Composition of common potassium-based cardioplegic solutions.
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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It looks at different perspectives of teacher professional development. Most chapters directly or indirectly present and discuss new approaches in teacher professional development in general. The purpose of the book is to inform readers that there are new ways of developing teachers professionally, and to equip readers with the skills needed to teach or behave in a professional manner. The book aims at providing new knowledge about professional development to academics, universities, education authorities, teachers, parents, and governing body members. 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(Vista University); B.Ed.; MEd; & Ph.D. degrees from the University of Pretoria, South Africa. He is an Associate Professor at the University of South Africa, Department of Educational Leadership & Management. He is responsible for teaching and research. He has presented papers at national and international conferences and is a recipient of Dean’s Award for Excellence in Teaching in the Faculty of Education (2011) at the University of Pretoria. He has published extensively in accredited journals and contributed a book and book chapters.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of South Africa",institutionURL:null,country:{name:"South Africa"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1316",title:"Higher Education",slug:"higher-education"}],chapters:[{id:"63634",title:"Introductory Chapter: Reimagining New Approaches in Teacher Professional Development",doi:"10.5772/intechopen.81120",slug:"introductory-chapter-reimagining-new-approaches-in-teacher-professional-development",totalDownloads:875,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Vimbi Petrus Mahlangu",downloadPdfUrl:"/chapter/pdf-download/63634",previewPdfUrl:"/chapter/pdf-preview/63634",authors:[{id:"196797",title:"Prof.",name:"Vimbi",surname:"Mahlangu",slug:"vimbi-mahlangu",fullName:"Vimbi Mahlangu"}],corrections:null},{id:"61736",title:"Reflection in Teacher Development",doi:"10.5772/intechopen.78257",slug:"reflection-in-teacher-development",totalDownloads:1500,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Correlative and empirical studies on reflection seem to have a lack of concern regarding teacher development. This chapter presents the reflective practitioner development model (RPDM) for professional development of teachers based on principles of reflection and measurement of the development of teachers’ reflective abilities and self-efficacy. The model focuses on reflective development of practitioners with self-efficacy, the procedure of the program, and the measurement of reflection and self-efficacy of teachers. It was tested through collecting quantitative and qualitative data. The findings suggest that the model had strong evidence for the educators to use, including the support to creating and promoting reflection and self-efficacy.",signatures:"Ulas Kayapinar",downloadPdfUrl:"/chapter/pdf-download/61736",previewPdfUrl:"/chapter/pdf-preview/61736",authors:[{id:"232425",title:"Dr.",name:"Ulas",surname:"Kayapinar",slug:"ulas-kayapinar",fullName:"Ulas Kayapinar"}],corrections:null},{id:"62224",title:"A Critical Review of the Kind of Training or Professional Development Typically Offered to the Teachers",doi:"10.5772/intechopen.78741",slug:"a-critical-review-of-the-kind-of-training-or-professional-development-typically-offered-to-the-teach",totalDownloads:857,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The main aim of this research was to review the type of professional development or training that was offered to the teachers so that they can implement policies on teaching and learning. The researcher used critical theory as the basis of his research. Qualitative research assisted the researcher to review the type of professional development or training that was offered to the teachers so that they can be able to implement policies on teaching and learning. Data analysis included sorting, conceptualising, refining and organising data into a coherent new structure. Furthermore, the researcher discovered after data interpretation that some of the teachers were professionally developed or trained on the different policies for teaching and learning. The Department of Basic Education should provide teachers with pre-service and in-service training programmes or professional development programmes. Such professional development programmes or pre-service and in-service training programmes should be provided in order to empower teachers with knowledge and skills that will enable them to fulfil their roles as mediators of teaching and learning.",signatures:"Tebogo Mogashoa",downloadPdfUrl:"/chapter/pdf-download/62224",previewPdfUrl:"/chapter/pdf-preview/62224",authors:[{id:"233676",title:"Prof.",name:"Tebogo",surname:"Mogashoa",slug:"tebogo-mogashoa",fullName:"Tebogo Mogashoa"}],corrections:null},{id:"61635",title:"Cyber Security Body of Knowledge and Curricula Development",doi:"10.5772/intechopen.77975",slug:"cyber-security-body-of-knowledge-and-curricula-development",totalDownloads:1324,totalCrossrefCites:2,totalDimensionsCites:2,hasAltmetrics:0,abstract:"The cyber world is an ever-changing world and cyber security is most important and touches the lives of everyone on the cyber world including researchers, students, businesses, academia, and novice user. The chapter suggests a body of knowledge that incorporates the view of academia as well as practitioners. This research attempts to put basic step and a framework for cyber security body of knowledge and to allow practitioners and academicians to face the problem of lack of standardization. Furthermore, the chapter attempts to bridge the gap between the different audiences. The gap is so broad that the term of cyber security is not agreed upon even in spelling. The suggested body of knowledge may not be perfect, yet it is a step forward.",signatures:"Evon M Abu-Taieh, Auhood Abd. Al Faries, Shaha T. Alotaibi and\nGhadah Aldehim",downloadPdfUrl:"/chapter/pdf-download/61635",previewPdfUrl:"/chapter/pdf-preview/61635",authors:[{id:"223522",title:"Dr.",name:"Evon",surname:"Abu-Taieh",slug:"evon-abu-taieh",fullName:"Evon Abu-Taieh"}],corrections:null},{id:"62448",title:"Moving from Training/Taming to Independent Creative Learning: Based on Research of the Brain",doi:"10.5772/intechopen.79373",slug:"moving-from-training-taming-to-independent-creative-learning-based-on-research-of-the-brain",totalDownloads:798,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Learning is the ability to cope with changes and to understand their interaction with the dynamic body. Animal brains, and specifically the human brain, are developed in such a way to make learning possible. Based on findings from brain research, we can show that this is the primary function of the brain. For survival and energy-saving purposes, the brain is developed in such a way that the learning process is as short as possible, while most energy is devoted to converting the results of learning into automatic activity. The move to automation of learning outcomes is based on mechanisms, which can be used to tame animals, including man. Humans yield most of the time to the processes of self-taming/training of the brain, even empowering them through the Western concept of learning, which idolizes focused narrow-specialization. I will present here findings from brain research and describe the characteristics of Western culture on which these claims are founded, as an expression of the threat to the continuing development of modern human culture due to characteristics which demonstrate a process similar to the cultural degeneration of past civilizations, which at their peak, could not have imagined such a fall to be possible.",signatures:"Yitzhak Ezuz",downloadPdfUrl:"/chapter/pdf-download/62448",previewPdfUrl:"/chapter/pdf-preview/62448",authors:[{id:"234256",title:"Ph.D.",name:"Yitzhak",surname:"Ezuz",slug:"yitzhak-ezuz",fullName:"Yitzhak Ezuz"}],corrections:null},{id:"62712",title:"Disciplinary Measures: A Survey from Selected Primary Schools",doi:"10.5772/intechopen.77992",slug:"disciplinary-measures-a-survey-from-selected-primary-schools",totalDownloads:1767,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Corporal punishment as a disciplinary measure has been abolished in South African schools since 1994. The chapter is about the views of the teachers on the different disciplinary measures they use as alternative to corporal punishment at the selected primary schools in Tembisa, South Africa. It used a descriptive research design, and it is quantitative in nature. A population of 100 teachers who are based at Tembisa was considered. Probability sampling techniques were used, whereby 28 teachers were sampled. Data were collected by means of a structured questionnaire. Data collected were analyzed using descriptive statistics. The findings revealed that the majority of teachers had not received any training pertaining to the management of discipline after the abolishment of corporal punishment in Tembisa schools. Teachers view poor academic performance of learners as affected by the lack of proper discipline.",signatures:"Welcome Mswazi Kubeka",downloadPdfUrl:"/chapter/pdf-download/62712",previewPdfUrl:"/chapter/pdf-preview/62712",authors:[{id:"224363",title:"Dr.",name:"Welcome",surname:"Kubeka",slug:"welcome-kubeka",fullName:"Welcome Kubeka"}],corrections:null},{id:"61588",title:"Hiding Techniques in Physical Education – Categories, Causes Underlying and Pedagogy",doi:"10.5772/intechopen.77983",slug:"hiding-techniques-in-physical-education-categories-causes-underlying-and-pedagogy",totalDownloads:944,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Previous research shows that some pupils find physical education (PE) demanding and difficult. Some pupils then use strategies to avoid participation in PE when this is the case. The chapter aims to illuminate and describe strategies used by pupils to avoid negative self-perception in difficult situations and activities in PE classes. This behaviour, called hiding techniques, arises out of the need to protect self-perception and save academic or social face in the PE subject. Research findings show that hiding techniques are experienced and practised in many different ways and that there is a wide range of causes behind them. Pupils’ hiding techniques are categorized into main types, and the causes underlying them are summarized in the chapter. In the last part, pedagogical issues are discussed in the light of research findings.",signatures:"Idar Lyngstad",downloadPdfUrl:"/chapter/pdf-download/61588",previewPdfUrl:"/chapter/pdf-preview/61588",authors:[{id:"226630",title:"Associate Prof.",name:"Idar",surname:"Lyngstad",slug:"idar-lyngstad",fullName:"Idar Lyngstad"}],corrections:null},{id:"62073",title:"Professional Development and Physics Teachers’ Ongoing Learning Needs",doi:"10.5772/intechopen.78711",slug:"professional-development-and-physics-teachers-ongoing-learning-needs",totalDownloads:911,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"This study sought insight into the professional learning and development needs of physics teachers in New Zealand high schools. It used a mixed methods approach that comprised a national survey of high-school physics teachers as well as interviews with high-school physics teachers and physics teacher educators. Data from the teacher survey were analysed using descriptive statistical methods. Audio recordings from interviews were transcribed, analysed and used to triangulate and add depth to the survey data. Findings indicated that physics teachers were dissatisfied with the lack of formal physics-focussed professional development opportunities available to support their professional growth. Instead, teachers tended to rely on personal critical inquiry and infrequent practitioner meetings to inform practice. Suggestions for how to support the professional development needs of physics teachers better are discussed.",signatures:"Isaac Buabeng, Lindsey Conner and David Winter",downloadPdfUrl:"/chapter/pdf-download/62073",previewPdfUrl:"/chapter/pdf-preview/62073",authors:[{id:"232147",title:"Dr.",name:"Isaac",surname:"Buabeng",slug:"isaac-buabeng",fullName:"Isaac Buabeng"},{id:"249754",title:"Prof.",name:"Lindsey",surname:"Conner",slug:"lindsey-conner",fullName:"Lindsey Conner"},{id:"249756",title:"Dr.",name:"David",surname:"Winter",slug:"david-winter",fullName:"David Winter"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"1990",title:"International Perspectives of Distance Learning in Higher Education",subtitle:null,isOpenForSubmission:!1,hash:"e9f445b89a42e6221004f529ac247127",slug:"international-perspectives-of-distance-learning-in-higher-education",bookSignature:"Joi L. 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\r\n\tThis book “Bacterial Biofilms” will aim to describe both negative and positive impacts of bacterial biofilms in the medical and environmental arena. This book is dispensed into different chapters that describe the role of bacteria in human day-to-day life. The content of this book will be written in a simple scientific language that would accommodate and enlighten audiences from different scientific backgrounds not limited to scientists, higher degree and undergraduate research students in the field of environmental microbiology, infectious diseases, immunologist, pharmacist, medical practitioner, and school students. Bacteria that prefer to exist in colonized forms i.e., in biofilm state have been responsible for detrimental effects on humans, animals, birds, and plant's health in terms of biofilm-associated infections and morbidity, and mortality. The problem of biofilm-associated infection is drastic in lower- and middle-income countries in comparison to developed countries. One big aspect of biofilms is its resistance to antibiotics and antibacterial agents that constitutes collapse of the healthcare system and hindrance of global economic development. On the other hand, biofilms are essential and have been promising in terms of bioremediation of organic pollutants, water purification system, and great acquaintance in the extraction of mineral ores in the mining industry.
