The main genes associated with hereditary dilated cardiomyopathy and the cellular structure that they regulate.
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",isbn:"978-1-83969-234-5",printIsbn:"978-1-83969-233-8",pdfIsbn:"978-1-83969-235-2",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"a5f5277a1c0616ce6b35f4b44a4cac7a",bookSignature:"Dr. Basel I. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"65295",title:"Play as a Mechanism of Promoting Emergent Literacy among Young Children: The Indian Context",doi:"10.5772/intechopen.82363",slug:"play-as-a-mechanism-of-promoting-emergent-literacy-among-young-children-the-indian-context",body:'\nInternationally early childhood years are defined as the period from birth to 8 years and are regarded as the most important years in a child’s life. Research has indicated that period from birth to 8 years has a crucial impact on children’s overall development and learning. There is a rapid growth in the brain during this period and any stimulation provided at this stage rapidly promotes the growth of the brain. By the time a child reaches 3 years of age, the brain has tripled in size [1]. The structural changes in the brain take place faster during the first 8 years than at any other stage of one’s life. Synaptic connections are also made during the early years of a child’s life. The strength of these synaptic connections is determined by the early life experiences as they respond strongly to outside stimulation. Since development and learning are directly related to the number of these synaptic connections, early childhood becomes the crucial period to help build a strong foundation and promote development and learning in young children.
\nResearch evidence over decades also suggests that the experiences during the early years influence the overall health, behaviour and learning of an individual throughout his/her life. The Council for Early Child Development is a not-for-profit, charitable organization, founded in 2004 by Dr. Fraser Mustard and has worked on many research studies which advocate that the early childhood is the ‘period of opportunity’ and children’s experiences influence neural pathways for later development [2]. It is also suggested that the experiences young children have while their brain is developing will have an impact on their development and will remain with them for their entire lives [3]. Children’s experience during the early years set a critical foundation for their entire life-course [4]. Thus, early years are termed as the ‘critical period’ or ‘sensitive period’ which have an impact on the overall development of the child. The early childhood years are critical for the development of brain and its associated capacities like hearing, vision, numbers and language skills as well as social and emotional skills.
\nDevelopment of language and early learning capacities of children are inextricably linked. Interestingly the relationship between language, culture and identity are closely intertwined. Thus it is crucial to understand and have a common definition of emergent literacy for young. This term serves as a holistic package of language and literacy development in young children. This is especially with respect to biological, cognitive, social and emotional development among young children.
\n‘Emergent Literacy’ is a process of making an individual literate – that is positive reading and writing experiences by an individual in socially significant and personally meaningful ways. In addition to this, “emergent literacy” approach is characterized by looking at children “in the process of becoming literate” [5, 6]. Thus, it is significant for children to read books to have pleasure, co-read to make meanings, understand that print/script has association and directionality, writing and drawing can be used for expression and communication among others.
\nTo summarize, the ability to read and write in young children or ‘emergent literacy’ is understood to be interrelated and interconnected, developing mutually through everyday play and other activities conducted by children. It is through these activities, children understand that written words make sense and have a meaning. The concept of emergent literacy also appreciates that the understanding about reading and writing in young children develops much before they enter formal school. In fact, young children are already in the process of understanding and constructing their language skills through interactions with family members and friends. Research into young children’s spontaneous engagements with written language before school-going age led to many new insights about the literacy acquisition process.
\nResearch and related theories of child development and early learning suggest that early childhood from birth to 8 years is a critical period of development [7]. The foundation for future development and learning is laid down during this critical period from birth to 8 years, covering the pre-primary and early primary years.
\nThe crucial early years are known to be critical for early learning and positive educational outcomes in later years, especially related with language and literacy skills [8]. This chapter focuses to highlight the status of emergent literacy in India, discussing the significance of play in early years. This will provide an overview of diverse play opportunities available to young children in the Indian setting and the impact on their holistic development.
\nEarly childhood educational programs play a significant role in a child’s life as they provide appropriate stimulation to young children at a ‘critical’ stage of their life and help them develop their full potential. Early learning in the first 5–8 years of childhood has decisive consequences for academic performance in school, as well as overall welfare and performance at work [9]. The importance of the early childhood educational programs has been further advocated by the results and findings of various research studies. Recent research on cognitive development provides reinforcing evidence that early education is crucial in getting children off to a good start in life [10]. It is also reiterated that early childhood services, including preschools can have a major beneficial impact on young people’s lives and give meaning to the long espoused social aim of children attaining their full potential in life [11].
\nThe positive impact of early childhood education is observed on different outcomes in children, including increase in academic skills of the children. A longitudinal study reported that children enrolled in child care and preschool environments scored higher in reading, mathematics and fine motor assessment than children with no regular attendance in preschool or participation in early childhood programs [12]. Similarly, it is also reported that preschool has a positive net effect on English and Math scores [13].
\nIn addition to academic benefits, early childhood programs also have a positive impact on other early outcomes, as children who attend preschool or other early education programs have been reported to have enhanced cognitive, verbal, and social development, and these benefits are maintained into the first few years of school. Moreover, children who attend an early childhood educational program exhibited enhanced pro-social behaviour like cooperation, sharing among peers and displayed less antisocial traits like delinquency. Findings from various research studies also report a positive impact of early childhood educational programs on cognitive, non-cognitive skills, school achievement, job performance and social behaviors and leads to lower juvenile delinquency and arrests [8].
