\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"7016",leadTitle:null,fullTitle:"Cardiovascular Risk Factors in Pathology",title:"Cardiovascular Risk Factors in Pathology",subtitle:null,reviewType:"peer-reviewed",abstract:"This book provides a broad overview of the molecular mechanisms associated with relevant and significant cardiovascular conditions that continue to plague humanity. It also discusses potential and promising therapeutic avenues targeted at addressing these conditions. The overarching goal of this multifaceted work is to entice future and current members of the scientific community to direct their endeavors towards improving our current knowledge of cardiovascular disease conditions and curb their impact on our everyday lives.",isbn:"978-1-83881-950-7",printIsbn:"978-1-83881-949-1",pdfIsbn:"978-1-83881-951-4",doi:"10.5772/intechopen.73773",price:119,priceEur:129,priceUsd:155,slug:"cardiovascular-risk-factors-in-pathology",numberOfPages:142,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"7937d2c640c7515de372282c72ee5635",bookSignature:"Alaeddin Abukabda, Maria Suciu and Minodora Andor",publishedDate:"April 21st 2021",coverURL:"https://cdn.intechopen.com/books/images_new/7016.jpg",numberOfDownloads:3746,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:3,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:4,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"August 20th 2019",dateEndSecondStepPublish:"March 5th 2020",dateEndThirdStepPublish:"May 4th 2020",dateEndFourthStepPublish:"July 23rd 2020",dateEndFifthStepPublish:"September 21st 2020",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"307873",title:"Ph.D.",name:"Alaeddin",middleName:null,surname:"Abukabda",slug:"alaeddin-abukabda",fullName:"Alaeddin Abukabda",profilePictureURL:"https://mts.intechopen.com/storage/users/307873/images/system/307873.png",biography:"Dr. Abukabda graduated from Al Fateh Dental College, Libya, in 2007. He obtained a master`s degree in Molecular Biology from Clarion University, Pennsylvania, in 2011. He later obtained a Ph.D. in Cellular Physiology from West Virginia University in 2018 and a Certification in Biostatistics from the West Virginia University School of Public Health. In 2018, Dr. Abukabda worked as a postdoctoral research associate at the Vascular Medicine Institute at the University of Pittsburgh. He has been involved in the submission and writing of several National Institutes of Health (NIH) and National Science Foundation (NSF) grants and intramural seed grants. Dr. Abukabda has published and presented many papers in immunology, toxicology, and cardiovascular physiology. He has also served as a reviewer for many journals in his field of expertise.",institutionString:"Lake Erie College of Osteopathic Medicine",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Lake Erie College of Osteopathic Medicine",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"198005",title:"Dr.",name:"Maria",middleName:null,surname:"Suciu",slug:"maria-suciu",fullName:"Maria Suciu",profilePictureURL:"https://mts.intechopen.com/storage/users/198005/images/system/198005.jpeg",biography:'Dr. Maria Suciu is Assistant Professor of Pharmacology and Clinical Pharmacy in the Faculty of Pharmacy, \\"Victor Babes\\" University of Medicine and Pharmacy Timisoara, Romania. She received an MD in Family Medicine in 2003, an MPharm in 2011, and an MD in Cardiology in 2013, all from \\"Victor Babes\\" University of Medicine and Pharmacy Timisoara. Dr. Suciu has published one book chapter, eight scientific papers, and seventeen abstracts in international journals. She has also co-authored five books.',institutionString:"Victor Babeș University of Medicine and Pharmacy",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Victor Babeș University of Medicine and Pharmacy Timișoara",institutionURL:null,country:{name:"Romania"}}},coeditorTwo:{id:"219242",title:"Dr.",name:"Minodora",middleName:null,surname:"Andor",slug:"minodora-andor",fullName:"Minodora Andor",profilePictureURL:"https://mts.intechopen.com/storage/users/219242/images/system/219242.jpg",biography:"Assistant Professor Minodora Andor, Ph.D., graduated from the University of Medicine and Pharmacy “Victor Babes” Timisoara, Romania, in 1997. She completed her studies with a Ph.D. thesis addressing negative prognostic factors in the evolution of patients with acute myocardial infarction. Over the last twenty-three years, her personal research activity has focused on the study of cardiovascular pathology, particularly early diagnosis of atherosclerotic cardiovascular disease as well as the evolution of cardiac diseases in different pathological contexts. Her research interests include cardiovascular risk factors and endothelial dysfunction. Her professional work includes activities as a member of Timis College of Physicians and an expert with the European Commission for evaluating scientific projects within the Horizon 2020 frame.",institutionString:"Victor Babeș University of Medicine and Pharmacy",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Victor Babeș University of Medicine and Pharmacy Timișoara",institutionURL:null,country:{name:"Romania"}}},coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"170",title:"Cardiology and Cardiovascular Medicine",slug:"cardiology-and-cardiovascular-medicine"}],chapters:[{id:"71921",title:"Endothelial Dysfunction and Disruption in Pulmonary Hypertension",doi:"10.5772/intechopen.92177",slug:"endothelial-dysfunction-and-disruption-in-pulmonary-hypertension",totalDownloads:695,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"A number of systemic diseases lead to pulmonary hypertension (PH), a serious disorder with a high morbidity and mortality rate. Irrespective of the underlying disease, endothelial dysfunction or disruption plays a key role in the initiation and progression of PH. Endothelial dysfunction and disruption result in impaired vascular relaxation response, activation of proliferative pathways leading to medial hypertrophy and PH. Endothelial cells (EC) play a crucial role in regulating vascular tone and maintaining homeostasis. Caveolin-1, a 21-22 kD membrane protein, interacts with a number of transducing factors and maintains them in a negative conformation. Disruption of EC results in endothelial caveolin-1 loss and reciprocal activation of proliferative pathways leading to PH, and the accompanying loss of PECAM1 and vascular endothelial cadherin results in barrier dysfunction. These changes lead to the irreversibility of PH. Hypoxia-induced PH is not accompanied by endothelial disruption or caveolin-1 loss but is associated with caveolin-1 dysfunction and the activation of proliferative pathways. Removal of hypoxic exposure results in the reversal of the disease. Thus, EC integrity is an important factor that determines irreversibility vs. reversibility of PH. This chapter will discuss normal EC function and the differences encountered in PH following EC disruption and EC dysfunction.",signatures:"Rajamma Mathew",downloadPdfUrl:"/chapter/pdf-download/71921",previewPdfUrl:"/chapter/pdf-preview/71921",authors:[{id:"65828",title:"Dr.",name:"Rajamma",surname:"Mathew",slug:"rajamma-mathew",fullName:"Rajamma Mathew"}],corrections:null},{id:"71452",title:"Pathogenesis of Abdominal Aortic Aneurysm",doi:"10.5772/intechopen.91670",slug:"pathogenesis-of-abdominal-aortic-aneurysm",totalDownloads:574,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Abdominal aortic aneurysms (AAAs) are encountered by many healthcare providers such as interventional radiologists, vascular surgeons, cardiologists, and general practitioners. Much effort has been placed in the screening, diagnosis, and treatment of AAA with somewhat little understanding of its pathophysiology. AAA is a complex disease typically segmented into a process of proteolysis, inflammation, and vascular smooth muscle cell (VSMC) apoptosis with oxidative stress balancing its components. AAA and other aortic syndromes such as aortic dissection share this same process. On the other hand, AAA formation and aortic pathology may be acquired through infection like in mycotic aneurysm or may be genetic in origin such as seen with Ehlers-Danlos and Marfan syndromes.",signatures:"Michael Patel, Daniel Braga, Brad Money, Andres Pirela, Adam Zybulewski, Brandon Olivieri and Robert