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Genetic events lead to the disruption of normal regulatory mechanism that control basic cellular function of the body including cell division, differentiation and cell death [1]. Boyd and Reade (1988) described the mechanisms involved in carcinogenesis of the oral mucosa and distinguished between three major groups: chemical mechanisms, physical mechanisms, and viral mechanisms. Later Hanahan and Weinberg (2000) described six hallmarks of cancer (hallmarks I): acquisition of growth signaling autonomy (oncogenes), growth-inhibitory signals (tumor suppressor genes), evasion of apoptosis, cellular immortalization, angiogenesis, and finally, invasion and metastasis [2]. A decade later, an updating review (henceforth termed hallmarks II) added two emerging hallmarks: reprogramming energy metabolism and evading immune response, and two enabling traits: genome instability and mutation, and tumor-promoting inflammation [3].
Oral squamous carcinogenesis is the sixth most common cancer worldwide and commonest cancer in India, accounting for 50–70% of total cancer mortality rate. It predominantly affects anterior tongue, cheek, floor of mouth, retro molar area, gingiva or the buccal mucosa [4]. In carcinogenesis multiple genetic events alter the normal functions of both oncogenes and tumor suppressor genes. However, the importance of both the known gene alterations is unidentified and is still not fully understood. The histologic progression of oral carcinogenesis from hyperplasia to dysplasia, followed by severe dysplasia and eventual invasion and metastases, are believed to reflect the accumulation of these changes [5, 6] (Figure 1). Genetic alterations occurring during the carcinogenesis may present in the form of point mutations, amplifications, rearrangements, and deletions [5].
Molecular model of oral carcinogenesis. The diagram shows the genetic progression from dysplasia to oral squamous cell carcinoma (OSCC), through changes in the p or q arm of chromosomes 3, 4, 8, 9, 11, 13, and 17 [
Oral carcinogenesis is a complex, multistep process in which genetic events within signal transduction pathways governing normal cellular physiology are quantitatively or qualitatively altered.
Under normal conditions, cell biology of oral epithelia is tightly controlled by excitatory and inhibitory pathways which include cell division, differentiation, and senescence [1]. Cellular pathways of the oral keratinocyte may be diverse and contain the same fundamental elements. Binding of an extracellular ligand to a cell surface receptor forms a receptor-ligand complex that generates excitatory or inhibitory signals which are transferred intracellularly and further nuclear messengers can either directly alter cell function or can stimulate the transcription of genes which can affect protein synthesis [1] (Figure 2).
Signal—transduction pathway.
On contrary, oral cancer is the result of an accumulation of changes in these excitatory and inhibitory cellular signals that can occur at any level of a given pathway. Oral epithelial cells collect these alterations or mutations from cellular signals and become functionally independent from the surrounding oral epithelium made up of normal oral keratinocyte neighbors. These tumor cell divide more rapidly, sequester blood vessels to feed that growth, delete or amplify signals to produce abnormal structural or functional changes, and start invading normal tissue at local or distant sites [6].
Oncogenes and tumor suppressor genes constitute the cellular growth-regulatory genes which are widely expressed in normal cells and their protein products are required for cell to work normally. Any alteration or inappropriate expression of these genes can induce neoplasia [7].
The genetic damage of these genes found in cancer cells is of two sorts:
Dominant type: proto-oncogenes and oncogenes.
Recessive type: tumor suppressor genes, growth suppressor genes, recessive oncogenes, or anti-oncogenes.
The Former typically results in a gain of function, whereas latter causes loss of function [8].
The hallmark of cancer is rapid and uncontrolled growth. Cell cycle regulatory molecules (cyclin-CDK complex and retinoblastoma protein RB) play a key role in pathogenesis of head and neck cancers. Phosphorylation of RB by the cyclin/CDK there is a release of E2F, which transcribe the necessary components of the cell to continue through the G1/S transition. Specifically, RB function is mediated by cyclin E/CDK2 activity. In contrast, CDK4 and CDK6 act upstream of RB and inhibit RB function by phosphorylation [5]. In head and Neck cancers, both up and down regulation of RB function has been observed conferring a greater degree of malignancy and aggressiveness, dependent upon cellular context. Downregulation of RB function—cell cycle to remain unchecked and leads to continual cell division and cell proliferation; up-regulation of RB leading to a decrease in pro-apoptotic signals that are triggered during the cell cycle. In either case, changes in the RB pathway alter cell-cycle transition and allow for greater cancer cell survival [1].
Oncogenes can be classified according to the roles of their normal counterparts (protooncogenes) in the biochemical pathways that regulate growth and differentiation. These include the following
Growth factors (TGF, FGF, PDGF)
Cell surface receptors (EGFR, FGFR)
Intracellular signal transduction pathways (RAS)
DNA binding nuclear proteins transcription factors (MYC, FOS, JUN)
Cell cycle proteins (cyclins and cyclin dependent protein kinases)
Inhibitors of apoptosis (bcl-2)
Oncogenes are defined as “altered growth-promoting regulatory genes, or proto-oncogenes that govern the cell’s signal transduction pathways” [5]. These genes were initially discovered in retroviruses which cause cancers in birds and cats by virtue of a highly tumorigenic ‘molecular hitchhiker’, a mutated gene (oncogene) not native to the virus but picked up from a homologue in the eukaryotic genome. Alteration or mutation of these proto-oncogenes results in either an overproduction or a “gain-of-function” alteration in these excitatory proteins. Although oncogenes alone are not sufficient to transform a normal oral keratinocyte to a malignant one, they are initiators of the process [6].
Aberrant expression of several oncogenes play a crucial role in development of oral carcinogenesis which includes proto-oncogene epidermal growth factor receptor (EGFR/c-erb 1), members of the ras gene family, c-myc, int-2, hst-1, PRAD-1, and bcl-1 (Figure 3) [6].
Oral cancer progression model. The histopathologic progression of normal oral mucosa from hyperplasia to malignancy and metastasis appears driven by interplay of activation of oncogenes in early cellular transformation and inactivation of tumor suppressor genes closer to the initiation of malignancy and metastasis.
The potential of proto-oncogenes to participate in tumorigenesis arises from the fact that their protein products are relays in the elaborate biochemical circuitry that governs the phenotype of vertebrate cells polypeptide hormones that act on the surface of the cell, receptors for these hormones, proteins convey signals from the receptors to the deeper cell machinery, and nuclear functions that orchestrate the genetic response to afferent commands [5].
Three biochemical mechanisms which proto-oncogenes act are [8]:
The first mechanism is phosphorylation of proteins, with serine, threonine, and tyrosine as substrates.
The second mechanism by which the genes act is transmission of signals by GTPases. The role of these signaling devices in tumorigenesis was first appreciated through the discovery of RAS oncogenes, which encode a previously unknown variety of GTPase.
The third mechanism consists of control of transcription from DNA. A still growing variety of transcription factors (FOS and MYC) are encoded by proto-oncogenes which may also participate directly in the replication of DNA.
Activation of growth factor receptors in human tumors include mutations, gene rearrangements, and overexpression. Signaling pathways involved in the development of both cancer and stem cells are: the JAK/STAT pathway, NOTCH signaling pathway, the MAP-Kinase/ERK pathway, the PI3K/AKT pathway, the NFkB pathway, the Wnt pathway and the TGFβ pathways.
In the normal forms of growth factor receptors, the kinase is transiently activated by binding of the growth factors ligand to receptor, leads to rapid receptor dimerization and tyrosine phosphorylation of several substrates that are a part of the signaling cascade. The oncogenic growth factor receptors cause dimerization and activation without binding to the specific growth factor ligand. Hence, the mutant receptors deliver continuous mitogenic signals to the cell [1].
In oral carcinogenesis deregulation of growth factors receptors occurs through increased production and autocrine stimulation. Aberrant expression of transforming growth factor alpha (TGF-α) and beta (TGF-β) occur in carcinogenesis. TGF-α work in association with EGFR and TGF-β follows a pathway along with SMAD2 and 3.
TGF-α is reported to occur early in oral carcinogenesis, following the histological progression of hyperplastic epithelium first, and later in the invasive carcinoma within the inflammatory cell infiltrate, especially the eosinophils, surrounding the infiltrating epithelium. TGF-α stimulates cell proliferation by binding to EGFR and stimulates angiogenesis and has been reported to be found in “normal” oral mucosa in patients who subsequently develop a second primary carcinoma.
Microscopically “normal” oral mucosa of head and neck cancer patients who later develop second primary carcinomas overexpresses TGF-α suggesting a ‘premalignant” lesion having rapid proliferation and genetic instability of the epithelium. Prognostically patients with oral tumors overexpressing TGF-α along with EGFR have been shown to have a significantly shorter survival than patients overexpressing EGFR alone [6].
TGFβ1 signals through the TGFβ receptors and these transduce the signal by phosphorylating SMAD2 and SMAD3, which, together with SMAD4, regulate the transcription of target genes.
Recently, a connection of TGFβ signalling pathway and nuclear factor-κB (NF-κB)99 has been studied, it’s a transcription factor that provides an important survival signal to cells. Cohen et al. showed that abrogation of the TGF-β pathway was associated with activation of NF-κB, and this intriguing finding suggests that decreased TGFβ signalling is linked to NF-κB activation [9].