\nMany economists have also reported that investing in early childhood programs has economic benefits in addition to the benefits to the individual. Investing in programs that provide education for young children also produces large economic returns. Every $1 invested in services to help families with young children, between $4 and $7 was saved on child protection, health, education and justice system [14]. It is further elaborated that interventions at an early age have positive long-term benefits for the child and are also more cost-effective than interventions at a later age [15].
\nHowever, the quality of early childhood education is an important factor and influences the impact of an early educational program on children’s learning and development. Various research findings have supported this statement. Two longitudinal studies, the Perry Preschool Project and the Abecedarian project have yielded sound empirical evidence and reported that high-quality early childhood programs have significant positive benefits for both the children and society in general. Similarly, the publication of The Effective Provision of Preschool Education (EPPE) research findings have provided robust evidence that the provision of high quality early childhood education make a significant difference to the learning outcomes of young children [13]. This report on EPPE Project also stated that there is no single factor that determines preschool attainment but good quality early learning provision is important. Similarly other researchers and studies also reported that programs that provide high quality to children are more likely to provide long lasting benefits to the young children attending these programs. High quality programs are especially beneficial for children at risk and belonging to disadvantaged sections of the society. Evidence for the influence of high-quality, comprehensive preschool experiences to mitigate the negative effects of risk on disadvantaged children’s emerging academic, social and self-regulatory competencies are reported by many studies. Moreover, high quality programs have also been reported to have a positive impact on overall development of children.
\nEmergent literacy is a term used to describe early reading and writing development among young children. It refers to children acquiring some language, reading and writing skills before formally entering the primary school. It includes listening, speaking, reading, writing and thinking. Literacy development does not begin upon entering a formal primary school, but it begins early in life and is an ongoing process. Emergent literacy is influenced in the context of home, with family members and peers. It is also viewed as the reading and writing behaviour that precedes and eventually develops into conventional literacy. It is thus, important to understand the sequence of changes and development that occur in young children.
\nThe sequence of changes that occur in children’s physical, motor, language, cognitive and socio-emotional skills are referred to as growth and development among children. These changes occur from birth and continue till the children reach adolescence stage. Children’s holistic growth and overall development is often observed through their enhanced skills in the five domains of development mentioned above. Cognitive abilities include abilities of children to learn and problem solving, while socio-emotional abilities involve skills of interacting with others and mastering self-control. Language abilities include understanding and use of language for communicating with others. Physical skills include fine motor skills and gross motor skills.
\nPlay has a major influence in developing the abilities and skills of children. It is argued, however, that free-flow play is at the centre of humanity across all parts of the world and within ancient civilizations [16].
\nAccording to popular beliefs, play is a concrete, manipulative, fun, hands-on, and creative activity. Play provides open-ended, self-discovery and theme-based teaching for children’s learning and development. Varied play activities and opportunities lead to better physical, language, cognitive and socio-emotional skills among young children. As children engage in play activities, they tend to use language skills to communicate among each other, develop strategies to play and win, learn social skills to cooperate and share among friends. Thus, group play activities are especially relevant for enhancing overall development of children. Individual play activities are also equally important for overall development of young children.
\nAll aspects of development and learning are thus influenced by play. Children are intrinsically motivated to engage in play activities even when they are very young. A 3-month old child loves to look at familiar face and smiles on recognizing the mother and enjoys participating in vocal exchange with the mother. An 8 month old child eagerly looks forward to playful exchanges with an older sibling and takes interests in games like peak-a-boo or hiding of objects. As children grow, their play grows in complexity and becomes more cognitively and socially demanding. Through play children learn to explore and discover, use their understanding to play imaginatively, express their emotions and inner feelings.
\nPlay also helps young children in development of abstract thought by understanding the use of symbols as forms of representation. Play is also a beautiful medium for young children to understand and develop a sense of who they are, learn social skills of sharing, turn-taking and negotiation and deal with conflict with friends and family and learn to negotiate and solve problems. Play also helps children to cope with emotional loss and come to terms with any traumatic experiences.
\nA few important features of play that describe in more detail how children behave, and learn while playing have also been outlined. Children use the first-hand experiences from life in their play [17]. They make up the rules as they play and make play props. Children choose to participate in play on their own; they cannot be made to play. Children also rehearse the future in their role-play and pretend play. Children play alone sometimes, or they may play with adults or other children.
\nChildren playing get deeply involved while playing and it is often difficult to distract them from their deep learning. Children try out their earlier learning, skills and competencies when they play. Also children at play coordinate their ideas, feelings and make sense of their relationships with their family, friends and culture.
\nBased on the experiences as an early childhood educator and conducting observations in pre-primary and primary classrooms, the following play and learning activities were observed as helpful in developing and promoting emergent literacy among young children:
Activities which encourage children to speak in the classrooms like show-n-tell, individual recitations, group recitations.
Theme based, short-term, coordinated planning of play activities. The curriculum and activities to be conducted need to be planned keeping in mind theme-based planning and provide children with opportunities or experiences that integrate language and literacy activities.
Efforts to integrate language and literacy activities during free play of children.
Opportunities for listening to music or musical instruments in all classrooms. Planned musical classes for children should be included in the curriculum. Children need to be exposed to different musical instruments.
Fun activities that help children experiment with reading and writing need to be planned and organized. These also help children to experiment with different writing materials.