Beasley",downloadPdfUrl:"/chapter/pdf-download/71452",previewPdfUrl:"/chapter/pdf-preview/71452",authors:[{id:"311726",title:"Dr.",name:"Michael",surname:"Patel",slug:"michael-patel",fullName:"Michael Patel"},{id:"311728",title:"Dr.",name:"Robert",surname:"Beasley",slug:"robert-beasley",fullName:"Robert Beasley"},{id:"312400",title:"BSc.",name:"Brad",surname:"Money",slug:"brad-money",fullName:"Brad Money"},{id:"312403",title:"Dr.",name:"Daniel",surname:"Braga",slug:"daniel-braga",fullName:"Daniel Braga"},{id:"312905",title:"Dr.",name:"Andres",surname:"Pirella",slug:"andres-pirella",fullName:"Andres Pirella"},{id:"315077",title:"Dr.",name:"Brandon",surname:"Olivieri",slug:"brandon-olivieri",fullName:"Brandon Olivieri"},{id:"315078",title:"Dr.",name:"Adam",surname:"Zybulewski",slug:"adam-zybulewski",fullName:"Adam Zybulewski"},{id:"412210",title:"Dr.",name:"Michael",surname:"Patel",slug:"michael-patel",fullName:"Michael Patel"},{id:"412211",title:"Dr.",name:"Daniel",surname:"Braga",slug:"daniel-braga",fullName:"Daniel Braga"},{id:"412212",title:"Dr.",name:"Brad",surname:"Money",slug:"brad-money",fullName:"Brad Money"},{id:"412213",title:"Dr.",name:"Andres",surname:"Pirela",slug:"andres-pirela",fullName:"Andres Pirela"},{id:"412214",title:"Dr.",name:"Adam",surname:"Zybulewski",slug:"adam-zybulewski",fullName:"Adam Zybulewski"},{id:"412215",title:"Dr.",name:"Brandon",surname:"Olivieri",slug:"brandon-olivieri",fullName:"Brandon Olivieri"},{id:"412216",title:"Dr.",name:"Robert",surname:"Beasley",slug:"robert-beasley",fullName:"Robert Beasley"}],corrections:null},{id:"72533",title:"The Importance of Autophagy and Proteostasis in Metabolic Cardiomyopathy",doi:"10.5772/intechopen.92727",slug:"the-importance-of-autophagy-and-proteostasis-in-metabolic-cardiomyopathy",totalDownloads:576,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Metabolic cardiomyopathy and other heart disorders are associated with proteostasis derailment and subsequent autophagy. Proteostasis is a process of protein homeostasis, and autophagy is a mechanism of self-degradation for surviving cells facing stressful conditions. Metabolic challenges have been linked to excess reactive oxygen species. Cardiomyocyte proteotoxicity, an important underlying pathologic mechanism in cardiac disease, is characterized by chronic accumulation of misfolded or unfolded proteins that can lead to proteotoxic formation or aggregation of soluble peptides. Autophagic processes are mediated by the ubiquitin-proteasome and autophagy-lysosome systems, fundamental for cardiac adaptation to physiological and pathological stress. Cellular proteostasis alterations in cardiomyopathy are represented by myocardial remodeling and interstitial fibrosis with reduced diastolic function and arrhythmias. Autophagy regulation may be a potential therapeutic strategy for metabolic cardiomyopathy necessary for the treatment of fibrosis and cardiac tissue remodeling alterations. Furthermore, autophagy has been shown to be active in the perimeter of cardiovascular fibrotic tissue as mechanism of fibrosis recovery and scarring secondary to cell apoptosis. In the present work, we review the current knowledge on the role of autophagy and proteostasis in the pathogenesis of heart failure to resolve the ever-expanding epidemic of metabolic cardiomyopathy and heart failure associated with substantial morbidity and mortality.",signatures:"María Cristina Islas-Carbajal, Ana Rosa Rincón-Sánchez, Cesar Arturo Nava-Valdivia and Claudia Lisette Charles-Niño",downloadPdfUrl:"/chapter/pdf-download/72533",previewPdfUrl:"/chapter/pdf-preview/72533",authors:[{id:"84149",title:"Dr.",name:"Ana Rosa",surname:"Rincon Sanchez",slug:"ana-rosa-rincon-sanchez",fullName:"Ana Rosa Rincon Sanchez"},{id:"317039",title:"Prof.",name:"Claudia Lisette",surname:"Charles Niño",slug:"claudia-lisette-charles-nino",fullName:"Claudia Lisette Charles Niño"},{id:"317040",title:"Prof.",name:"Cesar Arturo",surname:"Nava Valdivia",slug:"cesar-arturo-nava-valdivia",fullName:"Cesar Arturo Nava Valdivia"},{id:"317056",title:"Dr.",name:"María Cristina",surname:"Islas-Carbajal",slug:"maria-cristina-islas-carbajal",fullName:"María Cristina Islas-Carbajal"}],corrections:null},{id:"72726",title:"Familial Hypercholesterolemia: Three “under” (Understood, Underdiagnosed, and