Heart Septal Defects

Cardiovascular Examination

The Cardiovascular examination is typically focused in cardiac and blood vessels. Cardiovascular disease may present with a number of diverse symptoms; non-cardiac causes must also be considered. It allows for an initial assessment of symptoms and is crucial for determining the differential diagnoses and further steps in cardiac diseases. The present chapter gives students details in manual cardiac examination and makes it easy for medical students and junior doctors.

Medical and Social Outcomes in the Management of Cardiac Diseases in Children

Children with cardiovascular diseases, especially congenital heart diseases are exposed to socioeconomic burdens ranging from poverty, economic difficulties, and emotional breakdown to parental schism. There are various ways by which cardiac diseases affect children. These include the effect of the disease on the child, the family and the nation as a whole. Management of cardiovascular diseases in children comprises diagnosis, investigations, medical and surgical rehabilitation/ergonomics and follow-up. All these steps in management have both medical and social implications on the child. The effects of cardiovascular diseases are not limited to health, but can seep into social life, as well. Affected individuals tend to forgo a lot of things, including restrictions in their life, depression and even family structure disintegration, decrease life expectancy and family disharmony in some cultures. The socio-economic burden of pediatric cardiovascular diseases is quite huge both for the individual, household and society. The impact includes loss in financial resources, productivity, increased disability-adjusted life years, decreased quality of life, catastrophic expenditure and premature death. These burdens are more in the low and middle-income countries. This chapter aims at eliciting the various social and economic burdens that children with heart diseases encounter in the course of their illness.

Management of Children with Systemic Diseases

Significant oral problems are associated with many medical disorders. Close cooperation and consultation between the dentist and the child’s physician are essential to render optimum medical care. Prevention of oral disease is the primary consideration for these children. Medically compromised children can be challenging to treat and affect dental care [30]. To treat medically compromised patients safely, it is essential to Obtain a relevant and thorough medical history and understand the possible implications of the illness on dental treatment and the potential importance of the condition on treatment planning and the caries risk associated with the medical condition. With advances in medical treatment, significantly more children survive longer with more complex medical needs, and these children will present to the general dentist for dental treatment.

Activity Methods for Cardiovascular System Diseases

This chapter provides a collection of methods generally used in experimental pharmacology to test compounds with different activities in the cardiovascular system. There are many models in vitro and in vivo and we have highlighted those used in the field of natural compounds research. For the in vitro procedures, the focus was on the inhibition of enzymes, such as an angiotensin-converting enzyme or nitric oxide synthase, which plays a pivotal role in maintaining vascular control and overall blood pressure. Moreover, test procedures on isolated vessels were also considered for compounds whose activity is exerted on specific targets expressed in the vasculature. Regarding the in vivo methods, heart failure and hypertension models were highlighted for their high incidence of overall deaths cause. In particular, we have analyzed models of heart failure in rats and mice, animals generally used in preclinical studies. In addition, it also evaluated useful models of hypertension involving mainly rats; however, in many cases, the procedure could be translated to different animal species.

Congenital Heart Disease

Subject Index

Clinical Application of Circulating MicroRNAs as Novel Biomarkers for Different Diseases

Biomarker research has become increasingly interesting in many areas nowadays. Biomarkers are indicators of the biological process that can show changes in disease and health status and reveal pathological conditions. There is always a need for markers that divide patients into risk categories that can help in early diagnosis, detect complications ahead of time, guide treatment, and predict adverse outcomes in a chronic complex and certain diseases such as cancer. microRNAs (miRNAs) are ~ 22 nt long npcRNAs involved in post-transcriptional arrangements. miRNAs regulate messenger RNAs (mRNA), especially through negative regulation of gene expression. The fact that miRNAs have come to the fore in many disease mechanisms brings up their use as biomarkers in the early stage. The purpose of this review is to gather the latest information on this subject by bringing together recent articles and reviews to contribute to understanding the role of miRNAs, which act as biomarkers in different ways in vital processes, in the formation, early diagnosis, and treatment of diseases. miRNAs have an important potential to become a next-generation biomarker and therapeutic. But, each miRNA molecule can bind to a large number of different mRNAs, and different miRNAs in each mRNA. Therefore, new findings are needed to determine the expression activities and targets of miRNAs.

COVID-19 and Pulmonary Diseases

The coronavirus disease 2019 (COVID-19) primarily affects the respiratory system, commonly manifesting as pneumonia. The clinical presentation of COVID-19 is challenging to distinguish from community-acquired pneumonia due to other etiologies and respiratory exacerbations of pre-existing chronic respiratory diseases. Fortunately, the majority of patients have an asymptomatic or mild illness. However, some patients may develop profound hypoxemia secondary to diffuse alveolar damage and occlusion of alveolar capillaries by microthrombi. When patients with compromised lung function due to pre-existing respiratory diseases develop this disease, they face a setback. The management of the pre-existing illness is often suboptimal due to COVID-19-related restrictions. Further, these patients are more likely to develop severe manifestations of COVID-19 resulting in more severe morbidity and mortality. Diagnosis is established by performing a reverse transcription-polymerase chain reaction (RT-PCR) on samples from the respiratory tract. Treatment of the mild disease is primarily supportive, while supplemental oxygen and mechanical ventilation may be indicated for more severe cases. Several treatment options, including antiviral agents, corticosteroids, immunomodulators, and convalescent plasma therapy, are being investigated. Currently, there is no evidence to indicate that the diagnosis and treatment of COVID-19 are different in those with preexisting respiratory conditions. In the absence of an effective antiviral agent or vaccine, disease prevention is assumed to be of paramount importance. Social distancing and proper use of personal protective equipment are critical in the prevention of transmission.

Anesthesia for Pediatric Patients with Common Comorbidities Part III

There have been dramatic improvements in the survival of neonates and children with many diseases and disorders due to advancements in medicine over the past several decades. These advances are attributed to the better understanding of these disease processes, the advent of multidrug combinations, molecularly targeted therapies, critical care and various surgical interventions. In the wake of this rapidly developing wide range of treatment protocols, the anesthesiologist needs to have a clear understanding of these disorders and their comorbidities, and stay abreast of the various treatment modalities, including their safety and toxicity profiles. This review attempts to emphasize some of the clinical conditions unique to these patients and special considerations for the conduct of anesthesia in this population. Some of the disease processes and comorbidities discussed here include anesthetic considerations for ex-premature infants, diabetes mellitus, obesity, childhood cancer, and children with congenital heart disease who present for non-cardiac surgery. The objective of this discussion is to provide an updated and comprehensive review of current perioperative anesthetic management of pediatric patients with these conditions. We also delineate the effects of anesthesia during the perioperative course, including major metabolic changes that may result in increased morbidity. We provide guidelines for any anesthesia provider involved in the care of these vulnerable patients. Special considerations need to be taken to promote the physical and mental wellbeing of these children and their families. Collaborative coordination with all providers involved in care is essential to provide safe and effective anesthesia to this subset of patients.

Anesthesia for Pediatric Patients with Common Comorbidities Part I

Children undergoing anesthesia have many considerations of disease processes that require careful attention to details and addressing specific needs. There are several comorbidities that are frequently encountered in a pediatric setting. A common scenario is a child with an upper respiratory tract infection presenting for elective surgery. We will discuss the criteria to be considered regarding when it is safe to proceed with elective surgery and when the risk is high. Asthma is common among children, and exacerbation can occur during an anesthetic. Anesthetic management of children with these respiratory illnesses is discussed. Children with Down syndrome frequently present for various cardiac and non-cardiac surgical interventions. Anesthetic issues relating to their non-cardiac surgeries will be discussed. Children with sickle cell disease is yet another group of patients frequently admitted to the hospital with sickle cell crisis. They warrant attention to specific details to ensure getting through surgery safely and require optimal pain management. Obstructive sleep apnea is increasingly encountered in children presenting for surgical procedures. Anesthetic challenges and risks they pose will be discussed.

Subject Index

Introduction of Common Pediatric Diseases

Pediatric health has improved over the past decades and there is a decline in deaths caused by infectious diseases. Yet, the top three causes of disease in children younger than 10 years in 2019 include neonatal disorders, lower respiratory tract infections, and diarrheal diseases. While in the adolescence age group, the major causes are road injuries, headache disorders, and self-harm. Preterm birth complications, pneumonia, and birth asphyxia are the most leading cause of death in children under five years. While in the five to nine years of age group, injuries, including road traffic injuries, drowning, burns, and falls, are the leading causes of death.

Recent Advances in the Diagnosis and Management of Pulmonary Embolism

Acute pulmonary embolism (PE) is a form of venous thromboembolism

(VTE) and has varied clinical manifestations with significant morbidity and mortality.

The general population's overall incidence is on the rise due to the increasing

availability of D-dimer and computed tomographic pulmonary angiography. The

incidence is higher in males than females (58 versus 48 per 100,000, respectively),

increasing with age. In the United States, PE accounts for approximately 100,000

deaths annually. Specific populations, including patients with malignancy, pregnant

females, hospitalized medical and surgical patients, or patients with total joint

replacement, or arthroplasty, are at a higher risk for PE. Patients presenting with

hemodynamic compromise due to PE need to be treated with intravenous thrombolytic

therapy unless contraindicated, followed by anticoagulation. For over six decades,

traditional anticoagulants like unfractionated heparin (UFH) are used for short-term

anticoagulation. For patients who require long-term anticoagulation, low molecular

weight heparin (LMWH) like enoxaparin and a vitamin K antagonist like warfarin are

used to achieve therapeutic anticoagulation. Options for anticoagulation have been

expanding steadily over the last decade with the introduction of the first direct oral

anticoagulant (DOAC). Since their introduction, DOACs have changed the landscape

of anticoagulation. This narrative review aims to summarize for clinicians managing

pulmonary embolism (PE) the main recent advances in patient care, including risk

stratification, current data regarding the use of thrombolytic treatment, and direct oral

anticoagulants.

Thoracic Surgery

This chapter will include the most common cases of thoracic surgery in the pediatric age group, it ranges from congenital such as diaphragmatic hernia, lung emphysema to acquired conditions such as corrosive injury.Usually two types of deformities considered as Congenital are found to be associated with the chest wall. One may cause depression or protuberance due to overgrowth of the cartilages and the other one causing aplasia or dysplasia. Pectus carinatum (PC), is a protuberance of chest all which makes up to 10% of the chest wall abnormalities while combined PE/ PC makes up 5%, while Pectus excavatum (PE) cause a depression in the chest, thus may be called as sunken, or funnel chest. Jeune syndrome is another syndrome that may exhibit mixed features of PE/PC but is rarely found.

Biomaterials for Cardiac Regeneration

Globally, cardiovascular disease is one of the predominant clinical conditions, which accounts for about 50% of human mortality and morbidity. No doubt pharmacological and surgical interventions have dramatically improved the quality of life of patients with cardiovascular diseases. However, the demand for new therapeutic interventions as well as regenerative strategies is currently increasing. Biomaterials, both natural and synthetic, have exhibited great potential in cardiac regenerative therapy. Therefore, the development of biomaterials based extracellular matrix, grafts or stents, etc. would be highly beneficial for supporting the natural function and physiology of heart tissues.

