Epidemiology: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease in all age groups, constitutingapproximately8%ofcongenitalheartdiseaseoverall.TOFoccursinapproximately0.

19 0.26/1,000livebirths.IntheUnitedStates,theprevalenceofTOFisapproximately3.9per10,000live births. Definition:TetralogyofFallotischaracterizedbythepresenceoffouranatomicalfindings: 1. Ventricularseptaldefect 2. Pulmonarystenosis(rightventricularoutflowobstruction) 3. Dextropositionoftheaorta(overridingaorta) 4. Rightventricularhypertrophy Pathophysiology: The figure below compares the normal anatomy and blood flow of the heart to that found in TetralogyofFallot.TheinitialdefectinTOFisanarrowingoftherightventricularoutflowtractinto the pulmonary artery. This prevents deoxygenated blood from entering the pulmonary circuit. In responsetothisoutflowobstruction,themyocardiumoftherightventriclehypertrophiesinorderto contract forcefully enough to push blood past the stenosis. Additionally, patients have a large ventricularseptaldefectwhichallowsshuntingofbloodbetweentheventricles.Inapatientwithan isolated VSD, the blood flow is shunted initially from lefttoright. However, in TOF, the right ventricularoutflowobstructionmayimpedethenormalbloodflowsosignificantlythattheleftside oftheheartbecomesthepathofleastresistance.Bloodfromtherightventricleisthenforcedinto theleftventricle,creatingarighttoleftshuntandsubsequentcyanosis.Finally,theaortaoverrides theventricularseptaldefect,straddlingtheVSD.Thisallowsdeoxygenatedbloodshuntedfromthe rightventricletoimmediatelyexittheheartmixedwithbloodfromtheleftventricle.

TetralogyofFallot

The most important determinant of the severity and clinical consequences of TOF is the degree of rightventricularoutflowobstruction.Withalesserobstruction,bloodisshuntedfromlefttoright and permitted to preferentially enter the pulmonary circulation, allowing for oxygenation. With a greater degree of obstruction, however, blood is forced in the opposite direction, away from the pulmonary circulation, leftward across the VSD and ultimately blood exits the heart before being oxygenated. Patients will present with differing degrees of outflow obstruction, and this may fluctuatethroughoutthecourseoftheillness. 1

 OtherAssociatedAbnormalities: Of note, approximately 40% of patients with TOF have additional congenital heart defects. This includesfrankpulmonicstenosis,rightaorticarch,abnormalitiesofthecoronaryarteries,collateral vesselssupplyingthepulmonaryarteries,patentductusarteriosusorotherdefects.Itisimportantto evaluatethepatientforallassociatedheartdefectsasthismayaffectsurgicalinterventionormedical therapy. Additionally,cliniciansshouldrecallthatTOFisassociatedwithanumberofgeneticsyndromes.This includesTrisomy21(DownSyndrome)aswellasDiGeorgeSyndromeandvelocardiofacialsyndromes. PresentingSignsandSymptoms: The timing and features of presentation depend on the degree of right ventricular outflow obstruction.Patientswithmoresevereobstructionwillpresentearlierduetocyanosis.Thismaybe asearlyastheimmediatenewbornperiod.Forpatientswithmoremoderatedisease,thepresenting signmaybeaheartmurmur(seebelow).Finally,forpatientswithmilddisease,withsocalledpink tetralogy due to the lack of cyanosis, their presentation may consist of signs and symptoms of congestiveheartfailureduetothelefttorightshuntingacrosstheVSDandsubsequentpulmonary overcirculation. Ultimately, most patients with mild disease will become cyanotic as the degree of outflowobstructionincreasesovertime. ClinicalFeatures: PatientswithTOFhaveanumberofdistinguishingsignsandsymptomsthatcanbefoundonphysical examandelucidatedwithadetailedhistory. Cardiacexam:Mostimportantly,theheartmurmurheartinTOFisnotduetotheVSD!Itisin fact due to the right ventricular outflow obstruction. The murmur is typically crescendo decrescendowithaharshsystolicejectionquality;itisappreciatedbestalongtheleftmidto upper sternal border with radiation posteriorly. (Remember, an isolated VSD murmur is a holosystolicmurmur,bestheardinthetricuspidarea.Itmayradiatetotherightlowersternal border.) Patients will have a normal S1 and possibly a single S2 due to diminished P2 component. Cyanosis:Ifpatientsarecyanotic,thisismostcommonlyseenonthelipsornailbeds. Tetspells:Tetspellsarehypercyanoticepisodesprecipitatedbyasuddenincreaseinrightto leftshuntingofblood.Theycanbeelicitedbyactivity(e.g.feeding,crying),ortheymayoccur without warning. The classic description is of a patient who becomes cyanotic and then assumesasquattingpositiontorelievethecyanosisandhypoxia.Squattingservestoincrease peripheral vascular resistance, thereby increasing the pressure in the left heart, and subsequentlyforcingbloodbackintothepulmonarycirculation. ChestXRay:Asseenonthechestxraybelow,patientswithTOFhaverightventricularhypertrophy, abootshapedheartanddecreasedpulmonaryvascularmarkings. Electrocardiogram: On EKG, patients with TOF will show increased right ventricular forces as evidencedbytallRwavesinV1.Additionally,rightatrialenlargementismanifestedbyprominentP wavesinV1(*).Rightventricularhypertrophyisdemonstratedbyarightwarddeviatedaxis. 2