Undertreated) Disease",doi:"10.5772/intechopen.93042",slug:"familial-hypercholesterolemia-three-under-understood-underdiagnosed-and-undertreated-disease",totalDownloads:256,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Familial hypercholesterolemia (FH) is one of the most prevalent genetic disorders leading to premature atherosclerosis and coronary heart disease. The main cause of FH is a mutation in the LDL-receptor gene that leads to loss of function of these receptors causing high levels of blood cholesterol. The diagnosis of FH is not very easy. Wide screenings are needed to reveal high levels of LDL cholesterol among “healthy” population. If the patient has MI or stroke at an early age, high levels of LDL cholesterol, and tendon xanthomas, the diagnosis of FH becomes much more clear. Genetic testing is a gold standard in the diagnosis of FH. There are several factors, influencing the time course of FH. Smoking males with low levels of HDL cholesterol have an extremely higher risk of death than nonsmoking females with high HDL cholesterol. Management of FH includes low cholesterol diet, statin and ezetimibe treatment, PCSK inhibitors, and LDL aphaeresis. Early and effective treatment influences much the prognosis in FH patients.",signatures:"Vladimir O. Konstantinov",downloadPdfUrl:"/chapter/pdf-download/72726",previewPdfUrl:"/chapter/pdf-preview/72726",authors:[{id:"317670",title:"Prof.",name:"Vladimir O.",surname:"Konstantinov",slug:"vladimir-o.-konstantinov",fullName:"Vladimir O. Konstantinov"}],corrections:null},{id:"71227",title:"Statin Therapy in Children",doi:"10.5772/intechopen.91367",slug:"statin-therapy-in-children",totalDownloads:627,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Landmark studies such as the Bogalusa Heart study, Pathobiological Determinants of Atherosclerosis in Youth study, and Muscatine and Young Finns studies established that the atherosclerotic process begins in childhood. Early precursors of atherosclerosis may increase risk of cardiovascular morbidity in adulthood. Follow-up studies of children with familial homozygous hypercholesterolemia showed that initiation of statin therapy slowed the progression of carotid intima-media thickness and reduced cardiovascular disease risk. Despite the growing evidence on the efficacy of statins and a rising prevalence of dyslipidemia, there are concerns regarding long-term safety and efficacy. Moreover, data on statin use in children with secondary dyslipidemia are sparse. This chapter provides a comprehensive review of the current state of literature on the indications, contraindications, efficacy and safety data on the use of statins in pediatric dyslipidemia.",signatures:"Bhuvana Sunil and Ambika Pallikunnath Ashraf",downloadPdfUrl:"/chapter/pdf-download/71227",previewPdfUrl:"/chapter/pdf-preview/71227",authors:[{id:"314228",title:"Prof.",name:"Ambika Pallikunnath",surname:"Ashraf",slug:"ambika-pallikunnath-ashraf",fullName:"Ambika Pallikunnath Ashraf"},{id:"314519",title:"Dr.",name:"Bhuvana",surname:"Sunil",slug:"bhuvana-sunil",fullName:"Bhuvana Sunil"},{id:"411782",title:"Dr.",name:"Bhuvana",surname:"Sunil",slug:"bhuvana-sunil",fullName:"Bhuvana Sunil"},{id:"411783",title:"Dr.",name:"Ambika Pallikunnath",surname:"Ashraf",slug:"ambika-pallikunnath-ashraf",fullName:"Ambika Pallikunnath Ashraf"}],corrections:null},{id:"71581",title:"Pharmacokinetic Aspects of Statins",doi:"10.5772/intechopen.91910",slug:"pharmacokinetic-aspects-of-statins",totalDownloads:1018,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Statins are the most used therapeutic group in the treatment of hypercholesterolemia and reduce the risk of cardiovascular events and mortality. Long prescription periods and their pharmacokinetic characteristics increase the possibility of interactions, especially at the metabolism level. Simvastatin, lovastatin, and atorvastatin are metabolized by CYP3A4 isoenzymes, so they will have more significant interactions than fluvastatin, pitavastatin, and rosuvastatin that require CYP2C9. The main interactions are with macrolides, azole antifungals, antiretrovirals, platelet antiaggregants, anticoagulants, oral antidiabetics, calcium channel