Subject Index

Congenital Heart Defects

Congenital heart disease is congenital anomalies that having heart defects origin form the birth. The structural abnormality of the heart, great vessels is diagnosed at the time of birth. It affects childbirth during pregnancy. Congenital heart defects change the blood flow to the heart. The defect ranges from mild to severe clinical symptoms that can lead to developing life-threatening conditions. The progression of congenital heart disease associated with genetic and non-genetic factors. The risk factors for include diabetes mellitus, viral infections, medications like ACE inhibitors, drinking alcohol and smoking during pregnancy, genetics may increase the more health care burden to diagnosed patients. The improper treatment of congenital heart defects can lead to the development of heart failure, cyanosis, stroke, and arrhythmia. The clinical symptoms of congenital heart defects include shortness of breath, chest pain, cyanosis, rapid heartbeat, cardiac murmur, edema can elevate the risk of heart defects. Physical examination of the patient, echocardiographic investigations are useful for the detection of heart defects. Effective prescribing pattern of ace inhibitors, arrhythmias, beta blockers, antiplatelet, and diuretics is used to enhance health condition of the patients.

Introduction to Heart Anatomy and Physiology

The cardiac system represents the heart and blood vessels. The blood is distributed to multiple organs present in the body. Capillaries are minute blood vessels, allow the gas exchange processes. Veins send blood to the heart from the capillaries. The heart is situated in the thorax, posterior to the sternum and superior surface of the diaphragm. The heart has four chambers, and two atria above and two ventricles below. The oxygenated blood moves to left portion of the heart and enters into the left atria and ventricle. The deoxygenated blood pumped into the right side of the heart and moves into the right ventricle and flows towards the lungs. The heart is covered with three protective layers which include an epicardium, myocardium, and endocardium. The cardiac physiological functions are controlled by a group of electrical impulses. The electrical impulse origin from the sinoatrial node and located on the top side of the right atrium. It causes atria muscle contractions and thereby sends blood into the ventricles. A cardiac cell demonstrated the electrical activity and transmits the cardiac impulses to the heart to maintain the normal heart beating and initiation of the cardiac cycle. The cardiac event causes the opening and closing of valves results in contraction and relaxation of cardiac chambers. The cardiac cycle consists of systole and diastole events, during the systole, ventricles contract and send blood to arteries and during diastole, the ventricle relaxes and collects blood from atria. The electrical activity of the heart originates from SA node and causes atria to initiate contraction of cardiac muscles and supply of blood into the ventricles.

Postnatal Surgical Approach of Congenital Heart Disease

The advances in neonatal care and pediatric cardiac surgery have allowed repairing of complex congenital heart disease in the newborn and young infants with excellent results. The most common congenital heart defects that may need early surgical treatment are tetralogy of Fallot (TOF), transposition of the great arteries (TGA), univentricular heart, total anomalous pulmonary veins connection, hypoplastic left heart syndrome, critical aortic stenosis, and truncus arteriosus. TGA, characterized by atrioventricular concordance with ventriculoarterial discordance, is the most common cyanogenic cardiopathy, which requires treatment in the neonatal period. Atrioseptostomy with Raskind balloon must be performed in the newborn with TGA, who presents significant hypoxia and restrictive atrial septal defect. Surgical treatment of TGA depends on the gestational age diagnosis, associated defects and evaluation of the left ventricle anatomy and function. TOF is the cyanogenic cardiopathy that requires therapy more frequently within the first year of life. Those newborns with TOF who present severe cyanoses and or hypoxic crises may become ductus dependent, requiring surgical shunting procedure, percutaneous ductal stenting or total repair. Currently, there is a trend to perform neonatal total surgical repair in the centers of excellence, based in the low surgical risk. In univentricular hearts, medical decision depends on some anatomical aspects. While in case of significant pulmonary flow obstruction, it will require shunting procedure, in case of pulmonary overflow, it may need pulmonary banding. Total anomalous pulmonary venous return, critical aortic valve stenosis, and pulmonary atresia patients will require surgical or interventional heart catheterization procedures as a newborn. While, newborns with Ebstein’s anomaly have about 60% chance of requiring early surgical intervention.

Clinical Management of Congenital Heart Diseases in Neonates

Management strategies for congenital heart disease (CHD) in the neonate have evolved significantly. Advances in surgical technique, medical technology, and perioperative care have resulted in excellent post-repair survival, even for complex types of CHD. Furthermore, with the increased availability and accuracy of prenatal diagnosis by fetal echocardiography, the postnatal management of these newborns can often be anticipated and planned. The prenatal diagnosis of CHD has been associated with decreased morbidity and mortality for some forms of major CHD. As most cases of major CHD are not identified prenatally, clinical examination of the newborn and pulse oximetry are also important means of identifying additional cases. In summary, to improve the outcomes of a neonate with CHD, surgical repair or catheter intervention may be offered. For this purpose, early recognition of a neonate with CHD is necessary for stabilization and timely intervention.

Fetal Cardiac Intervention

Fetal heart interventions have been developed for select cardiac defects in order to alter the natural history of disease and improve patients´ outcomes. Intervention rationale and patient selection criteria, as well as associated risks and procedural technical considerations have been reviewed. Fetal aortic valvuloplasty is performed in fetuses with severe aortic stenosis with evolving hypoplastic left heart syndrome, with improving rates of biventricular outcome and early survival; and in rare cases of fetuses with aortic stenosis with severe mitral insufficiency and restrictive foramen ovale. Fetal atrial septoplasty with atrial septal stent placement in patients with hypoplastic left heart syndrome with intact or highly restrictive atrial septum has not yet demonstrated a decrease in the disease´s associated mortality. There is limited data regarding the results of fetal pulmonary valvuloplasty in fetuses with pulmonary atresia with intact ventricular septum with evolving hypoplastic right ventricle. Pericardiocentesis for severe pericardial effusion secondary to heart tumors or a cardiac diverticulum or aneurysm continues to be a rare procedure in an exceptional condition. Key aspects regarding selection criteria for intervention and technical and clinical results, require further study in a multicenter collaborative approach.

Labor Management of Pregnant Women with Fetuses with Congenital Heart Diseases

Congenital heart defects (CHDs) are the most common defects at birth. Thus, their prenatal diagnosis is extremely important, since early intervention, when required, dramatically reduces newborn mortality. CHDs, that occur both at the intrauterine phase and during the first hours of life, are well tolerated and do not require specialized care during delivery. However, some severe CHDs have an increased risk of hemodynamic instability and may require maintenance of fetal shunts after birth. In these cases, planning the time of delivery and selecting a tertiary hospital are necessary. In some cases, there may be maternal or fetal indications to anticipate delivery, including a variety of obstetric ones. Thus, the birth of a newborn with CHD is a multidisciplinary event, involving obstetricians, neonatologists, and cardiologists.

Environmental Factors Associated with Congenital Heart Diseases

Congenital heart diseases (CHD) are common, of largely unknown etiology, with high mortality. This chapter presents the available information on environmental factors that may alter the risk for CHD. Information regarding parental characteristics and conditions, maternal therapeutic drug exposures, parental nontherapeutic drug exposures, and environmental exposures are presented. Aside from some cardiac teratogens and prenatal maternal conditions or exposures associated with an increased risk for CHD, such as thalidomide, and retinoids, smoking, maternal rubella infection, phenylketonuria, hypertension, and diabetes, studies investigating most of environmental risk factors have yielded conflicting results. Associations were found for febrile illness, in vitro fertilization, stressful life events, hyperhomocysteinemia, obesity, hypertension, antihypertensives, bronchodilators, anticonvulsant drugs, nontherapeutic drugs, alcohol, air pollution, disinfectant products, pesticides, solvents, metals and landfill/hazardous waste sites. Some principles for prevention can be useful, as preconception and prenatal care with specific attention to the intake of folic acid, vaccination for rubella, detection and effective management of phenylketonuria, hypertension, and diabetes, discussion of any medicine use, avoidance of infections and chemical exposures, alcohol, smoking, and non-therapeutic drugs. Women receiving therapeutic drugs should be regularly monitored. In addition, screening for CHD should be performed when environmental risk factors are present. Further investigations for the development of prevention and intervention are needed.

Genetics and Congenital Heart Disease

Congenital defects are frequent, occurring in 2-3% of live births, with high morbidity and mortality. Congenital heart defects are the most frequent, occurring in 1% of all live births. Most occur as isolated malformations, but approximately 1/3 are part of a syndrome, usually of genetic etiology. The correct etiological diagnosis is important for useful clinical follow-up and genetic counseling. Children born with congenital heart defects should be carefully examined for other malformations and dysmorphia.

Extra Cardiac Defects in Fetuses with Congenital Heart Diseases

Extracardiac malformations (ECMs) and chromosomal abnormalities are common in fetuses with some congenital heart defects (CHD). The frequency and type of ECMs and chromosomal abnormalities vary according to the type of CHD and the studied population. The detection rate of CHD and ECMs depends on the first-trimester screening through nuchal translucence (NT) measurement, second trimester anomaly scan, and fetal echocardiography. The CHDs most frequently associated with ECMs are atrioventricular septal defect (AVSD), ventricular septal defect (VSD), tetralogy of Fallot (TOF), hypoplastic left heart syndrome (HLHS), tricuspid atresia (TA), aortic arch, coarctation of the aorta (CoA) and interruption of the aortic arch (IAA). Conversely, the association of ECMs and chromosomal abnormalities with the transposition of the great arteries (TGA) is low. CHD such as: Ebstein's anomaly, left ventricular outflow tract obstruction (aortic stenosis) and obstruction of the right ventricular outflow tract (atresia and pulmonary stenosis) are associated with extremely low ECMs and chromosomal abnormalities, and are limited to a few sporadic cases.

Premature Closure of the Foramen Ovale and the Ductus Arteriosus

The foramen ovale and the ductus arteriosus are fetal circulation shunt sites, and the appropriate flow profile in these shunts allows the maintenance of fetal hemodynamic stability. The presence of restrictive or closed foramen ovale and/or ductus arteriosus may lead to poor fetal outcomes, such as right ventricular failure, neonatal pulmonary hypertension, or even death. Fetal echocardiography is the main tool for the diagnosis and assessment of premature closure of the foramen ovale and/or ductus arteriosus, and its intrauterine and/or postnatal management. In some cases, fetal intervention or soon after birth may be required in the presence of fetal hemodynamic instability.

