ec Ro Pen) Congenital heartctees| eat develope Genetic seen Wessidvave Putmonary wave or sin ntti eink ‘Site tpt el a Congenital heart disease ‘The mammalian heart is essential for pumping blood around the body, but its complexity poses a huge challenge during development. This How science works explains how the heart is formed, what ‘can go wrong and how understanding the intricacies of ts formation could help us in treating defects, i estimated that between 1% an 59% of the human [population are born with steuctural or functional problems with their hearts — known ax congenital heart ‘isete, These problens reel Foe errors that happen ‘when the Baby’ heart is forming in the wombs, They are ‘the most common birth defect, and afethe most common ‘non-lnfectious couse of chil death ‘The impact of congenial heart disease varies — some defecs an be coteted with suery but some defets ae so severe that newborn bales de. However, many defects 9 unnoticed, o icy ae found they may not tequite any weatment. Therefore, is possible that the prevalence of congenital umenaryarery Rémonary wees Seaspisvave fir vie poral Lett ventice Inet disease inthe population may be even higher than centimite suges ‘There are thre main types of congenital heart disease: 1 septation detects ~ where te diferent areas ofthe heat do not separate properly from each other when the heart is formed © unilateral blocks — defects ofthe heart valves = routing abnormalies — defcets caused by a failure to nnect the main vesels that supply the heat with Blood 19 1 cortet chambers ofthe beat Before we can develop methods to prevent or cure congenital heart disese, we mis fit tnestand normal beat development and what ci cause this development to ppwrong ‘The mammalian heart During development, our heart is tansformed from 2 single veto afourchambered, muscular organ The Fully formed mammalian heart has four chambers — wo alia and two ventricles (see Figure 12) The atria are filled with ‘Mood! entering the heart and the ventricles expel Mood fiom the heat ‘eoxygenated blood returning from the body flows into ‘he right atrium via a large vein called the vena cava The blood is then pumped through the right atioventricuat ‘valve the ricuspi vale) fom the right auium imo the right Cy reuwrieg ood ves aking Grongented ‘gered boos Sadie ‘round heb rere Figre 1 (an stl human heat, showing the discon f blood flow though he heart) The human cicaltory yet. The pulmonary ieatory system takes deongenated blood trom the heat to the lungs, where itbecomes oxygenated ands retuned back to the hear 22 Bolgea Sees Reviewventi, and then fom the ight wentrcle to the langs via the palmonary artery. ‘Oxygenated blood is uansported back wo the lf atrium ‘of dhe heat va dhe pulmonary veins. Ics then pumped though the let aseventicular valve (the bcos valve) Into the lef ventricle and aroun the boy via the aorta (ee eure 0) "The sracture of the heat i elated to function, For ‘example the wall ofthe left venti has the thickest Lager ‘of muscle — it propels blood around the bod. In order to pump blood efectively,theheart mustalso have an excellent Sipply of oxygen and nutrients Thin wien the comet evebppment of the coronary blood vessels that supply the heart muscle with blood. To generate rhythmic heart ‘eats, the nervous stimulation of heart muscle must also Be conect. Heart muscle is sefstimulating — myogenic — but specialised structures called the sinoateal node and the ‘dsioventticular node ae required to control and coordinate ‘the beating of te hear. ‘Mammalian heart formation ‘The heatis the fs organ required in the embryo. ebegins to develop ean pregnancy (se Fgure 2). tstans offasa crescent-shaped trite at about 2 weeks of gestation This ‘sracture thea joint the cate w form alineat ube, which transforms into a V-shaped tube, The hear stats beating ‘when itis sil n this simple form, which ia early as day 22 of gettin, ‘The next stage of development — cardiac looping — ‘ings the different ateas of the hear wo their correct positons relative w each other During cana loping the heartube end a precise manne. Thisproces tightly ‘oniolled ensue