blockers, immunosuppressants, and other hypolipidemic agents, among others. A review of all medications that are taken by patients treated with statins should be performed at each medical consultation and during all healthcare transitions.",signatures:"Lucía Cid-Conde and José López-Castro",downloadPdfUrl:"/chapter/pdf-download/71581",previewPdfUrl:"/chapter/pdf-preview/71581",authors:[{id:"171329",title:"Dr.",name:"José",surname:"López-Castro",slug:"jose-lopez-castro",fullName:"José López-Castro"},{id:"313205",title:"Mrs.",name:"Lucía",surname:"Cid Conde",slug:"lucia-cid-conde",fullName:"Lucía Cid Conde"},{id:"412474",title:"Dr.",name:"Lucía",surname:"Cid-Conde",slug:"lucia-cid-conde",fullName:"Lucía Cid-Conde"},{id:"412475",title:"Dr.",name:"José",surname:"López-Castro",slug:"jose-lopez-castro",fullName:"José López-Castro"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"6209",title:"Endothelial Dysfunction",subtitle:"Old Concepts and New Challenges",isOpenForSubmission:!1,hash:"f6e76bbf7858977527679a6e6ad6a173",slug:"endothelial-dysfunction-old-concepts-and-new-challenges",bookSignature:"Helena Lenasi",coverURL:"https://cdn.intechopen.com/books/images_new/6209.jpg",editedByType:"Edited by",editors:[{id:"68746",title:"Dr.",name:"Helena",surname:"Lenasi",slug:"helena-lenasi",fullName:"Helena Lenasi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7220",title:"Congenital Heart Disease",subtitle:null,isOpenForSubmission:!1,hash:"f59bacfffcccc636ec3082869d10a82e",slug:"congenital-heart-disease",bookSignature:"David C. 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The magnitude of the effect of interventions that modify one Quality Adjusted Life Years (QALYs) will be compared, and the transferability of these interventions globally will be investigated by comparison between different socio-economic countries with different government structures (from socialist to autocratic). The reproducibility and cost of the lifestyle interventions (e.g., exercise, sleep, nutritious diet, national child care, pollution limitations) on QALYs will also be documented. The ratio of (QALY/Cost) weighted by reproducibility and transferability should give a rank-ordered list of actions humans can take to increase the quality years of human consciousness. Differences in the optimized list of rank-ordered interventions to maximize the quality of life between nation-states with varying GDP and government types (i.e., the lack of transferability) will be discussed. 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El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/3083.jpg",editedByType:"Edited by",editors:[{id:"54719",title:"Prof.",name:"Hany",surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},onlineFirst:{chapter:{type:"chapter",id:"81570",title:"Prenatal Diagnosis of Diaphragmatic Hernia",doi:"10.5772/intechopen.104103",slug:"prenatal-diagnosis-of-diaphragmatic-hernia",body:'Congenital diaphragmatic hernia (CDH) is a congenital malformation of diaphragm, which leads to a defect in separation between the thoracic and abdominal cavities [1, 2]. It appears to be due to an error in the development of the pleuro-peritoneal canals and therefore develops around 6 weeks of gestation [1]. Its incidence is 1:3000 live births. Progress in the management of these patients has significantly increased survival rates (up to 90% [3]), but disease-related morbidity remains very high: the main problem is the compression exerted by the herniated viscera on the developing lungs, development, which causes pulmonary hypoplasia and hypertension [4].
CDH can be classified, depending on the location of the defect, into postero-lateral, or Bochdalek’s hernia (70–75%), anterior or Morgagni’s hernia (23–28%) and central or hiatal hernia (2–7%) [4]. Morgagni’s hernia is often discovered incidentally in older children, as it rarely causes such a mass effect on the thoracic level as to compromise the development of the lungs. Bochdalek’s hernia is the form that is classically referred to when talking about this pathology and to which we will refer accordingly in the next paragraphs (26). Most often it is located on the left side (85%), but it can also be right (13%) or bilateral (2%) [4].