Fetal Cardiac Tumors

Fetal cardiac tumors (FCT) are rare anomalies (about 1% among prenatal cardiac problems). There are more frequent multiple FCT and less frequent single FCT. The FCT occur in the population of healthy young mothers and risk factors are not easily detectable, but environmental factors (benzapirin?) could play a role. Basic ultrasound (US) anatomy in the 1st and 2nd trimester usually is normal and FCT are usually detected in the second half of pregnancy. In the majority of cases the fetus’s growth is normal. In each case, targeted fetal echocardiography should be performed in a fetal cardiology center. The very first problem is to discriminate between normal heart anatomy and congenital heart defect. The second goal of fetal echocardiography in FCT is to make an assessment of the hemodynamic status of the fetus. Extracardiac and additional anomalies coexisting in cases of FTC can be divided into two types i.e., frequent and rare. An experienced fetal cardiologist can not only make a proper diagnosis but also should counsel parents about the short-term prognosis for the fetus (about his future during prenatal life) as well as long term prognosis (after birth and later on). In cases of maternal decision to continue the pregnancy, fetal echocardiography monitoring should be offered to evaluate possible hemodynamic changes, to prepare both fetus and pregnant woman for optimal time for delivery and perinatal care. The main goal would be to avoid prematurity and to confirm fetal wellbeing, despite the cardiac abnormality. Details of echocardiography and postnatal outcome are presented in rhabdomyoma, teratoma, fibroma, myxoma and hemangioma. The way of delivery in surgical resection of cardiac tumors in newborns is discussed. In differential diagnosis, “bright spot” is discussed. Suggested management – algorithm of perinatal care in cases of FCT is presented with emphasis on cooperation of a perinatal team. FCT can be diagnosed at 20 weeks of pregnancy, which allows to start echocardiographic monitoring, taking into consideration the potential risk of hemodynamic progression. FCT (both multiple and single) can be the first sign of tuberous sclerosis complex in later prenatal or postnatal life. Single FCT other than rhabdomyoma can be asymptomatic in newborns, but may require an early surgical resection, therefore delivery in tertiary centers is recommended. FCT are a good example of the practical value of prenatal cardiology development.

Fetal Myocardial and Pericardial Diseases

This chapter provides an overview of the most frequent pathologies of the myocardium and pericardium during fetal life. Considering that some of these pathologies constitute a group of uncommon conditions, they are of interest from the point of view of their prognostic and therapeutic value. Besides, they are also within the most striking pathologies found in the screening of the fetal heart, and the ones which cause greater anxiety in the family and professional environment. Progress has been made in different diagnostic techniques, outlining some therapeutic advancements, as well as in the importance of new technologies that allow to deepen our knowledge of the functional defects of the cardiac muscle during fetal life.

Fetal Ventricular Inflow Anomalies

Congenital heart diseases (CHDs) are largely known as an important cause of fetal perinatal mortality. Currently, the accuracy of fetal echocardiography enables the detailed diagnosis of a significant variety of congenital cardiac anomalies, and it has also been demonstrated that prenatal outcomes may improve in critical CHDs. Accordingly, this chapter provides a detailed overview of the important anatomic aspects of some of the ventricular inflow anomalies, focusing on currently available information, to enable the prenatal diagnosis of such CHDs by ultrasound or echocardiography. Information regarding prenatal management, delivery plan strategies, and differential diagnosis of such anomalies is presented. The chapter also discusses the parental counseling and fetal and neonatal therapeutic management of such congenital cardiac anomalies. Univentricular atrioventricular (AV) connections, straddling and overriding of AV valves, and crisscross hearts are described in the current chapter. The concept of “functionally single ventricle” encompasses a group of CHDs in which the dominant ventricular chamber is responsible for maintaining the systemic and pulmonary circulations and not suitable for a biventricular repair. The central feature of such hearts is the univentricular AV connection. Regarding the type of the straddling of an inlet valve, it is based on the insertion of the tension apparatus of the AV valve into the crest of the ventricular septum or in the contralateral ventricle. Meanwhile, overriding of an inlet valve is related to the annulus of the AV valve and may interfere in the AV connection. Depending on the degree of the overriding of the straddled valve, the ventricles are in a dominant and rudimentary relationship, and a double-inlet AV connection, primarily the double-inlet left ventricle is the most frequent type of AV connection. In general, straddling and overriding of an AV valve requires a ventricular septal defect, and straddling may occur alone or in the presence of an overriding. In “crisscross” hearts, the ventricular inlet flows are in a cross shape and the ventricles are arranged in a superoinferior relationship. During an ultrasound examination, the crossed AV valves produce false images of the mitral valve or tricuspid atresia in a standard 4-chamber view, which makes the diagnosis difficult. In fact, the knowledge about the detailed anatomy, the assessment of the ventricular outflow tracts, and the identification of other possible associated cardiac anomalies are important for improving In Utero and postnatal management in ventricular inlet anomalies described in the current chapter.

Subject Index

Fetal Aortic Arch Anomalies

The normal left aortic arch courses from the ascending aorta to the left, upwards and backwards in relation to the trachea. The aortic arch branches into the right innominate, left common carotid and the left subclavian artery in sequence. The aortic arch is divided into the proximal transverse arch and the distal transverse arch and the aortic isthmus. Abnormalities of the aortic arch involve obstructive lesions, e.g. coarctation of the aorta, and abnormalities of branching and position of the aortic arch and the latter are topic of this article. Branching and position abnormalities of the aortic arch have clinical meanings: mechanical compression of airway and esophagus by forming a vascular ring or sling, association with cardiac abnormalities, and association with chromosomal abnormalities. This chapter describes anatomical, genetical and echocardiographic features as well as clinical postnatal implications of abnormalities of branching and position of the aortic arch.

Fetal Conotruncal Anomalies

Conotruncal anomalies are characterized by abnormalities of the great vessels of the heart. There are five types of conotruncal anomalies named as tetralogy of Fallot, double outlet of the right ventricle, transposition of the great arteries, truncus arteriosus and corrected transposition of the great arteries. These lesions known as “conotruncal anomalies” are caused by aberrant development of the conotruncal region of the embryonic heart. Prenatal diagnosis of congenital heart disease optimizes obstetric and neonatal care. Identification of these anomalies in prenatal life allows a variety of treatment with options to be considered, including delivery at a tertiary center, termination of pregnancy in some cases and in utero therapy. Majority of fetuses with conotruncal anomalies will undergo surgery in the neonatal period or in the first year of life. This chapter will discuss the fetal echocardiographic findings, extracardiac and chromosomal anomalies associations, prenatal and postnatal outcomes of conotruncal anomalies.

Fetal Left Cardiac Malformations

Congenital heart defects (CHDs) represent the most common congenital malformations, especially those affecting the left side of the fetal heart. During fetal life, the presence of the ductus arteriosus is responsible for the low intrauterine mortality rate if compared with the postnatal life. Prenatal diagnosis of CHDs has improved over the past 20 years and diagnostic enhancement has been obtained with the introduction of standardized examination of the fetal heart together with the technological advancement of the ultrasound equipment, particularly with the introduction of the four-dimensional (4D) ultrasound technique based on spatiotemporal- image correlation (STIC) or the application of the three-vessels and trachea view (3VT). The chapter describes and reports the evolution of the antenatal detection of left cardiac malformations, with emphasis regarding the echocardiographic characteristics that need to be evaluated in order to assess the hemodynamic state of the fetus. An extending search and analysis of the medical literature has been sought and describe in relation to the prenatal ultrasound diagnosis of aortic coarctation (CoA), aortic stenosis (AS), interrupted aortic arch (IAA), hypoplastic left heart syndrome (HLHS), aortic arch abnormalities and aorto-pulmonary window (APW). Understanding the cardiac performance of the fertus is of vital and critical importance to plan appropriate management and prognosis. Cardiac defect as critical aortic stenosis (CAS), IAA and HLHS are described as a potential emerging pathogenetic continuum. Attention has been paid to the latest improvement of in utero surgery and technique such as fetal aortic valvuloplasty in case of CAS or severe CoA and the use of multiple scoring system to predict postnatal biventricular circulation are described in great details. Notewithstanding, the chapter is enriched by a series of 2D- as well as 3D/4D ultrasound imaging and videos for each type of left cardiac malformation.

Fetal Right Heart Malformations

The fetal right heart malformations are a heterogeneous group of anomalies that basically involve the tricuspid and pulmonary valves. Ebstein´s anomaly usually consists of the existence of a downward displacement of the insertion of the septal and posterior leaflets of the tricuspid valve. Tricuspid dysplasia is an abnormality of the chordae tendinae and/or the leaflets, which are thickened, of a normally inserted tricuspid valve. Both conditions are characterized by an incomplete closure of the valve in systole, causing tricuspid regurgitation that may cause cardiomegaly, heart failure and hydrops. Chromosomal defects are rare and the mortality for prenatally detected forms is high, with survival rates at 5 years less than 25%. In tricuspid atresia there is a replacement of the valve by a fibromuscular tissue and is almost always associated with a ventricular septal defect. The right ventricle is invariably hypoplastic, and in up to 25% of cases there is ventriculo-arterial discordance. Chromosomal abnormalities are rare, and the outcome is usually good, with survival rates at 20 years of 61-75%. In mild to moderate forms of pulmonary stenosis, the pulmonary valve appears thickened and/or narrowed, and is visible continuously throughout the cardiac cycle. The fourchamber view is usually normal. On color Doppler, there is high-velocity turbulent flow across the pulmonary valve. The outcome is good in most cases. In severe forms of pulmonary stenosis or pulmonary atresia with intact ventricular septum there is an almost complete obstruction of the right ventricle outflow tract due to severe dysplasia or complete absence of the pulmonary valve, respectively. This can be assessed both in B-mode and with color Doppler. The only route for blood supply to the lungs is the ductus arteriosus. Depending on the tricuspid valve, the right ventricle can be severely small or normal sized, which has a paramount importance on the final outcome. Acquired forms of premature closure of the ductus arteriosus can be idiopathic or secondary to the administration to the mother of some medical treatments. It often appears abruptly, in the third trimester of pregnancy. The Doppler study shows an acceleration of the transductal flow, with a peak systolic velocity greater than 140 cm/s, a diastolic peak greater than 35 cm/s, and a pulsatility index lower than 1.9 m/s. When the closure is complete, there is an asymmetric cardiomegaly because of dilatation of the right chambers, right ventricle hypertrophy and dilatation of the pulmonary artery and branches, while the duct is narrowed.

Fetal Septal Defects

The frequency of the different fetal septal defects and their presentation prenatally is described, including atrial septum defects (ASDs), ventricular septum defects (VSDs) and atrioventricular septum defects (AVSDs). Embryology of the defects and the association with underlying aneuploidy and genetic syndromes are discussed. Image findings in the fetal period are presented alongside diagrams to aide comprehension of the ultrasound views. A brief summary of prognosis and postnatal course of these conditions is also included.

Prenatal Diagnosis of Cardiac Malposition’s and situs Anomalies

Cardiac position refers to the physical location of the heart relative to the thorax irrespective of cardiac axis. Deviation from its normal location can be due to extrinsic factors, embryologic defects, or as a result of structural cardiac abnormalities. In cardiology, situs refers to the position, arrangement and orientation of the various organs found in the abdomen (visceral) and thorax (atrial situs). In general, more complex congenital heart diseases (CHD) are associated with abnormalities of the situs such as situs ambiguous (isomerism or ‘heterotaxy’). The heterotaxy syndrome has been linked to mutations of different genes and environmental factors (e.g. diabetes and retinoic acid exposure in utero) during the establishment of left-right asymmetry within earliest embryonic stages. Left atrial isomerism is associated with complete heart block and an increased risk of fetal hydrops, leading to poor in utero outcome. Conversely, right isomerism results in poorer postnatal outcomes since anomalous pulmonary venous return and complex cardiac anomalies are common findings in such cases. Prenatal diagnosis of cardiac position and situs abnormalities by cardiac ultrasound echocardiography can help guide recommendations concerning in utero and postnatal outcome.