Reading a variety of story books also helps children to become aware of different writing styles.
Writing has a communicative purpose; thus writing can be more meaningful when children write letters to their grandparents or friends make a list, make birthday invites and so on.
Children need to be encouraged to participate in discussions and sharing their views.
Teachers also need to provide opportunities to learn from peers. Creating learning corners, providing access to a variety of books and other literacy objects helps children in expressing themselves, thinking and sharing with their friends. Thus, more opportunities for collaborative learning can be provided by providing the appropriate classroom materials and planning such activities in the curriculum for the children.
In addition, traditional play activities in the Indian context are also useful in promoting emergent literacy among young children.
\nSeveral researches and innovative early childhood care and education programs have recognized that children learn best through play and learning by doing. Children in the younger age group are naturally curious and exploratory in nature. They want to discover their immediate world using their senses and physical attributes. Many researchers in the field of child development have noticed children in constant interaction with their environment, and they want to touch, feel and experience everything they see. All that matters to children is to play and enjoy with everything they come across. Furthermore children learn by doing, by being the active participants in the learning process. Although play promotes growth and development among children, children do not engage in different play activities for these outcomes. Rather play among children is self-initiated and is often described as being natural, spontaneous, enjoyable and is a reward in itself.
\nOne of the most common elements of childhood across cultures is play. Considering the diversity in India, it is utmost important to understand the diverse play opportunities available to young children in the Indian setting.
\nMoreover, exploring the relationship of play and cultural diversity is important for following reasons. First, a rapidly growing enrollment of young children from culturally diverse backgrounds is entering schools; this is significant in most urban cities where the migration is denser.
\nSecond, play is a way for children to learn about the world around them. They not only learn about themselves but also about diversity in principles, ideologies etc. among other people. And finally, play can encourage positive bonding and relationships among children with diverse cultural settings and enhance a positive awareness of individual differences as well. Playing traditional games enhances friendships or health but it is deeply connected towards making children prepared for the journey called life.
\nImparting cultural beliefs & values to young children is a way to orient young minds about their tradition in every society. There is also another thought that stresses upon the cultural influence on children and that it can come from many sources including the family, neighborhoods, child care and education centers, and the media. Play in early years also helps in developing a sense of pride and understanding of people in various cultures from the very beginning. Play is one of the mostly adapted techniques used with children to help them know and understand about their culture, practices, norms, customs, and values. It is also indicated that many traditional games with specific rules, provide a great means of communicating social norms of a society and form an integral part of that culture [18]. These games and their rules help in integration and solidarity among group members while providing aspects for segregation from other group members. Moreover, the types of play organized by children and play materials used are associated with their culture, for example, kaudi (small shells), pebbles and coconut shells are associated with communities living on beaches or near oceans and sea. Play during the early years also provides ample opportunities for young children to practice skills that will be useful to them as adults in that community. Play thus, serves an important role in enculturation.
\nThis aspect is also enumerated in book on the history of toys [19]. The book describes that although some play materials such as toy animals or balls appear to be common among children everywhere, often toys and play materials mirror the culture in which children live. The author describes that at times children’s play material might have religious significance, while at other times they may be related to skills of the adults in the community. The author also gives the example of Eskimos and how they made toys with ivory as ivory was easily available. Similarly people living near sea often made toy boats.
\nSimilarly in India the play material available for children from different regions of the country depends on the locally available material to them. In Odisha, an east Indian state, children play with toys made of jute materials, while children living in the remotest village of Nandubar in Maharashtra, a west Indian state, have toys made out of wooden twigs, sticks etc.
\nChildren can connect with their heritage through traditional games and this has a deep lifelong positive impact on their learning. Early childhood researchers and practitioners have been actively discussing the importance of play in the lives of young children and guiding ECE educators through different sources about the use of play and traditional games, stories & lullabies as a means of promoting cultural awareness.
\nChildren have been observed to play in diverse settings. Regardless of city, suburban, or rural settings, throughout the world, children play. If they grow up in an agrarian economy and accompany their mothers into the fields, they find ways to play within that environment, and there are reports that mothers who work in such settings also find ways to make the time with their children pass in playful ways [20]. Children play whether they live in rural or urban settings; belong to rich or poor families. One of the most common essentials of childhood across cultures is play.
\nChildren’s play is influenced by cultural backgrounds and it is imperative to recognize the importance of cultural influences on children’s play. It is also important for early childhood educators to recognize the importance of play in the lives of young children in order to make use of play as a means of promoting cultural awareness.
\nIt is important to understand the relationship of play and cultural diversity as a large population of young children belonging to culturally diverse backgrounds are entering early educational setups. It is through play that children learn about the world around them and learn about their own and other cultural values. Play helps children understand and enhance a positive awareness of individual differences and cultural diversity of other children around them. Thus, play experiences provide an excellent way to teach children about differences among communities and negate any negative perceptions or stereotypes.
\nPlaying games has always been an exciting and the most loving part of growing up for us. Numerous times we fondly recollect the happiness experienced while playing childhood games. Most of us have definitely played traditional games when we were young, going to the terrace or outside on the streets or nearby park to play with our friends, was the most enjoyable part of our daily routine.
\nIndian traditional games like—Kho kho, stapu, Langadi tang (one-leg hopping), skipping rope, kancha, gilli danda, luddo, and many more do not require exorbitant play materials or accessories like sports gear or specific shoes, all that is required is young enthusiastic & energetic children and space to play in.