The pathogenesis of CDH is complex and currently still little known. Some studies have shown that pulmonary hypoplasia in these patients arises before the development of the diaphragm itself. This discovery opened the door to the so-called “double hit theory” which sees pulmonary hypoplasia as the result of two insults: the first, affecting both lungs, would be due to genetic and environmental factors (for example alcohol, smoking, obesity, low intake of retinoids during pregnancy); the second, which would affect only the lung ipsilateral to the defect, would consist of the compressive effect of the herniated viscera and their interference with normal fetal respiratory movements. Multiple studies have demonstrated the importance of the genetic component in the pathogenesis of ECD: they often fall within syndromic pictures, and about 40% of cases are associated with other congenital anomalies, especially cardiovascular (11–15% of ECD) [4].
Given the potential severity of the disease, prenatal counseling represents a fundamental phase of the diagnostic-therapeutic process of CDH: parents must be adequately informed about all the steps to be taken and the risks in terms of mortality and morbidity.
Ultrasound currently represents the gold standard in CDH diagnosis, although it has been calculated that less than two-thirds of CDHs are detected on prenatal screening ultrasound scans. The mean gestational age at diagnosis is 24–25 weeks, more advanced in cases of isolated defects than in CDHs associated with other anomalies. The typical ultrasound sign is the presence of abdominal organs (intestinal loops, stomach, liver) in the chest. Indirect signs of CDH can be changes in the heart axis, polyhydramnios, mediastinal shift. The differential diagnosis includes all congenital pulmonary malformations, bronchial atresia, intestinal duplications and mediastinal masses [5, 6]. The execution of genetic tests and second-level imaging tests is essential for defining the prenatal management strategy, whether it is inclined towards termination of pregnancy, or whether it is oriented towards fetal therapies. One of the main prognostic factors is represented by the lung to head ratio (LHR), which by measuring the length of the lung contralateral to the hernia normalized for the head circumference, provides an indirect estimate of pulmonary hypoplasia. More specifically, since the LHR changes with advancing gestational age, we prefer to use the ratio between observed LHR and expected LHR (observed/expected LHR or o/and LHR).
One or/and LHR <25% is indicative of severe hypoplasia, while one/and LHR of 25–35% or an LHR of 35–45% with herniated liver are indicative of moderate hypoplasia. In fact, another prognostic factor is represented by the position of the liver: since the liver and the fetal lung are poorly distinguishable ultrasonographically, there may be an indication to perform a fetal magnetic resonance [3, 4, 5, 6]. It allows to evaluate not only the presence or absence of liver in the thoracic cavity, but also to quantify the observed/expected total fetal lung volume (or/and TFLV), which was a better predictor in terms of postnatal survival. As an alternative to magnetic resonance evaluation of the or/and TFLV, some authors have demonstrated a close relationship between the liver herniation, the position of the stomach (which being anechoic is much more easily identifiable) and the postnatal outcome. Finally, given the high frequency with which EDC is associated with cardiovascular anomalies, there is an indication to perform fetal echocardiography [7, 8].
The prenatal management of fetuses affected by CDH essentially provides for an ultrasound monitoring of the ultrasound parameters described above, associated in doubtful cases with second level examinations such as resonance. In recent years, however, fetal therapy has become increasingly popular on the international scene, indicated in cases where negative prognostic factors are detected in screening investigations (liver herniation, LHR <1.0). The purpose of these interventions is essentially to stop the mechanisms that induce the onset of complications such as pulmonary hypoplasia and pulmonary hypertension as early as possible. The technique currently most used is fetal tracheal occlusion (FETO): it is based on the principle that the occlusion of the trachea prevents the leakage of fluids, increasing the pressure in the airways and promoting lung growth. However, animal models have shown that tracheal occlusion reduces the maturation of type II pneumocytes, inducing a surfactant deficiency: for this reason the so-called “plug-unplug” sequence was devised, in which the patency of the trachea is first interrupted by the introduction of a balloon (or plug) and then re-established before delivery to allow lung maturation. This procedure can be performed percutaneously under ultrasound guidance or fetoscopy, typically between 27 and 32 weeks of gestational age, with the plug removed at 34 weeks. This procedure appears to be associated with increased survival in children with moderate and severe CDH, although further risk-benefit studies are certainly needed.