Normal Fetal Cardiac Rhythm and Arrhythmias

Fetal arrhythmias are rare but they are an important avoidable cause of perinatal mortality. Timely diagnosis is therefore crucial, as treatment can be life saving. Careful evaluation of cardiac structure and function using different echocardiographic modalities can exclude structural cardiac anomalies as well as provide accurate information about the atrial and ventricular contraction rates, their relationship, conduction pattern and hemodynamic consequences of arrhythmia. Although observation and reassurance will suffice in a substantial proportion of pregnancies complicated by fetal arrhythmia, some will require intrauterine therapy or early delivery followed by postnatal treatment to prevent heart failure and fetal/neonatal demise. Fortunately, most common fetal arrhythmias are few of those conditions that can be managed successfully in utero with good results. In this chapter, we describe the normal and abnormal fetal cardiac rhythms, their diagnosis and prenatal management.

Early Fetal Echocardiography

The role of first-trimester ultrasound has evolved from the measurement of crown-rump length (CRL), nuchal translucency (NT) and nasal bone to involve more detailed assessment of fetal anatomy. The majority of cardiac malformations are properly defined and potentially detectable by the time of the 11-13+6 week ultrasound examination. The sensitivity of ultrasound screening for cardiac abnormalities varies according to the marker being assessed (increased NT, tricuspid regurgitation, abnormal ductus venous flow), operator experience and the extent of a protocol for formal sequential structural assessment of the heart. All cardiac structures can be visualised from 13 weeks onwards. Early fetal echocardiography has been shown to be feasible and highly sensitive and specific in experienced hands. Early identification of cardiac abnormalities allows the assessment of chromosomal abnormalities/genetic syndrome at an early stage, giving parents more reproductive autonomy. Operators should be aware of the limitations of an early cardiac examination: Some lesions progress as pregnancy advances and there is still a need for a follow up ultrasound at 20 weeks’ gestation.

Fetal Echocardiographic Evaluation

Congenital heart diseases are more common than chromosomal abnormalities or neural tube defects. Although been one of the cause of mortality in infants, early diagnosis of heart defects increases survival. It is of utmost importance to perform adequate cardiac screening. The International Society of Ultrasound in Obstetrics and Gynecology standardized the basic echocardiographic planes, in order to facilitate its use, increasing diagnosis. Therefore, in this chapter, we will discuss the anatomy and a systematized technical description of the fetal heart by two-dimensional (2D) echocardiography, emphasizing its indications, essential points for a good cardiac evaluation, and notions about some heart defects.

Utero-Placental Circulation Development

With increasing obesity and diabetes in our population, and alcohol, marijuana, and tobacco use among women of child-bearing years, there is a high probability of embryonic exposure to risk factors before pregnancy is recognized. These metabolic changes and environmental factors are known in animals to induce birth defects and specifically, congenital heart defects (CHDs). This study discusses an interrelationship between placental and heart development in which blood flow between these developing organs needs to be maintained at specific levels. When blood flow is altered in the mouse by embryonic exposure to environmental factors, dysmorphogenesis occurs. Additionally, with gene expression analysis of the embryonic heart it was demonstrated that with elevated homocysteine (HCy) a natural metabolite, and alcohol exposures, numerous Gene Ontology classifications relating to lipid metabolism were altered. As for example, relative to the female embryo, significantly more alterations occurred in the male embryonic heart transcriptome with homocysteine exposure. That lipid metabolism was altered was validated by staining for localization of neutral lipids in the embryonic mouse embryos. We demonstrated that lipid droplet amount and the localization patterning were changed with exposures in both the fetal four-chambered heart and in the placenta. More changes occurred, however, in the placental tissue. We have demonstrated that a regimen of high folic acid supplementation of the pregnant mouse diet started with the morning after conception prevented the environmentally induced alterations. The importance of lipids in trophoblast and placental development, the relationship to gender, and how folate supplementation normalizes development through epigenetic programming is reviewed.

Cardiovascular Development

An understanding of normal cardiovascular development is essential to appreciating the abnormalities seen in congenital heart disease. The cardiovascular system develops within the mesoderm and through the process of folding, and establishment of the body axis, patterning and laterality it transforms from blood islands into the primitive heart tube and then the complex cardiac structures that supply the fetus. This chapter will discuss the embryological formation of the cardiovascular system and how deviations from normal development result in common cardiac defects.

Classification of Prenatal Congenital Heart Diseases

The in utero progression of congenital heart diseases (CHDs) can be observed in almost all CHDs during the first, second, and third trimesters of pregnancy. The progression of a cardiac disease can be associated with worsening of structural defects, new onset of foramen ovale restriction, decreased ventricular inflow or outflow, or worsening arch obstruction. The role of contemporary fetal cardiologists is to not only diagnose CHDs but also foresee the condition of the newborn after delivery and plan potential treatment in the first hours-or even minutes-of life. For this reason, pregnancy and delivery management of newborns with a prenatal diagnosis of CHD requires a multidisciplinary team composed of fetal and pediatric cardiologists, obstetricians and maternal–fetal specialists, neonatologists, and other pediatric specialists. The potential progression of CHD severity in utero and changes occurring during the transition from fetal life to infancy led to the creation of new classifications of CHDs dedicated to fetuses only. Severest heart defects are defined as CHDs in fetuses whose treatment results in death in nearly all cases, and potential treatment is needed immediately after birth; severe urgent heart defects are defined as CHDs in fetuses who need to undergo an invasive cardiologic treatment or cardiologic surgery within the first hours of postnatal life; severe planned heart defects are defined as CHDs in fetuses who need to undergo cardiologic surgery within the first month after birth, usually with ductal-dependent circulation and prostaglandin infusion to prolong prenatal physiology; and planned heart defects are defined as CHDs in fetuses who do not need to undergo cardiologic surgery within the first month after birth (usually surgery may be postponed to infancy). The only tool for the proper qualification of fetuses to one of the groups in the new classification system is fetal echocardiography.

Subject Index

New Techniques and Methods in Explosive Analysis

In forensic analytical chemistry, chemical investigation of the liquid/gas/solid evidences from the crime scene after the explosion (soil, water, concrete/glass/ wood pieces, metal, clothes taken from suspects, etc.) and reliable identification of explosive residues on such evidences remain an active area of research due to increased demand for homeland security against terrorist and warfare threats, as well as environmental monitoring. GC-MS, LC-MS, and LC-MS/MS offer distinct advantages for laboratory analysis of explosives in post-blast samples, including soil/ water/plant matrices, etc. Time-of-Flight, Ion-Trap, and Orbitrap technologies provide high resolution, better analyte identification, and accurate mass information at sub-ppm levels. Direct analysis techniques, such as ambient MS has a wider range of applications and offer high sensitivity/selectivity and direct analysis from the surface of interest. Techniques like Direct Analysis In Real Time (DART) and Desorption electrospray ionization (DESI), which can ionize substances directly on surfaces, offer new opportunities for security screening of explosives. Orbitrap MS was also used together with Raman microscopy for detailed molecular-level characterization of explosives and the chemical analysis of latent fingerprints. Electro-flow focusing ionization with in-source collision-induced dissociation can be used for MS detection and chemical imaging for speciation of the signatures of explosive devices and to detect proper spatial discrimination of explosive traces. Miniaturization to be used infield analysis with low cost is a technique work on currently. Multi-analyte detection with high selectivity/sensitivity to be able to use in as many different matrices and to be able to analyze without or with a very short and simple sample preparation methods are targeted for future analyses. Despite other reviews focussing on a certain group of techniques, this chapter summarizes some important developments in the standard MS techniques and ambient MS techniques used in laboratory, on-site, and miniaturized mass spectrometric analysis of high energetic materials in the last two decades, mostly conducted in the last decade.

Chemometrics as a Powerful and Complementary Tool for Mass Spectrometry Applications in Life Sciences

Because of its unique capabilities, mass spectrometry is an indispensable part of life science research. In this chapter, a review is made on aids of chemometrics in life sciences applications of mass spectrometry. Because of the increasing complexity of biological samples and ongoing technological enhancements of mass spectrometers, huge sum of data are provided for each biological sample. If the routine exploratory tools are used for data exploration, much of the information is not extractable and hence it gets lost. However, chemometrics helps to explore data thoroughly and extract maximum amount of information. The most common aids of chemometrics in bio-based mass spectrometry data is for experimental design, noise reduction, classification, library search, identification of biomolecules, finding the biomarkers, data compression and data mining.

This chapter is focused on the different aspects of using chemometrics for the analysis of mass spectrometry data in omics and biomedical images. In the first part, chemometrics applications for mass data in omics sciences (metabolomics and proteomics) are revealed. The mass data in omics are mainly provided by hyphenation of mass spectrometry with chromatographic techniques, i.e., gas chromatography (GC), liquid chromatography (LC) and electrophoretic techniques. In the second part of the chapter, the benefits of using chemometrics for mass spectrometry images are revealed. The data of these images are gathered by mass spectrometer itself or hyphenation with chromatographic techniques. Since, hyphenated methods are used for both omics and biomedical imaging, some of the chemometrics methodologies used in these two disciplines may be the same.

Qualitative and Quantitative LC-MS Analysis in Food Proteins and Peptides

LC-MS combines high separation ability of liquid chromatography with strong mass spectrometric structure identification. The advantages of LC-MS include high sensitivity and selectivity, minimal sample throughput, fast analysis speed and extensive structural information. It has been widely used in many fields, such as natural product analysis, pharmaceutical and food analysis, and environmental analysis.

In recent years, a great deal of researches have been conducted on the qualitative and quantitative aspects of food proteins and peptides. A variety of qualitative analyses of food proteins and peptides have been performed by LC-MS, such as accurate analysis of relative molecular weight, primary structural sequence, disulfide bond position, post-translational modifications (PTMs), etc. The quantitative analysis of proteins and peptides by LC-MS has been mainly achieved by two methods, i.e., label-free methods (peak intensities approach and spectral counting approach) and labeled methods (chemical labeling, metabolic labeling and enzymatic labeling methods). This chapter focuses on the application of qualitative and quantitative analysis of proteins and peptides in food sources.