thatthe cach ten fthe heat isbeought ino the eontect position athe corect time Problems with ‘thisprocesscan cause mlformationsin thebeats whichean lruptorprevent ater stages of development. Abnormalities ax this stage can also prevent thecertect attachment of blood ‘esels wo the diffent chambers ofthe heat, leading to routing abpormalites — meaning that the bieed may not fle though the heart corte. Aer looping, chamber formation occurs. This process involves separating the atria and ventricles fom each athe, and connecting the growing beart to the earonary blood vessels (se Figure 20), This happens during weeks 6-8 ‘of pregnancy. The heat vakesalio develop during this ‘sage. Disruptions at this poine in development can cause malformations auch as a Tule in the bear’ — a primary ata septal defect (see Bor 1). This ype of defet may not ‘Bve any symptoms — the individual may note aware chat theresa problem. isthe most common spe of congenital heart disease that ie only revealed aftr an individual reaches adulthood “The developing fetal heat alo contains severalspeciaised sacar thatare not present in the adult heart One ofthese is elled the foramen ovale, which isa smal gap through ‘which blod pases fom the igh atria ino the ef atrium ‘Thisstrucireis present because the Fes reeves oxygenated ood fom the placena and so the blood doesnot nee to Stee 203 oo ‘Outta gn b Abc (8) Asvovenscle ee ourtiow oe porte Pulmonary ary = Figure2 Heart development in human embryo fa) D3y 21: the Yeahoped heart tube withthe uilow act heared that gos on to form the major blood vrs, ight venti left vente, ight ram | Sndlefe sum (0) Day 28: the heart tbe ster looping. Te ight and iets are now lacated above the ventricles ana are separated bythe {voventicdor cana, which wil frm the stovertricla valves ofthe ear the major blood vests are ala stating to for from he autfow tract (Day 50: ho heart ou formed ad the man blood vssse the aorta and the pulmonary artery aren their comet postions ete ‘Aroventrcnlar nade Asal reac mucin the wal ct thee Deter the tia nd the enides. pays an param ok n cordate thebestof the ear Sone mutations change nthe gnats na cl = tation inte the substitution a single bas in tha DNA saquence — pat ‘utaon-— it may reins cans in a gl arin ae ory haven ect a #3 mustion mes the deletion or aston of ther sngle Sat cea Resin the DN, il ange te ana se eqn ‘he estat poten. Gestation The tine ped over wich es develps — am ertston ‘euinh Pulmonary hypertension Ossse haractersad by messed oe presi Ine plonary arteres ie leo vss that upoy he ns wid causes shrtesftreth dsess end toting ean lel to deserted ‘ere tolerance and eve to eat fae Shoat nade smal a of msicleln he val of th ight atu of he arta ons he at es. Stroke A seriou mea cntion that eu when baad tin vee ‘tolled ply othe ino when nkened lod ves the bran burst, causing bain damage Gee Bove Sans Riven VL 25, No.1-pp.2-8) 232 ata septal defect someon kro a5 aon fe heat ee Figueo The dle caused hen ho wal ben th to an — tho spur — doesnot dase rer ang hart develop Theatr {ae cerhwots aera rth ea forme aloo. they set be cided Inky the uth othe sept. Ith atin dbs nats elt, "os rome learn flows bck rate right rm This canes ng of aqgensted bond wi denygenaedlos in he it tom. Inceasng Bad ow theungs and cestng whats roan a hear mr Doctors can detect heart murmur stein oe eat th 2 Stencope, Norah ty ho the a sound ales doug a ted ms hou he et Her gs re xr oF Ses (ase by tbe Hood ne moving tro the hee ews Wey The impact of he defect depends on the zee theo srl Poles great rik of pulmonary typertension ee stroke ater in ite. Large Fok an couse poo grow and lng probles inden. Grea, _perasior to cse the lee ean are contd ete before bith (Finer Heo prevent aes conpaters Figure a left atm Henrtwth an Atal septal sual septa defect detect lef Conygensted) ond Fig (ronygeratea) aria passthrough the developing babys lungs. This gap usually ‘loses naturally afer birt, when the babys hear tarts 0 pump blood atound svn body. But occasionally i does ‘ot close, an thts another way that & Roe in the heart fan occur, Again, this can be asymptomatic (¢hveing