In children with CDH, the only medical treatment for which there is evidence of efficacy is corticosteroid therapy: maternal administration of one or two doses of corticosteroids at 34–36 weeks of gestation appears to be correlated with a reduction in respiratory morbidity at birth. Promising studies are also underway on the prenatal use of retinoids and phosphodiesterase inhibitors (Sildenafil) and on the use of stem cells from amniotic fluid in combination with FETO [4].
The optimal timing and modality of delivery for children with CDH are still under discussion today. There seem to be no indications for induced delivery before 38 weeks of gestation, as well as there do not seem to be any advantages in performing a cesarean section. On the other hand, a unanimous consensus was found on the importance of planning the birth in a third-level center, where a multidisciplinary group (gynecologists, neonatologists, surgeons and pediatric anesthetists) is available, capable of managing the disease [4].
At birth, the main objective must be to ensure adequate ventilatory support (without triggering a vasospasm or further lung damage) and induce not too deep sedation (which would further compromise respiratory function). In case of respiratory distress, endotracheal intubation is carried out directly: in fact, ventilation with a facial mask must be avoided, as it would lead to distension of the stomach and intestinal loops, worsening the respiratory dynamics.
For the same principle, the positioning of a nasogastric tube is indicated at the same time, in order to decompress the stomach as much as possible. It is considered acceptable to maintain reduced saturation levels and a certain degree of hypercapnia, as long as the pH is kept above 7.2: in the presence of acidosis, in fact, vascular resistance would increase and consequently the risk of pulmonary hypertension. Another major problem in these patients is hemodynamic instability: to assess the need for inotropic support, these patients must be continuously monitored from a pressure point of view and postnatal echocardiography (within 48 h of life) must be performed if necessary repeated at 2–3 weeks. The indication for the ECMO, as a bridge to surgery in the most compromised patients, is still much debated. One of the biggest challenges remains the management of pulmonary hypertension: currently the most widely used treatment is inhaled nitric oxide, although encouraging new studies are underway on the use of Sildenafil [2, 4, 5].
Surgical treatment of CDH should be planned in election, after the achievement of hemodynamic stability. The only case in which it is acceptable to perform an emergency operation is when there are signs of ischemia of the herniated intestinal loops. As for the surgical technique, this can be performed openly (in thoracotomy or laparotomy) or by minimally invasive techniques. The intervention consists in the repositioning of the herniated organs within the abdomen and consequently in the closure of the defect, which can be primary or with a patch depending on the size of the defect. Minimally invasive techniques and the use of a patch were associated with a higher relapse rate [3, 4].
In light of the increased survival of newborns with CDH, long-term outcomes, especially in terms of quality of life, have assumed increasing importance over time. The most compromised organs are certainly the lungs: in addition to the well-known pulmonary hypertension, these children experience alterations both in a restrictive sense (due to pulmonary hypoplasia) and in an obstructive sense (similar to bronchodysplasia of the premature infant) [8]. Pulmonary function seems to gradually restore during childhood, but recent studies have shown a slight deterioration of the same from childhood to adulthood. The respiratory system is not the only one affected by this disease. Gastroesophageal reflux is present in 45–89% of children with CDH and appears to be correlated with the size of the defect. Stunted growth is also a frequent finding, affecting 69% of these children at 1 year of age. Neurological alterations (in terms of delay in neurodevelopment but also sensorineural deafness) represent one of the most feared and also most frequent complications of CDH, with incidence rates ranging from 12 to 77%, especially in children undergoing ECMO. Finally, musculoskeletal deformities (chest anomalies, hemithorax asymmetries, scoliosis) were reported in 21–48% of patients treated for CDH [3].
All this, together with the fact that a good percentage of CDHs fall into syndromic pictures or are associated with other congenital anomalies, justifies the importance of a long-term follow-up program.
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