\nPlaying traditional games have always brought children together, encouraging teamwork and social interaction. Team games like gilli danda, kho-kho, encourages children to develop maneuvers to strategize and win the game. Unstructured play has a vital role in developing children’s physical, behavioral and interpersonal skills, therefore the need to re-establish traditional play in children’s lives.
\nChildren also have an immense love for stories and lullabies. Stories help in creating an enchanting and delightful world for young children and help them in learning nuances of life. Storytelling provides an inimitable way to understand, respect and appreciate one’s own as well as different cultures. This further helps in encouraging positive beliefs and attitudes towards diversity including people from different religion, communities, ethnicities and regions.
\nFolk-tales or folk-stories are constructed and told in captivating ways, and they carry huge entertainment prowess. Diversity exists in terms of stories considering the Indian setting and cultures they have. A common version of any story entails characters–human or animal–with the simple structure of a beginning, highlights, and conclusion. Often, these stories take shape of puzzles, with leading questions for children to express and solve it and further facilitates moral values among them. Almost all children are motivated by the suspense entailed in the stories, the characters and situations they are already familiar with. Children also learn to pay attention and to follow instructions, when the levels of stories extend from simple to complex. Moreover, many folk-tales, although essentially similar in situation, have been adapted in specific languages and therefore provide children with an opportunity to expand and learn their first language. Through the folk-tale activities, children use their short and long-term memory, exercise abstract thinking, and gain collective problem-solving skills [21]. Storytelling when narrated to children in various ways can Enhance intercultural understanding and communication among young children (Figure 1).
\nWhile listening to folktales and traditional lullabies, children participate actively, rather than listening passively. Children enjoy stories which are dramatic, vivid and involve situations that they have not heard about. Narrating stories and forming conversations around the characters and things in it, is the oldest form of imparting education about culture, family values and traditions. People around the world have always told tales as a way of passing down their cultural beliefs, traditions and history to future generations. We all have a story to tell and a drive to tell it.
\nStory telling by ‘Katha’ teacher.
In India, children generally go out and play with their friends or cousins on the streets or nearby parks. These street games have been played by previous generations as children. Parents or grandparents often narrate stories and share their experiences of playing these games as young children. Some of these traditional games played through generations are described below:
‘Kanchas’ or playing with small stones or marbles was a caveman’s game (Figure 2).
Kancha or glass balls.
The origin of Kancha can be marked out to the early days of mankind. Kancha also known as Goti is an Indian traditional game which is mostly played by children and is cherished and fondly remembered by people of all ages. Kanchas are absolute fun to play with. The objective of this game is to hit a few marbles on the ground with your own marbles using a particular technique. Whoever is successful in hitting the targets takes the marbles of all other players and is the winner.
‘Gilli Danda’ another traditional cricket-like game played on the Indian streets and villages (Figure 3).
Boys playing Gili Danda on the streets.
It is believed to be more than a thousand years old – dating back to the Mauryan Dynasty [22]. Gilli danda is known by various other names as well: like Tipcat in English, Lappa-Duggi in Pashto, Kon ko in Cambodian, Pathel Lele in Indonesian, Celikçomak in Turkish, Ciang sat in Zomi language, Đánh Trỏng in Vietnam and Quimbumbia in Cuba so on so forth. Gilli danda is played using two small wooden sticks which can either be prepared at home or with the help of the carpenter. While gilli is small, about 3 inches in length, the danda is 2 feet long with tapering ends, serving as a bat. The game is usually played in teams making a metre diameter circle on the ground and an oval shaped hole is dug in the centre of the circle and the Gilli is placed across the hole. The games allow the players to develop exceptionally good hand-eye coordination, ability to catch and strong wrists.
Kho kho is a traditional game that originated in Maharashtra one of the Indian western state (Figure 4).
Children playing kho kho.
This game is played widely on Indian streets and on special sports events like children’s sports day in schools. The game hosts two teams, each containing 12 members, out of which 9 play at a time. The purpose of the game is to tag all the opponents in the team and the team with the shortest time to do so, wins. The game is one of the most popular sports in India and is enthusiastically played among children and adults alike. Besides the obvious health benefits, the game helps to propel sportsman spirit and camaraderie among the players. Since the game involves running, good for cardiovascular system. Hence, a kho kho game can help with a plethora of things.
A popular playground game ‘hopscotch’ in which players toss a small object into numbered spaces of a pattern of rectangles outlined on the ground and then hop or jump through the spaces to retrieve the object (Figure 5).
A popular playground game of Hopscotch.
This popular game is also played in other countries and is loved by all. In India it is called Stapu (Hindi), Nondi (Tamil), in Spain and some Latin American countries, it is rayuela, although it may also be known as golosa or charranca.
‘Ludo’, one of the most played indoor board game of India (Figure 6).
A board game—‘Ludo’.
This board game is an effective tool to develop child’s numeracy skills and positional language. Ludo is a great platform to reinforce the pre-number concept (counting, colors, and shapes) among young children. And just like any other game, the benefits of playing Ludo go beyond learning math.
\nThe benefits of the game include sharpening the concentration and enhancing the presence of mind. They also ensure the improvement in the focus and dedication of the child, this allows children to work on their eye-hand coordination, judgment skills, calculation as well. These games improve the concentration power of the player and further enhance their focus.
