with mutations in many genes associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy. It is a rare entity found at autopsy and is more common in children than adults. In the past the prognosis has been considered worse in children then in adults. Treatment is usually empirical, dealing with the cardiac failure, arrhythmias, and thromboemboli.
Developmental aspects of cardiac arrhythmias
Authors: Postma Alex V. , Sedmera David , Vostarek Frantisek , Christoffels Vincent M. , Bezzina Connie R. 
Published: August 2018

Abstract
The rhythmic and synchronized contraction of atria and ventricles is essential for efficient pumping of blood throughout the body. This process relies on the proper generation and conduction of the cardiac electrical impulse. Electrophysiological properties differ in various regions of the heart, revealing intrinsic heterogeneities rooted, at least in part, in regional differences in expression of ion channel and gap junction subunit genes. A causal relation between transcription factors and such regionalized gene expression has been established. Abnormal cardiac electrical function and arrhythmias in the postnatal heart may stem from a developmental changes in gene regulation. Genome-wide association studies have provided strong evidence that common genetic variation at developmental gene loci modulates electrocardiographic indices of conduction and repolarization and susceptibility to arrhythmia. Functional aspects are illustrated by description of selected prenatally occurring arrhythmias and their possible mechanisms. We also discuss recent findings and provide background insight into these complex mechanisms.
Advanced therapies to treat cardiovascular diseases: controversies and perspectives
Authors: Giacca Mauro , Ibáñez Borja 
Published: August 2018

Abstract
There is a pressing need to develop novel therapies for myocardial infarction and heart failure, two conditions that affect over 20% of the world population. Despite important advances in achieving revascularization of the ischaemic myocardium and the usefulness of devices in assisting failing hearts, therapy for these conditions remains poor. The final extent of myocardial tissue loss after infarction is a major determinant of post-infarction mortality due to heart failure. In this chapter we review the current strategies aimed at counteracting injury due to acute myocardial ischaemia–reperfusion and the experimental approaches to achieve cardiac and vascular regeneration once damage has occurred. We critically discuss the possibility of inducing tissue restoration by gene transfer or exogenous cell implantation, and report on the exciting possibility of stimulating the endogenous capacity of cardiac regeneration using growth factors and small regulatory RNAs.
The zebrafish as a model for cardiac development and regeneration
Authors: Chaudhry Bill , de la Pompa José Luis , Mercader Nadia 
Published: August 2018

Abstract
The zebrafish has become an established laboratory model for developmental studies and is increasingly used to model aspects of human development and disease. However, reviewers and grant funding bodies continue to speculate on the utility of this Himalayan minnow. In this chapter we explain the similarities and differences between the heart from this distantly related vertebrate and the mammalian heart, in order to reveal the common fundamental processes and to prevent misleading extrapolations. We provide an overview of zebrafish including their husbandry, development, peculiarities of their genome, and technological advances, which make them a highly tractable laboratory model for heart development and disease. We discuss the controversies around morphants and mutants, and relate the development and structures of the zebrafish heart to mammalian counterparts. Finally, we give an overview of regeneration in the zebrafish heart and speculate on the role of the model organism in next-generation sequencing technologies.
Cells to repair the infarcted myocardium
Authors: Salvatori Daniela , Devalla Harsha D. , Passier Robert 
Published: August 2018

Abstract
The adult mammalian heart has poor regenerative capacity. Loss of functional cardiomyocytes following myocardial infarction leads to the replacement of functional muscle by scar tissue. This has a detrimental effect on cardiac function and may lead to heart failure. Potential regeneration of severe cardiac damage would require replacement of dead and damaged cardiomyocytes by transplantation, recruitment of endogenous progenitor cells, or induction of cardiomyocyte proliferation. For more than a decade, clinical trials to ameliorate the injured heart have been under way. However, after evaluation of the outcome of these trials it is evident that the beneficial effects of these cell-based transplantations are only marginal, and beneficial effects, if any, are not caused by regeneration of cardiomyocytes. In recent years, alternative approaches and various cell sources have been studied and suggested for cardiac repair. Recent advances in these cell-based therapies or strategies to activate endogenous cardiac repair are discussed.
The role of non-coding RNA/microRNAs in cardiac disease
Authors: Reckman Yolan J. , Pinto Yigal M. 
Published: August 2018