Applications of Mass Spectrometry for the Determination of Microbial Crude Protein Synthesis in Ruminants

The importance of quantifying ruminal microbial crude protein synthesis has promoted the development and comparison of several different methods for precise determination of both the amount and rate of synthesis. One major challenge is in estimating and differentiating protein in the rumen between microbial, dietary, and endogenous fractions, and to correctly isolate the solid and liquid microbial fraction of the rumen contents. This is further complicated by the goal of using non-invasive methods as much as is feasible, such as avoiding the use of fistulated animals; the selection of an appropriate microbial marker, specifically one that behaves similarly in the solid-associated and liquid-associated microbial fractions. It is also vital to be able to accurately estimate the contribution of microbial protein to overall nitrogen used by the animal, which can be accomplished by the use of 15N labeled, as assimilated by ruminal bacteria, and by the quantification of labeled nitrogen via mass spectrometry (15N/14N). This review focuses on challenges regarding accurate quantification of microbial crude protein synthesis in the rumen, as well as providing the methodology for quantification using the 15N marker. This review is based on the collection of scientific papers from the main research groups in feed and animal nutrition in ruminants.

Subject Index

The Application of Intelligent Instrument: A Mobile Robot Instrument

In this chapter, the concept of the moving robot and the intelligent instrument will be introduced, followed by the smart small car and the intelligent instrument, and the micro UAV and the intelligent instrument. In the end the state-ofthe- art instruments and their applications will be presented.

The Advance of the Intelligent Instrument Applied in an Online Equipment Monitoring System

In this chapter, we will introduce the state-of-the-art instruments of online equipment monitoring system. Meanwhile, the technology of fault tolerance, fault analysis and the fault identify problem will be discussed.

The Application of Intelligent Instrument: A Mobile Intelligent Instrument

In this chapter, the advances of the wearable and IoT intelligent instrument are discussed; some state-of-the-art instruments and their applications will be also introduced.

Arduino and MATLAB in Intelligent Instrument

In this chapter, we will introduce two interesting domains in intelligent instrument: MATLAB and Arduino. As they easily combine with the theory and technology, some MATLAB design examples or demos are introduced including the modern signal process, machine vision, and so on. Similar to MATLAB, as the opensource hardware is easy to combine with the device, the Arduino SLAM, PHM and other intelligent instrument applications are introduced.

Proteus and its Simulation Design Examples

In this chapter, we will introduce two kinds of proteus designs, one is the foundational instrument hardware design example, and the other is its advance instrument design example.

The Data Communication and Input-output Technology of Intelligent Instrument

In this chapter, the IIC, SPI, EPA communication technology will be discussed, and the input-output technology includes HMI, OLED will be introduced and analyzed.

The Data Processing Technology of Intelligent Instruments

In this chapter, we will discuss the measurement uncertainty in intelligent instruments; the data processing algorithms in industrial intelligent instruments; the inverse problem and its processing method; the intelligent computing includes the deep learning and machine learning arithmetic in the intelligent instrument design.

The Signal Detection and Analysis Technology in Intelligent Instrument

The fundamental modern intelligent instrument is signal detection and analysis technology. Although it is the classic content of intelligent instruments, the noise analysis technology, the weak signal detection technology developed largely in many test fields. Therefore, in Chapter 2, the structure principle of data acquired system, the noise analysis technology, and the weak signal detection technology are introduced.

The Concept of Intelligent Instrument

One of the most fundamental principles in science and technology is that the discovery can be reproduced or the results can be measured. So, at the beginning of the book “modern intelligent instruments-theory and application”, the introduction of measurement, the intelligent instrument and its composition, and the example of an intelligent instrument are present.

Non-Compaction Cardiomyopathy from Infancy to Adulthood

Accepted as an unclassified cardiomyopathy by the American Heart Association or a genetic cardiomyopathy by the European Society of Cardiology, left ventricular non-compaction is an intriguing, but poorly understood condition characterized by the presence of a non-compacted extensive myocardial layer lining the cavity of the left ventricle which potentially leads to malignant arrhythmias, cardiac failure, and thromboembolism. Whether it is distinct cardiomyopathy or a morphological heterogeneous clinical condition with phenotypic morphologic traits often overlapping other types of cardiomyopathies remains very much debated. Ventricular trabeculation and compaction are two of the many essential steps for generating a functionally competent ventricular wall whereas, hyper trabeculation and the lack of ventricular wall compaction (non-compaction) are also one of the significant cardio-embryogenic defects associated with left ventricular noncompaction. This chapter aims to discuss in detail the current knowledge on embryology, epidemiology, clinical spectrum, genetics as both an isolated trait, and as part of other cardiac diseases or complex syndromes. It also explains the physiology, and the present pathophysiological concepts of non-compaction cardiomyopathy, provide an up-to-date view on imaging and also reevaluate the current diagnostic criteria and its impact on overdiagnosis of left ventricular non-compaction as well as the available data on prognosis, and therapy. The chapter will even go further to describe the challenges, and uncertainties facing the medical community, and the future directions in diagnosing left ventricular non-compaction.

Arrhythmogenic Right Ventricular Cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is a myocardial disease that primarily affects the right ventricle where the right ventricular free wall is partially or almost entirely replaced by fatty or fibrofatty tissue, providing a substrate for lifethreatening ventricular arrhythmias in young, apparently healthy individuals and athletes. However, whether fatty or fibrofatty infiltration of the right ventricle has been considered to be a sufficient morphologic hallmark of arrhythmogenic right ventricular cardiomyopathy is still a source of controversy as it is crucial that arrhythmogenic right ventricular cardiomyopathy is kept distinct from both fatty infiltrations of the right ventricle and Adipositas cordis. The autosomal dominant inheritance pattern is typical of this myocardial disease, and the identification of causative mutations in cell adhesion proteins has shed new light on its pathogenesis with familiar studies highlighting the need to broaden the diagnostic criteria, which are highly specific but lacking in sensitivity. This chapter will provide a detailed insight into arrhythmogenic right ventricular cardiomyopathies pathology, pathophysiology, clinical presentations, diagnosis, and management. It will however also highlight the genetic basis of arrhythmogenic right ventricular cardiomyopathy, risk stratification, phenotypic manifestations, and arrhythmia mechanisms with an analytical review of the evolving role of cardiac magnetic resonance and late gadolinium enhancement with contrastenhanced imaging in the diagnostic workup of arrhythmogenic right ventricular cardiomyopathy.

Cardiac Catheterization and Endomyocardial Biopsy for the Diagnosis of Heart Failure in Children

The most likely etiology of cardiac failure in neonates, children and young adults varies greatly by age and is often different from the type of etiology seen in adult patients. As such, the need for cardiac catheterization and endomyocardial biopsy depends on the (potential) underlying diagnosis and has to be carefully evaluated for every case, including the need for anesthesia, angiography and cardiac output evaluations.

Subject Index

Heart Failure in Pediatric Patients with Congenital Heart Disease

Heart failure may occur in structurally normal heart or in congenitally diseased heart. Some congenital heart diseases may predispose to heart failure, in different mechanisms and different pictures, as Fallot tetralogy, single ventricle, muscular dystrophy associated cardiomyopathy and left ventricular non compaction. The etiology of heart failure in those patients may be due to volume overload, pressure overload or valve insufficiency. The medical treatment for such patients includes diuretics, B blockers, ACE inhibitors, digoxin and anticoagulations.

Heart Failure in Pediatric Patients

The diagnosis of heart failure in children remains challenging. It precipitates changes in circulatory abnormalities, multiple cellular processes and neuro-hormonal status. Many cases are due to congenital disorders .Clinical picture in children ranges from being asymptomatic to having severe life-threatening symptoms. Ross classification was originally developed to determine the presence and severity of heart failure in infants and younger children. Non-invasive imaging studies are necessary in order to make the diagnosis of heart failure in children. Management ranges from medical, interventional to surgical procedures. Heart transplantation remains an acceptable treatment for children with end-stage heart failure.

Fatty Acid Imaging from Basic to Clinical

A number of radiolabeled fatty acids have been developed to assess myocardial fatty acid metabolism. Radioactive fatty acid analogues are classified into PET and SPECT tracers; carbon-11 is the most common isotope for PET, while iodine- 123 is typically used in SPECT. The main approaches for the development in fatty acid tracers include shift from PET tracers to SPECT tracers, iodine stabilization, and prolonged retention of tracers in the myocardium. 15-(p-iodophenyl)-3-(R, S)-methyl pentadecanoic acid (BMIPP), an iodine-123 labeled branched-chain fatty acid analogue, has been widely available for routine clinical SPECT in Japan, and provides useful information on abnormal fatty acid metabolism in ischemic heart disease as well as nonischemic cardiomyopathy. This agent plays a crucial role in the diagnosis of these diseases, and the prediction of therapeutic effect and prognosis. Reduced BMIPP uptake than perfusion is often observed in ischemic heart disease such as myocardial infarction and angina pectoris. This mismatched uptake may reflect ischemic but viable myocardium, and is associated with stunned or hibernating myocardium. In addition, BMIPP can serve as a memory marker of transient myocardial ischemia because BMIPP abnormality may persist even after perfusion recovery following ischemia. On the other hand, heart-to-mediastinum (H/M) ratio is commonly used as an index of BMIPP uptake in nonischemic cardiomyopathy. This topic will overview basic principles and clinical applications of fatty acid metabolic imaging.

Cardiac Anesthesia

Cardiac anesthesia encompasses the care of patients with cardiac disease; it is not limited to the care of patients undergoing cardiac surgery. In order to provide a successful cardiac anesthetic, it is imperative to understand fundamental aspects of cardiovascular physiology. These concepts include preload, afterload, and contractility; and how they relate to pressure-work versus volume-work for the heart. These concepts guide the management of specific disease conditions such as aortic stenosis, aortic insufficiency, mitral stenosis, mitral insufficiency, hypertrophic cardiomyopathy, as well as systolic heart failure and diastolic heart failure. A brief introduction to ventricular assist devices is included as well.

Complex Exodontia and Guidelines in Management of Medically Compromised Patients in Dental Chair

Many dental practitioners do not differentiate between the complex extraction and the surgical (trans-alveolar) extraction. By definition, the surgical extraction is one of complex extraction procedures, but the complex extraction is not limited to surgical extraction. In this chapter, the complex extraction has been defined. The pre-operative, intra-operative and post-operative factors that may contribute to the complexity of dental extraction have been discussed. This chapter contains a separated part about the management of medically compromised patients, as those patients can be considered under the definition of complex extraction. This chapter also contains a separated part about physics of elevator’s uses.

Synthetic Biopolymers

The striking role of tissue engineering in saving people’s life is inevitable. The number of patients waiting for an organ donor is increasing every minute. On the other hand, life expectancy has increased which results in a growing demand of scaffold production. The developed technology seeks for materials which target specific cells, proliferate, regenerate the targeted tissue and restores its function. To fulfill this, not only the material type but also the fabrication techniques should be engineered carefully. Among various materials, synthetic polymers have attracted more attention due to their tailorable properties. In this chapter an overview of various synthetic polymers, their degradation, application and their various blends is discussed. The polymeric nanocomposites used as scaffold have been introduced briefly and the future research in the material selection for porous scaffolds has been reviewed.