Binding of cell surface receptor with ligands translates signals which are present extracellularly through the cell membrane by activating a cascade of biochemical reactions. Mutations or amplifications of genes encoding growth factor receptors can result in an increased number of receptors or production of continuous ligand-independent mitogenic signals.
EGFR, a 170,000-Da phosphoglycoprotein, is believed to be an important oncoprotein in oral cancer. Currently, three mechanisms have been postulated to activate the EGFR gene in carcinogenesis:
Deletion or mutations in the N-terminal ligand-binding domain.
Overexpression of the EGFR gene concurrent with the continuous presence of EGF or TGF-α.
Deletion in the C-terminus of the receptor that prevents downregulation of the receptor after ligand binding.
In human oral carcinogenesis EGFR is overexpressed as this gene is amplified. Therefore, it has been identified that in comparison to the normal counterpart, malignant oral keratinocytes possess 5–50 times more EGF receptor. Moreover, in oral carcinogenesis the mechanism of signal transduction is either because of overexpression of normal receptors due to mutated gene or because of the formation of many new receptors is not understood yet. Henceforth, oral tumors, having EGFR overexpression, have been shown to exhibit a higher response to chemotherapy than EGFR-negative tumors, presumably because of higher intrinsic proliferative activity leading to higher sensitivity to cytotoxic drugs [6].
Like growth factor receptors, intracellular messengers can be intrinsically activated, thereby delivering a continuous rather than a ligand-regulated signal [6]. An oncogene can be activated either by gene amplification and/or mutation. In OSCC, the ras is one of the most frequently genetically altered oncogene. The mutations of three isoforms of ras gene such as Hras, Kras and Nras produce the same phenotype in the in vitro transformation assays. Mutations of the Hras appear to be highly prevalent in OSCC when compared to the Kras and Nras have been reported approximately from 0 to 55%.
These genes encode closely related proteins that are located on the cytoplasmic side of the cell membrane and transmit messages from the cell surface receptors to intracellular regulatory enzymes [6].
RAS present on the cytoplasmic side of cell membrane get activated by growth factors through enhanced exchange of guanine nucleotide by forming Grb2 SOS complex. The molecular mechanism underlying in the functions activation of ras depends on the whole super family of small G-proteins because there exist a switch between GTP bound active and GDP-bound inactive state [10].
In normal human cell, an equilibrium is strictly maintained by the activity of GAPs (GTPase activating proteins) and GEFs (Guanine nucleotide exchange factors) between the active and inactive state because ras proteins have a minimal and a measurable activity on their own. The GAPs accelerate the GTP hydrolysis of ras and the antagonist GEFs such as ras-GRFs and ras-GRPs catalyze and weakens the GDP replacing with GTP. In a cell where ras is mutated, the equilibrium between the GTP and GDP-bound state is impaired. The ras is mutated predominantly at codon G12, G13 and Q61. In K-RAS and H-RAS because of point mutations GAP catalyzed hydrolysis of GTP to GDP, thereby generate constantly active ras and is responsible for the activation of downstream effectors whereby cell undergoes aberrant malfunctioning leading to malignancy (Figure 4) [10].
Mechanisms of the ras activation.
The ras oncogenes are associated with proteins that are involved in the transduction of extracellular growth, differentiation and survival signals. Ras activate receptor tyrosine kinases (RTKs), which further activate two key signal transduction components:
Small GTPase
Lipid kinase PI(3)K.
The activated ras stimulates mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI3K)/Akt pathways. The key downstream steps involve phosphorylation by RAF1 kinase on two distinct serine residues MEK1/2. The MEK1/2 further phosphorylates specific threonine and tyrosine residues in the activation loops of ERK1/2 and leads to growth and differentiation. On the other hand ras transduces PI3K/Akt signaling pathway which lead to cell cycle proliferation and survival [10].
Transcription factors, or proteins that stimulate other genes to be activated, are also altered in oral cancer. A growing number of the known proto-oncogenes encode nuclear proteins. These nuclear proteins are further regulated by receptor activated second messenger pathways. Neutralization of these encoded genes result in cell cycle arrest which prevents mitogenic and differentiation responses to growth factors. C-myc is a gene which helps regulate cell proliferation and apoptosis and is frequently overexpressed in oral cancers as a result of gene amplification. C-myc is often overexpressed in poorly differentiated tumors, although more recently c-myc has been shown to be overexpressed in moderate and well differentiated oral carcinomas, in which cell proliferation far outweighed the number of apoptotic cells present. For apoptosis, c-myc requires p53 for regulating cell proliferation. c-Myc interacts with retinoblastoma tumor suppressor gene Rb-1 nuclear protein pR6, preventing its transcription, and thus inhibiting cell proliferation. However, on phosphorylation of pR6, c-Myc is increased and cell proliferation proceeds. Another transcription factor which is also amplified in head and neck cancers is PRADl (also CCNDl or cyclin Dl) which acts too as a cell cycle promoter [5, 6, 8].
Particular order of oncogene activation has not been shown in oral cancers; instead the accumulation of activated oncogenes should be of primary importance. The importance of the currently identified oncoproteins to oral carcinogenesis is under investigation. Other oncogenes linked to oral cancer development are hst-1, k-2, bcl-1, sea, men-1, and eM1s-1.3.4. Oncogenes alone, however. Not sufficient to result in oral cancer but appear to be initiators of the process and should work along with the inactivation of tumor suppressor genes. The critical event in the transformation of a “premalignant” cell to a malignant cell is the inactivation of cellular negative regulators, tumor suppressor genes.
The cell cycle is a mammalian cells proliferation regulation process and has 4 functional phases:
S phase (DNA replication)
G2 phase (cells prepare for mitosis)
M phase (DNA and cellular components division into two daughter cells)
G1 phase (cells commit and prepare for another round of replication).
S and M phases are the major and common process in all cell cycles for replication of cells. It requires interplay of expression of cyclins and cyclin dependent kinases in response to growth factors.
Cdk2 and cdk1, together, direct S and G2 phase transit, while cdk1 governs the G2/M transition and mitotic progression. Cdks can be divided into two groups:
‘Cell cycle’ cdks, which orchestrate cell cycle progression.
‘Transcriptional’ cdks, which contribute to mRNA synthesis and processing.
The first group encompasses cyclin D-cdk4 and 6, as well as cyclin E-cdk2 complexes, which sequentially phosphorylate the retinoblastoma protein (RB), to facilitate the G1/S transition. Cyclin A-cdk 2 and 1 are required for orderly S phase progression, whereas cyclin B-cdk1 complexes control the G2/M transition and participate in mitotic progression [11].
The second group includes cyclin H-cdk7 and cyclin T-cdk9 (pTEFb). It phosphorylates the carboxy-terminal domain of RNA polymerase II to promote elongation of mRNA transcription. Cyclin T-cdk9 also regulates mRNA processing [12].
CDK’s and cyclins are the biochemicals play a pivotal role in cell cycle progression and transcription. Errors and dysregulation like amplification, mutation, deletion and hypermethylation of cyclins and its cdk partners activity results in loss of cell cycle check points and apoptotic activity which is a major cause for proliferative disorders such as cancer and which has been directly linked to the molecular pathology of cancer [11].
Cell cycle progression through the G1 phase is regulated by the action of cyclin D-cdk4, cyclin D-cdk6, and cyclin E-cdk2. This transition is mediated through the RB, which is regulated through sequential phosphorylations by CDK. Various genetic and epigenetic alterations in human cancer including mutations and amplification of Cdk and positive regulatory Cyclin subunits, lead to a hyperactivation of Cdk regulatory pathways. Henceforth, alteration in cell cycle checkpoints causes abnormal cell proliferation and results in tumor progression. Although mutations of cdk genes in tumor cells are rather infrequent with the exception of Cdk4 and Cdk6 amplification, overexpression or hyperactivation of basic cell cycle regulators is a general feature of human tumors like leukemia or carcinomas and were associated with poor prognosis [11].
Apoptosis “programmed cell death’—is a physiologic process of cell to undergo death following sequence of events once the function is over. Any alterations in the mechanism of cell undergoing apoptosis not only contribute to abnormal proliferation of cell but also enhance resistance to anticancer therapies, such as radiation and cytotoxic agents. One of the suggested mechanisms for developing resistance to cytotoxic antineoplastic drugs is the alteration in expression of B-cell lymphoma-2 (Bcl-2) family members.
A balance between newly forming cells and old dying cells is maintained by Bcl-2 family of proteins which consists of 25 pro- and anti-apoptotic members. When there is alteration or disbalance in ratio of distribution of pro and antiapoptotic proteins resulting in the overexpression of anti-apoptotic Bcl-2 family members, apoptotic cell death can be prevented. Targeting the anti-apoptotic Bcl-2 family of proteins can improve apoptosis and thus overcome drug resistance to cancer chemotherapy [6].
Two major pathways of apoptosis are the intrinsic and extrinsic cell-death pathways.
The intrinsic cell death pathway/mitochondrial apoptotic pathway: mainly triggers apoptosis in response to internal stimuli and is activated by a wide range of signals, including radiation, cytotoxic drugs, cellular stress, DNA damage and growth factor withdrawal. This mechanism involves the release of proteins cytochrome
The extrinsic cell-death pathway: pathway functions independently of mitochondria and executes cascade activation of caspases. Activation of cell-surface death receptors, such as Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, directly activate the caspase cascade via an “initiator” caspase (caspase-8) the role of which is to cleave other pro-caspases into active “executioner” caspases which induces degradation of cytoskeleton and nucleus [13].
Bcl-2 family members can be divided into three subfamilies based on structural and functional features [13].
Recent studies have shown that Bcl-2 expression is upregulated in oral SCC. Bcl-2 inhibits cell death via inhibiting apoptosis. Hence, Bcl-2-mediated inhibition of apoptosis may be an important factor in the pathogenesis of oral SCC. Bax forms heterodimers with Bcl-2 and when present in excess, Bax overrides the anti-apoptotic activity of Bcl-2.
P53 tumor-suppressor protein is a direct transcriptional activator of the human Bax gene suggesting that p53 may, in some instances, induce apoptosis via Bax-mediated suppression of Bcl-2 activity. In mutagenesis experiments, single amino acid substitutions in Bcl-2 homology domains disrupted Bcl-2-Bax heterodimers. The Bcl-2 mutants that failed to complex with Bax could no longer inhibit apoptosis. According to the study done by Oltvai et al. (1993) it was suggested that anti-apoptotic activity of Bcl-2 was inhibited by Bax, whereas the findings of Yin et al. (1994) is converse to that of the previous findings, i.e. that the function of Bcl-2 is to inhibit the apoptotic activity of Bax. But it was further hypothesized that the possible mechanism was the formation of Bcl-2-Bax heterodimers which inhibits both apoptotic and anti-apoptotic activity and is only seen when there is a functional excess of Bax or Bcl-2, respectively.