Echocardiogram: FindingsonechocardiogramarethemainstayofdiagnosisinTOF.Echocardiogram will demonstrate a ventricular septal defect with an overriding of the aorta, pulmonic stenosis and rightventricularhypertrophy.ThisconstellationoffindingsservestoclinchthediagnosisofTOF. In about25%ofcases,patientswillalsohavearightaorticarch.Asseenintheechocardiogrambelow, theblood(blue)fromboththerightventricleandleftventricleenterstheoverridingaortaacrossthe VSD.

Treatment: OnceTOFisdiagnosed,almostallpatientsundergocorrectivesurgicalrepairwithinthefirstyearof life.Intheinterimperiod,prostaglandintreatmentmaybenecessarytomaintainthepatencyofthe ductusarteriosus.Additionally,somepatientsmayrequiredigoxinordiureticsifsignsofheartfailure arepresent. Treatment of hypercyanotic spells is directed towards improving pulmonary blood flow. These include oxygen, knee/chest position, morphine, intravenous fluids, sodium bicarbonate, beta blockersorpharmacologicallyincreasingsystemicvascularresistancebyadministrationofdrugs,such asphenylephrine. Onceaninfanthasdevelopedprogressivecyanosisorhasevidenceofhypercyanoticspells,surgical correctionisindicated.Therearetwocommonsurgicalprocedures: 3

BlalockTaussig shunt creates a shunt between the aorta and the pulmonary artery using the subclavian artery. This is used as a palliative procedure in infants who are not acceptable candidatesforintracardiacrepairduetoprematurity,hypoplasticpulmonaryarteries,orcoronary arteryanatomy.Patientswillrequireadditionalsurgeryasthisisnotacurativesurgery.

IntracardiacrepairisthedefinitiverepairforpatientswithTOFandisthepreferableprocedure. Thisconsistsofpatchclosureoftheventricularseptaldefect,andenlargementoftheRVOTwith reliefofallsourcesofobstruction.Insomecases,thepulmonaryvalvemayneedtoberemoved toeliminatetheobstruction.

Intracardiac repair for TOF. The ventricularseptaldefectisclosedwitha patch.Therightventricularoutflowtract is enlarged by opening the RVOT and pulmonary valve, resecting the subinfundibular muscle bundles, and patchingtheareaopen.Insomecases,a conduitmaybeinsertedtofurtheropen theRVOT.

OutcomeandComplications: Overall, patients undergoing surgical repair for TOF have an excellent prognosis with a 20year survival rate of over 90%. Complications of surgical repair of TOF include arrhythmias particularly ventricular tachycardia (VT), and atrial arrhythmias. Furthermore, patients may experience right ventricularhypertrophyorenlargementduetoresidualpulmonarystenosisandbackwardbloodflow into the right ventricle. Longterm complications include the need for additional surgeries, neurodevelopmentaldelayandmyocardialfibrosis.Patientsshouldbefollowedcloselybyapediatric cardiologisttomonitorfortheseshorttermandlongtermcomplications. 4

 References: 1. Uptodate:Pathophysiology,clinicalfeaturesanddiagnosisofTetralogyofFallot 2. SCGreenwayetal.DeNovoCopyNumberVariantsIdentifyNewGenesandLociinIsolated, SporadicTetralogyofFallot.NatureGenetics41,931935(2009). 3. MSilberbach,DHannon.PresentationofCongenitalHeartDiseaseintheNeonateandYoung Infant.PediatricsinReview.Vol28,No.4.(2007). 4. Uptodate:OverviewoftheManagementofTetralogyofFallot 5. TetralogyofFallotRepair,ChildrensHospitalofPennsylvannia, http://www.chop.edu/img/cardiaccenter/tetralogyoffallotrepair. 6. DVReddy.CaseBasedPediatricsforMedicalStudentsandResidents:CyanoticCongenital HeartDisease.http://www.hawaii.edu/medicine/pediatrics/pedtext/s07c03.html,Dec2002. 7. TetralogyofFallot.NationwideChildrensHospita,Columbus,OH. http://www.nationwidechildrens.org/tetralogyfallot.