Cardiogenesis and Repair: Insights from Development and Clinical Trials

Cardiovascular diseases are major contributors to global mortality. Myocardial infarction represents a significant complication of one such disease that affects a very large population worldwide, with the ischemic region and the resultant scar tissue generated reducing cardiac function and becoming a focus for recurrent infarctions. Several stem cell therapy approaches aimed at regenerating the nonfunctional myocardium have emerged using multipotent and pluripotent stem cells. However, many of the pre-clinical and clinical trials have not yielded the anticipated outcomes, and so different strategies are now being explored to achieve regeneration. The failure of these stem cell therapies may be partially attributable to the dearth of information on human cardiac developmental and regenerative pathways. However, numerous studies have investigated cardiogenesis and heart regeneration in model organisms, which have provided considerable insights into the processes of cardiac development, and other studies on the differentiation of pluripotent stem cells have largely corroborated these findings. Here we review heart development in different organisms, supplemented with insights from stem cell biology and clinical studies, which will underpin the development of effective stem cell treatments for myocardial infarction and other cardiac insults.

Iatrogenic Pathology of the Cardiovascular System

This chapter includes a synthesis of data regarding cardiovascular-related lesions induced by medical drugs or radiotherapy, and also relates to the specific injuries that can be caused by diagnostic and/or therapeutic interventions. The effects of chemotherapeutics and non-chemotherapeutic drugs on the myocardium are analyzed in detail, with a focus on anthracycline-induced cardiovascular effects in children. Some of the disorders are illustrated using representative pictures taken during autopsies. Although a common technique, insertion of prosthetic grafts can lead to complications, such as thrombosis, aberrant neointimal hyperplasia or dehiscence. Percutaneous vascular intervention complications can be related to the catheter or to the intervention itself. The differences between in-stent restenosis and postoperative thrombosis are also presented. The final part of this chapter is dedicated to open heart surgical intervention complications.

Basics of Radiation Protection in Cardiac Imaging Studies

Cardiology is responsible for a large part of the radiation exposures that every person receives per year from all medical sources. Fluoroscopically guided and other cardiology procedures are increasing in number and complexity. Catheterization PCI, interventional electrophysiology procedures and repeated procedures can result in patient skin doses high enough to cause deterministic skin injuries. Cancer risk from a single NST is small, but projected on a population level, NSTs may result in thousands of radiation-attributable cancers annually. Several epidemiological studies involving various levels of radiation exposure all show increased cancer risk, and allow risk projection. The occupational radiation exposure of cardiologists and nuclear cardiology staff must be considered; exposure of interventional cardiologists and cardiac electrophysiologists can be two to three times higher than that of diagnostic radiologists. In recent years, intensive efforts have been initiated to reduce the radiation dose associated with cardiology. Staff radiation protection is related to patient protection, as radiation received is mainly the scattered radiation from patients. The correlation between occupational and patient doses is very dependent on equipment, the specialist, and protocols followed throughout the procedure. Radiation data collection and documentation procedures, QA programmes, application of Diagnostic Reference Levels (DRLs), research, training and education are among the very basic tools also to enhance radiation protection and exploit all the advantages of radiation imaging and therapy in Cardiology.

Artifacts and Pitfalls in Cardiac Molecular Imaging

Single Photon Emission Computed Tomography (SPECT) has the unique ability to evaluate myocardial perfusion, at the cellular level, under peak stress conditions. In that sense, by evaluating viability, SPECT myocardial perfusion imaging (MPI) can establish prognosis and assess the effectiveness of therapy, thus becoming a valuable modality in diagnosing and managing cardiac patients. Nevertheless, SPECT MPI can be exposed to various pitfalls and artifacts that may affect negatively the reliability of the technique, arising from a number of sources at any stage of this complex imaging process that includes patient-related, software- and equipment-related and user-related factors. By understanding and recognizing the sources of these pitfalls and artifacts, the reader should be able to make all the necessary steps to limit the sources of error, and more importantly to interpret the results of a study by taking into account their relative influence.

Radioisotopic vs Non-Radioisotopic Methods for Myocardial Viability Identification

Left ventricular (LV) systolic dysfunction associated with coronary artery disease (CAD) comprises a major diagnostic and therapeutic dilemma. Hibernating myocardium refers to a chronic dysfunctional condition, as a result of repeated episodes of ischemia, of a still viable myocardium. In viable dysfunctional myocardium, the integrity of myocyte membrane and contractile fibers are preserved. Revascularization may promote LV function in cases of residual myocardial viability in dysfunctional segments of the heart. The identification of viability is pivotal for patients’ management, and viability testing is a valuable tool to guide therapeutic options in these patients. Various non-invasive viability assessment procedure can be used in the clinical practice and novel applications are emerging which are likely to provide higher diagnostic accuracy in the future. Nuclear myocardial perfusion imaging with single photon emission computed tomography (SPECT) has been used for several decades and is a well-established method for viability evaluation, while positron emission tomography (PET) has been considered the “gold standard” for this scope. Other non-radioisotopic cardiac imaging modalities have been also developed, such as cardiac magnetic resonance (CMR) and echocardiography with high image quality and no radiation exposure, and lastly cardiac computed tomography (CCT). In the last years, great advances have been made in image processing software, as well as in hybrid imaging for the simultaneous analysis of functional and anatomical datasets based on different modalities.

Assessment of Myocardial Viability Using SPECT and PET Techniques

Heart failure is a significant health problem and coronary artery disease is by far the leading cause. Despite advances in medical and device therapy the prognosis of patients with ischemic cardiomyopathy remains unfavorable, but revascularization may further improve the outcome in terms of contractile function, symptomatic relief, exercise capacity and mortality. Over the years, the presence of myocardial viability has been considered a significant determinant of the benefit from revascularization and a variety of noninvasive techniques have been developed to assess viable and nonviable myocardium in patients with ischemic systolic dysfunction. Viability imaging with 201Tl and 99mTc-agents SPECT can evaluate perfusion, cell membrane and mitochondria structural and functional integrity, whereas 18F-FDG PET is used for the assessment of glucose metabolism in myocytes. Dobutamine stress echocardiography provides information on the contractile reserve and cardiac magnetic resonance imaging can delineate the transmural extent of scar. In general nuclear imaging techniques have a higher sensitivity for the detection of myocardial viability, whereas techniques evaluating contractile reserve display a lower sensitivity but a higher specificity. This review focuses primarily on the radionuclide modalities for the assessment of myocardial viability and discusses the clinical value of viability imaging, including earlier retrospective work and the more recent prospective data.

Hybrid Imaging (SPECT/ CT, PET/CT, PET/MR)

Multi-modality imaging achieves the integration of structural and functional or metabolical information in a single examination. Apart from patient convenience and improved workflow, this “one-stop shop” approach is featured by enhanced diagnostic accuracy compared to either modality alone or side-by-side image interpretation. These advantages also apply on cardiovascular and molecular-targeted imaging where hybrid systems facilitate the detection of molecular signals and their accurate localization by fusion with anatomical structures. The role of SPECT/CT, PET/CT and PET/MR in studying patients with heart failure is reviewed in this chapter. Before mentioning the potential clinical utility, various issues concerning the principles of hybrid imaging, commercially available devices, image interpretation, possible technical errors and diagnostic pitfalls are addressed. Due to its wider availability, lower cost and the author’s experience, the value of cardiac hybrid SPECT/CT is emphasized.

Myocardial Perfusion (SPECT) Imaging: Radiotracers and Techniques

Heart failure remains a highly prevalent disease with significant morbidity and mortality. Millions of patients are affected worldwide and their treatment is associated with a significant cost for the healthcare systems, especially in developed countries. In approximately two-third of the cases, ischemic heart disease is the cause of the syndrome. Therefore, myocardial perfusion single photon emission computed tomography (SPECT) imaging is a key element in the diagnostic investigation, prognostication, and management of patients with heart failure. Perfusion images are obtained according to various well-established protocols, after the administration of either thallium-201 or technetium-99m labelled radiotracers in combination with several stress techniques. In the future, technological innovations and improvements of reconstruction methods are expected to strengthen the role of myocardial perfusion SPECT imaging as a useful tool for the investigation of heart failure and patient’s management.

Magnetic Resonance Imaging in Heart Failure

Heart failure (HF) may be the endpoint of various cardiac diseases. This emphasizes the need for a diagnostic method that can accurately establish the diagnosis of HF and define the underlying mechanisms of the condition. This is necessary for the selection of the appropriate therapeutic method (medication, revascularization or resynchronization therapy) in order to achieve the optimal response. Cardiac magnetic resonance imaging (MRI) is an emerging imaging method that can be used for quantification of ventricular function, as a baseline and also for follow-up of HF patients after treatment. It has great contribution in differentiation of the cardiac diseases (e.g. ischemic and non-ischemic cardiomyopathies, cardiomyopathies with myocardial hypertrophy, etc.) by providing tissue characterization. This chapter describes the technique of cardiac MRI examination and focuses on typical imaging characteristics that aid in the differentiation among cardiac conditions that may result in HF, according to their frequency and their importance in treatment selection. The parameters measured by cardiac MRI that play a role in the prognosis of the disease and therapeutic decision, are also discussed. Finally we present the role of cardiac MRI in cardiac resynchronization therapy and its predictive role in the therapeutic outcome.

Computed Tomography in Heart Failure

Multidetector computed tomography is an imaging modality which constantly gains ground in the field of cardiovascular imaging. Accurate imaging of coronary arteries, cardiac structure and function, pulmonary and cardiac venous anatomy can be explored with this non-invasive, easily reproducible technique, providing valuable information in the diagnosis and management of patients with heart failure. Computed tomography can support invasive techniques used in patients with heart failure, as in cardiac resynchronization and ablation for atrial fibrillation, with all necessary anatomic data, increasing the safety and efficacy of the procedures. In addition, patients after heart transplantation can be evaluated with multidetector computed tomography, avoiding more invasive procedures.

Interventional Therapy and Device Therapy

Despite therapeutic advances in the medical treatment of HF patients, the prognosis remains poor. Coronary revascularization in patients with ischaemic cardiomyopathy is associated with amelioration of symptoms and survival benefit. Percutaneous coronary intervention with stenting is associated with excellent outcome, high procedural success rate, low event rates, and can be safely performed in patients with ischaemic cardiomyopathy. Patients with complex coronary artery disease require surgical revascularization (Coronary Artery Bypass Grafting - CABG). Cardiac resynchronization therapy (CRT) aims to re-establishing synchronous contraction between the left ventricular free wall and the interventricular septum, resulting in an increase in stroke volume. In clinical terms, this is translated in functional class improvement. This generally involves biventricular pacing (pacing of the left and right ventricle through separate leads). Surgical strategy for the management of patients with end-stage ischaemic heart disease includes “conventional” techniques (surgical revascularization, the most common surgical procedure, surgical ventricular restoration in patient with a dyskinetic part in the left ventricle and mitral valve surgery for mitral regurgitation). Mechanical circulatory support aims to restore blood flow and pressure, and thus end-organ function, in patients with profound cardiogenic shock or in endstage patients (stage D) with advanced NYHA III-IV symptoms as a bridge to transplantation or as lifelong support (destination therapy). Heart transplantation is associated with excellent long-term results in terms of symptomatic relief and prognostic benefit under strict criteria involving the recipient and the donor. In the face of evolving technology, lifetime mechanical support provides a realistic alternative to heart transplantation.