Bcl-x and Bcl-2 form heterodimers with Bad. This dimerization displaces Bax from Bcl-x, and Bcl-2 thereby enhances apoptosis. Therefore, the Bcl-2 family of related proteins (as with the Myc family) functions in part through protein-protein interactions.
In conclusion, Bcl-2-mediated inhibition of apoptosis may be an important factor in the pathogenesis of oral SCC. Furthermore, by blocking apoptosis, Bcl-2 can increase tumor cell resistance to anti-neoplastic drugs.
Genes that encode the proteins for negative signal transduction pathways and modulate excitatory pathways and negate their effect in a “checks and balances” have been called as growth regulatory genes, recessive oncogenes or anti-oncogenes, but they are most often referred to as tumor suppressor genes. Negative regulatory pathways allow the cell to perform its function in the face of changing internal and external stresses [1, 14].
As been mentioned earlier in the chapter “Oncogenes alone are not sufficient to cause oral cancer and appear to be initiators of the process”.
The transformation of a premalignant cell to a malignant cell is due to the inactivation of tumor suppressor gene which is a major event leading to the development of malignancy.
This mechanism of inactivation is may be due to point mutations, deletions, hypermethylation and rearrangements in gene copies. It was identified that many tumor suppressor genes were initially identified in pediatric tumors that formed early in life because one mutated tumor suppressor gene was inherited [1].
This mechanism led the evolution of “Knudson two hit hypothesis” This theory suggested a genetic model for retinoblastoma development. According to this RB gene mutation is inherited is described as the first hit and the tumor-restricted mutation as the second hit. This model further includes genetic aberrations, such as inactivation of a tumor suppressor and activation of an oncogene, as hits. Currently an extensive research on “chromosomal walking” is highlighted in pediatric tumors were the first tumor suppressor genes isolated with large chromosomal alterations. Therefore, although the identification of these “cancer genes” is one of the primary focuses of molecular biologists today, still far less is known about tumor suppressor genes [1].
The many roles of p53 as a tumor suppressor include the ability to induce cell cycle arrest, DNA repair, senescence, and apoptosis. Due to many genotoxic or chemical insults when genomic DNA damage is being identified, p53 gene activated and stop cell to divide further at the G1-S boundary and it repairs rather than replicates the error in the genetic code. If the chromosomal damage is too great, p53 gene activate apoptotic pathways [15].
Mutation of p53 allows tumors to pass through the G1-S boundary and propagate the genetic alterations that may lead to other activated oncogenes or inactivated tumor suppressor genes. In addition to the loss of function that a mutation in TP53 may cause, many p53 mutants are able to actively promote tumor development by other means like:
Dominant negative manner
Gain of function
In a heterozygous situation, where both wildtype (WT) and mutant alleles exist, mutant p53 can antagonize the activity of WT p53 tumor suppressor functions in a dominant negative (DN) manner. The transcriptional activity of WT p53 depends on forming tetramer where mutant p53 interfered in DNA binding activity of WT p53. However, such a heterozygous state is often transient, as TP53 mutations are frequently followed by loss of heterozygosity (LOH) during cancer progression as WT p53 allele is either deleted or mutated [14].
This term refers to the acquisition of oncogenic properties by the mutant form of p53 protein, compared with the mere inactivation of the protein. During tumorigenesis both the dominant negative and GOF effects may play a significant role in missense mutations of TP53 protein [15].
Various mechanisms by which mutant p53 works in tumor progression:
GOF properties acquired by mutant p53 drive cells toward migration, invasion, and metastasis. Recent work demonstrates that mutant p53 can augment cell migration and invasion. It was studied that “oncogenic” Ras and “Tumor Suppressor” mutant p53 activities occurs in early neoplasms to promote growth and survival, they play an equally important role at late stages of tumor progression in empowering TGFβ-induced metastasis.
EMT—metastasis follow the properties of epithelial to-mesenchymal transition (EMT), including loss of cell-cell adhesion and an increase in cell motility., Mutant p53 was found to promote EMT by facilitating the function of the key transcriptional regulators of this process, TWIST1 and SLUG whereas WT p53 was shown to inhibit EMT mechanism.
Tp63—an additional mechanism through which mutant p53 was shown to augment cell invasion is via the inhibition of transcriptional activity of TAp63α, but is unable to inhibit this function of TAp63γ indicating a protooncogenic activity of TP 53 [14].
It appears that in certain cancers, p53 is mutated late in the tumorigenesis process or plays a significant role in those advanced stages, whereas other studies indicates its expression in early stages of tumor progression. Therefore, it was hypothesized that TP53 mutations at early stages of tumorigenesis results in uncontrolled proliferation, a feature of both benign and malignant tumors, whereas mutations at later stages synergize with additional oncogenic events to drive invasion and metastasis, the hallmark of malignant tumors. p53 inactivation as a single event results in the high proliferation rate. Inactivation of p53 in conjunction with oncogenic H-Ras expression activates the expression of a large set of chemokines and interleukins reported to promote angiogenesis, invasion, and metastasis.
In general, tumor suppressor genes are thought to act recessively so that both copies of the gene must be inactivated for malignancy to occur. LOH and p53 mutations have been reported in several tumors. There is also controversy about the relation between mutated p53 and detection of its expression by immunohistochemistry. Some authors have commented on high correlation between p53 expression and point missense mutation, whereas others have reported discrepancy in oral cancer and lack of expression of p53 as immunocytochemistry have been attributed to insensitive methods of detecting p53 mutation. In Li-Fraumeni syndrome, mutant p53 is unstable, like the wild-type p53 protein, which suggests that some other event may be necessary for stability, and that stability of p53 is not intrinsic to the mutant p53 structure but might vary in different cell backgrounds. This mechanism can be highlighted by p53 and mdm2 relation because when normal p53 is bound to mdm2 it is targeted for destruction by the ubiquitin dependent pathway. However, it appears that mutant p53 fails to stimulate transcription of mdm2 and therefore mutant p53 is not degraded. Another mechanism tells that if E6 protein forms complexes with wild-type p53 and promotes p53 degradation this could account for the lack of concordance between p53 mutation frequency and LOH [16].
Other tumor suppressor genes include doc-1, the retinoblastoma gene, and APC.
The role of HPV in pathogenesis of human malignancies has become convincingly established. HPV is a strictly epitheliotropic, circular double-stranded DNA virus that is known to be the primary cause of cervical cancer and currently establishing important role in oral carcinogenesis. There are more than 100 subtypes of HPV, some of which are involved in oral carcinogenesis and have been designated as high-risk HPVs. Approximately 85% of squamous cell carcinoma patients. The viral DNA gets incorporated into the host genome and is responsible for malignant transformation. The virus contains two oncogenes, E6 and E7, E1 and E2 open reading frames will be interrupted and can lead to overexpression of E6 and E7 proteins. This E7 protein binds to underphosphorylated form of retinoblastoma results in the enhanced phosphorylation and degradation. Degraded form of pRb displaces E2F form of transcription factor and subsequent activation of gene promoting cell proliferation. E6 protein degrades p53 protein causing perturbation of cell cycle regulation in the infected cells which is considered to be the onset of HPV-mediated carcinogenesis. The virus is not easily cultured, therefore determining the role of virus in pathogenesis of OSCC is usually determined by detection of the viral DNA genome or expression of the viral genes using PCR methods. E6 and E7 have a crucial role in cervical cancer were also involved in HPV mediated carcinogenesis of the upper aerodigestive tract (Figures 5 and 6) [9, 17, 18].
Cell cycle deregulation by human papilloma virus activated by E6 and E7.
Proposed molecular model for the genetic events in squamous cell carcinoma of the head and neck [
Cellular signaling pathways are not isolated from each other but are interconnected to form complex signaling networks. Any change or diversification in this cellular signaling network such as increased production of growth factor or cell surface receptors, increase transcription or translation or intracellular messenger levels will give rise to abnormal proliferation of cell and is one of the reason for multifactorial oral carcinogenesis These changes can, in turn, cause a activation of protooncogene or loss of tumor suppressor activity which give rise to a phenotype capable of increasing cellular proliferation, weakening cell cohesion, and causing local infiltration and metastasis.
Intracellular and blood potassium levels have crucial effects on cardiovascular system homeostasis. At the most fundamental level, the potassium concentration gradient across cardiac muscle cell (cardiomyocyte) cell membranes is a chief determinant of cardiomyocyte resting membrane potentials. Indeed, disruptions to this concentration gradient (e.g. via increasing or decreasing extracellular blood potassium levels) can lead to altered cardiomyocyte contractility and excitability. Potassium is also vasoactive, with different effects at different extracellular concentrations. At low (5-8 mM) to moderate (8-16 mM) extracellular levels, potassium relaxes the smooth muscle in blood vessel walls by promoting hyperpolarization of vascular smooth muscle. However, at higher levels (16-25 mM and above) (e.g. cardioplegic concentrations), potassium promotes vasoconstriction by facilitating depolarization. Moreover, potassium is released by vascular endothelial cells in response to various chemical mediators and shear stress, thereby contributing to the action of endothelium-derived hyperpolarizing factor [1]. For all of these reasons and more, keeping track of daily potassium intake is often recommended as a lifestyle modification for chronic cardiovascular diseases such as hypertension.
Harnessing the pivotal role of potassium in cardiovascular physiology has proved quite useful for cardiovascular surgery, namely in the form of hyperkalemic (high potassium) cardioplegia. Indeed, throughout the past several decades, a large body of research has testified to the ability of externally administered hyperkalemic solutions to arrest cardiac contractility [2]. This, in conjunction with the development of cardiopulmonary bypass (CPB, also known as the “heart-lung machine”), revolutionized cardiac surgery [3]. These days, many highly invasive procedures like coronary artery bypass grafting are routine with minimal risk of postoperative mortality.
However, hyperkalemic cardioplegia is not without its consequences. Hyperkalemic cardioplegia and reperfusion following CPB have been associated with perioperative and postoperative tissue damage and microvascular dysfunction across several different vascular beds. Moreover, hyperkalemic cardioplegia is also associated with postoperative myocardial dysfunction and reduced cardiac output. Furthermore, blood potassium abnormalities after hyperkalemic cardioplegia-reperfusion, chiefly hypokalemia (but also hyperkalemia, to a lesser degree) are common postoperative challenges in the cardiac ICU. Both abnormalities significantly elevate the risk of arrythmias and, if not managed properly, cardiac arrest and sudden death.