\nFascinatingly one can observe the expansion in child’s interactions with friends and at the same time attaining gross motor and physical strength [23]. Children also obtain better understanding of numbers and number related concepts like counting, sequencing, addition and subtraction. By grouping, regrouping, adding and reducing pebbles, children learn to do skip count of two, three, and four and so on and thus eventually learn multiplication tables. Thus, for early childhood practitioners working with young children and promoting developmentally appropriate practices, play becomes an important vehicle for advancing children’s social, emotional and cognitive development and also helps in promoting numeracy and emergent literacy skills [24].
\nCardiomyopathies are categorized based on their phenotype. In that context, dilated cardiomyopathy (DCM) is characterized by a dilated left ventricle (LV), typically with thin walls, and systolic dysfunction (\nFigure 1\n). Sometimes the dysfunction is not limited to the left ventricle but also affects the right ventricle. It is estimated that approximately 1 in 2500 people suffer from DCM [1]. The causative pathways are often complex, and several risk factors work together. In the vast majority of patients, there is a history of hypertension. Other well-known etiologies are myocarditis, chemotherapy, toxins, radiation, and coronary artery disease. However, when a causative reason for the dilation of the heart cannot be identified, DCM is considered idiopathic. About 20–50% of idiopathic DCM is considered to be of a genetic origin, being consequently hereditary [2]. Interestingly, only in 30–40% of cases of familial DCM can a specific gene be identified [3].
\nNormal and dilated left ventricle in parasternal short-axis view.
In hereditary DCM, there is variability among phenotypes, and the manifestation of LV dysfunction is heterogeneous. More than 50 genes are associated with the disease [4] (\nTable 1\n). Many of the gene mutations responsible for DCM affect the cell structure called sarcomere, which is involved in cardiac contractility. That is why some of those genes may be responsible for the development of hypertrophic cardiomyopathy as well. In 20% of the cases of hereditary DCM, mutations of the titin (TTN) gene are found, which encodes the protein titin found in the sarcomere [5].
\nGene | \nCellular structure | \n
---|---|
ABCC9 | \nCalcium/sodium handling | \n
ACTC1 | \nSarcomere and cytoskeleton | \n
ACTN2 | \nSarcomere and cytoskeleton | \n
ANKRD1 | \nSarcomere and transcription factor | \n
BAG3 | \nSarcomere | \n
CRYAB | \nCytoskeleton | \n
CSRP3 | \nSarcomere and cytoskeleton | \n
DES | \nCytoskeleton | \n
DMD | \nCytoskeleton | \n
DSG2 | \nDesmosome | \n
EYA4 | \nOther | \n
FLNC | \nCytoskeleton | \n
GATAD1 | \nOther | \n
LAMA4 | \nExtracellular matrix proteins | \n
LCB3 | \nCytoskeleton | \n
LMNA | \nNuclear envelope | \n
MYBPC3 | \nSarcomere | \n
MYH6 | \nSarcomere | \n
MYH7 | \nSarcomere | \n
MYPN | \nCytoskeleton | \n
PLN | \nCalcium/sodium handling | \n
PSEN1 | \nOther | \n
PSEN2 | \nOther | \n
RBM20 | \nOther | \n
SCN5A | \nCalcium/sodium handling | \n
SGCD | \nCytoskeleton | \n
TAZ | \nOther | \n
TCAP | \nSarcomere and cytoskeleton | \n
TMPO | \nNuclear envelope | \n
TNNC1 | \nSarcomere | \n
TNNI3 | \nSarcomere | \n
TNNT2 | \nSarcomere | \n
TPM1 | \nSarcomere | \n
TTN | \nSarcomere | \n
VCL | \nSarcomere and cytoskeleton | \n
The main genes associated with hereditary dilated cardiomyopathy and the cellular structure that they regulate.
The inheritance pattern is autosomal dominant in the vast majority of the cases, which means that an individual has a 50% chance to inherit the gene if one of the parents carries it. In other cases, the pattern is autosomal recessive, which means that if both parents are affected, there is a 25% chance of inheriting the disease genotype. X-linked patterns, in which the gene is inherited through an X chromosome, have also been reported. In some cases, it is possible that the carrier may not develop the phenotype of the disease due to variable penetrance of the disease.
\nInherited DCM is defined by (a) the presence of two or more affected individuals in a single family who fulfill DCM criteria; fractional shortening <25% and/or ejection fraction <45% and left ventricular end diastolic diameter > 117% of the upper reference level corrected for age and body surface area based on Henry’s formula or (b) the presence of a first-degree relative with unexplained sudden death before the age of 35 years [6].
\nSymptoms of DCM are due to ventricular dysfunction and compensatory left ventricular remodeling as well as the involvement of the electrical conduction system of the heart [7]. Symptoms vary among patients, even if they are members of the same family [5]. Symptoms can occur at any age; typically, they first appear in mid-adulthood. Patients often report breathlessness, swelling of the legs, fatigue, chest pain, and arrhythmias, ranging from palpitations and syncope to fatal arrhythmias that cause SCD. Unfortunately, SCD is sometimes the first manifestation of the disease.
\nSudden cardiac death (SCD) is defined as the sudden and unexpected death of a person who was otherwise stable prior to the event [8]. If the death is witnessed and occurs within 1 hour of onset of symptoms, it is classified as SCD. If the sudden and unexpected death is not witnessed, then SCD is declared if it occurs within 24 hours of the person last being seen alive and well.