Uncommon Cause of Stroke: Diagnosis and Treatment (Part II)

This chapter contains detailed, up-to-date information about the nature, diagnosis, and treatment of those relatively uncommon types of cerebrovascular disease that cause strokes. Although many of the conditions discussed are rare, the chapter covers the causes of up to 10% to 15% of all strokes and of up to 40% of strokes in young adults. This chapter may be an essential resource to help physicians diagnose and treat stroke patients who do not fit well into the usual clinical categories.

Discussed in this chapter are the various form of inherited small vessel disease such as CADASIL but even the less known Col 4A1/2 related syndromes, CARASIL, TREX1- gene mutations disorders and the cerebroretinal microangiopathy with calcifications and cysts. Three form of metabolic disorders causing stroke such as Fabry disease, Homocystinuria and MELAS as well as the most relevant form of hematological disorders (antifospholipid syndrome and sickle cell disease) are discussed. Finally intriguing disorders such as migrainous infarction and drugs related stroke disorders are detailed as well as some other rare disease such as Kohlmeier–Degos disease and acute posterior multifocal placoid pigment epiteliopathy.

Invited Lectures

Cardiovascular Actions of Estrogens

The actions of estrogens on the cardiovascular system occur either indirectly through the modification of cardiovascular risk factors [reduction of plasma LDL cholesterol, elevation of HDL cholesterol, effect on hemostatic factors (reduction of fibrinogen and inhibitors of fibrinolysis)] or directly mediated by the estrogen receptors (ERs, defined as genomic action of estrogens) or other receptors. In this chapter, the overall actions of estrogens on the cardiovascular system and particularly on the vascular wall, as well as actions of estrogens on many different metabolic pathways affecting the cardiovascular system will be analyzed. The indirect actions of estrogen on the circulatory and hematological system, body composition, lipids and glucose metabolisms will be analyzed. There are several causes leading to the development of early onset of coronary heart disease in young women. These causes can be classified into five categories: 1) Vasculitis and autoimmune diseases, 2) Hypercoagulable states, 3) Non-atherosclerotic coronary heart disease, 4) Myocardial infarction in hallucinogenic drug abusers, and 5) Atherosclerotic coronary heart disease. The causes leading to an early onset of coronary heart disease in young women will be analyzed.

Dental Problems in Down Syndrome Children

Down syndrome (DS) is a common malformation affecting the whole body with a unique craniofacial and distinctive oral feature and anomalies. These dental anomalies and the associated systemic manifestations of children with DS pose real challenges to the dentist as well as the pediatrician which necessitate a multidisciplinary team to be involved in taking care of children with this syndrome. It is important that the dentist can recognize the types of structural soft tissue and dental abnormalities which are part of the classic features and developmental prototype of D children. The dentist should also be able to detect and to appropriately manage these problems through an integrated team work including the family and the child primary physician. Good oral hygiene and healthy dental life are of paramount importance for an integrated health and better quality of life for such children.

Anesthesia in Down Syndrome Children

Down syndrome (DS) Children are more liable for frequent sedation and anesthesia either for imaging procedure or for surgical intervention. They have many risk factors that increase the anesthesia related complications. These risk factors include cardiac, esophageal, gastrointestinal or urinary tracts, eyes, ears, and joints anomalies. There is also an increased risk of infection due to immune deficiency. Proper preoperative, operative and post operative management are mandatory to decrease the anesthesia-related complications. In this chapter; these co morbidities and the factors that increase the risk of complications during anesthesia will be addressed, as well as pre-operative, intraoperative and post-operative management will be discussed.

Neurological Manifestations of Down Syndrome

Down syndrome is the most common chromosomal abnormality. A variety of neurological manifestations including stroke, epilepsy, cervical spinal cord compression, and basal ganglia damage may complicate the syndrome. As the neurologists have little chance to see a good number of DS patients and hence their expertise in this field is lesser than psychiatrists, it is suggested that cooperation between both neurologists and psychiatrists especially the learning disability might lead to better outcome of neurological complications of DS. This chapter reviews the commonest neurological complications associated with DS.

Respiratory Problems in Children with Down Syndrome

Children with Down syndrome (DS) are more prone to have respiratory disorders which can be categorized into congenital structural disorders of the airways and lungs, acquired disorders, and sleep-related disorders and obstructive sleep apnea. Children with DS have a high incidence of airway anomalies; both upper and lower compared to non-DS children. The most important findings are hypoplasia of midface with dysfunction of malformed Eustachian tube, a short palate, hypoplastic nasal bones, choanal stenosis, macroglossia, enlarged adenoids and tonsils, lingual tonsils, and narrow oropharynx, and nasopharynx, abnormal oropharyngeal structures, laryngomalacia, tracheomalacia, congenital subglottic stenosis, tracheo-oesophageal fistula, bronchomalacia and branching and lung anomalies. Among the acquired respiratory disorders encountered in children with DS are respiratory infections including acute bronchiolitis due to infection with respiratory syncytial virus, pneumonia, infection with H1n1 stains of flu virus, high incidence of acute lung injury, occurrence of pulmonary hemosiderosis, increase incidence of pulmonary hypertension, GERD, and the possibility of having asthma. Sleep disorders are common and important problems, frequently under-recognized in children with DS and can be a significant distressing factor to their families. The prevalence of these disorders in children with DS is very high, particularly in boys. Vaccinations help to prevent a considerable number of infectious diseases. The immune dysfunctions of DS are not a contraindication for the currently available vaccines: their immunogenicity and safety are not significantly different from those observed in the general population.

Cardiovascular Disorders in Children with Down Syndrome

Down syndrome (DS) is commonly associated with cardiovascular disorders either congenital or acquired. Congenital cardiac diseases (CHDs) occur in about half of children with DS. They also are more liable to have pulmonary hypertension, mitral valve prolapse, aortic regurgitation and many other acquired cardiac conditions. Meanwhile, they are also of a higher risk for developing obesity than the control children which predisposes them to an increased risk of atherosclerosis. Antenatal detection of DS as well as CHDs can be detected by presence of some soft signs during routine antenatal 4-chamber view. Children with this syndrome should have echocardiographic examination in the first month of life for all neonates, before any cardiac surgery, as follow-up after cardiac surgery, for serial evaluation of pulmonary hypertension, before involvement in major non-cardiac surgery and before involvement in physical exercise as well as serial follow up for early detection of any cardiac disorder. In this chapter, prevalence, pathomechanism and methods of detection of cardiac disorders in children with DS as well as their management are discussed.

Neonates with Down Syndrome

Neonates with DS have many co morbidities that jeopardize this critical period of life with increased morbidity and mortality. They have more incidences of congenital heart diseases, pulmonary disorders, epilepsies, gastrointestinal anomalies, hematological problems as well as feeding disorders. They need to recognize their problems and for early intervention that could improve their medical conditions as well as their quality of life.

Genetics of Down Syndrome: An Update

Since the discovery of the chromosomal basis of Down syndrome (DS) in 1959, researches are still trying to understand the genetic basis of this particular unique common disorder that cannot be simply explained by an additional chromosome 21. Recent advances in molecular genetics had shed the light on several genes peculiar to this disorder like DYRK1A involved in cognitive dysfunctions and GATA1 involved in transient myeloproliferative disease. Some of these genes are actually beneficial when found in excess like COL18A1 which encodes endostatin, a potent angiogenesis inhibitor that inhibit the progression of solid tissue tumors and thus may have a potential therapeutic effect as anticancer therapy, as an anti-inflammatory agent and for protection against diabetic retinopathy. Gene therapy - or better to say chromosome therapy - for patients with DS is a recent break through where scientists were able to silence the extra chromosome and reverse the neuron proliferation dysfunction. This will not only help patients with DS but could be applied to all chromosomal trisomies. By understanding the pathogenetic mechanisms of DS, the near future is holding hope not only for treatment of DS cognitive dysfunction but also cures for solid tumours and certain disorders that will be done through inducing trisomy 21 in affected cells!

Marfan Syndrome and Marfan-like Disorders

Aortic aneurysms are challenging surgical entities of the utmost importance to cardiovascular surgeons; when coupled with a connective tissue disorder, the complexities are multifold. The prevalence of these diseases is low, but Marfan, Ehlers- Danlos, and Loeys-Dietz syndromes are ubiquitous, affect both genders, and occur in all ethnic groups and geographical locations. Because of this, knowledge of the genetic and clinical manifestations of each syndrome is indispensible to the physician. A comprehensive overview incorporating the biomolecular and physical anomalies described in the literature is essential to providing optimal care for patients with these diseases.

General Health Topics Associated with Consanguinity; Genetic Disorders and Congenital Malformations; Benefits

In the main, the detrimental health effects associated with consanguinity are caused by the expression of rare, recessive genes inherited from a common ancestor(s). The closer the biological relationship between the parents, the greater is the probability that their offspring will inherit identical copies of disease-causing recessive genes. However, in spite of all the potential health problems associated with consanguineous marriages, in the vast majority of the societies where these are common, it is generally accepted that the advantages of consanguinity outweigh the disadvantages. The rate of congenital malformations among the offspring of consanguineous marriages is approximately 2.5 times higher than that among the offspring of unrelated parents. First cousin consanguinity has been shown to be significantly associated with an increased risk of congenital heart defects, congenital hydrocephalus and neural tube defects, susceptibility to infectious diseases, underweight, and having an adverse effect on cognitive performance in some consanguineous populations. Another disadvantage is the high rate of hospitalization and utilization of the health care facilities in consanguineous communities, causing a major financial burden, much of which could be saved if the rate of consanguineous marriages were lower. However, in certain situations consanguineous marriages can actually be advantageous. The culture of consanguineous marriages and the genetics of protection against malaria may have coevolved by fostering survival against malaria through better retention of protective genes in the extended family, and also the circle of family members who can act as successful tissue donors is significantly extended. There are also many social advantages.

Ventilation-Perfusion Distribution, Blood Shunts and Alveolar Dead Space

This chapter focuses on the relationship between alveolar ventilation and blood perfusion in normal and diseased states. In particular, it explains the reasons for different ventilation-perfusion ratios among lung regions. It explains the functional consequences of pulmonary diseases that alter the ventilation-perfusion ratio, and demonstrates how ventilation-perfusion abnormalities can be quantified. It describes in more detail the “three compartment model” (equivalent of the real lung), the methods used to quantify the fraction of pulmonary blood that does not undergo gas exchange (right-to-left blood shunt or venous admixture) and those used for differentiating between the two major components of venous admixture: maldistribution shunt-like effect and conductive (anatomical) shunt. The various normal and abnormal conditions that result in venous admixture (right-to-left blood shunt) are schematically represented, and the method for quantifying the fraction of alveolar ventilation wasted in alveolar dead space is described. Finally, pros and cons of oxygen therapy and potential complications of prolonged lung exposure to high O2 fractions, leading to oxygen toxicity, are detailed.