This chapter will discuss the basics of potassium cardioplegia with an emphasis on clinical relevance, beginning with a brief history. Subsequent sections will elaborate on the basic physiology, before considering several perioperative and postoperative adverse effects of hyperkalemic cardioplegia. When possible, information about treatment and clinical management is included. The chapter will conclude with a brief mention of up-and-coming alternatives to hyperkalemic cardioplegia.
As early as the late 1800s, physiologists were starting to become aware of the ability of potassium compounds to arrest cardiac contractility, beginning with individuals like Sidney Ringer who observed that potassium chloride froze the heart in diastole and calcium stimulated the heart during systole [2]. Moving into the start of the 20th century, further investigations revealed associations between high serum potassium and cardiac arrest following ventricular fibrillation; studies also revealed associations between cardioplegia and restoration of sinus rhythm following coronary artery administration of potassium chloride solution and subsequent washout [2]. However, in most of these cardioplegic experiments (often conducted in dogs), refractory ventricular fibrillation and post-procedure reperfusion damage to the myocardium limited discussion of the clinical usefulness of these findings.
During the 1950s, British physician Dennis Melrose hypothesized that the problem with potassium chloride cardioplegia was chloride; therefore, he created a cardioplegic solution using potassium citrate, and tested it on a canine model of cardiopulmonary bypass [4]. Injection of the “Melrose solution”, of potassium citrate plus warm oxygenated whole blood in a 9:1 blood:potassium ratio, into the aortic roots of hypothermic dogs, produced near-immediate cardiac arrest. Reperfusion and washout of cardioplegic solution resulted in restoration of heart function to pre-procedure levels [2]. Within a few years, the Melrose group successfully induced potassium citrate cardioplegia in humans.
Unfortunately, future studies would reveal that in many cases, the Melrose potassium citrate solution still produced post-cardioplegia ventricular fibrillation and myocardial dysfunction [5]. This led to a general pause in clinical application of potassium cardioplegia between the 1960s and early 1980s, in favor of other options mostly involving induction of hypothermic cardiac arrest, which turned out to be no better with respect to postoperative damage than the Melrose solution.
Eventually, research into techniques for potassium cardioplegia would pick up again, and the result would be development of novel solutions for cardioplegia and intraoperative organ preservation. Numerous studies in animal models have validated the principles of diastolic cardiac arrest due to depolarizing potassium cardioplegia [2, 3, 6, 7, 8, 9, 10]. In addition, invention and refinement of heart-lung machines to accompany cardioplegia in the operative room (CPB) opened many new possibilities for cardiac surgery. Today, potassium cardioplegia is an integral tool for cardiac surgeons performing a variety of highly invasive procedures such as coronary artery bypass grafting and aortic valve replacements.
Despite variability in composition, delivery, and temperature, most cardioplegic solutions in use today involve some level of potassium chloride as the main inducer of cardiac arrest, along with ions such as magnesium, low-dose calcium and bicarbonate, the latter of which is particularly important for controlling solution pH [6]. The “original” hyperkalemic cardioplegic solution was the Melrose formula of the 1950s that was discussed earlier, consisting of potassium citrate and warm blood in a 9:1 blood:potassium ratio. However, due to the high incidence of postoperative complications including ventricular fibrillation, this solution is no longer in major clinical use.
In general, cardioplegic solutions fall under two broad umbrellas: crystalloid vs. blood, and warm vs. cold (Table 1). Two crystalloid cardioplegic solutions worth noting are the Custodiol (also known as Bretschneider) and St. Thomas solutions [7]. The St. Thomas solution, introduced first by Hearse and colleagues in 1975, is an example of a short acting cardioplegic solution involving potassium chloride concentrations between 10 and 30 mM [8]. In general, the St. Thomas solution requires repeat dosing, roughly every 20 minutes, to sustain cardioplegia for long durations [7, 9]. Furthermore, myocardial acidosis has been noted between doses of St. Thomas solution [10].
St. Thomas Cardioplegia | Custodiol Cardioplegia | Del Nido Cardioplegia | Buckberg Cardioplegia | Warm Calafiore Cardioplegia (one variant) | |
---|---|---|---|---|---|
K+ | 16 mM | 9 mM | 26 mM | Cold induction: 36 mM Maintenance: 36 mM Reperfusion: 15 mM | 18–20 mM for inducing arrest, repeat delivery every 20 min with decreasing K concentrations |
Ca | 1.2 mM | 0.015 mM | 1.3 mM | ||
Mg | 16 mM | 4 mM | 2 g of 50% magnesium sulfate | 15.5 mM | |
Na | 110 mM | 15 mM | |||
NaHCO3 | 10 mM | 13 mM | |||
Other Components | 18 mM Histidine hydrochloride 18 mM histidine 2 mM tryptophan 30 mM mannitol 1 mM potassium hydrogen 2-ketoglutarate | 13 mL of 1% lidocaine 3.2 g/L of 20% mannitol | 62.5 mL glutamate/aspartate | 500 mL 5% dextrose 4 mM tris(hydroxymethyl)aminomethane Core body temperature maintained at 37 degrees Celsius | |
Blood vs. Crystalloid | Crystalloid | Crystalloid | 4:1 crystalloid: blood ratio | 4:1 crystalloid: blood ratio | Normothermic blood |
Composition of common potassium-based cardioplegic solutions.
In contrast, the Custodiol solution is a form of long acting, single dose cardioplegia consisting primarily of potassium chloride, sodium chloride, and magnesium sulfate as the chief electrolytes [11]. Additional components of the Custodiol solution include tryptophan (membrane stabilization) and histidine buffer (to maintain pH and buffer against byproducts of anaerobic glycolysis that build up during cardioplegia). Curiously, the relatively low levels of potassium (9 mM) and sodium (15 mM) in Custodiol appear to induce cardioplegia through a form of hyperpolarized arrest as opposed to depolarized arrest, unlike most other potassium cardioplegic solutions that have potassium concentrations in the range of 16-36 mM and sodium concentrations in the range of 10-110 mM (see Table 1 for detailed solution ion concentrations).
The general rationale for blood-based cardioplegia has centered on the theory that cardioplegic solutions containing blood are more “physiologic” than crystalloid solutions. For example, blood can support aerobic respiration and may be able to preserve normal myocardial metabolism during surgery. Therefore, blood cardioplegia may reduce the negative consequences of prolonged ischemia during CPB [11]. However, insufficient evidence exists currently to verify that hypothesis, and so any purported advantages of blood over crystalloid cardioplegia are for the time being mainly speculative.
Three hyperkalemic cardioplegic solutions in clinical use that contain blood are the Del Nido, Buckberg, and Calafiore solutions. The Del Nido solution uses a crystalloid:blood ratio of 4:1, and like the Custodiol solution is a long-acting cardioplegic solution, with one dose of 20 ml/kg providing myocardial protection for up to 60–90 minutes [7, 12]. Chief ionic ingredients include potassium chloride for rapid depolarized arrest, sodium bicarbonate to scavenge protons and buffer intracellular pH, and magnesium to block calcium channels and prevent intracellular calcium accumulation during cardioplegic arrest, thereby promoting postoperative myocardial recovery [12, 13]. Lidocaine in the Del Nido solution acts as a sodium channel blocker to mitigate against the sodium “window current” and reduce intracellular sodium accumulation [14].
Buckberg’s cardioplegia is a dextrose and saline-based solution that, similar to the Del Nido solution, consists of a crystalloid:blood ratio of 4:1 [15]. Other components include potassium chloride as the primary depolarizing agent, a tromethamine buffer, and citrate phosphate double dextrose to serve as a calcium chelator. However, unlike the Del Nido solution, Buckberg cardioplegia must be given as three separate formulations, some of which must be administered in multiple doses [15]. First, an induction solution stops the heart, and additional infusions of induction solution must be given every 15 to 20 minutes throughout the procedure. Second, a maintenance solution must be administered to sustain cardiac arrest and provide oxygen and nutrients to the cardiomyocytes. Finally, a reperfusion solution containing glutamate and aspartate is administered prior to removal of the aortic cross clamp to provide the heart with nutrients prior to restarting myocardial contractions.
Calafiore cardioplegia differs from Buckberg and Del Nido in that blood forms the sole foundation of Calafiore cardioplegic solution [16]. Indeed, the original rational proposed by Calafiore et al. was that blood alone, without any crystalloid component, contained everything necessary to prevent ischemia–reperfusion damage. Therefore, simply administering a cardioplegic solution consisting of blood plus extra potassium would be enough to safely stop and later, restart the heart [16]. Moreover, unlike most other forms of cardioplegia in use, the original Calafiore solution was normothermic throughout administration; however, some subsequent variations of Calafiore cardioplegia have used cold blood [16, 17].
Most current methods for administering cardioplegic solutions involve cold cardioplegia, most often cold crystalloid solutions delivered after reducing core body temperature to hypothermic levels [18]. For example, the induction and maintenance solutions for Buckberg cardioplegia are delivered at 4 degrees Celsius after cooling core temperature to below 30 degrees Celsius, with reperfusion solution delivered at 37 degrees Celsius [15]. Similarly, del Nido and Custodiol cardioplegia are often given at 4 degrees Celsius after induction of systemic hypothermia [15, 19].
This practice stems from experimental evidence suggesting that mild hypothermia can protect the myocardium from ischemic damage during cardioplegia [20]. Hypothermia reduces the basal metabolic rate of the heart, which in turn reduces oxygen consumption—an effect augmented by potassium-induced arrest during hyperkalemic cardioplegia [21]. A variety of potential mechanisms may be at play. In animal models of cardiac arrest, mild hypothermia (32–35 degrees Celsius) has been shown to reduce post-arrest infarct size, possibly through various signal transduction pathways, such as Akt and mTOR signaling, both of which are altered during the course of hypothermia [20]. Another potential cardioprotective mechanism of hypothermia may be reduced phosphorylation of various mitogen activated protein kinases (MAPK) like ERK1/2 that normally activate pro-inflammatory mediators like COX-2 (arachidonic acid metabolism) [18]. In general, many details concerning mechanisms of hypothermic myocardial protection during cardioplegia remain to be elucidated.