\nIn the case of hereditary cardiomyopathies, such as DCM, SCD occurs due to the development of fatal ventricular arrhythmias: ventricular tachycardia (VT) and ventricular fibrillation (VF) are most common, but prolonged bradycardia does occur. Possible underlying mechanisms for the initiation of a fatal re-entry arrhythmia in a DCM patient may include: (a) conduction block caused by a reduction of myocytes and hypertrophy and (b) continuous re-entry regeneration due to increased fibrosis, interstitial, and perivascular as well as post-necrosis fibrosis [9, 10]. Non re-entry mechanisms, such as focal automaticity, electrolyte disturbances, and stretch-induced arrhythmias, also contribute to the presentation of arrhythmias [10]. In particular, focal automaticity predisposes a patient to nonsustained VT (NSVT) [11].
\nDCM ranks third as the cause of SCD among cardiomyopathies, after arrhythmogenic right ventricular cardiomyopathy (ARVC) and hypertrophic cardiomyopathy. SCD accounts for roughly a third of all-cause mortality among hereditary DCM patients. Rates of SCD vary among the patients in regard to their New York Heart Association (NYHA) functional status (\nTable 2\n). Notably, in patients with NYHA class I and II, 50–60% of deaths are classified as sudden, while in NYHA class IV patients, only 20–30% of deaths are sudden [10]. This is explained by the fact that in NYHA class IV, most patients die from progressive heart failure [12]. In most cases, potentially fatal arrhythmias present in a setting of systolic ventricular dysfunction, although the proportion of SCD is higher among patients with lower NYHA status. However, there is a subset of patients (reported to vary from 2% to one third of the DCM population) who present early in the disease course with life-threatening arrhythmias (Table 3) or unexplained syncope that are not related to the severity of LV dysfunction [13, 14]. This specific entity is referred to as arrhythmogenic DCM (AR-DCM). Patients who suffer from AR-DCM, compared to other DCM patients, have a higher risk of experiencing major arrhythmic events and SCD. Thus, a family history of SCD in an AR-DCM patient results in a higher burden of life-threatening arrhythmias and a higher risk of SCD [7]. It is important to mention that DCM patients, due to their high incidence of atrial fibrillation, also have a higher risk for ischemic stroke. However, it should be noted that if a cause of death other than arrhythmia is confirmed, the death will not be classified as sudden.
\nNYHA | \nRisk of SCD | \n
---|---|
Class I | \n50–60% | \n
Class II | \n50–60% | \n
Class III | \n20–30% | \n
Class IV | \n20–30% | \n
Risk of sudden cardiac death as a proportion of overall mortality according to New York Heart Association classification.
Factors associated with a high risk of arrhythmias | \n|
---|---|
Clinical | \nLow LVEF (<25–30%) Absence of beta-blockers AR-DCM Family history of SCD | \n
Ambulatory | \nQRS duration QT dynamicity T-wave alternans NSVT on Holter monitoring | \n
Imaging | \nMidwall late gadolinium enhancement Impaired global longitudinal strain Mechanical dispersion | \n
Genetic | \nDesmosomal mutations LMNA mutation SCN5A mutation FLNC mutation RBM20 mutation PLN mutation | \n
Factors associated with a high risk of life-threatening arrhythmias.
It is crucial to identify patients at high risk of a fatal arrhythmia. There are clues in the clinical history, electrocardiographic, imaging characteristics, and specific genetic features that need to be taken into account. Factors such as QRS duration, QT-interval dispersion, and T-wave alternans have been suggested as risk markers [15]. A considerable burden of ventricular arrhythmias (runs of VT) is usually present in a setting of advanced ventricular dysfunction with left ventricular ejection fraction (LVEF) <25%, which is a validated risk factor. Survived cardiac arrest and sustained ventricular tachycardia with hemodynamic compromise imply a high risk of recurrent arrhythmia and are classified as secondary prevention for an implantable cardioverter defibrillator (ICD) [16]. Unexplained syncope may be secondary to arrhythmia and constitutes a risk factor [15]. In the Marburg Cardiomyopathy study (MACAS), which excluded patients with a history of sustained VT or VF, unexplained syncope within the previous 12 months, and amiodarone therapy, it was shown that a low LVEF (<30%) was the only independent factor for major arrhythmic events. Patients with NSVT and patients who were not on beta-blockers upon enrollment also run a high risk for ventricular arrhythmias. Thus, the combination of documented NSVT on Holter monitoring with a low LVEF (<30%) increased the arrhythmic risk by eight-fold [17]. Family history of SCD, defined as SCD in a first degree relative <40 years of age or SCD in a relative with confirmed DCM at any age, is also an established risk factor.
\nImaging can be used to predict arrhythmia risk. In cardiac magnetic resonance imaging, midwall late gadolinium enhancement (LGE) can detect fibrosis. Even if magnetic resonance imaging is not able to detect fibrosis, it may still be found by advanced T1 mapping techniques before and after gadolinium infusion. This is a prominent finding due to the fact that it corresponds to macroscopic midmyocardial fibrosis on postmortem examination [18]. In echocardiography, an impaired global longitudinal strain, a marker of myocardial regional contractility, may reflect myocardial fibrosis [19]. It has been demonstrated that an impaired global longitudinal strain is associated with increased arrhythmic events [20]. A predictor of arrhythmias is also mechanical dispersion, which is defined as the standard deviation of the time to peak negative strain among the different myocardial segments [20].