Immunotherapy with Anti-Aβ Monoclonal Antibodies in Alzheimer’s Disease: A Critical Review on the Molecules in the Pipelines with Regulatory Considerations

Alzheimer’s disease (AD) is the most common dementia in the industrialized world with prevalence rates far over 30% in the over 80 years old population. The dementia causes enormous cost to the social health care systems besides the personal tragedies for the patients, families and caregivers.

One of the pathological protein aggregations that occur in AD is the Amyloid-beta (Aβ) aggregation in extracellular plaques, accompanied by Tau hyperphosphorylation, chronic neuroinflammation and oxidative stress, leading to severe neurodegeneration of brain areas involved in learning and memory. Plaques, thus Aβ, appeared to be the more druggable and promising target for disease-modifying therapeutic strategies like passive immunotherapy with monoclonal antibodies (mAbs) against Aβ, though today it is clear that Aβ is a dreadful target. Meanwhile, the first-in-class mAb Bapineuzumab and the fast-follower mAb Solanezumab failed in Phase III whereas several other candidates – some of them modified 2^nd generation mAbs – now entered Phase I (PF-05236812, BAN2401, SAR228810 and BIIB037) and Phase II (Gantenerumab and Crenezumab) respectively. Others are known to be in preclinical stages. On the first view, the above-cited mAbs cleared or improved amyloid burden and validated the proposed Aβ read-out biomarkers, but have yet not shown relevant improvement in the major aim in AD therapy: cognition. Also, currently under Phase III investigation, are human IgG from healthy donors. The latest, so-called IVIG, are nowadays interestingly reported to stabilize cognition in AD patients.

In this review we discuss the immunological basis for the mechanism of action of passive Aβ immunotherapy, anti-Aβ mAbs and scaffolds in the pipelines and patents, their preclinical and clinical outcome and strategies for 2^nd generation biobetters.

Cell Encapsulation Technology: An Alternative Biotechnological Platform for the Treatment of Central Nervous System Diseases

Cell encapsulation technology is based on the immobilization of cells that secrete active therapeutic agents, in structures made from different biomaterials and surrounded by a semipermeable membrane that protects the cells from the host immune response and the mechanical stress. This technology has proven to be a suitable treatment strategy for different kinds of diseases such as diabetes, heart failure, anemia, cancer or central nervous system (CNS) diseases since promising results have been obtained in numerous works that have been carried out in this field. For this last application, cell encapsulation technology presents exceptional features as it allows direct, continuous and long-lasting release of the desired therapeutic product, next to the affected tissue and without crossing the blood-brain-barrier (BBB). Numerous studies have been carried out using this technology, in different animal models of CNS diseases, in which encouraging results have been obtained. Moreover, the rapid developments achieved in recent years, have allowed the application of these strategies in several advanced clinical trials, reflecting the potential of these techniques. However, there are still some features that must be optimized before cell encapsulation technology can be applied in clinical practice. This chapter will focus on the application of cell encapsulation technology in the treatment of CNS diseases, such as epilepsy, different neurodegenerative disorders- Parkinson, Alzheimer, Amyotrophic lateral sclerosis or Huntington-, pathologies caused by traumas or ischemic processes and brain tumors.

Surgeons and Cardiologist Working Together in Interventions in Congenital Heart Disease

Hybrid therapy is an emerging field of cardiology in which the skills of surgeons and cardiologists (both interventional and imaging experts) are co-operatively combined during a procedure to improve patient outcome. A hybrid approach is defined as a combined intervention performed in a single setting or in a planned close sequential fashion. Hybrid therapies aim to “play to the strengths and minimize the weaknesses” of the different disciplines in order to tackle lesions otherwise inaccessible without a combined procedure or with suboptimal outcomes when tackled using a single approach. Inevitably this philosophy has been used to extend the boundaries of therapy in patients at or beyond the limits of traditional surgery or transcatheter treatment for example very small infants with hypoplastic heart syndrome and patients with large and potentially inaccessible muscular ventricular defects. Hybrid therapy has the potential to reduce patient morbidity and systemic stress and can offer a bridge to definitive treatment in vulnerable patients.

In addition to the more “traditional” and accepted hybrid treatments for hypoplastic left heart syndrome, ventricular septal defect closure and intra-operative stenting a number of other techniques have been described including intra-operative valvoplasty, coarctation stenting and atrial septal defect closure.

Ideally hybrid therapy requires a dedicated operating facility although many procedures can be adequately performed in ordinary catheter laboratories or operating suites with relatively minor modifications.

Given that the majority of hybrid techniques are novel the precise indications and limitations of procedures require further definition.

Trans-Catheter Treatment in Children and Adults with Congenital Heart Disease

Thanks to significant advances in techniques and devices, trans-catheter treatment of congenital heart disease has taken important steps forward over the last decades. This paper summarizes the most relevant advances in percutaneous therapy of congenital heart malformations, highlighting the available procedures in 3 main groups: balloon dilatation and/or stenting of valves and vessels, device closure of intra-cardiac or extra-cardiac communications and pulmonary valve implantation.

1- Percutaneous treatment of valve stenosis can now be effective in a high percentage of cases either in newborns or in adult patients. Indeed, pulmonary or aortic valve dilation can be performed using one or two balloons with very good early and long-term results. Systemic or pulmonary vessel stenosis (either native or post-surgical) can be effectively treated by balloon angioplasty or stent implantation. High-pressure or cutting balloons are highly useful for native lesions, while the relief of post-surgical stenoses can be achieved by stent implantation. To date, the only significant limitation to this latter approach is the size of the patient in terms of potentiality of growth, although the use of bio-absorbable stents could overcome this drawback, allowing the treatment of even newborns or small infants. Native aortic coarctation can be effectively approached by balloon dilatation in newborns and infants, while stent implantation is suggested in patients older than 8 years of age. However, post-surgical re-coarctation can be successfully treated by balloon angioplasty (preferably in low-weight patients) or stent implantation.

2- Percutaneous closure of atrial septal defect and patent foramen ovale is possible in most patients using devices with different mechanism and physiology. This approach makes it possible to tailor the device to the defect anatomy and size. Early and longterm results of this technique are very satisfactory, with closure rate near to 100% and very low complications rate. Device closure of muscular ventricular septal defects is possible and safe also in low-weight infants, while the percutaneous approach to membranous ventricular septal defect should be indicated in patients older than 6 years due to high risk of heart block in younger patients. Patent ductus arteriosus can be safely approached by percutaneous techniques at any age, although this treatment is more challenging in patients weighting less than 5 kg. The most used device are detachable coils or Amplatzer Duct Occluder devices, with very high success rate and low complication rate.

3- The first percutaneous pulmonary valve replacement was performed almost 10 years ago by Bohnoeffer et al. Nowadays, this approach is widely used in patients older than 5 years and/or weighting more than 20 kg with pulmonary conduit stenosis and/or insufficiency. In these patients the Melody® valve can be effectively implanted with a high rate of success and anticipated good effectiveness over a mid-term follow-up.

Magnetic Resonance Imaging in Congenital Heart Disease

Magnetic Resonance Imaging (MRI) has emerged as a valuable non-invasive diagnostic tool in congenital heart malformations providing anatomical and functional data regardless of patient’s size and quality of thoracic window. This technique is particularly indicated to avoid cardiac catheterization in post-surgical adult patients in whom the echocardiographic window is often poor. MRI is able to provide both accurate 3-dimensional images of the cardiovascular system as well as precisely quantify volumes and mass of the cardiac chambers and functional data of any single segment of the heart. MRI is now considered a Class I indication in pediatric or adult patients with congenital heart malformations. It is able to define morphological data of cardiac malformation and its functional consequences at the same time. This paper summarizes the most relevant technical aspects of MRI in congenital heart disease and reports on useful protocols to evaluate the most common malformations.

New Echocardiographic Techniques in Congenital Heart Disease

Echocardiography has a primary role in the diagnosis and management of congenital heart diseases. However conventional echocardiography has two major limitations in the evaluation of congenital heart diseases: quantification of both right and left ventricular function and morphological evaluation. The availability of a new high-frequency transthoracic pediatric three-dimensional probe the same size as a standard 2D echo-Doppler probe now makes 3D echocardiography available in for pediatric cardiology echo-lab. In pediatric cardiology 3D echo can be used for a more accurate evaluation of left or right ventricle mass and volume, or to improve anatomical definition either of simple and of complex congenital heart disease.

Strain and strain rate are very helpful tools to establish segmental myocardial contractility. In addition, strain and strain rate are less load dependent. In pediatric cardiology, many studies have demonstrated the impact of S and SR on the echocardiographic evaluation of CHD, helping in assessment of left and right ventricular function, in clinical management and in surgical planning.

Genetics of Structural Congenital Heart Defects

Epidemiological studies, clinical observations and recent advances in molecular genetics are shedding increasing light on the genetic origin of congenital heart disease (CHD). Chromosomal anomalies, Mendelian syndromes or associations account for nearly 30% of all congenital cardiac malformations. These developmental anomalies may be part of well-defined syndromes due to chromosomal or submicroscopic genomic anomalies or may be non-syndromic as a consequence of still unidentified genes with sporadic occurrence in families. This paper summarizes the available findings from literature on the inference of genetics on cardiac development by classifying the congenital heart diseases as cono-truncal defects, atrio-ventricular canal and septal defects, right-sided obstruction and left-sided obstruction.

Cono-truncal defects represent an anatomically heterogeneous group of CHDs affecting the outflow tract of the ventricles and the arterial pole of the heart. The most common malformations of this group are tetralogy of Fallot, pulmonary atresia with ventricular septal defect, truncus arteriosus and interrupted aortic arch. These CHDs are associated with genetic syndromes in 25-40% of cases and even in non-syndromic forms show a high incidence of mono-genic abnormalities.

Atrio-ventricular canal is a complex malformation due to abnormal septation of the “crux cordis” resulting in ostium primum atrial septal defect, inlet ventricular septal defect and common atrio-ventricular valve. It is almost always associated with genetic syndromes, being non-syndromic in only 25% of cases. However, septal defects other than atrio-ventricular canal are rarely due to genetic syndromes, ranging from 3% to 25% of cases, yet with a high rate of segregation in some families.

Valvular or vascular-elicited right sided obstructions, are due to genetic syndromes in about 10% of cases and this association results in difficult treatment due to the ineffectiveness of any percutaneous treatment and extent of the lesions along the pulmonary trunk.

Among left heart obstructions, supra-valvular stenosis is a well-know malformation due to disruption of the elastin gene associated with Williams syndrome in many cases.

Conversely, aortic coarctation and other left-sided heart stenosis or hypoplastic malformation are often non-syndromic, being associated with genetic syndromes in less than 10% of cases.

In conclusion, improved molecular genetic technologies has led to the discovery of several causes of syndromic and non-syndromic CHDs. Nevertheless, much work remains in identifying in etiology of non-syndromic CHDs, since the number of genes known to be involved is still limited.