However, cold hyperkalemic cardioplegia may also inhibit myocardial enzymes that are important for the metabolic and functional recovery of the heart after surgery [22, 23]. Moreover, sustained systemic hypothermia (especially at temperatures below 20 degrees Celsius) during cardiac surgery has also been associated with ventricular fibrillation after rewarming [21]. Given these negative consequences, an increasing amount of attention has been given to the possibility of warm hyperkalemic cardioplegia, primarily warm blood hyperkalemic cardioplegia. Unlike cold hyperkalemic cardioplegic solutions, warm cardioplegic solution is typically administered at between 30 and 35 degrees Celsius under normothermic, as opposed to hypothermic, CPB [24]. Potential advantages of warm blood hyperkalemic cardioplegia over cold crystalloid may include improved myocardial restoration, reduced intracellular swelling, improved membrane stabilization, and reduced hypoxic red blood cell deformation [25].
Of course, warm hyperkalemic cardioplegia is not without its own consequences. Some studies have reported increased likelihoods of perioperative strokes and encephalopathy [26]. Moreover, warm hyperkalemic cardioplegia may contribute to vasodilation during cardiopulmonary bypass, requiring increased use of alpha agonists during operation to maintain stable arterial perfusion pressures [25]. There are also several variations of warm cardioplegia; one common technical variant is “hot shot” cardioplegia, which involves warm induction and subsequent cold cardioplegia, followed by a warm reperfusion [27].
Comparing the effectiveness of warm vs. cold hyperkalemic cardioplegia remains an inconclusive subject of intense debate. A meta-analysis by Fan et al., reported no differences between length of stay, stroke incidence, and atrial fibrillation between patients undergoing warm vs. cold cardioplegia [28]. However, warm cardioplegia correlated with better postoperative cardiac indices and lower peak creatine kinase MB concentrations than cold cardioplegia [28]. The latter findings, along with reduced postoperative cardiac troponin levels, have been replicated in other studies [29, 30]. Meanwhile, other studies comparing warm blood and cold crystalloid hyperkalemic cardioplegia do not show significant differences with respect to perioperative myocardial infarction and low cardiac output syndrome [31].
In general, administration of hyperkalemic cardioplegic solution can be done in either retrograde or anterograde fashion. Prior to both, IV heparin is administered, and the patient’s core body temperature is lowered to hypothermic levels, after which the aortic cross-clamp is placed and cardiopulmonary bypass is initiated [7]. Anterograde cardioplegia refers to delivering cardioplegic solution through a cannula inserted just proximal to the aortic cross-clamp. From there, the solution can flow into the left and right coronary arteries that supply the myocardium [32]. With anterograde cardioplegia, arrest usually occurs within 30 to 60 seconds. Retrograde cardioplegia may be considered in patients with complications such as severe coronary artery damage (e.g. severe stenosis) or aortic valve damage. Unlike anterograde administration, in retrograde administration the cardioplegia catheter is inserted into the coronary sinus from the right atrium, and solution is injected at a lower pressure (given the lower tolerance of the coronary sinus walls to turbulent flow) to avoid coronary sinus perforation [32].
Under physiological circumstances, the cardiomyocyte resting membrane potential is largely determined by two key factors: action of the sodium-potassium ATPase, and the high resting permeability of cardiomyocyte cell membranes to potassium [33]. First, the sodium-potassium ATPase hydrolyzes ATP to continuously pump potassium into the cell and sodium out of the cell, with a relative ratio of 3Na out/2 K in per molecule of ATP. Because it is the primary ion pump active while the cell is at rest, the sodium-potassium ATPase plays a critical role in generating the characteristic sodium and potassium electrochemical gradients across the cardiomyocyte cell membrane (high potassium and low sodium inside the cell relative to out). Second, at rest the cardiomyocyte cell membrane is most permeable to potassium while being relatively impermeable to other ions. This results in a resting membrane potential for cardiomyocytes that is close to the Nernst equilibrium potential for potassium, roughly −85 to -90 mV.
During cardiac muscle contraction, sinoatrial node stimulation induces a transient increase in the resting membrane potential of cardiomyocytes, which in turn opens voltage-gated sodium channels once the membrane potential surmounts -65 mV. Due to the high inward ion driving force on sodium (based on the considerable difference between the Nernst potential for sodium and the resting membrane potential), sodium ions flow through the sodium channels into the cardiomyocyte and further depolarize the cell until it reaches about 20 mV. At this point, sodium channels inactivate and L-type voltage gated calcium channels take over the maintenance of the action potential, allowing influx of calcium ions and producing the classic plateau depolarization of cardiac ventricular action potentials. Eventually, as calcium channels close and membrane potential begins to dip, delayed rectifier potassium channels open and restore membrane potential to the resting state. By this point, enough calcium has entered the cardiomyocyte to promote calcium-induced calcium release from intracellular calcium stores in the cardiomyocyte sarcoplasmic reticula, allowing muscle contraction to occur.
Extracellular hyperkalemia is the core principle underpinning most warm blood and cold crystalloid cardioplegic solutions. Essentially, administration of hyperkalemic solution takes advantage of the pivotal role of the potassium electrochemical gradient in determining cardiomyocyte resting membrane potential in order to elevate the resting membrane potential to a less negative value than typical baseline level. For example, physiologic extracellular potassium levels are often in the range of 3.5–5 mM, producing a resting membrane potential around -85 mV. During cardiac surgery involving cardioplegia, hyperkalemic solutions often raise extracellular potassium to the range of 10-40 mM (often midway in this range, around the 25 mM level), elevating cardiomyocyte resting membrane potentials to anywhere between −65 to -40 mV [34]. Arresting cardiomyocytes at this new range of elevated membrane potentials promotes fast sodium channel inactivation, thereby blocking myocardial action potential conduction. It also blocks repolarization, which is why hyperkalemic cardioplegia induces what is called “depolarized arrest.” Finally, it is important to note that cardioplegic arrest also significantly reduces cardiomyocyte oxygen consumption in a manner reminiscent of how severe ischemia depletes cellular ATP reserves [33].
Despite its clinical usefulness in reversibly arresting the heart during cardiac surgery, sustained depolarized hyperkalemic cardioplegia is not without some negative perioperative consequences. First, while most voltage-gated “fast” sodium channels are inactivated at membrane potentials above -50 mV (a frequent target cardiomyocyte membrane potential for potassium cardioplegia), resulting in generally poor membrane sodium conductance, not
Similarly, ATP depletion and reduced myocardial oxygen consumption during hyperkalemic cardioplegia leads to myocardial ischemia. Ischemia forces myocardial cells to resort to anaerobic glycolysis for energy production, which generates lactate as a byproduct. Increasing lactate levels in cardiomyocytes produces a metabolic acidosis and promotes increased activity of the H+/Na antiporter to move protons out of the cells at the expense of bringing in more sodium [36]. Finally, the combination of high extracellular potassium, intracellular acidosis, and hypothermia due to cold cardioplegic solution inhibits action of the sodium-potassium ATPase, which further facilitates the buildup of intracellular sodium [34].
Note that -50 mV is also in the vicinity of the reversal potential of the sodium/calcium exchanger [37, 38]. Under normal circumstances, the sodium/calcium exchanger moves 3 Na in for every 1 Ca moved out of the cell. However, due to the sodium window current and depolarized arrest in hyperkalemic cardioplegia, the sodium/calcium exchanger eventually begins operating in reverse, moving 3 Na out for every 1 Ca in, producing a so-called calcium “window current.” Moreover, if the hyperkalemic cardioplegic solution holds cardiomyocyte membrane potentials above -50 mV, e.g. at around -40 mV, then voltage-gated slow calcium channels will begin to activate, causing further calcium influx [39]. All of these reasons help explain why many hyperkalemic cardioplegic solutions in clinical practice are also hypocalcemic relative to physiological extracellular calcium levels (or contain calcium channel blockers), to attempt to mitigate the severity of myocardial calcium loading [34].
Cytosolic calcium loading during hyperkalemic cardioplegia contributes to cardiomyocyte damage through several mechanisms [40]. Enhanced activation of calcium dependent proteases and lipases (e.g. phospholipases) contributes to plasma membrane phospholipid degradation, ultrastructural changes in the sarcolemmal membrane, and accumulation of pathological catabolic byproducts. Enhanced activation of calcium-dependent ATPases accelerates depletion of intracellular ATP stores that have already been lowered following hypothermic arrest. This further perturbs cardiomyocyte sarcolemmal calcium transport channels that rely on ATP to maintain intracellular calcium homeostasis. Moreover, hypoxia during hyperkalemic cardioplegia increases mitochondrial calcium uptake via reversal of mitochondrial sodium/calcium exchangers in a manner akin to reversal of cardiomyocyte cell membrane sodium/calcium exchangers [41].
Mitochondria can only endure so much calcium uptake before the onset of irreversible damage. Indeed, following reperfusion after hyperkalemic cardioplegia arrest, mitochondria exhibit increased oxygen free radical production and reduced superoxide dismutase activity, indicative of heightened oxidative stress [41]. Sustained oxidative stress can lead to opening of mitochondrial permeability transition pores (MPTP), which promote mitochondrial swelling and mitochondrial membrane rupture. An assortment of mitochondrial enyzmes and molecules, such as cytochrome c, leak out into the cytosol through the MPTPs [41]. Cytochrome c is implicated in intrinsic apoptotic pathways through activation of cytosolic caspases and subsequent formation of myocardial apoptosomes [41].
Myocardial apoptosis during hyperkalemic cardioplegic ischemia–reperfusion merits further consideration for two major reasons. First, several studies have shown associations between hyperkalemic cardioplegic arrest and endothelial cell and cardiomyocyte apoptosis [42, 43, 44]. Second, several independent pathways of myocardial cell injury converge on apoptosis. Examples include mitochondrial oxidative stress and activation of an intrinsic apoptotic pathway (introduced earlier), or an extrinsic pathway driven by elevated humoral factors such as Fas or TNF-alpha acting on pro-apoptosis cell membrane receptors [44, 45]. Both intrinsic and extrinsic pathways converge upon a similar final common pathway that is chiefly regulated by two key protein groups: the Bcl-2 and cysteine protease caspase families [46, 47].
Within the Bcl-2 family, two proteins are particularly significant: Bcl-2 itself, and Bad. The former is anti-apoptotic while the latter is pro-apoptotic. Phosphorylation inhibits Bad, blocking it from inactivating Bcl-2 [48]. Farther downstream in apoptotic signaling, cleavage of caspase 3 and poly ADP-ribose polymerase (PARP) is essential for ensuring final progression towards apoptosis. Meanwhile, apoptosis may also proceed via a caspase-independent pathway involving release of the mitochondrial flavoprotein apoptosis-inducing factor (AIF) from the mitochondria into the cytosol through MPTPs [49, 50].