\nRegarding genetic factors, DCM patients who carry a desmosomal or LMNA (lamin A/C) mutation run a higher risk of life-threatening ventricular arrhythmias and SCD, regardless of their LVEF. Patients who carry the LMNA gene, which encodes the type V intermediate filament protein, tend to have more life-threatening arrhythmias compared to other variant carriers and variant-negative patients [21, 22]. LMNA mutations are associated with high morbidity and mortality and with a high clinical penetrance [23]. For the LMNA carriers, various risk factors have been identified. These include NSVT during electrocardiogram monitoring, truncating mutations, LVEF <45–50%, and male sex [24, 25]. More recently, 1st degree AV block has been identified as another risk factor in LMNA carriers [26]. Desmosomal gene mutations are present in around 3% of DCM patients. They are also frequent in ARVC patients, creating a genotype overlap between the two cardiomyopathies. They have been associated with a high risk of potentially fatal arrhythmias, independently from the LVEF [21]. The SCN5A (sodium voltage-gated channel alpha subunit 5) gene, which provides instructions for making sodium channels, is also associated with conduction defects and ventricular arrhythmias [10]. Also associated with a higher risk of arrhythmic events are mutations in the FLNC gene, which encodes filamin proteins; the RNA-binding motif protein 20 gene (RBM20 gene), which encodes a protein that regulates splicing and the phospholamban (PLN) gene, which encodes a protein that inhibits a sarcoplasmic ATPase [21, 27]. In a 2019 study, it was demonstrated that RBM20 mutation carriers were more likely to have NSVT and sustained VT than idiopathic DCM cohorts [28]. The AR-DCM phenotype is associated with a high risk of fatal arrhythmias. Spezzacatene et al. identified the AR-DCM phenotype as well as a family history of SCD or sustained VT/VF as the only early significant predictors for SCD or sustained VT/VF in the overall DCM population. Interestingly, the AR-DCM phenotype is associated with a higher risk of arrhythmias, irrespective of LV dilatation and dysfunction, which is in contradiction to the general DCM population, where a low LVEF is associated with a higher arrhythmic risk [14]. However, AR-DCM is not associated with a poorer prognosis due to non-arrhythmic events, including heart failure [14].
\nMost DCM patients present with heart failure and are at a high risk of death. The primary management of such patients lies in the stabilization of progressive heart failure. Drugs like renin-angiotensin-aldosterone system (RAAS) antagonists and beta-blockers are first-line management in patients with DCM and reduce the risk of SCD by preventing ventricular remodeling. Angiotensin converting enzyme inhibitors (ACEs)/angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and beta-blockers are recommended, unless contraindicated or not tolerated. Furthermore, the combination of sacubitril/valsartan has been shown to be superior to ACE inhibitors and tends to replace them in the treatment of patients who are still symptomatic patients despite optimal medical treatment [16]. The anti-diabetic drug, dapagliflozin, seems to reduce the risk of worsening heart failure and death in patients with a reduced LVEF as well, regardless of the presence of diabetes mellitus, as proven in Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) study [29]. In NYHA IV patients, asystolic arrest and pulseless electrical activity are a frequent cause of death [10]. Cardiac resynchronization therapy (CRT) and CRT with defibrillator (CRT-D) treatment also has a place in both symptomatic treatment and preventive management of such patients.
\nArrhythmia management in hereditary DCM patients follows the general recommendations as SCD prevention in patients with reduced LVEF (<35%) [7]. Thus, patients with diagnosed DCM must be carefully evaluated for ventricular arrhythmias. Regarding drug management, amiodarone has not been proven to further reduce overall mortality or arrhythmic risk in the Amiodarone versus Implantable Defibrillator (AMIOVIRT) study, which showed that DCM patients who were on amiodarone did not have a statistically significant difference in terms of survival, compared to patients who received an ICD [30]. However, in the Sudden Cardiac Death in Heart Failure trial (SCD-HeFT) which enrolled patients with an LVEF <35% and NYHA II or III despite optimal medical therapy and compared ICD insertion vs. amiodarone vs. placebo, ICD therapy conferred a significant benefit in patients in NYHA class II, but not in class III. Furthermore, amiodarone, when compared to placebo therapy, showed no benefit in NYHA Class II patients and decreased survival among NYHA Class III patients. Results varied among NYHA classes but did not vary between heart failure of ischemic or nonischemic origin [31]. The Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure (DANISH) trial concluded that prophylactic ICD implantation in symptomatic patients with nonischemic heart failure did not offer a significantly lower long-term rate of death from any cause when compared to standard clinical care but decreased the incidence of SCD by 50% [32].
\nICD implantation remains the main therapy in preventive management for DCM patients with impaired LV function, who run a high risk of fatal arrhythmias. Guidelines, as well as the Expert Consensus Statement, recommend an ICD implantation in DCM patients with an LMNA gene mutation and risk factors such as NSVT observed during monitoring, male sex, truncating mutations (class IIa, level B), and an LVEF <45%, which is a higher cutoff value than used in heart failure population guidelines [22, 33].