no symptoms) orit may need 1 be crtecied by sugery Genetic investigation ‘Thestagesof developmen ofthe heart have been established by eximining the hearts of embryos x various times, ovwever, what controls these sages requires more than anatomical study — the genes and signalling pathways Tavolved and their interactions must be underwood, To fain this understanding, reeatch aclentiate ate examining the effects that mutations in DNA sequences hive on the development ofthe heart In this way, they hope wo diacaver hich mutations cause specific heart defects The genetic cole dictates the sequence of amin acids forminga poten, DNA can be thought of asthe instruction ‘manual hat controls how we arbi, fash inthe finished product (inthis cave the heat ca usally be traced back to froin this instruction mana Eros inthe sequence of DNA ate gene mutations Forward and reverse genetics (One method that has been used by sient wo work ut hove heart formation is regulated is called mutantscreening. ‘There ae dillere way that mutant seen investigations can be conducted Forward genetics involves studying individuals with Certain characteristics of interest, The genetic sequences of Indwiduals eth the selected characteristic are analysed to establish which gene or genes cause the particular characterise Reverse genetics involves examining the fect of own gene on a specific characteristic. This ena ether knocking out (temoving) or mutating a gene in mice 0 establish the impact that it has om heart development (see ox 3} ‘An example of how reverse genetics used to inmestigate the function of apeific protein in heart formation invalves ‘knocking cut he gene encoding that protein. This will mean {atthe proteia that the gene encodes sot produced. Knock ‘ut mutations have been used to establish the functions of Box 2 How to find a heart defect gene tations in DUA can be goneated ung mutagen — hele pyscal agents tha change genetic rat ‘thy Wivesoures ENU) is amatagon that hasbeen wed Inrevtc ert soeensn mice eget pent tation (changing a single ONA basen mouse ste cls — usually ne testes the os that goerare spe. the ge ‘mutated by ENU is impart er heart development he llspig of th nuts expen th tage ll ay ahert elect. Ths show genet eget dey which ‘erm case a spec phnotpeFabrice Muamba hod to rete pierre — a several genes in heart development Fr example, knocking ‘ut a gene called Nkx2.3 in mice disrupts the formation of the heart, and genetic stds im mans have shown that ‘tations in cis gene ave inked to atrial septal defect Reverse genetics has also allowed the Mentification of « gene responsible fr several types of congenital heart disease ey Iniematenencongental heart disease can be url on the NAS (ws tnyurl eomiet3b82) ne Bt art Foto bee tiny comidTbocrp) websites. ‘guide to cars evelopren ww sinyurlcomibttwpmh ‘Se fot Fabrice Mam cold onthe dopa eto heart defect thre as been an ncemed fees on undetected sr robles: worctnyarzombananb ‘in humans. This gene found on chromosome 22, and i encodes a prten called TAXI. Studies in mice have shown {hates protein is important in aapeciic set of calls uring the ealy stages of heat formation. Is the most common deletion syndrome ied in humans (Lin 4000 live births) and the los of THXL is now known to conteibute wo congenital heat defects Developments like this allow us to screen embryos for thieruatation, making detection and treatment of congenital heart disease easier One day, may be possible to intervene ring development, overtding oe coreting the damaging ‘mutation, thus enabling the heart to develop normally Katherine Powel suse Cero pated cera Peet Success in all your A-level subjects! Did you know we publish all these A-level ‘magazines to help you get the grades you need? From ae te £2.60 an fasu, each print magazine topical content for your studies, print and one! iches your subject knowledge ad gives you focussed Go to wwwr.hoddereducation.co.uk/magazines fr: {Al thellet information on each fle + Simpl erdering opons, incusing subscitions sont straight 1 your home ‘toratily, cortact our customeeeorvices department rect on 01298 627827, September 2013