A possible framework for understanding myocardial apoptosis after hyperkalemic CPB is as follows [48]. Activation of the intrinsic (mitochondrial) pathway leads to increased Bad activation/decreased Bcl-2 activation, which initiates the caspase cascade. Activation of the extrinsic pathway bypasses Bcl-2/Bad to directly activate the caspase cascade. As more and more caspases become activated, eventually terminal caspases, such as caspase 3, will be cleaved, leading to PARP cleavage. By this point, apoptosis has been irreversibly induced; DNA fragmentation and cell death quickly follow. In contrast, AIF translocation from the mitochondria to the cytosol may directly activate downstream/terminal caspases, bypassing initial/intermediary constituents of the caspase cascade.
Studies have shown that caspase 3 cleavage and Bcl-2/Bad phosphorylation are significantly increased in myocardial tissue following hyperkalemic cold-blood cardioplegia and reperfusion, even as total protein levels do not change [48]. Meanwhile, myocardial AIF levels increase slightly, accompanied by a trend towards nuclear translocation, consistent with a model of AIF induced chromatin condensation and DNA fragmentation as a mechanism of cell injury [48]. Note that both pro-apoptotic (e.g. caspase 3) and anti-apoptotic (e.g. phosphorylated Bad) mediators are activated—nevertheless, given the downstream terminal position of caspase 3, the overall balance in myocardial cells appears to be tipped in favor of pro-apoptotic signaling.
Different formulations of hyperkalemic cardioplegia (e.g. cold crystalloid, warm blood, etc.) may exhibit differing degrees of myocardial protection and prevention of apoptosis. Indeed, evidence exists suggesting that cold blood hyperkalemic cardioplegia is superior to warm blood, warm crystalloid, and cold crystalloid cardioplegia, in terms of increased Bad phosphorylation and decreased caspase 3 activation [51]. Taken together, this combination of events appears to result in less apoptosis. In addition, these effects are associated with improved left ventricular function following cardioplegic arrest. However, this is not a universal finding in the literature. More work must be done to verify these conclusions and confirm if there truly is a definitive benefit to any one technique of hyperkalemic cardioplegia with respect to prevention of apoptosis.
An extensive body of research has established that hyperkalemic solutions induce significant vasoconstriction when experimentally applied to coronary artery and aortic ring preparations [2]. Thus, it is no surprise that hyperkalemic cardioplegia induces significant functional changes to the microcirculation, especially the coronary circulation [52]. For example, a sizeable number of patients undergoing hyperkalemic cardioplegia experience coronary artery spasm [52].
Potassium can influence coronary vasoconstriction in several ways. Holding coronary vascular smooth muscle membrane potentials at sustained depolarization during hyperkalemic cardioplegia increases the likelihood of generating contractions [53]. Potassium may also act indirectly to cause vasospasm through action on the coronary endothelium. Indeed, endothelial vasoconstrictive and vasorelaxant factors govern homeostatic regulation of coronary vasomotor tone. These factors influence vascular smooth muscle through modulation of various cell membrane potassium channels, including calcium-activated potassium channels and ATP-activated potassium channels [54, 55]. Important endothelial-derived relaxing factors include nitric oxide, endothelial-derived hyperpolarizing factor (EDHF), and cyclooxygenase enzymes. Important endothelial-derived constricting factors include endothelin-1 and thromboxane A2.
Porcine models of hyperkalemic cardioplegia showed that hyperkalemia significantly attenuated EDHF-mediated relaxation in coronary artery preparations [56, 57]. Moreover, hyperkalemic vasoconstriction has also been linked with impaired nitric oxide release [58] and impaired acetylcholine-dependent vascular relaxation [59, 60]. Potential mechanisms at play may involve potassium-induced inhibition of G protein and non-G protein signal transduction pathways, increased reactive oxygen and nitrogen species generation, decreased activity of endothelial nitric oxide synthase, and increased arachidonic acid metabolism [2]. Curiously, hyperkalemic cardioplegia has also been associated with decreased responsiveness of human coronary arterioles to the endothelial vasoconstrictors endothelin-1 and thromboxane A2 [61, 62]. These findings testify to the complexity of mechanisms underpinning coronary vasomotor dysfunction following hyperkalemic cardioplegia, most of which remain to be elaborated.
Despite its cardioprotective effects, hyperkalemic cardioplegia-reperfusion can exert detrimental effects on the myocardial and coronary endothelium, promoting endothelial dysfunction [63, 64]. One aspect of endothelial dysfunction—production of various endothelium-derived relaxing and contracting factors—was discussed earlier due to its relevance in coronary vasospasm. Other important features of endothelial dysfunction during hyperkalemic cardioplegic arrest include endothelial injury, inflammation, reactive oxygen species production, coagulation cascade dysfunction, and endothelial tight junction degradation [52, 65, 66, 67]. All these adverse effects may occur with potassium levels as low as 10 mM, well within the realm of most hyperkalemic cardioplegic solutions [2]. To elaborate, potassium concentrations of 30 mM in St. Thomas and Custodiol cardioplegic solutions proved considerably more damaging to the vascular endothelium than potassium concentrations of 20 mM, demonstrating the importance of strict potassium limits in hyperkalemic cardioplegic solutions [6].
A variety of structural changes to the vascular endothelium have been observed in experimental models of hyperkalemic cardioplegia. Key examples include endothelial intracellular vacuolization, membrane blebbing, adventitial fibrosis, and overall reduced viability [68, 69]. Furthermore, hyperkalemic cardioplegia promotes increased lipid uptake and cholesterol deposition in vascular intimae in primate models of post-graft venous atherosclerosis [70]. In addition, compromised endothelial adherens junctions during hyperkalemic cardioplegia mediate increased vascular permeability and tissue edema [67]. Indeed, animal models of cardioplegia/CPB show increased post-procedure VE cadherin, beta-catenin, and gamma-catenin fragments, all of which are important structural components of adherens junctions [71]. In humans, increased endothelial cadherin phosphorylation, and decreased overall beta-catenin levels, have been observed in atrial tissue following hyperkalemic cardioplegia/CPB [72].
Details of specific mechanisms underlying these endothelial disturbances remain largely unclear; however, many possibilities exist. For example, it is generally agreed that depolarization induced by hyperkalemic cardioplegia is a critical initiating step of the underlying pathophysiology [2]. Endothelial depolarization increases activation of neutrophils, inflammation, voltage sensitive NAPDH oxidases, and platelets [62, 63, 73, 74]. Inflammation and neutrophil activation often reinforce each other, as pro-inflammatory cytokines like IL-1, IL-6, and TNF-alpha further stimulate endothelial changes that promote neutrophil extravasation. NADPH oxidase catalyzes formation of important reactive oxygen species such as superoxide anions, which if left unchecked are severely cytotoxic. The amount of superoxide production during hyperkalemic cardioplegia has been linked to the extent of endothelial depolarization and translocation of the small G protein Rac from the cytosol to plasma membrane [75].
With respect to coagulation, potassium depolarization appears to have a direct stimulatory effect via enhancing ADP and collagen-induced platelet aggregation, along with an indirect effect through increased superoxide production [76, 77]. The latter appears to act through inhibition of endothelial NTPDases [78]. Membrane hyperpolarization reverses all these actions.
When left unchecked, sustained myocardial dysfunction following hyperkalemic cardioplegia-reperfusion may lead to myocardial stunning, a form of postoperative left ventricular dysfunction [1]. Myocardial stunning often manifests as markedly reduced cardiac output without obvious evidence of infarction or injury (e.g. no signs of elevated troponin or CKMB in blood). Like myocardial apoptosis, myocardial stunning represents another final common pathway of convergence for several different pathophysiological mechanisms of hyperkalemic cardioplegia, chiefly dysregulated free radical production, coagulation imbalances, and excessive catecholamine release [1]. However, unlike with apoptosis, in this scenario injury results from abnormal myocardial contractility as opposed to myocardial cell death.
Postoperative imbalances in a variety of different electrolytes, including calcium, magnesium, potassium, and phosphate, have been observed following cardioplegia/CPB. Here, we will focus on potassium, beginning with hypokalemia. Hypokalemia can be defined as a serum potassium level that is less than 3.5 mEq/L [78]. Postoperative hypokalemia is a common finding after cardiac surgery involving hyperkalemic cardioplegia and CPB, and manifests almost immediately after the patient is weaned off the bypass circuitry [79]. Hence IV potassium supplementation during cardioplegia is extremely important to mitigate against the most severe manifestations [80].
However, even with electrolyte supplementation in the operating room, CPB poses a high risk of post-procedure electrolyte depletion [81]. The pivotal role of potassium in normal cardiac contractility means that disturbances in potassium homeostasis significantly increase the risk of arrythmias and, in severe cases, sudden cardiac arrest. Indeed, arrythmias, especially atrial tachyarrhythmias (e.g. atrial fibrillation, atrial flutter) and, less frequently, ventricular arrhythmias, are a major source of morbidity and mortality following cardiac surgery [82, 83].
Specific mechanisms underpinning this phenomenon remain largely unclear; however, a variety of possibilities exist [78]. For example, poor oral intake of potassium-rich foods prior to cardiac surgery may contribute to enhanced depletion during surgery. In addition, prolonged preoperative use of digoxin, along with thiazide and loop diuretics may play a role. These agents may cause hypomagnesemia (low magnesium levels), which can contribute to extracellular potassium depletion. Under normal circumstances, intracellular magnesium binds to and blocks the pores of renal outer medullary potassium (ROMK) channels in the distal nephron, preventing outward flux of potassium into the renal tubular network [78]. Thus hypomagnesemia may remove this physiologic limiter, leading to increased renal clearance of potassium.
A hyperactive aldosterone response to stress may also be implicated, particularly in the context of congestive heart failure [78, 80]. Moreover, increased catecholamine (norepinephrine and epinephrine) release during cardiopulmonary bypass may facilitate hypokalemia given the influence of catecholamines on plasma potassium [84, 85]. Animal models have shown that elevated catecholamine levels can produce first, a transient hyperkalemia due to activation of hepatic calcium-dependent potassium channels by alpha adrenergic stimulation and second, a sustained hypokalemia by stimulation of skeletal muscle Na-K ATPase [86]. Such studies need to be replicated in humans undergoing cardiopulmonary bypass-hyperkalemic cardioplegia in order to verify the applicability of these putative mechanisms.