\nIn addition, a primary-prevention ICD should be considered in DCM patients with both an arrhythmogenic phenotype and a family history of SCD or ventricular arrhythmias, irrespective of their LVEF or LV end-diastolic diameter, as they compose a high-risk group for major arrhythmic events and SCD [14]. However, in individual cases, it can be challenging to determine in which particular patients the benefits of ICD implantation would outweigh the risks. The DEFINITE study (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation) randomized 458 patients with nonischemic DCM (LVEF <36%) and premature ventricular complexes or nonsustained VT, between standard medical therapy and ICD implantation. SCD by arrhythmias during a mean follow-up of 29 months was far fewer in the ICD group, proving the efficacy of defibrillation [34]. Yet, the use of LVEF alone is not always helpful in determining which patients would most benefit from an ICD. This was made clear in the Oregon and Maastricht Registries, in which 80% of SCD victims had an LVEF >35% [35, 36].
\nCRT is recommended in patients with sinus rhythm, NYHA class III/IV heart failure, LVEF ≤35%, and QRS >120 ms and/or evidence of mechanical dyssynchrony. It has been shown to offer great survival benefits as well as improvement of LV function in DCM patients [37]. This has been observed especially in women, who seem to benefit more than men from CRT [38]. Furthermore, it has been proven that in patients with nonischemic DCM with an LVEF ≤30%, NYHA class II, and QRS duration ≥130 ms, CRT-D device implantation was also beneficial in reducing the risk of death or heart failure when compared with defibrillation only [39]. On the other hand, patients with low LVEF heart failure and permanent atrial fibrillation do not seem to derive extra benefit from a CRT-D device compared with standard ICD treatment, as suggested by the Resynchronization for Ambulatory Heart Failure Trial (RAFT) trial [40]. Of interest in DCM patients, LGE was proven to be a strong, independent predictor of arrhythmic events and was suggested to improve risk stratification for SCD and better identify the need for ICD therapy [41].
\nDecisions about ICD therapy should incorporate genetic factors. In patients with mutations, i.e. LMNA mutations, the conventional LVEF-threshold based guidelines for ICD do not apply. In fact, an ICD may be considered for a patient with higher LVEF thresholds [26, 42]. Regarding FLNC mutations, 20% of patients with a primary-prevention ICD who carry the mutation had an appropriate ICD shock, much higher than in unselected DCM populations [43]. Appropriate ICD shocks are also more likely in PLN carriers, especially in R14del variant, along with a family history of SCD before the age of 50 years compared to those who do not carry the mutation [44]. These findings support the hypothesis that genetic factors should be considered early in the disease progression.
\nThe CMR-Guide (Cardiac Magnetic Resonance Guided Management of Mild-Moderate Left Ventricular Systolic Dysfunction) trial, which is expected to be completed in 2020, is randomizing ischemic and nonischemic cardiomyopathy patients with an LVEF between 36 and 50% and presence of LGE to either an ICD or an implantable loop recorder in an attempt to determine whether LGE is a sufficient marker alone or whether genetic characterization is also necessary in risk stratification. In general, a polyparametric integration is being introduced in the primary prevention of SCD through ICD implantation in DCM patients that includes family history of SCD, LVEF, late gadolinium enhancement, and possibly genetic parameters [45].
\nThe evaluation and treatment of hereditary DCM constitutes an emerging field. Still, risk stratification regarding SCD is based on general knowledge. Larger registries and long-term follow-up may elucidate more specific risk markers associated with genotypes in addition to phenotype.
\nHereditary DCM is a heterogeneous condition, which may lead to advanced HF as well as SCD. Risk stratification and preventive management strategies are challenging. Many factors must be considered in the management of patients with hereditary DCM. Gene mutations are surfacing and have already been proven to play a very significant role in clinical decisions. Moreover, based on new data and studies, the profile of each DCM patient tends to be better understood. As a result, both therapy and prevention evolve and ameliorate in a way that will become individualized. ICDs are lifesaving but their role in different genotypic settings remains to be elucidated.
\nPeter Magnusson has received speaker fees or grants from Abbott, Alnylam, Bayer, AstraZeneca, Boehringer-Ingelheim, Lilly, MSD, Novo Nordisk, Octopus Medical, Pfizer, and Zoll. Joseph Pergolizzi is a principal at Native Cardio, Inc. Marianna Leopoulou and Jo Ann LeQuang have no relevant disclosures.
ACE | angiotensin converting enzyme |
ARB | angiotensin receptor blocker |
AR-DCM | arrhythmogenic dilated cardiomyopathy |
ARVC | arrhythmogenic right ventricular cardiomyopathy |
CMR | cardiac magnetic resonance |
CRT | cardiac resynchronization therapy |
CRT-D | cardiac resynchronization therapy defibrillator |
DCM | dilated cardiomyopathy |
ICD | implantable cardioverter defibrillator |
LGE | late gadolinium enhancement |
LMNA | lamin A/C |
LV | left ventricle |
LVEF | left ventricular ejection fraction |
NSVT | nonsustained ventricular tachycardia |
NYHA | New York Heart Association |
RAAS | renin-angiotensin-aldosterone system |
PLN | phospholamban |
RBM20 | RNA binding motif protein 20 |
SCD | sudden cardiac death |
SCN5A | sodium voltage-gated channel alpha subunit 5 |
TTN | titin |
VF | ventricular fibrillation |
VT | ventricular tachycardia |
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