Abstract
In the past two decades, our knowledge about non-coding DNA has increased tremendously. While non-coding DNA was initially discarded as ‘junk DNA’, we are now aware of the important and often crucial roles of RNA transcripts that do not translate into protein. Non-coding RNAs (ncRNAs) play important functions in normal cellular homeostasis and also in many diseases across all organ systems. Among the different ncRNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have been studied the most. In this chapter we discuss the role of miRNAs and lncRNAs in cardiac disease. We present examples of miRNAs with fundamental roles in cardiac development (miR-1), hypertrophy (myomiRs, miR-199, miR-1/133), fibrosis (miR-29, miR-21), myocardial infarction (miR-15, miR17~92), and arrhythmias/conduction (miR-1). We provide examples of lncRNAs related to cardiac hypertrophy (MHRT, CHRF), myocardial infarction (ANRIL, MIAT), and arrhythmias (KCNQ1OT1). We also discuss miRNAs and lncRNAs as potential therapeutic targets or biomarkers in cardiac disease.
Epigenetics and post-transcriptional regulation of cardiovascular development
Authors: Yang Jin , Han Pei , Li Wei , Chang Ching-Pin 
Published: August 2018

Abstract
Cardiac organogenesis requires the control of gene expression at distinct developmental windows in order to organize morphogenetic steps in the correct sequence for heart development. This is facilitated by concerted regulation at three levels: chromatin, transcription, and post-transcriptional modifications. Epigenetic regulation at the chromatin level changes the chromatin scaffold of DNA to regulate accessibility of the DNA sequence to transcription factors for genetic activation or repression. At the genome, long non-coding RNAs work with epigenetic factors to alter the chromatin scaffold or form DNA-RNA complexes at specific genomic loci to control the transcription of genetic information. After RNA transcription, the expression of genetic information can be further modified by microRNAs. Each layer of gene regulation requires the participation of many factors, with their combinatorial interactions providing variations of genetic expression at distinct pathophysiological phases of the heart. The major functions of chromatin remodellers and non-coding RNAs are discussed.
Complex network interactions: cardiovascular systems biology
Authors: Grunert Marcel , Perrot Andreas , Rickert-Sperling Silke 
Published: August 2018

Abstract
A large quantity of molecular information on heart development, function, and disease has been generated over recent decades. However, most recent studies have been dominated by reductionistic approaches, and thus many aspects remain unclear, particularly regarding the primary causes of complex cardiovascular diseases such as congenital heart malformations. With the advent of high-throughput technologies, systems-based approaches have developed rapidly in biology and medicine. In the biology of cardiovascular systems complex data within or across different molecular levels of biological systems or pathways can be integrated and combined to identify the causes underlying cardiac diseases, which might not be possible otherwise. This is in agreement with data suggesting that biological molecules in individual regulatory layers, such as transcripts, proteins, and metabolites, act within networksrather than independently of each other. Thus systems biology provides a promising approach to fully addressing the complexities of congenital heart disease.
Emergency Department Visits After Elective Spine Surgery
Authors: Hills Jeffrey M , Khan Inamullah , Sivaganesan Ahilan , Weisenthal Benjamin , Daryoush Joshua , Butler Marjorie , Bydon Mohamad , Archer Kristin R , Asher Anthony , Devin Clinton J 
Published: August 2018

Abstract

BACKGROUND
Emergency department (ED) overuse is a costly and often neglected source of postdischarge resource utilization after spine surgery. Failing to investigate drivers of ED visits represents a missed opportunity to improve the value of care in spine patients.

OBJECTIVE
To identify the prevalence, drivers, and timing of ED visits following elective spine surgery.

METHODS
Patients undergoing elective spine surgery for degenerative disease at a major medical center were enrolled in a prospective longitudinal registry. Patient and surgery characteristics, and patient-reported outcomes were recorded at baseline and 3 mo after surgery, along with self-reported 90-d ED visits. A multivariable regression model was used to identify independent factors associated with 90-d ED visits. For a sample of patients presenting to our institution's ED, charts were reviewed to identify the reason and time to ED postdischarge.

RESULTS
Of 2762 patients, we found a 90-d ED visit rate of 9.4%. One-third of patients presented to our institution's ED and of these, 70% presented due to pain or medical concerns at 9 and 7 d postdischarge, respectively, with 60% presenting outside normal clinic hours. Independent risk factors for 90-d ED visits included younger age, preoperative opioid use, chronic obstructive pulmonary disorder, and more vertebral levels involved.

CONCLUSION
Nearly 10% of elective spine patients had 90-d ED visits not requiring readmission. Pain and medical concerns accounted for 70% of visits at our center, occurring within 10 d of discharge. This study provides the clinical details and a timeline necessary to guide individualized interventions to prevent unnecessary, costly ED visits after spine surgery.