Because glucose is often given during cardioplegia, insulin may also be administered to minimize the chances of hyperglycemia. However, given that insulin acts as a regulator of potassium distribution between intracellular and extracellular fluid compartments by stimulating Na-K ATPase activity, it is possible that insulin administration during and after cardioplegia may contribute to potassium depletion [87]. Next, given that many cardioplegic solutions in current practice are cold hyperkalemic solutions, any potential impact of hypothermia on potassium homeostasis during cardiac surgery cannot be ignored. As with insulin, hypothermia has been linked to an intracellular shift of potassium away from the extracellular space through as-yet unelaborated mechanisms [88]. Finally, the CPB circuit itself has been shown to significantly dilute overall blood plasma protein concentrations, which may also affect plasma ion homeostasis [89].
In general, treatment of postoperative hypokalemia largely centers on administration of potassium chloride (KCl) solution to elevate extracellular potassium concentrations to physiologic levels. Indeed, in the case of pediatric cardiac ICU patients for whom enteral potassium supplementation is contraindicated, IV KCl administration is one of the only available tools for correcting hypokalemia [90]. For most patients, this proves sufficient to correct the imbalance and stave off the development of hypokalemia-induced arrhythmias. However, in a small minority, external KCl solution does not reverse the hypokalemia—and so in these patients, the chances of arrhythmias increase exponentially.
Although hypokalemia is the most common potassium electrolyte abnormality following hyperkalemic cardioplegia-CPB, postoperative hyperkalemia may occur under certain, albeit rarer, circumstances. In general, postoperative hyperkalemia is a concern mainly in patients with renal failure undergoing CPB, most likely due to renal tubular dysfunction [91]. Severe hyperkalemia may be treated with IV calcium gluconate, an insulin-dextrose regimen, and diuretics [92]. If a patient has end-stage renal disease, dialysis may be the best option to treat hyperkalemia, along with IV calcium to stabilize the myocardium and IV insulin to shift potassium into cells [93].
Hyperkalemic cardioplegia is by far the most widely used method of cardioplegia in current clinical practice. However, because of the numerous perioperative repercussions of hyperkalemic cardioplegia, a variety of attempts have been made to explore alternative approaches. Given that many adverse effects of hyperkalemic cardioplegia stem from its induction of depolarized arrest, one popular avenue of investigation has been the possibility of hyperpolarized arrest. Hyperpolarization is the natural resting state of cardiomyocytes, so in theory, arresting the heart at its baseline hyperpolarized state may better preserve physiological integrity. In isolated animal heart models, hyperpolarized arrest has been achieved via pharmacologic activation of ATP-sensitive potassium channels [94, 95]. Following reperfusion, this form of hyperpolarized arrest appeared to lead to improved postischemic functional recovery when compared to hearts protected with depolarized arrest.
Meanwhile, so-called “polarized arrest” has been proposed as another alternative to hyperkalemic cardioplegia. The core principle behind this concept is administration of sodium channel blockers, such as procaine in humans or tetrodotoxin in animal models [96]. Sodium channel blockade prevents depolarization-induced activation of calcium currents, which normally carry out the bulk of the cardiomyocyte action potential. Overall, in animal models, tetrodotoxin-induced polarized arrest reduces metabolic demands during ischemia, including myocardial oxygen consumption, more so than hyperkalemic cardioplegia [96]. Furthermore, polarized arrest may produce less significant postoperative ionic imbalances, with further protection provided by coincident administration of sodium/potassium/chloride transporter and sodium/proton exchanger inhibitors [96]. Nonetheless, more work needs to be done to verify the broader clinical applicability of these alternatives to hyperkalemic cardioplegia.
By taking advantage of the pivotal role of potassium in cardiomyocyte physiology, hyperkalemic cardioplegia has become an integral tool for cardiac surgery. From the early days of Dennis Melrose’s simple potassium citrate solution to complex modern-day formulations such as the Del Nido and Buckberg media, approaches to developing and administering hyperkalemic cardioplegic solutions have evolved considerably, with a continuing focus on developing the most cardioprotective and least damaging solutions possible. While initial approaches to hyperkalemic cardioplegia revolved around hypothermic solutions, normothermic/“warm” solutions, along with blood as opposed to crystalloid-based solutions, are gaining momentum as potential alternatives to mitigate adverse perioperative consequences of cold hyperkalemic cardioplegia. Some of those consequences include myocardial calcium loading, myocardial apoptosis, coronary vasomotor dysfunction, myocardial endothelial dysfunction, and myocardial stunning. With any form of hyperkalemic cardioplegia, plasma potassium abnormalities following reperfusion, mainly postoperative hypokalemia, remain a persistent clinical concern. And while most patients respond well to IV KCl supplementation, some do not and proceed to develop fatal arrythmias, underscoring the need for further research to understand the mechanisms at play and develop new treatments. In the future, it is possible that other approaches such as hyperpolarized or polarized arrest may challenge the widespread use of depolarized hyperkalemic cardioplegic arrest. Nevertheless, for the time being, hyperkalemic cardioplegia remains dominant in cardiac surgery, and will likely continue to be so for some time to come.
The authors have no acknowledgements.
The authors declare no conflicts of interest.
The authors have no other notes or declarations.
This is a brief overview of the main steps involved in publishing with IntechOpen Compacts, Monographs and Edited Books. Once you submit your proposal you will be appointed a Author Service Manager who will be your single point of contact and lead you through all the described steps below.
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He previously worked as a post-doctoral fellow at the Ben-Gurion University of Negev, Israel; University of the Free State, South Africa; and Central University of Technology Bloemfontein, South Africa. He obtained his Ph.D. in Organic Chemistry from Nagaoka University of Technology, Japan. He has published more than seventy-four journal articles and attended several national and international conferences as speaker and chair. Dr. Kendrekar has received many international awards. He has several funded projects, namely, anti-malaria drug development, MRSA, and SARS-CoV-2 activity of curcumin and its formulations. He has filed four patents in collaboration with the University of Central Lancashire and Mayo Clinic Infectious Diseases. His present research includes organic synthesis, drug discovery and development, biochemistry, nanoscience, and nanotechnology.",institutionString:"Visiting Scientist at Lipid Nanostructures Laboratory, Centre for Smart Materials, School of Natural Sciences, University of Central Lancashire",institution:null},{id:"428125",title:"Dr.",name:"Vinayak",middleName:null,surname:"Adimule",slug:"vinayak-adimule",fullName:"Vinayak Adimule",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/428125/images/system/428125.jpg",biography:"Dr. Vinayak Adimule, MSc, Ph.D., is a professor and dean of R&D, Angadi Institute of Technology and Management, India. He has 15 years of research experience as a senior research scientist and associate research scientist in R&D organizations. He has published more than fifty research articles as well as several book chapters. He has two Indian patents and two international patents to his credit. Dr. Adimule has attended, chaired, and presented papers at national and international conferences. He is a guest editor for Topics in Catalysis and other journals. He is also an editorial board member, life member, and associate member for many international societies and research institutions. His research interests include nanoelectronics, material chemistry, artificial intelligence, sensors and actuators, bio-nanomaterials, and medicinal chemistry.",institutionString:"Angadi Institute of Technology and Management",institution:null},{id:"284317",title:"Prof.",name:"Kantharaju",middleName:null,surname:"Kamanna",slug:"kantharaju-kamanna",fullName:"Kantharaju Kamanna",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284317/images/21050_n.jpg",biography:"Prof. K. Kantharaju has received Bachelor of science (PCM), master of science (Organic Chemistry) and Doctor of Philosophy in Chemistry from Bangalore University. He worked as a Executive Research & Development @ Cadila Pharmaceuticals Ltd, Ahmedabad. He received DBT-postdoc fellow @ Molecular Biophysics Unit, Indian Institute of Science, Bangalore under the supervision of Prof. P. Balaram, later he moved to NIH-postdoc researcher at Drexel University College of Medicine, Philadelphia, USA, after his return from postdoc joined NITK-Surthakal as a Adhoc faculty at department of chemistry. Since from August 2013 working as a Associate Professor, and in 2016 promoted to Profeesor in the School of Basic Sciences: Department of Chemistry and having 20 years of teaching and research experiences.",institutionString:null,institution:{name:"Rani Channamma University, Belagavi",country:{name:"India"}}},{id:"158492",title:"Prof.",name:"Yusuf",middleName:null,surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/158492/images/system/158492.jpeg",biography:"Prof. Dr. Yusuf Tutar conducts his research at the Hamidiye Faculty of Pharmacy, Department of Basic Pharmaceutical Sciences, Division of Biochemistry, University of Health Sciences, Turkey. He is also a faculty member in the Molecular Oncology Program. He obtained his MSc and Ph.D. at Oregon State University and Texas Tech University, respectively. He pursued his postdoctoral studies at Rutgers University Medical School and the National Institutes of Health (NIH/NIDDK), USA. His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. He has developed various compounds including a drug for acute promyelocytic leukemia.",institutionString:"Tokyo Medical and Dental University",institution:{name:"Tokyo Medical and Dental University",country:{name:"Japan"}}},{id:"94311",title:"Prof.",name:"Martins",middleName:"Ochubiojo",surname:"Ochubiojo Emeje",slug:"martins-ochubiojo-emeje",fullName:"Martins Ochubiojo Emeje",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94311/images/system/94311.jpeg",biography:"Martins Emeje obtained a BPharm with distinction from Ahmadu Bello University, Nigeria, and an MPharm and Ph.D. from the University of Nigeria (UNN), where he received the best Ph.D. award and was enlisted as UNN’s “Face of Research.” He established the first nanomedicine center in Nigeria and was the pioneer head of the intellectual property and technology transfer as well as the technology innovation and support center. Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"436430",title:"Associate Prof.",name:"Mesut",middleName:null,surname:"Işık",slug:"mesut-isik",fullName:"Mesut Işık",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/436430/images/19686_n.jpg",biography:null,institutionString:null,institution:{name:"Bilecik University",country:{name:"Turkey"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a scientist and Principal Investigator at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering the lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via artificial intelligence-based analyses of exosomal Raman signatures. Dr. Paul also works on spatial multiplex immunofluorescence-based tissue mapping to understand the immune repertoire in lung cancer. Dr. Paul has published in more than sixty-five peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award and the 2022 AAISCR-R Vijayalaxmi Award for Innovative Cancer Research. He is a senior member of the Institute of Electrical and Electronics Engineers (IEEE) and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"2",type:"subseries",title:"Prosthodontics and Implant Dentistry",keywords:"Osseointegration, Hard Tissue, Peri-implant Soft Tissue, Restorative Materials, Prosthesis Design, Prosthesis, Patient Satisfaction, Rehabilitation",scope:"